Life extension – Blitz Age

Unveiling the mTOR Pathway – A Gateway to Life Extension and Immune Modulation

blitzage — Mon, 26 Aug 2024 05:41:05 +0000

In the quest to extend human lifespan and improve overall health, researchers have identified several key biological pathways that play crucial roles in aging and longevity. Among these, the mechanistic Target of Rapamycin (mTOR) pathway has emerged as a pivotal regulator. Originally studied for its involvement in cell growth and metabolism, mTOR is now recognized for its broader influence on immune function and its potential to enhance life extension. This article explores the mTOR pathway, its modulation through drugs like rapamycin, and how these insights can be leveraged to develop comprehensive life extension strategies.

The mTOR Pathway: A Master Regulator of Cellular Processes

The mTOR pathway is central to many essential cellular functions, including growth, metabolism, and immune responses. It acts as a sensor that integrates signals from nutrients, growth factors, and energy levels to determine the cell’s response. The pathway operates through two main complexes:

1. mTORC1 (mTOR Complex 1):
• Role: mTORC1 primarily drives anabolic processes, such as protein synthesis and lipid production, and inhibits autophagy, a vital cellular cleanup process.
• Implications for Aging: Persistent activation of mTORC1 is associated with accelerated aging and various age-related diseases due to the accumulation of cellular damage and metabolic imbalances.
2. mTORC2 (mTOR Complex 2):
• Role: mTORC2 is involved in regulating cell survival, metabolism, and cytoskeletal organization. Although its role in aging is less well understood, mTORC2 is crucial for maintaining metabolic homeostasis and cellular integrity.
• Implications for Health: Disruptions in mTORC2 activity can lead to metabolic disorders and reduce the body’s ability to manage stress, affecting overall healthspan.

Rapamycin and Rapalogs: Targeting mTOR for Health and Longevity

Rapamycin, a naturally occurring compound discovered in the soil of Easter Island, is a potent inhibitor of mTORC1. By binding to the protein FKBP12, rapamycin forms a complex that inhibits mTORC1 activity. This inhibition triggers several beneficial cellular responses, including increased autophagy, reduced inflammation, and improved metabolic function.

Rapamycin in Autoimmune Disease Management:

• Modulating Immune Responses: In autoimmune diseases like Systemic Lupus Erythematosus (SLE) and Rheumatoid Arthritis (RA), rapamycin helps control the overactive immune system, reducing inflammation and preventing damage to tissues.

• Correcting Immune Dysregulation: Through mTORC1 inhibition, rapamycin reduces the proliferation of autoreactive immune cells and decreases the production of pro-inflammatory cytokines, offering a more balanced immune response.

Rapamycin and Longevity:

• Promoting Autophagy: One of the key mechanisms by which rapamycin extends lifespan is by enhancing autophagy. This process helps remove damaged proteins and organelles, maintaining cellular function and delaying the onset of age-related diseases.

• Reducing Inflammaging: Chronic low-grade inflammation, or “inflammaging,” is a significant factor in the aging process. Rapamycin’s ability to modulate immune function and reduce systemic inflammation positions it as a promising agent for extending healthy lifespan.

Rapalogs: Enhancing the Benefits of mTOR Inhibition:

• Everolimus and Other Rapalogs: These derivatives of rapamycin are designed to improve its pharmacokinetic properties, making them more effective in clinical applications. Like rapamycin, rapalogs inhibit mTORC1 and offer similar benefits for immune modulation and life extension.

• Clinical Applications: Rapalogs are currently used in cancer treatment and organ transplantation to prevent rejection. Their dual role in modulating the immune system and promoting cellular health makes them valuable tools for both disease management and anti-aging strategies.

Comparing mTOR Inhibitors with Other Therapeutic Agents

To fully grasp the significance of mTOR inhibitors, it’s important to compare them with other drugs commonly used in immunosuppression and metabolic regulation.

Calcineurin Inhibitors (e.g., Tacrolimus):

• Mechanism of Action: Calcineurin inhibitors suppress the immune system by blocking T cell activation, which is essential for initiating immune responses. This makes them highly effective in preventing organ rejection and treating autoimmune diseases.

• Differences from mTOR Inhibitors: Unlike rapamycin, calcineurin inhibitors do not promote autophagy or have a known impact on lifespan extension. Their primary function is immune suppression, which can lead to side effects such as nephrotoxicity, hypertension, and an increased risk of infections.

• Clinical Use: While calcineurin inhibitors remain vital in transplantation and autoimmune therapies, their long-term use is associated with side effects that could accelerate age-related conditions, contrasting with the potential anti-aging benefits of mTOR inhibitors.

Metformin:

• Mechanism of Action: Metformin, a widely used drug for type 2 diabetes, activates AMPK (AMP-activated protein kinase), which indirectly inhibits mTORC1. This leads to enhanced insulin sensitivity, reduced inflammation, and increased autophagy.

• Potential as an Anti-Aging Drug: Metformin’s ability to modulate metabolic processes and reduce inflammation has made it a subject of interest in anti-aging research. Current studies are exploring how metformin might be used alongside mTOR inhibitors to maximize healthspan and lifespan.

• Comparative Insights: While both metformin and mTOR inhibitors promote autophagy and offer potential anti-aging effects, metformin’s primary impact is on metabolic health, making it a complementary rather than alternative approach to mTOR inhibition.

Integrating mTOR Inhibition into a Comprehensive Life Extension Strategy

The benefits of mTOR inhibition are most effectively realized when combined with other life extension strategies. Below, we outline how mTOR inhibitors like rapamycin can be part of a holistic approach to health and longevity.

Nutritional and Lifestyle Interventions:

Caloric Restriction and Fasting: Both caloric restriction and intermittent fasting have been shown to naturally reduce mTOR activity, leading to increased autophagy and improved metabolic health. These dietary strategies can complement the effects of rapamycin, enhancing its benefits for longevity.
Exercise: Regular physical activity promotes autophagy and improves mitochondrial function, both of which are critical for maintaining cellular health. When paired with mTOR inhibition, exercise can help sustain the positive effects on lifespan and healthspan.

Skin Aging and External Appearance:

• Topical Applications of mTOR Inhibitors: The potential use of mTOR inhibitors in dermatology is an emerging area of research. By promoting autophagy and reducing inflammation, these compounds may help maintain skin elasticity, reduce wrinkles, and improve overall skin health, aligning with broader life extension goals.

Addressing Chronic Inflammation:

• Managing Inflammaging: Reducing chronic inflammation is essential for extending healthspan. mTOR inhibitors, through their ability to modulate immune responses and lower systemic inflammation, play a crucial role in combating inflammaging, thereby delaying the onset of age-related diseases.

Potential Synergies with Other Therapies:

• Combining Metformin and Rapamycin: Since both metformin and rapamycin enhance autophagy through different pathways, their combined use is an area of active research. This combination could provide a more comprehensive approach to targeting aging, addressing both metabolic health and immune regulation.
• Exploring Novel Rapalogs: The development of new rapalogs with greater specificity for mTORC1 and improved safety profiles could further expand the therapeutic potential of mTOR inhibition, making these drugs more accessible for broader use in anti-aging protocols.

The Future of mTOR Modulation in Life Extension

The mTOR pathway is a pivotal regulator of aging, immune function, and cellular health. By understanding and harnessing its potential through mTOR inhibitors like rapamycin, we can open new avenues for extending healthy lifespan and managing chronic diseases. As research continues to unravel the complexities of mTOR’s role in the body, it becomes increasingly clear that this pathway holds the key to unlocking the secrets of longevity.

For those interested in staying at the forefront of life extension research, Blitzage.com offers comprehensive insights into the latest developments in this exciting field. Explore our resources to learn more about how you can integrate these cutting-edge strategies into your own journey toward a longer, healthier life.

This article has been carefully tailored for publication on Blitzage.com, offering an in-depth exploration of the mTOR pathway, its inhibitors, and their implications for life extension and immune modulation. If there are any further details or adjustments needed, please let me know!

Unlocking the Future of Life Extension: The Power of Organ Regeneration and Genetic Innovation

blitzage — Sun, 25 Aug 2024 02:51:46 +0000

As we push the boundaries of science and technology, the dream of extending human life is becoming an increasingly tangible reality. At BitsAge.com, we are at the forefront of exploring the latest advancements in life extension, focusing on how innovations in organ regeneration and genetic manipulation are not only redefining healthcare but also offering new avenues for economic growth and societal development. This article delves into the importance of these cutting-edge methods, extending their potential beyond kidney health to the broader scope of organ regeneration, genetic innovation, and their implications for the future of humanity.

The Crucial Role of Organ Regeneration in Life Extension

One of the most promising fields in the quest for life extension is organ regeneration. Our organs naturally deteriorate with age, leading to a range of health problems that shorten lifespan and reduce quality of life. Traditional medicine has focused on treating symptoms and managing chronic diseases, but what if we could replace or rejuvenate these organs entirely? This is where organ regeneration comes into play, offering the potential to significantly extend human lifespan by addressing one of the root causes of aging: organ failure.

Kidney Regeneration as a Model: The kidney is a prime example of how regenerative medicine can revolutionize healthcare. Chronic kidney disease (CKD) is a leading cause of death worldwide, and the ability to regenerate kidney tissue using stem cells or even create entirely new kidneys through cloning could drastically improve survival rates and overall quality of life. This approach goes beyond simply treating the disease; it offers the possibility of restoring kidney function to a youthful state, effectively reversing some of the effects of aging.

Expanding to Other Organs: The principles behind kidney regeneration can be applied to other organs as well. Research is ongoing in the fields of heart, liver, and lung regeneration, with the goal of growing these organs in the lab using a patient’s own cells. This would eliminate the risk of organ rejection and could provide a renewable source of healthy organs as people age. The ability to replace aging organs with new, fully functional ones could be a game-changer in the quest for life extension, offering a practical solution to one of the most significant challenges of aging.

Genetic Innovation: The Blueprint for Longevity

While organ regeneration addresses the physical aspects of aging, genetic innovation targets the underlying biological processes. Advances in genetic manipulation, particularly through technologies like CRISPR-Cas9, are enabling scientists to edit genes associated with aging and disease, potentially delaying or even reversing the aging process.

Preventing Age-Related Diseases: Many chronic diseases, such as cardiovascular disease, diabetes, and neurodegenerative disorders, have a genetic component. By editing these genes, we can reduce the likelihood of developing these conditions as we age. This not only extends lifespan but also improves the quality of those additional years by reducing the burden of chronic illness.

Enhancing Organ Function: Genetic manipulation can also be used to enhance the function of regenerated organs. For example, by editing genes to increase resistance to oxidative stress or improve cellular repair mechanisms, we can create organs that not only last longer but also perform better than their natural counterparts. This approach could lead to significant improvements in healthspan—the period of life spent in good health—as well as lifespan.

Addressing the Fundamental Causes of Aging: Beyond treating specific diseases, genetic innovation holds the promise of addressing the fundamental causes of aging at the cellular level. By targeting processes like cellular senescence (where cells stop dividing and begin to secrete harmful substances) and telomere shortening (the gradual loss of protective DNA sequences at the ends of chromosomes), scientists are working to slow down or even reverse the aging process itself. This could lead to a future where people not only live longer but also maintain their vitality and quality of life well into old age.

Broader Applications: Beyond Human Health

The implications of organ regeneration and genetic innovation extend far beyond individual health. These technologies have the potential to drive significant economic growth and societal development, with applications in a variety of fields.

Agriculture and Environmental Sustainability: The same genetic manipulation techniques used to extend human lifespan can also be applied to plants and animals, offering solutions to global challenges such as food security and environmental sustainability. For example, genetically modified crops that are more resistant to pests, diseases, and extreme weather conditions could help ensure a stable food supply in the face of climate change. Similarly, genetically engineered animals that are more resilient to disease or have improved growth rates could contribute to more sustainable livestock production.

Economic Growth Through Biotechnology: The development of organ regeneration and genetic therapies is driving growth in the biotechnology sector, creating high-paying jobs and new industries. As these technologies become mainstream, they could reduce healthcare costs by decreasing the prevalence of chronic diseases and the need for long-term care. Countries that invest in life extension research and development could see significant economic benefits, positioning themselves as leaders in the global biotechnology market.

Collaborative Research and Innovation: Life extension research requires collaboration across multiple fields, including medicine, biotechnology, genetics, and even environmental science. By fostering cross-disciplinary collaboration, we can accelerate the development of new technologies and solutions that benefit both human health and the environment. This collaborative approach not only drives innovation but also ensures that the benefits of life extension are widely distributed, contributing to global economic and social progress.

The Path Forward: Encouraging Research and Investment

To realize the full potential of organ regeneration and genetic innovation, it is crucial to encourage investment and collaboration in this field. Governments, private investors, and academic institutions must recognize the importance of these technologies for extending human life and improving societal well-being.

Policy Support and Funding: Governments should implement policies that support research in regenerative medicine and genetic therapies, providing funding and resources to accelerate development. Public-private partnerships can also play a key role in bringing these technologies from the lab to the clinic, ensuring that they are accessible to those who need them.

Public Engagement and Ethical Considerations: As we push the boundaries of what is possible, it is important to engage the public in discussions about the ethical implications of these technologies. Issues such as access to life extension treatments, the potential for genetic inequality, and the long-term impacts on society must be carefully considered. By fostering an open and inclusive dialogue, we can ensure that advancements in life extension are implemented in a way that is ethical, equitable, and beneficial for all.

Global Collaboration for a Healthier Future: The pursuit of life extension is a global endeavor, requiring collaboration across borders and cultures. By working together, we can pool resources, share knowledge, and accelerate the development of life-saving technologies. This global approach not only enhances the potential for success but also ensures that the benefits of life extension are shared by all, contributing to a healthier, more prosperous world.

Conclusion: A New Era of Longevity

At BitsAge.com, we believe that the future of life extension lies in the integration of organ regeneration and genetic innovation. These technologies offer the promise of not only extending lifespan but also enhancing the quality of life as we age. By focusing on the renewal of our bodies at both the organ and genetic levels, we can unlock new possibilities for longevity and wellness.

The journey to longer, healthier lives is just beginning, and the advancements in organ regeneration and genetic manipulation are key steps along this path. With continued research, collaboration, and investment, we can turn the dream of life extension into a reality that benefits individuals, economies, and societies worldwide.

Investing in the Future: The pursuit of life extension is not just a scientific endeavor—it’s an investment in the future of humanity. By supporting research and development in this field, we can create a world where people live longer, healthier lives, free from the burdens of chronic disease and aging. This is the future that we at BitsAge.com are working towards, and we invite you to join us on this exciting journey.

This article for BitsAge.com highlights the transformative potential of organ regeneration and genetic innovation in extending human lifespan. By exploring the broader applications of these technologies and their economic impact, it emphasizes the importance of continued research, collaboration, and investment in the field of life extension, positioning it as a key driver of future societal progress and economic growth.

Comprehensive Analysis: Peroxisomes, PPARs, AMPK, and Life Extension

blitzage — Sun, 25 Aug 2024 02:41:07 +0000

This article explores the significance of peroxisomes, their functions, and the implications of various pharmacological interventions on longevity. Additionally, it delves into the roles of PPARs (Peroxisome Proliferator-Activated Receptors) and AMPK (AMP-activated protein kinase) in metabolic regulation and aging. We also examine the latest life extension methodologies, including pharmacological, genetic, and lifestyle interventions, highlighting cutting-edge research and advancements.

Aging is a complex, multifactorial process influenced by genetic, environmental, and lifestyle factors. It involves the gradual decline of physiological functions, increased susceptibility to diseases, and eventual death. Key mechanisms of aging include telomere shortening, DNA damage, epigenetic alterations, and mitochondrial dysfunction. Understanding these processes is crucial for developing interventions that can slow down or reverse aging.

Several theories have been proposed to explain the mechanisms of aging, including the Free Radical Theory, which suggests that aging results from the accumulation of oxidative damage caused by free radicals; the Telomere Theory, proposing that the progressive shortening of telomeres leads to cellular senescence and aging; the Mitochondrial Theory, attributing aging to the decline in mitochondrial function and increased production of reactive oxygen species (ROS); and the Epigenetic Theory, focusing on changes in gene expression regulation due to epigenetic modifications, such as DNA methylation and histone modification.

Recent Advancements in Aging Research

Recent advancements in molecular biology, genetics, and bioinformatics have significantly enhanced our understanding of aging. Research is increasingly focused on identifying biomarkers of aging, understanding the role of cellular senescence, and exploring the potential of interventions such as caloric restriction, pharmacological agents, and gene therapy to extend lifespan and healthspan.

Mitochondrial Function and Aging

Mitochondria, known as the powerhouses of the cell, generate ATP through oxidative phosphorylation. They are also involved in apoptosis, calcium homeostasis, and the regulation of metabolic pathways. The integrity and function of mitochondria are vital for maintaining cellular energy balance and overall health. Mitochondrial dysfunction is a hallmark of aging and is associated with numerous age-related diseases. Factors contributing to mitochondrial dysfunction include oxidative stress, mutations in mitochondrial DNA (mtDNA), and impaired biogenesis. Strategies to improve mitochondrial function, such as enhancing mitochondrial biogenesis and reducing oxidative damage, are being explored for their potential to extend lifespan.

Research into mitochondrial-targeted therapies is ongoing, with a focus on antioxidants, mitochondrial uncouplers, and agents that enhance mitophagy (the selective degradation of damaged mitochondria). These interventions aim to maintain mitochondrial function and reduce the accumulation of damaged mitochondria, thereby promoting cellular health and longevity.

Peroxisomes and Their Functions

Peroxisomes are essential cellular organelles involved in various metabolic processes, including lipid metabolism and detoxification. They are thought to have originated from an endosymbiotic relationship between ancestral eukaryotic cells and actinobacteria. This theory is supported by the presence of peroxisomes in nearly all eukaryotic cells and their crucial role in lipid metabolism and detoxification processes.

Key Functions of Peroxisomes:

1. Beta-Oxidation of Fatty Acids:
• Peroxisomes play a crucial role in the breakdown of very-long-chain fatty acids through beta-oxidation, a process that generates acetyl-CoA for energy production.
2. Detoxification:
• Peroxisomes contain enzymes such as catalase that detoxify hydrogen peroxide, converting it into water and oxygen. This reduces oxidative stress within the cell.
3. Synthesis of Plasmalogens:
• Peroxisomes are involved in the synthesis of plasmalogens, a type of phospholipid essential for the normal function of cell membranes, particularly in the brain and heart.
4. Lipid Raft Formation:
• Plasmalogens are important components of lipid rafts, specialized domains in the cell membrane that play a key role in cellular signaling and membrane fluidity.
5. Bile Acid Synthesis:
• Peroxisomes contribute to the synthesis of bile acids from cholesterol, aiding in the digestion and absorption of dietary fats.
6. Metabolism of Reactive Oxygen Species (ROS):
• By breaking down hydrogen peroxide, peroxisomes help manage ROS levels, protecting the cell from oxidative damage.

Roles of PPARs

PPARs are a group of nuclear receptor proteins that function as transcription factors regulating the expression of genes involved in fatty acid storage and glucose metabolism. They play critical roles in cellular differentiation, development, and metabolism.

1. PPAR-α:
• Regulates genes involved in fatty acid oxidation and energy homeostasis.
• Primarily expressed in the liver, heart, kidney, and muscle.
2. PPAR-γ:
• Predominantly found in adipose tissue, colon, and macrophages.
• Improves insulin sensitivity, enhances glucose uptake, and reduces inflammation.
3. PPAR-δ:
• Involved in regulating fatty acid oxidation and energy expenditure.
• Promotes the utilization of fatty acids.

PPARs function as transcription factors by forming heterodimers with retinoid X receptors (RXRs). These heterodimers bind to specific DNA sequences called peroxisome proliferator response elements (PPREs) in the promoter regions of target genes. Upon activation by ligands (such as fatty acids or synthetic agonists), PPARs modulate the transcription of genes involved in lipid metabolism, glucose homeostasis, and inflammation. By modulating these metabolic pathways, PPARs play a crucial role in maintaining energy balance and metabolic health.

Role of AMPK

AMP-activated protein kinase (AMPK) is an enzyme that plays a crucial role in cellular energy homeostasis. It is activated in response to low cellular energy levels, functioning as an energy sensor that helps restore energy balance by regulating metabolic pathways. AMPK activation increases energy production by enhancing glucose uptake, fatty acid oxidation, and mitochondrial biogenesis. It also inhibits energy-consuming processes such as protein and lipid synthesis. By maintaining energy homeostasis, AMPK helps cells adapt to metabolic stress and supports overall metabolic health.

AMPK activation promotes autophagy, a process that degrades and recycles damaged cellular components. Autophagy is essential for maintaining cellular homeostasis and preventing the accumulation of damaged proteins and organelles. Enhanced autophagy contributes to cellular repair and longevity, reducing the risk of age-related diseases.

Pharmacological Interventions and Longevity

1. Metformin:
• A widely used antidiabetic drug that activates AMPK, contributing to its beneficial effects on glucose metabolism and insulin sensitivity.
• By activating AMPK, metformin also inhibits mTOR signaling and promotes autophagy, supporting cellular health and longevity.
• Its ability to modulate multiple metabolic pathways makes it a valuable drug for managing metabolic health and promoting longevity.

2. Caloric Restriction and Physical Exercise:
• Natural activators of AMPK.
• Enhance energy metabolism, promote autophagy, and improve overall health.
• Support cellular health and longevity, reducing the risk of metabolic diseases and age-related conditions.

3. Peroxisome Proliferators:
• Enhance the breakdown of long-chain fatty acids and improve lipid profiles.
• By activating PPAR-α, these drugs increase the number and efficiency of peroxisomes, enhancing lipid metabolism.
• Boost the detoxification capacity of peroxisomes, reducing cellular damage from ROS.
• Manage cholesterol and glucose levels, contributing to overall metabolic health.

Pharmaceutical Development and Peroxisome-Related Drugs

1. Pioglitazone:
• A PPAR-γ agonist that improves insulin sensitivity and glucose metabolism.
• Enhances peroxisome function and supports lipid metabolism.

2. Dual PPAR Agonists:
• Drugs that activate both PPAR-α and PPAR-γ, offering comprehensive metabolic benefits.
• Improve lipid and glucose metabolism, reduce chronic inflammation, and enhance peroxisome function.

3. Fibrates (e.g., Fenofibrate):
• Activate PPAR-α, promoting fatty acid oxidation and reducing triglycerides.
• Enhance peroxisome function, improving lipid metabolism and reducing oxidative stress.
• Reduce inflammation and improve metabolic health.

4. Statins:
• Primarily used to lower cholesterol.
• Indirectly support peroxisome function by reducing oxidative stress.
• Inhibit HMG-CoA reductase, reducing cholesterol production and cardiovascular risk.

Latest Research in Life Extension

Proteomics and Genomics

• Proteomic Technologies: Advances in proteomics are providing insights into the protein interactions and pathways involved in aging. By understanding the protein profiles associated with longevity, researchers can identify potential targets for therapeutic intervention. • Genomic Studies: Genomic technologies, such as CRISPR-Cas9, are enabling precise genetic modifications to study the effects of specific genes on aging and longevity. These tools also hold potential for developing gene therapies to enhance lifespan.

Novel Pharmacological Agents

1. Senolytics: Drugs that selectively induce death in senescent cells, which accumulate with age and contribute to inflammation and tissue dysfunction. Examples include dasatinib and quercetin. 2. NAD+ Precursors: Compounds like nicotinamide riboside and nicotinamide mononucleotide that boost levels of NAD+, a coenzyme involved in cellular metabolism and DNA repair, shown to decline with age. 3. mTOR Inhibitors: Drugs like rapamycin that inhibit the mTOR pathway, which is involved in cell growth and metabolism. Inhibition of mTOR has been associated with increased lifespan in various organisms.

Lifestyle Interventions

1. Caloric Restriction: Reducing caloric intake without malnutrition has been shown to extend lifespan in various organisms by promoting metabolic efficiency and reducing oxidative stress. 2. Intermittent Fasting: Patterns of eating that involve regular short-term fasts can mimic the effects of caloric restriction and have been associated with improved metabolic health and longevity. 3. Exercise: Regular physical activity is a natural activator of AMPK and has been shown to enhance mitochondrial function, promote autophagy, and improve overall health, contributing to increased lifespan.

Peroxisomes play a critical role in maintaining cellular health and longevity. Drugs that enhance peroxisome function, such as PPAR activators, are vital for reducing oxidative stress and improving metabolic health. By understanding the connections between mTOR inhibitors, insulin sensitizers, and peroxisome proliferators, we can develop comprehensive strategies to extend healthy human lifespan.

Practical Examples of Dual PPAR Agonists

1. Saroglitazar:
• Development and Discovery: Developed by Zydus Cadila, Saroglitazar is a novel dual PPAR agonist that targets both PPAR-α and PPAR-γ. It was primarily developed to manage dyslipidemia and hypertriglyceridemia in patients with type 2 diabetes mellitus.
• Mechanism of Action: Enhances lipid and glucose metabolism, reduces triglycerides, and improves insulin sensitivity.
• Clinical Trials and Potential: Clinical trials have demonstrated its efficacy in reducing triglycerides, improving glycemic control, and managing dyslipidemia. It holds potential for broader applications in metabolic disorders.
2. Elafibranor (GFT505):
• Development and Discovery: Developed by Genfit, Elafibranor is a dual PPAR-α/δ agonist. It was investigated for its potential in treating non-alcoholic steatohepatitis (NASH) and primary biliary cholangitis (PBC).
• Mechanism of Action: Improves lipid metabolism, insulin sensitivity, and reduces inflammation, targeting both PPAR-α and PPAR-δ receptors.
• Clinical Trials and Potential: Clinical trials have shown promising results in improving liver function and metabolic parameters in NASH patients. Its dual action makes it a candidate for treating a range of metabolic disorders.
3. Muraglitazar:
• Development and Discovery: Developed by Bristol-Myers Squibb, Muraglitazar is a dual PPAR-α/γ agonist initially investigated for its potential in managing type 2 diabetes.
• Mechanism of Action: Improves insulin sensitivity, lipid profiles, and glucose metabolism by activating both PPAR-α and PPAR-γ receptors.
• Clinical Trials and Potential: Despite initial promising results, concerns over cardiovascular safety led to discontinuation. Its development highlighted the need for careful evaluation of dual PPAR agonists’ safety profiles.

By understanding the development, mechanisms, and clinical potential of these dual PPAR agonists, we can appreciate their role in advancing metabolic health and longevity.

For more detailed information and cutting-edge research on life extension, continue exploring scientific literature and databases. Engage with ongoing studies and clinical trials to stay informed about the latest advancements.

This comprehensive article provides an in-depth analysis of the pathways and mechanisms involved in life extension, focusing on peroxisomes and their importance. For comprehensive insights and updates, keep abreast of the latest scientific findings and research publications.

Expanded Content on Life Extension and Related Areas

In addition to the previously covered areas, this article expands on related topics in molecular biology and pharmacological research to provide a comprehensive understanding of life extension.

Plasmalogens and Lipid Rafts

Plasmalogens are a type of phospholipid synthesized in peroxisomes, playing a crucial role in the structure and function of cell membranes. They are particularly abundant in the brain, heart, and immune cells. Plasmalogens are involved in:

1. Membrane Structure: Contributing to membrane fluidity and stability. 2. Antioxidant Defense: Protecting cells from oxidative damage by scavenging reactive oxygen species (ROS). 3. Signal Transduction: Facilitating communication between cells by participating in lipid raft formation.

Lipid Rafts are specialized microdomains in the cell membrane enriched with cholesterol, sphingolipids, and proteins. They play a critical role in:

1. Cell Signaling: Serving as platforms for receptor-mediated signaling. 2. Membrane Organization: Organizing proteins and lipids to facilitate cellular processes. 3. Endocytosis: Involved in the internalization of molecules into the cell.

Advanced Pharmaceutical Development

Development of Antioxidant Therapies

1. Synthetic Antioxidants: Compounds designed to mimic the action of natural antioxidants, protecting cells from oxidative stress. 2. Mitochondria-Targeted Antioxidants: Specialized antioxidants that accumulate in mitochondria, where they neutralize ROS and support mitochondrial function.

Gene Therapy and Life Extension

1. CRISPR-Cas9: A revolutionary gene-editing technology enabling precise modifications to the genome. It holds potential for correcting genetic defects and enhancing longevity-related genes. 2. Viral Vectors: Used to deliver therapeutic genes to target cells, potentially correcting metabolic disorders and extending lifespan.

Innovative Drug Development

1. Senolytics: Targeting senescent cells to reduce inflammation and tissue dysfunction, promoting healthy aging. 2. NAD+ Boosters: Enhancing levels of NAD+ to improve cellular metabolism and DNA repair, supporting longevity. 3. mTOR Inhibitors: Drugs like rapamycin that modulate the mTOR pathway to extend lifespan by promoting cellular maintenance and stress resistance.

Conclusion

Peroxisomes play a critical role in maintaining cellular health and longevity. By enhancing our understanding of peroxisomes, PPARs, AMPK, and related metabolic pathways, we can develop comprehensive strategies for life extension. This involves a combination of pharmacological, genetic, and lifestyle interventions aimed at promoting healthy aging and extending lifespan.

Decrease Oxygen to Boost Longevity?

Blitz Age — Sat, 26 Aug 2023 05:34:52 +0000

To test this idea, Mootha, Rogers, and their colleagues worked with a strain of mice that age prematurely. These animals succumb to age-related diseases at about 3 or 4 months of age, compared with normal, or “wild type” mice, who live about two years.

Once the mice were weaned at around four weeks after birth, the researchers moved them into a hypoxic chamber with an oxygen concentration of just 11 percent, the equivalent of the oxygen levels at the base of Mount Everest.

Rather than decreased barometric pressure — the reason for such low oxygen tension at high altitudes — the hypoxic chamber’s low oxygen content was caused by dilution with nitrogen gas.

The median life span of these mice living at normal 21 percent oxygen was just shy of 16 weeks. However, animals housed in the hypoxic chamber lived to about 24 weeks, on average, or about 50 percent longer than expected.

The maximum life span of these animals also increased under low-oxygen conditions — by about 30 percent, or about 31 weeks, compared with 26-week life spans of their peers living in normal oxygen concentrations.

Life span wasn’t the only outcome that changed for the animals residing under oxygen restriction, Rogers explained.

Mice living in the reduced oxygen environment also preserved neurologic function longer, as measured by their performance on a standard test of coordination and strength.

Seeking to understand the mechanism behind these effects, the researchers examined food intake to see if the animals ate less, since caloric restriction has proved to be a potent life span extender in multiple animal models.

To the researchers’ surprise, mice living in the hypoxic chamber ate slightly more food than those living under normal oxygen concentrations. A search for unusual gene activity, DNA damage, or changes in signaling pathways in the oxygen-restricted mice turned up some tantalizing clues but no definitive answers, Rogers said.

Future studies, he added, should examine whether oxygen restriction can similarly extend life span in wild-type mice, should seek to define what mechanisms might be responsible for the life-extending effects of restricted oxygen, and determine whether these mechanisms affect all organs.

Authorship, funding, disclosures

Additional authors included Hong Wang, Timothy Durham, Jonathan Stefely, Norah Owiti, Andrew Markhard, Lev Sandler, and Tsz-Leung To.

This work was funded by a gift from the J. Willard and Alice S. Marriott Foundation to Mootha. Mootha is an Investigator of the Howard Hughes Medical Institute. Rogers is supported by the Parker B. Francis Family Foundation Fellowship.

Mootha is on the scientific advisory board of 5am Ventures. He is listed as an inventor on patents filed by Massachusetts General Hospital on the therapeutic uses of hypoxia.

Study in mice suggests that oxygen restriction could extend life span
by CHRISTEN BROWNLEE May 23, 2023 Research
4 min read

At a glance:

Living in a low-oxygen environment extended life spans, preserved neurologic function in mice.
Findings add to a growing body of research showing oxygen restriction may ward off neurologic decline and extend life span in animal models.
Mechanisms behind the protective effects of oxygen deprivation remain to be elucidated.

A strain of mice born with abnormally short life spans defied expectations and lived 50 percent longer than expected when put in an environment with low oxygen roughly equivalent to a Mount Everest base camp, Harvard Medical School scientists report in a new study.

Get more HMS news here

The findings, published May 23 in PLOS Biology, add to a growing list of approaches shown to lengthen life in animal models and provide the first demonstration that oxygen restriction could extend life span in a mouse model of aging.

Life Extension Treatments: A New Era in Anti-Aging

Blitz Age — Tue, 15 Aug 2023 13:30:01 +0000

‍

In the pursuit of mitigating the effects of aging, the potential of stem cells, specifically mesenchymal stem cells, is gaining significant attention within the scientific community. These cells, characterized by their unique regenerative capabilities and capacity to differentiate into various cell types, present a promising avenue for delaying or potentially reversing age-related degeneration at a cellular level.

‍

What is Life Extension?

Life extension is a rapidly growing field that focuses on slowing the biological aging process to extend the average human lifespan and the health span – the period spent in good health. This concept has gained significant attention recently due to its potential for human longevity. Extending human life is not new; it has been a part of human culture and philosophy for centuries. However, it is only in recent decades, with the advent of modern science and medicine, that we have started to make tangible progress in this area.

‍

The Science Behind Life Extension

The science of life extension is complex and multifaceted, involving various biological, medical, and technological disciplines. At its core, it involves a deep understanding of the human body and the biological processes that cause us to age. Aging is a complex phenomenon involving various biological processes, such as cell death, cellular reprogramming, and age-related diseases.

Recent advances in aging research have shed light on these processes, paving the way for developing life-extension treatments. For instance, scientists have discovered that specific genes are associated with longevity, and manipulating these genes could slow the aging process. Similarly, research has shown that certain lifestyle factors, such as diet and exercise, can influence aging and extend lifespan.

‍

The Current Role of Drugs in Life Extension

One drug that has shown promise in extending lifespan is Metformin, a common medication for type 2 diabetes. Metformin works by improving the body’s sensitivity to insulin and reducing the amount of glucose produced by the liver. This helps to control blood sugar levels and prevent complications associated with diabetes.

However, some studies suggest that Metformin may also have anti-aging properties. It is believed to extend lifespan by reducing oxidative stress and inflammation, two critical factors in the aging process. Oxidative stress occurs when there is an imbalance between the production of free radicals and the body’s ability to counteract their harmful effects. Inflammation is a natural response to injury or illness, but chronic inflammation can lead to various health problems, including heart disease and cancer. Metformin could slow aging and extend lifespan by reducing oxidative stress and inflammation.

‍

The Power of Vitamin D3

Vitamin D3, often called the “sunshine vitamin,” is another compound that may play a role in life extension. Vitamin D3 is essential for bone health, immune function, and cardiovascular health. It is produced by the body when the skin is exposed to sunlight. However, many people do not get enough Vitamin D3 because they live in areas with limited sunlight or spend most of their time indoors.

Some research suggests that adequate levels of Vitamin D3 may help to extend life by reducing the risk of chronic diseases. For instance, Vitamin D3 has been shown to reduce the risk of heart disease by regulating blood pressure and cholesterol levels. It also plays a role in immune function and can help to prevent infections and autoimmune diseases. Furthermore, Vitamin D3 is involved in cell growth and differentiation, and it may help to prevent cancer by regulating cell growth and preventing the growth of cancer cells.

‍

The Impact of Technology on Lifespan

Genetic engineering and cellular reprogramming are two technological advancements that hold great promise for life extension. Genetic engineering involves manipulating the genes in the aging process to slow down or reverse biological aging. This could potentially extend lifespan and improve health span.

Cellular reprogramming involves changing the state of a cell, such as turning a skin cell into a heart cell or a nerve cell. This technology could potentially replace damaged or aging cells in the body, slowing the aging process and extending lifespan.

‍

Stem Cell Therapy: A Promising Future

Stem cell therapy is a form of regenerative medicine currently being explored for its potential for life extension. Stem cells are unique in that they can develop into many different types of cells in the body. This means they could be used to repair or replace damaged or aging cells, slowing the aging process and extending lifespan.

In particular, mesenchymal stem cells have shown promise in anti-aging and life-extension research. These cells, which can be found in various tissues in the body, can differentiate into various cell types, including bone, cartilage, muscle, and fat cells. They also have potent anti-inflammatory properties, potentially slowing the aging process.

Clinical trials are underway to explore stem cell therapy’s potential for life extension. For instance, a study conducted by the Mayo Clinic investigates using stem cells to treat heart disease, a major cause of aging and death. If successful, this could represent a significant breakthrough in life extension.

‍

The Future of Life Extension with Mesenchymal Stem Cells

Life extension is a rapidly evolving area of the life sciences, with new discoveries and advancements being made regularly. Among the most promising advancements is using mesenchymal stem cells in anti-aging research.

Mesenchymal stem cell (MSC) therapy has the potential for life extension due to the unique properties of MSCs, which are multipotent cells capable of self-renewal and differentiation. MSCs have shown therapeutic value in various clinical situations, thanks to their multi-differentiation potential, immunomodulatory and paracrine effects. These cells can regenerate and repair tissue, making them attractive candidates for treating age-related diseases and improving overall health.

‍

Rejuvenation Strategies

Stem cell aging and replicative exhaustion are considered hallmarks of aging and functional attrition in organisms. As MSCs age, they gradually lose their regenerative potential, and cellular dysfunction increases. Rejuvenating senescent MSCs could offer opportunities to prevent, postpone, or even reverse the kinetics with which MSCs age and ultimately provide avenues for promoting healthy aging and lifespan extension.

Various strategies have been investigated for rejuvenating senescent MSCs, including the use of induced pluripotent stem cell-derived MSCs (MSC), which can be passaged more than 40 times without exhibiting features of senescence. Other approaches involve manipulating gene expression, such as overexpressing SIRTs (Sirtuin genes) to delay senescence and maintain MSCs’ differentiation capacity. Furthermore, optimizing culture conditions to support MSC proliferation and prevent senescence is crucial for generating large numbers of MSCs required for clinical applications.

‍

Rejuvenation and Regeneration of Aged Cells

Mesenchymal stem cells are a type of immune cell with the unique ability to differentiate into various human cell types. Combined with their potent anti-inflammatory properties, this ability makes them a promising tool for slowing aging and extending healthy life expectancy.

‍

Tissue Repair and Regeneration

These cells could replace or repair damaged or aging cells in the body, slowing the human aging process and extending lifespan. For instance, they could be used to repair damaged blood vessels, a common issue in aging that can lead to conditions such as heart disease and lung cancer.

Clinical trials are underway to explore mesenchymal stem cells’ potential for life extension. These trials represent a critical step in the drug discovery process, allowing scientists to test the safety and efficacy of these cells in a controlled setting.

Using mesenchymal stem cells for life extension also represents a significant future development in experimental gerontology. Understanding and manipulating the processes that cause cells to age could prolong youthfulness, improve survival, and achieve a longer life.

However, it’s important to note that using mesenchymal stem cells for life extension is not without challenges. For instance, there are ethical considerations, particularly regarding access to these treatments. These treatments must be available to benefit most people, including those in developing countries.

‍

Benefits of Stem Cells in Anti-aging Treatments

Despite these challenges, the potential benefits of using mesenchymal stem cells for life extension are immense. With continued research and development, we may one day be able to significantly extend the human lifespan, allowing individuals to live healthier lives. This is the promise of life extension – not just more years in your life, but more life in your years.

In conclusion, while life extension is complex and multifaceted, using mesenchymal stem cells represents one of the most promising avenues for future research. As we explore this exciting frontier, we can look forward to a future where a long, healthy life is a possibility and a reality.

‍

Discover the potential of stem cells for yourself!

Learn more about the possibilities of using mesenchymal stem cells in a clinical setting.

Find out if you are a candidate

‍

The Benefits of Life Extension

One of the primary benefits of life extension is the potential to extend both lifespan and health span – the period of life spent in good health. By slowing down the aging process and reducing the risk of age-related diseases, life-extension treatments could allow individuals to live longer, healthier lives.

This could have a profound impact on quality of life. Imagine enjoying your favorite activities, spending time with loved ones, and experiencing new things well into your old age. This is the promise of life extension – not just more years in your life, but more life in your years.

‍

Economic and Societal Implications

The potential to extend human life expectancy also has significant economic and societal implications. For instance, it could lead to an increase in the productive years of individuals, thereby contributing to economic growth. Longer lifespans could also mean more time to contribute to society through work, volunteerism, or other forms of civic engagement.

Moreover, life extension could help to alleviate the burden of age-related diseases on healthcare systems. By reducing the incidence of diseases such as heart disease, cancer, and Alzheimer’s, life extension could potentially save healthcare systems billions of dollars each year.

‍

The Controversy Surrounding Life Extension

While the potential benefits of life extension are immense, it raises several ethical considerations. For instance, if life extension treatments become available, who should have access to them? Should they be available to everyone or only to those who can afford them? And if the lifespan is significantly extended, what would be the implications for population growth and resource use?

These are complex questions that do not have easy answers. They require careful consideration and dialogue among scientists, policymakers, and the public.

‍

Critics’ Arguments

Critics of life extension often argue that instead of focusing on extending life, we should focus on improving the quality of life for all individuals. They argue that rather than investing in treatments that will only benefit a small portion of the population, we should invest in public health measures that can improve health and longevity for everyone.

Critics also express concerns about the potential for life extension technologies to widen the gap between the rich and the poor. If these treatments are expensive and out of reach for many, they could exacerbate existing health disparities and lead to further inequality.

‍

Future Studies and Developments

Despite the controversy, research into life extension continues to progress. Future studies will likely focus on a deeper understanding of aging and developing more effective and accessible life-extension treatments. The next few decades could see significant advancements in this field.

Scientists are also exploring the potential of other technologies, such as artificial intelligence and nanotechnology, to contribute to life extension. For instance, artificial intelligence could analyze large amounts of health data and identify patterns to help us understand the aging process and develop effective interventions. On the other hand, nanotechnology could potentially be used to repair or replace damaged cells at a microscopic level.

‍

The Possibility of an Indefinite Lifespan

While an indefinite lifespan may seem like science fiction, some scientists believe it could be possible. With continued advancements in life extension technologies, we may one day be able to significantly extend the human lifespan or even achieve immortality.

However, the goal of life extension is not just to extend life for the sake of longevity. Instead, it is to extend healthy, productive life – to allow individuals to live longer, healthier lives, free from the diseases and disabilities that often come with old age. Whether or not we can achieve this goal remains to be seen, but the progress made so far gives us reason to be hopeful.

‍

The Impact of Diet and Physical Activity

A healthy lifestyle, including a balanced diet and regular physical activity, is crucial in life extension. Dietary restriction, mainly caloric restriction, has been shown in numerous studies to extend the lifespan of various organisms. This approach involves reducing calorie intake without causing malnutrition, leading to beneficial effects such as improved metabolic health, reduced inflammation, and delayed onset of age-related diseases.

On the other hand, physical activity contributes to life extension by improving cardiovascular health, boosting the immune system, and reducing the risk of chronic diseases such as heart disease and cancer. Regular exercise also promotes healthy aging by maintaining muscle mass and strength, improving balance and coordination, and enhancing cognitive function, thereby reducing the risk of cognitive decline.

‍

The Role of Weight Management

Weight management is another critical aspect of a healthy lifestyle that contributes to life extension. Maintaining a healthy weight can help to prevent a range of health problems, including cardiovascular disease, diabetes, and certain types of cancer, such as breast cancer and prostate cancer. Weight loss, mainly achieved through diet and exercise, can also improve metabolic health and longevity.

‍

Life Extension with Stem Cells

From a clinical perspective, strategies to mitigate aging using mesenchymal stem cells (MSCs) involve the administration of MSC therapies or utilizing MSC regeneration properties to treat age-related diseases and promote overall health. Some possible clinical applications include:

Cellular therapy: MSCs can be employed in cellular therapy to treat various age-related diseases, such as osteoporosis, osteoarthritis, and degenerative disc disease, by replacing or regenerating damaged tissues. This approach might help to improve the quality of life and functionality of an aging individual, thereby mitigating the effects of aging.
Immunomodulation: MSCs possess significant immunomodulatory properties, making them attractive candidates for treating immunosenescence, a decline in immune function associated with aging. MSC therapy could help reduce chronic inflammation and other age-related immune issues by modulating the immune response and supporting tissue repair.
Tissue and organ regeneration: MSCs can support the regeneration of organs that typically decline with age, such as the heart, liver, or kidneys. By enhancing tissue and organ function, MSC therapy can potentially mitigate the effects of aging and promote overall health.
Prevention and treatment of age-related neurodegenerative diseases: MSCs hold therapeutic potential in preventing or treating diseases like Alzheimer’s, Parkinson’s, and other neurodegenerative disorders by providing neuroprotective or immunomodulatory effects. These treatments could help slow down or even reverse the progression of such diseases while maintaining cognitive function and brain health as individuals age.
Combining MSC therapy with other interventions: In the clinical setting, MSC therapy may be combined with other strategies such as caloric restriction, pharmacological agents, and lifestyle changes to achieve cumulative benefits and better address the multifaceted aspects of aging.

Although MSC therapy has shown promise in various clinical applications, more research is needed to thoroughly understand the potential risks and benefits and establish standardized protocols for MSC isolation, expansion, and administration. Once these obstacles are addressed, MSC therapy could become a mainstream strategy to mitigate aging from a clinical perspective.

‍

Uncover the Cost of Stem Cell Therapy Now!

Dive into the world of stem cell treatment at DVC Stem in the Cayman Islands! Discover the incredible value and potential savings of this life-changing therapy. Click below to learn more about our pricing.

View pricing structure

‍

The Future of Life Extension: Radical Approaches and Ethical Considerations

While the average human life expectancy has increased significantly over the past century due to improvements in healthcare and living conditions, some scientists and researchers in life extension aim to push these boundaries even further. This concept, known as radical life extension, involves extending the human lifespan significantly beyond the current maximum lifespan.

Radical life extension could be achieved through various strategies, including advanced biomedical research, anti-aging medicine, and therapeutic cloning. For instance, stem cells and genetic engineering could potentially replace or repair damaged or aging cells, slowing down the aging process and extending lifespan.

‍

Ethical Considerations and Future Developments

As with any rapidly advancing field, life extension raises several ethical considerations, particularly radical life extension. Critics argue that such technologies could widen the gap between the rich and the poor, as they may be expensive and out of reach for many. Concerns about the potential societal and environmental implications of a significantly increased human lifespan exist.

Despite these challenges, the field of life extension continues to progress, and the next few decades could see significant advancements. With continued research and development, and careful consideration of the ethical implications, we may one day be able to significantly extend the human lifespan, improving both the quantity and quality of life for individuals worldwide.

‍

Find out if you are a candidate.

Fill out a brief patient screening application and find out if you are a candidate for our IRB-approved clinical study.

Apply for treatment

‍

Frequently Asked Questions

‍

What is the maximum human lifespan?

The maximum human lifespan is currently believed to be around 122 years, a record held by Jeanne Calment of France. However, with advancements in life-extension treatments, this could potentially increase.

‍

Can we live up to 200 years?

While living up to 200 years may seem far-fetched with our current understanding of human biology and aging, it is not entirely impossible with future advancements in life extension technologies.

‍

What is the cure for aging in 2023?

While there is currently no “cure” for aging, several treatments and interventions, such as Metformin, Vitamin D3, and stem cell therapy, are being researched for their potential to slow down the aging process and extend lifespan.

‍

What are the benefits of extending the human lifespan?

Extending the human lifespan could have several benefits, including an increase in the productive years of individuals, a reduction in the burden of age-related diseases on healthcare systems, and the potential for individuals to experience more of what life has to offer.

‍

What are the ethical considerations of life extension?

Life extension raises several ethical considerations, including questions about access to life extension treatments, the potential for overpopulation and resource scarcity, and such technologies to widen the gap between the rich and the poor.

‍

References

(1) Liu, J., Ding, Y., Liu, Z., & Liang, X. (2020). Senescence in Mesenchymal Stem Cells: Functional Alterations, Molecular Mechanisms, and Rejuvenation Strategies. Frontiers in Cell and Developmental Biology, 8, 258. https://doi.org/10.3389/fcell.2020.00258

(2) Zhou, X., Hong, Y., Zhang, H., & Li, X. (2020). Mesenchymal Stem Cell Senescence and Rejuvenation: Current Status and Challenges. Frontiers in Cell and Developmental Biology, 8, 364. https://doi.org/10.3389/fcell.2020.00364

(3) Al-Azab, M., Safi, M., Idiiatullina, E., Al-Shaebi, F., & Zaky, M. Y. (2022). Aging of mesenchymal stem cell: machinery, markers, and strategies of fighting. Cellular & Molecular Biology Letters, 27, 69. https://doi.org/10.1186/s11658-022-00366-0

Recent Neurotherapeutic Strategies to Promote Healthy Brain Aging: Are we there yet?

Blitz Age — Sun, 06 Aug 2023 21:57:29 +0000

Abstract

Owing to the global exponential increase in population ageing, there is an urgent unmet need to develop reliable strategies to slow down and delay the ageing process. Age-related neurodegenerative diseases are among the main causes of morbidity and mortality in our contemporary society and represent a major socio-economic burden. There are several controversial factors that are thought to play a causal role in brain ageing which are continuously being examined in experimental models. Among them are oxidative stress and brain inflammation which are empirical to brain ageing. Although some candidate drugs have been developed which reduce the ageing phenotype, their clinical translation is limited. There are several strategies currently in development to improve brain ageing. These include strategies such as caloric restriction, ketogenic diet, promotion of cellular nicotinamide adenine dinucleotide (NAD⁺) levels, removal of senescent cells, ‘young blood’ transfusions, enhancement of adult neurogenesis, stem cell therapy, vascular risk reduction, and non-pharmacological lifestyle strategies. Several studies have shown that these strategies can not only improve brain ageing by attenuating age-related neurodegenerative disease mechanisms, but also maintain cognitive function in a variety of pre-clinical experimental murine models. However, clinical evidence is limited and many of these strategies are awaiting findings from large-scale clinical trials which are nascent in the current literature. Further studies are needed to determine their long-term efficacy and lack of adverse effects in various tissues and organs to gain a greater understanding of their potential beneficial effects on brain ageing and health span in humans.

Keywords: NAD+, anti-ageing, brain health, caloric restriction, cellular energetics

Go to:

1.Introduction

1.1.Why Population Ageing Matters

In the past century, the life expectancy of humans has almost doubled in developed countries due to improved healthcare, nutrition, and effective antibiotics against infectious diseases. In the United States alone, it has been estimated that today’s 65-year-olds can live for a further 19.4 years, or 5.5 years longer that 65-year-olds in the 1950s. The number of people over 65 years of age in the United States is expected to reach 98 million by 2060 (currently 46 million), or 25% of the total population. Age-related disorders such as cardiovascular disease, cancer, and neurodegenerative diseases are the primary causes of morbidity and mortality both nationally and abroad [1–7]. Unfortunately, the outcomes of brain health are not harmonised with the outcomes of lifespan extension.

Progressive ageing of tissue, cells and organs is associated with a gradual decline in function during the lifespan of an organism. Numerous studies have shown that physical frailty is associated with low cognitive function and mild cognitive impairment (MCI) [8–11]. MCI is a term used to describe the stage between the expected cognitive decline of normal ageing and the more serious pathological decline leading to the dementias, and includes impairments in learning, memory, language, thinking and judgment that exceed normal age-related changes. The severity of physical frailty is likely to predict a worse cognitive trajectory among participants with MCI and it is linked to a greater risk of developing MCI [12].

The process of developing and maintaining the functional ability that enables wellbeing in older age is defined as “healthy ageing”. More specifically, older individuals in their sixties, seventies, and eighties that age well do not show significant decline in physical and cognitive performance and are active in their lifestyle. Lifespan extension is the primary goal of anti-ageing research. However, a greater importance has been placed on maintaining physical and mental health during ageing since ageing is a major risk factor for age-related degeneration and neurocognitive disorders, which not only affect the quality of life of individuals but also their family members and carers and the global economy [13]. Identifying and developing strategies aimed at preventing the occurrence of age-related neurodegenerative diseases is crucial. Therefore, development of interventions that slow down the rate of ageing and reduce or postpone the incidence of debilitating age-related neurocognitive disorders are of considerable value to improve the quality of life and reduce medical costs [14, 15]. Studies in animal models have identified a variety of molecular mechanisms that are likely to lead to interventions which enhance lifespan and reduce cognitive decline [16–18]. In this review, we summarise mechanisms and effectiveness of recent anti-ageing strategies, using findings from recent animals and human studies, and highlight how they may contribute to brain health. We also examine how these strategies may represent a promising therapeutic strategy to counter ageing-associated pathologies in the brain and slow down and/or attenuate age-related cognitive decline.

1.2. Molecular mechanisms of brain ageing, biomarkers and potential intervention

Ageing has a profound negative impact on the brain and cognitive performance[19]. Ageing can affect cortical neurotransmission and synaptic function, neurogenesis, vasculature, gross morphology, and cognition via multiple processes. It is well established that as we age, the brain recedes in volume, particularly in the frontal cortex. Our aging vasculature can lead to elevated blood pressure and increased risk of stroke and ischemia and white matter lesions. Memory deficits also occur with advanced aging and brain activation becomes more bilateral for memory tasks, to compensate and recruit additional networks. Genetics, neurotransmitters, hormones, and experience all play a role in brain aging. However, higher levels of education or occupational attainment may slow down brain aging. As well, leading a healthy lifestyle including consuming good nutrition, low to moderate alcohol intake, and regular exercise exert a protective effect against brain aging.

Several factors that contribute to age-related decline in the brain have been previously discussed [20–23]. Oxidative stress is a critical factor in the aging brain (Fig. 1). The brain is especially vulnerable to oxidative stress compared to other organs. This is because it has a high-energy demand and processes approximately 20% of basal O₂ consumption in humans [24]. Oxidative damage to tissues, cells and organs occurs when there is an imbalance in the generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS), and the bodies endogenous antioxidant defence mechanisms. The ROS and RNS balance and redox regulation are integral to maintaining normal brain homeostasis. ROS/RNS can affect not only the immune response and inflammation, but also synaptic plasticity, learning, and memory [25]. Furthermore, the accumulation of oxidative stress can trigger damage to lipid, protein and nucleic acids [26, 27]. For instance, nuclear DNA (nDNA) and mitochondrial DNA (mtDNA) oxidation, modification of proteins, lipid peroxidation of membranes, and mitochondria dysfunction are induced by oxidative stress leading to accelerated brain aging, neuronal loss and cognitive impairment [28]. ROS can affect factors related to the pathobiology of neurodegenerative diseases such as hyperphosphorylation of tau and misfolding of amyloid beta (which are key components of intracellular neurofibrillary tangles (NFTs) and extracellular amyloid plaques), alpha-synuclein (present in Lewy bodies), and mutant Huntington protein. There is a strong association between these misfolded protein and neurodegenerative entities in Alzheimer’s disease (AD), Parkinson disease (PD), and Huntington disease (HD), respectively [29–31]. Mitochondrial dysfunction induced by oxidative stress can greatly contribute to physical and cognitive changes in the brain. Mitochondria are particularly sensitive to oxidative stress because they generate large amounts of ROS [32]. Mitochondrial dysfunction is specifically critical in organs where demand for energy is high [33]. Neuronal mitochondria play a crucial role in the brain such as regulating stress reactions and maintaining metabolic homeostasis [34]. Since the mitochondria is an important organelle, mitochondrial dysfunction can affect the brain significantly [35, 36]. For instance, mitochondrial dysfunction can increase the risk of AD via accumulation of amyloid beta [29, 37], and the risk of PD is associated with dysfunction of mtDNA and the mitochondria [33].

Figure 1.

Oxidative stress induced by an imbalance in ROS production can accelerate brain aging. Overload of RNS and ROS is the main factor leading oxidative stress. PGC-1α which is activated by AMPK and SIRT1 interacts with Nrf1 and Nrf2. Nrf2 plays a critical role to regulate antioxidant activity in the mitochondria. Imbalance between ROS and antioxidant can cause oxidative stress. This imbalance causes mitochondrial dysfunction and Ca2⁺ efflux transporter deficits. Mitochondria dysfunction is an important factor of brain aging and can impair Ca2⁺ efflux transporters. Ca2⁺ efflux transporter dysfunction promotes permeability of mitochondria and activates proapoptotic pathways. This mechanism can cause negative effects on brain aging.

Peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α), which is activated by sirtuin-1 (SIRT1), is a key regulator of mitochondrial biogenesis. PGC-1α is associated with nuclear factor erythroid 2-related factor 1 (Nrf1) and nuclear factor erythroid 2-related factor 2 (Nrf2), responsible for ROS detoxification [38]. The transcription factor Nrf2 modulates the level of antioxidant defences in mitochondria as well as is a key regulator of inflammation. Additionally, SIRT1, an NAD+ dependent deacetylase, is triggered by Adenosine Monophosphate-activated Protein Kinase (AMPK) through increasing NAD+ levels [39]. Sirtuins are known to be involved in processes such as DNA repair, neurogenesis, inflammation, metabolism, mitochondria homeostasis, autophagy, apoptosis, oxidative/anti-oxidative balance, and aging [40]. Among them, SIRT1 regulate forkhead box O (FOXO), p53, PGC-1α, and nuclear factor-κB (NF-κB) [41]. The induction of NAD+/SIRT1 and autophagy regulation by AMPK inhibited cellular senescence [42]. For example, AMPK activity not only prevented H₂O₂-induced senescence but also improved the impaired autophagic flux via promotion of NAD+ synthesis [43]. In Caenorhabditis elegans, AMPK improved the dysfunction of mitochondrial networks induced by age [44].

The accumulation of ROS also causes calcium ion (Ca²⁺) overload throughout the body and damages Ca²⁺ efflux transporters [45]. Moreover, since mitochondria and endoplasmic reticulum (ER) play a crucial role in the regulation of Ca²⁺, mitochondrial dysfunction also affects the imbalance of Ca²⁺ homeostasis [46, 47]. Although increasing Ca²⁺ level is associated with ATP generation, the overload of Ca²⁺ can stimulate apoptotic pathways and increase the permeability of the mitochondrial membrane [48]. Thus, excessive Ca²⁺ is shown to have a cobweb-like association with increasing mitochondrial damage and generation of ROS [49]. The imbalance of Ca²⁺ homeostasis can trigger age-related loss to neuronal performance and other molecular pathways leading to aging and death [50]. Ca²⁺ imbalance can also play a causal role on cognitive function and lead to a variety of pathologies [51, 52]. Additionally, Ca²⁺ homeostasis is related to age-related cognitive deficits as well as neurodegenerative diseases [24, 26].

Additionally, the Insulin/insulin-like growth factor 1 (IGF-1) signalling pathway has been identified as another factor associated with aging. Insulin produced throughout the liver induces IGF-1. Produced Insulin and IGF-1 can be transported by lipoprotein receptor-related protein-2 (LRP2) and can cross the blood brain barrier to enter the brain. Insulin and IGF-1 can bind to the IGF-receptor and insulin-receptor, which is phosphorylated to be activated. Moreover, IGF-receptor and insulin receptor can combine and then bind to both insulin and IGF-1. This phenomenon affects the cell stress response and metabolism related to phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT), mammalian target of rapamycin (mTOR), mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK), and FOXO signalling [53–55]. Decreased IGF-1 in the brain is highly associated with brain aging. IGF-1 is normally known as a positive factor in the brain. High levels of IGF-1 may be neuroprotective and maintain cognitive function [56, 57]. Short-term exposure of IGF-1 in mice showed recovery of learning and memory [58]. In a murine AD model, increasing insulin and IGF-1 reduced the accumulation of amyloid beta, which is connected to MAPK signalling [56].

Inflammation in the brain can be increased with age and disease [59]. The genetic and environmental factors of inflammation have been shown to accelerate aging and age-related diseases [60, 61]. For example, neuroinflammation is associated with the pathobiology of AD. Peripheral inflammation has been associated with cognitive decline and dementia at a certain age. Meanwhile, high inflammatory levels correlated to higher mortality in the elderly [62, 63]. Key inflammatory players in aging brain include activated cytokines, immune cells, microglia, astrocytes, brain-derived neurotrophic factor, and IGF-1 transport [64]. Among them, microglia are resident immune cells and key regulators of neuronal and synaptic function including protection and vascular re-modelling in the brain [65]. In addition, microglia is especially associated with regulating the levels of pro-inflammatory cytokines including interleukin 1β (IL-1 β), interleukin 6 (IL-6), and tumor necrosis factor alpha (TNF-α) [66]. Moreover, the neurotrophic factors derived by microglia are crucial for cognition. Microglial depletion decreased neuronal loss in AD mouse model [62].

Biological aging is unlikely to be tied absolutely with chronological aging. Recent strategies have been developed to potentially slow biological aging and lower the possibility of suffering from age related neurodegenerative diseases including the dementias. Several anti-aging strategies that can promote healthy brain aging are in development. This review examines the efficacy of the emerging anti-aging approaches for maintaining better brain function. These approaches include strategies such as caloric restriction, ketogenic diet, promotion of cellular nicotinamide adenine dinucleotide (NAD+) levels, removal of senescent cells, ‘young blood’ transfusions, enhancement of adult neurogenesis, stem cell therapy, vascular risk reduction, and non-pharmacological strategies, such as physical activity.

Go to:

2.Method

2.1 Search strategy

This systematic review followed the guidelines of Preferred Reporting Items for Systematic Review and MetaAnalyses (PRISMA). A systematic electronic search was conducted using PubMed Medline, Web of Science, and Embase (dated January 2018 to July 2021). The search was restricted to research articles that examined recent strategies for brain aging including CR, ketogenic diets (KD), nicotinamide riboside (NR), senolytics, ‘young blood’ transfusions, adult neurogenesis, stem cell therapy, vascular risk reduction, and non-pharmacological strategies. The search used the following keywords: CR, KD, NAD+, nicotinamide riboside, senolytics, blood transfusion, parabiosis, neurogenesis, vascular risk, hypertension, non-pharmacological, cognitive stimulation, brain health, brain aging, cognitive training, working memory, executive function, cognitive enhancement, elderly, and healthy older adults.

2.2 Inclusion/exclusion criteria

We only considered research articles which reported the impact of anti-aging strategies (CR, KD, NAD+, senolytics, ‘young blood’ transfusion, adult neurogenesis, stem cell therapy, vascular risk, hypertension, non-pharmacological, cognitive stimulation) on the brain or neurodegenerative diseases, and those published from 2018 to 2021 were included in order to provide up-to-date review. Review articles were excluded. Research articles that examined the impact of the above strategies on the brain but were not related to aging or neurodegenerative diseases were also excluded.

2.3 Data extraction and data items

The animal species/type of animal model or human clinical trial, sex, number of subjects, and functional outcomes on the brain physiology and cognition were included as data. Additional data were extracted to suit each strategy such as diet intervention for CR and KD, treatment and dose for senolytics, and adult neurogenesis, used serum and treatment for ‘young blood’ transfusion, cell type used in stem cell therapy, vascular risk factors, and non-pharmacological strategies.

Go to:

3.Results and discussion

3.1 Study selection

Figure 2 summarises the search strategy. A total of 300 studies were identified after searching with keywords. Subsequently, 122 review articles including editorials and erratums, and a further 54 studies published before 2018 were excluded. After that, 124 studies were remained. Since 57 studies did not meet our selection criteria, they were excluded. A total of 67 studies were included in this review.

Figure 2.

The selection process of inclusion or exclusion of articles.

3.2 Study characteristics

All the studies included in the review described the impact of anti-aging strategies on the brain or neurodegeneration. This review describes what the anti-aging strategies are and how they have been shown to impact on brain health and cognition.

3.3 Recent strategies to improve brain aging

3.3.1 Caloric restriction

CR has been defined as a strategy to reduce calorie intake by 10 – 40% without malnutrition. CR has been shown to extend the life span and health span in diverse animal species from yeast to primates [93–98]. This dietary intervention showed effects including improving general health, preventing various diseases, and attenuating cognitive deficits in memory and learning. Several age-related diseases including chronic inflammatory disorders and neurological diseases were also protected by CR in animal models [99, 100]. Furthermore, CR might extend health span to prevent various pathological conditions including cardiovascular disease, diabetes and cancer by retarding the onset of these diseases [101, 102]. The intervention has been enthusiastically studied (Table 1).

Table 1

Recent studies on caloric restriction and brain health.

Animal		Number of animals	Diet	Functional outcome	Ref^*
Animal type	Sex	Number of animals	Diet	Functional outcome	Ref^*
Mouse	Male	4-5 mice per group	30% less calories	– increased SIRT1 mRNA level in the hippocampus – increased FOXO1 mRNA level in the hippocampus	[119]
	Male	12 mice per group	30% less calories	– improved learning and memory – increased the level of IGF-1 protein – decreased glucose and malondialdehyde level in the serum – increased the number of AMPK and GLUT4 and the mRNA of those in the brain	[120]
	Male	8 mice per group	10% less calories at 14 weeks 25% less calories at 15 weeks 40% less calories at 16 weeks	– decreased the age-related CG methylation in the hippocampus – decreased the age-related CH methylation in the hippocampus	[407]
	Both	12 mice per group	20% less calories	– increased SIRT1 protein expression in female mice – increased PGC-1a protein expression in male mice – improved recognition indices of female mice in the novel object recognition test	[121]
	Male	5-12 mice per group	30% less calories	– improved sensorimotor function following ischemic injury – improved cognition and memory after ischemic injury – protected white matter tracts and neuron following ischemic injury	[124]
	Male	14 mice per group	40% less calories	– increased neurotransmitters – increased neuronal integrity markers – increased essential fatty acids – increased biochemicals associated with carnitine metabolism	[116]
	Male	3-11 mice per group	10% less calories	– prevented the cognitive impairment in traumatic brain injury mice model – increased SIRT1 protein levels in the cortex and the hippocampus in traumatic brain injury mice model	[122]
	Male	20 mice per group	40% less calorie for 12 weeks	– improved memory – increased SIRT1 and HSP70 mRNA expression in the hippocampus	[118]
	Both	5-10 mice per group	10% less calories at 14 weeks 25% less calories at 15 weeks 40% less calories at 16 weeks	– increased subventricular zone stem cell proliferation in young mice – prevented the loss of neurogenesis in aged mice – improved olfactory memory – decreased microglia expression – decreased the level of inflammation marker in the subventricular zone	[123]
Rat	Male	5 rats per group	40% reduction in food intake	– decreased glucose levels in the serum – increased AMPK and pAMPK levels in the cortex and hippocampus of the aged rats – decreased cholesterol precursors, lathosterol and lanosterol, in both hippocampus and cortex of the aged rats	[125]
	Male	45 rats	30% less calories	– improved acrolein-induced cognitive impairment – protected acrolein-induced GSH deletion in both cortex and hippocampus – improved acrolein-induced SOD activity decline in the hippocampus – positively regulated AD-associated proteins	[128]
	Male	7-8 rats per group	30%-40% less calories	– decreased total oxidant status in the brainstem, cerebellum, frontal lobe, parietal lobe, and hippocampus. – improved antioxidative capacity (Cu, Zn-SOD) in the frontal lobe – decreased the rate of lipid hydroperoxides formation in brain tissue	[126]
	Male	19 rats per group	40 % less calories daily for 11 months	– alleviated decrease the thiol level in the hippocampus, parietal cortex, and cerebellum – increased GSH concentrations in the hippocampus, striatum, and cerebellum – increased GSH peroxidase activity in the hippocampus and parietal cortex – increased GSH reductase activity in the hippocampus	[117]
	Male	11-19 rats per group	30% reduction in food intake	– improved the long-term memory of aged rats	[127]
Human		Number of subjects treated	Diet	Functional outcome	Ref^*
Trial type	Sex	Number of subjects treated	Diet	Functional outcome	Ref^*
Randomized order	Female	17	Very low-calorie diet (511 kcal/day)	– increased accuracy in the MSTT (Matching to sample test Reaction time) – decreased accuracy in the CRTT (Choice reaction time test Reaction time)	[130]
Parallel group, randomized clinical trial	Both	Total 220	25% reduction of the subject’s regular calorie intake for 2 years	– improved performance in SWMS^† – improved SWMTE at month 24 – improved working memory (measured by SWMTE^‡)	[129]

Open in a separate window

^*These references were published from 2018.

^†(SWMTE: This is the number of times a box is selected that is certain not to contain a blue token and therefore should not have been visited by the subject, ie, between errors þ within errors – double errors)

^‡(SWMS: For problems with 6 boxes or more, the number of distinct boxes used by the subject to begin a new search for a token, within the same problem)

The mechanism of CR is still unclear and remains controversial. However, there are a lot of hypotheses to explain the effects of CR including autophagy, apoptosis, mitochondrial activity, redox homeostasis, mTOR signalling, AMPK, and Sirtuin [103–106]. When calories are restricted, more carbons are oxidized in mitochondria via the electron transport chain-mediated cellular respiration, which produces NAD from NADH [107, 108]. Thus, under caloric restriction, the NADH levels are significantly decreased as a result of up-regulated mitochondrial respiration [109, 110]. Recent studies support the hypothesis that CR is associated with several aging pathway such as PGC-1α, SIRT1, and AMPK pathway which are dependent on the essential pyridine nucleotide, NAD+ (Fig. 3). SIRT1, one of key target factors in CR, is an NAD-dependent histone deacetylase that has multiple roles including life span extension, stress resistance, and reduction of apoptosis [111].

Figure 3.

Proposed mechanism of intervention of CR and KD in brain ageing. CR is associated with AMPK, SIRT1, PGC-1α, and FOXO1 pathways. These signalling pathways are inter-related. SIRT1 and increased NAD+ is regulated by AMPK. SIRT1 can activate PCG1 α which regulates Nrf1 and Nrf2. Nrf1 and Nrf2 work as antioxidants. SIRT1 is also associated with NF-κB, p53, and FOXO1. These relationships are essential factors for anti-brain ageing and protective activity in neurodegenerative disease. KD has similar mechanisms as CR. KD can also inhibit Fatty acid synthesis, glucose metabolism and protein synthesis. These factors may be associated with the pathobiology of AD, PD and HD.

CR showed impact on neurodegenerative diseases by reducing the number and size of amyloid beta plaques in AD transgenic animal models [104, 112]. In mice, cognitive function and long-term memory were improved by CR. As well, CR slowed the age-related mitochondrial function and maintained neuronal activity [113, 114]. In addition, CR decreased the accumulation of amyloid beta in an AD mouse model [104]. The intervention is shown to improve mitochondrial activity in rat cells by reducing ROS production, and this is associated with cognition [115]. Consequently, CR prevented decline of memory and cognition as well as the onset of neurodegenerative diseases in rodents [116, 117].

In mice, CR increased the mRNA level of SIRT1 and FOXO1in the hippocampus [118, 119], and the mRNA level of AMPK in the brain[120]. SIRT1 protein expression in the female and in traumatic brain injury model were increased by CR [121, 122]. CR showed increase of PGC-1α protein expression in male (Wahl et al., 2018) and IGF-1 protein level in serum [120], whereas CR decreased microglia expression and inflammatory markers [123]. Furthermore, the intervention also showed various beneficial effects such as enhancing recognition indices and olfactory memory [121, 123] and improving cognition, memory, and sensorimotor function after ischemic injury [124]. In rats, CR increased AMPK and pAMPK [125], glutathione (GSH) concentration, GSH peroxidase activity, and GSH reductase activity in specific parts of the brain in aged rats [117]. Additionally, the total oxidant status was observed to be at a lower rate in CR model while the antioxidative capacity such as Cu, Zn-SOD was improved [126]. Moreover, cognitive impairment, GSH deletion, and impaired SOD activity induced by acrolein were positively regulated and long-term memory of old rats was improved by CR [127, 128].

Most CR studies in animal models used male mice. However, one study using both sex mice identified sex-dependent effects of CR on brain aging [121]. For example, CR increased SIRT1 expression only in female mice, while PGC-1α expression increased only in male mice [121]. Sex is a limiting factor in CR studies in humans as well. For example, one study reported findings in women only, while another group studied both men and women, but the study is also limited because women distribution of sample was predominant [129, 130].

In humans, CR was shown to induce body weight loss, reduce mortality and improve general health, sleep quality and sexual function [129, 131, 132]. This enthusiastically studied intervention also displayed improved cognition in humans [129, 130]. The brain aging and degenerative diseases might be prevented by CR, while the brain factors of the age-related decline including long-term potentiation (LTP) and brain-derived neurotrophic factor (BDNF) were reduced [129, 133, 134]. However, evidence from human interventional studies is limited. [133] reported improvements in verbal recognition memory performance in healthy older normal to overweight subjects who were instructed to reduce calorie intake by 30% over a 3-month period. Memory improvement was associated with improved glucose metabolism and lower fasting plasma insulin concentration [135]. Most human studies involving CR report most effects improved energy homeostasis. Therefore, CR is likely to improve brain health by mimicking the effects of short-term negative energy balance [136], rather than reduced weight. However, it remains unclear whether the benefits of CR remain stable over time or are linked with negative energy balance during the weight loss phase. The issue of sustainability is of considerable importance as chronic CR has reported limited adherence [137], has not always demonstrated benefits on cognitive function (e.g., [138, 139]. and at times may present negative health effects in subjects with incipient dementia [140].

A recent two-year randomized controlled trial study reported that CR shows no significant side effects on factors related to quality of life including mood, self-reported hunger, sexual function, and cognition [141]. Moreover, mild CR for 2 years also showed no side effects on assessments of vitality, mental health and bodily pain (SF-36) [131]. These studies can support the safety of the intervention. However, it is still unclear how much caloric intake is ideal for optimal health.

3.3.2 Ketogenic diet

KD is a recent dietary intervention that is very high in fat and low in carbohydrates. The intervention was firstly initiated to reduce the symptoms of epilepsy. In rodents, KD not only improved memory in mice and cognition in rats but also reduced amyloid beta levels and cell death [142–144]. Moreover, KD showed improvements in overall brain function and stability in humans [145]. The KD has been reported to promote positive effects on brain aging and neurodegenerative diseases such as AD, PD, and HD [146, 147]. Recent studies showed positive effects of KD not only in animal models but also in humans (Table 2). KD demonstrated effects including decreasing mTOR protein expression and encouraging amyloid beta clearance in mice [148] as well as behavioural and cognitive enhancement [144] and increasing anti-aging factors such as the NAD+/NADH ratio and intracellular NAD+ level and NAD-dependent processes including sirtuin activity, and SIRT1 gene expression in rats [149]. In humans, memory and cognition were also improved by KD [150–152], in the patients with diabetes [153], with HIV [154], and with mild AD [155].

Table 2

Recent studies regarding ketogenic diet on brain health.

Animal		Number of animals	Diet	Functional outcome	Ref^*
Animal type	Sex	Number of animals	Diet	Functional outcome	Ref^*
Mouse	Male	9-10 mice per group	75.1% fat, 8.6% protein, 4.8% fiber, 3.2% carbohydrates, 3.0% ash,	– decreased mTOR protein expression – improved neurovascular function – increased Aβ clearance – decreased blood glucose level – increased ketone concentration	[148]
Rat	Male	5-8 rats per group	93.9% fat, 4.4% protein, and 1.7% carbohydrate	– increased NAD+/NADH ratio in the hippocampus – increased NAD+ levels in the hippocampus – increased nuclear sirtuins activity – increased SIRT1 gene expression in the hippocampus – decreased PARP1 and 8-OHdG levels in the hippocampus	[149]
Rat	Both	1-10 rats per group	75.85% fat, 20.12% protein, 3.85% carbohydrate mixed with MCT oil	– decreased blood glucose level – improved to acquire the correct alternation strategy – improved behaviour on both the elevated figure-8 maze alternation task and a cognitive dual task	[144]
Human		Number of subjects treated	Diet	Functional outcome	Ref^*
Trial type	Sex	Number of subjects treated	Diet	Functional outcome	Ref^*
Case study	Female	1	Low a carbohydrate/high fat diet, calorie restriction (fasting)	– improved memory with high intensity interval exercise – improved metabolic syndrome biomarkers	[152]
Case study	Male	1	The 10 weeks intervention incorporated a ketogenic diet	– improved memory with high intensity interval exercise – improved metabolic syndrome biomarkers	[151]
Randomized	Female	2	Carbohydrate consumption to less than 50 grams/day	– improved cognition in the patients with HIV	[154]
Randomized, two-phase crossover dietary and exercise trial	Both	12 (8 females and 4 females)	60% fat, 25% protein, and 15% carbohydrate	– improved cognition	[150]
Case study	Female	1	The 10 weeks intervention incorporated a nutrition	– improved memory with high intensity interval exercise – improved metabolic syndrome biomarkers – alleviated the symptoms of insulin resistance and risk induced by mild AD with daily brain training	[155]
Case study	Male	1	A clinically prescribed KD with moderate protein (based on lean mass and activity level) designed to reduce fasting insulin levels	– improved fasting glucose, fasting insulin, and blood lipids in diabetic patient – improved cellular insulin sensitivity in diabetic patient – improved memory, cognition, and verbal fluency in diabetic patient	[153]

Open in a separate window

^*These references were published from 2018.

The mechanism(s) for the beneficial effects of KD are various. For example, KD has similar influence to CR on NAD+ metabolism, AMPK, SIRT1, and antioxidant genes, and activation of PGC-1α which regulate mitochondrial function [144, 156] (Fig. 3). Moreover, beta-hydroxybutyrate (BHB), a ketone body generated by ketogenesis in KD, can rescue mitochondrial function and improve cognitive function [144, 147]. The ketone bodies are known to be used as energy source instead of glucose in KD condition [156]. Furthermore, KD inhibited fatty acid synthesis, glucose metabolism, and protein synthesis, while upregulating peroxisome proliferator-activated receptor α (PPAR α) target gene [96].

The standardization of KD is limited, although KD has been constantly studied in animal models. For example, there was a slight difference in regimen between recent studies [144, 148, 149]. Human studies not only had different dietary regimens, but also consisted mostly of case studies, and therefore were limited to a small sample size [151–153, 155]. Another major limitation has been patient compliance, owing to poor palatability and meagre food choice. Patients were also required to accurately measure all their food portions which introduces subjective bias in the studies [157]. A lack of understanding of potential side effects also exists. Some reported adverse effects of KD include constipation, menstrual irregularities, elevated serum cholesterol and triglycerides, hypoproteinemia, hemolytic anemia, elevated liver enzymes gall-stones, and renal stones [157]. The KD is contraindicated in patients treated with valproic acid which appears to increase the likelihood of adverse events [157]. On the other hand, although there is insufficient data to understand the side effects of KD administration, some effects can be predicted, and the other ones are unusual or caused by long-term treatment [142]. In obese patients, total 83 patients with KD for 24 weeks showed no adverse effects [158]. Moreover, a recent study reported how a low-fat diet or KD can affect motor and non-motor symptoms in PD. Consequently, the KD showed positive effects mostly in non-motor symptoms including cognitive impairment only mild adverse effects [159]. These studies support that KD show beneficial effects without side effects or side effects have a certain predictability.

3.3.3 Promotion of cellular NAD+ anabolism

NAD+ is a critical ‘longevity’ factor which has a major impact on aging hallmarks, including mitochondrial homeostasis, oxidative damage, Ca²⁺ homeostasis, neuronal networks, DNA repair, and inflammation [160]. NAD+ is also associated with sirtuin deacetylases or ‘lifespan extension’ genes involved in transcriptional regulation, the DNA repair protein PARP1, and CD38 which is related to Ca²⁺ homeostasis and immune response [161] but also affects mitochondrial biogenesis through SIRT1/PGC-1α signalling [156]. Thus, NAD+ seems to be a of crucial factor in the aging brain. We were the first to show that NAD+ levels decline with age in most catabolic tissues including the brain. This fact can support the beneficial role of CR and NAD+ in aging. Indeed, CR can increase NAD+ level [162]. as a mechanism to slow down aging. NAD+ levels also decline in neurodegenerative diseases including multiple sclerosis.

NAD+ anabolism in mammalian cells occurs de novo from tryptophan (TRYP). NAD+ synthesis through quinolinic acid (QUIN), a kynurenine pathway metabolite, has important immunoregulatory roles [163]. However, overconsumption of TRYP can increase the levels of the putative neurotoxin QUIN which has been associated with the pathogenesis of several neurodegenerative disorders [164]. Therefore, TRYP is an unlikely strategy to elevate NAD+ levels in the clinic.

NAD+ can also be produced via the salvage pathway from NAD+ precursors, nicotinic acid (NA), nicotinamide (NAM), nicotinamide mononucleotide (NMN) and NR [165]. NAD+ can be synthesised from NA via the Preiss-Handler process. However, NA therapy induces some negative adverse effects including significant skin flushing in most individuals below therapeutic doses, thus limiting its widespread clinical use [166]. NAM is generated as a by-product of enzymatic degradation of pyridine nucleotides. While supplementation with NAM raises NAD+ but does not cause flushing, it is not considered an ideal supplement to raise NAD+ due to its enzyme inhibiting (e.g., PARPs, sirtuins, CD38), methyl depleting and hepatotoxic potential [165].

The NAD+ biosynthesis contains NR and nicotinamide mononucleotide (NMN) (Fig. 4). NMN can also be synthesised from NR by the NR kinases, NRK1 and NRK2 [167]. Numerous studies have shown that NMN can attenuate degenerative conditions and slow down age-related cognitive decline [168–173]. For instance, NMN treatment maintained neural stem/progenitor cell population in the aged hippocampus and protected against mitochondrial and cognitive dysfunction in murine models for AD [168–173]. NMN appears to be rapidly absorbed from the gut and into the blood and transported into tissues [174]. The fast pharmacokinetics of NMN has suggested that there is specific NMN transporter that mediates uptake of NMN into the gut and other tissue. Recently, a genetic, pharmacological and kinetic study reported that NMN is dephosphorylated to NR before cellular internalization by the solute carrier family 12 member 8 (Slc12a8) [175]. However, a ‘Matters Arising’ to that article suggested that the analytical methodology and interpretation of those findings were not sound and did not support Slc12a8 as the ‘reclusive’ NMN transporter [176]. As well, NMN may also be neurotoxic and accumulation of NMN may promote axonal degeneration [177].

Figure 4.

Benefits of NR in brain ageing. The NR pathway is quite unclear. NR is the precursor for NAD+. During the process that converts NR to NAD+, NRK is the important kinase. NAD+ and SIRT1 can activate the PGC-1α. PGC-1α regulates some antioxidant factors. NR is also associated with CD38 and PARP1, which is related to Ca2⁺ transport efflux, DNA damage and has immunogenic roles.

Naturally, NR mainly exists in avocado, milk, cucumber, and beef [178]. NR is the precursor of nicotinamide adenine dinucleotide (NAD+) [179, 180]. Several studies have continually been undertaken (Table 3). Accordingly, NR increased NAD+ levels, which is related to anti-aging and age-related brain function [180, 181]. NAD+ has beneficial effects on reducing amyloid beta in AD mouse model and neuroprotection in Huntington’s disease (HD) [182]. NR reduced amyloid concentrations induced by high-fat chow diet [183] and lowered the levels of pTau level and amyloid beta plaques in AD mouse models [161, 184]. Through these results, it is assumed that NR might be related to brain aging with NAD+ or other pathways. One of the evidences is that treatment of NR showed recovery of synaptic plasticity and behaviour while NAD+ level and PGC-1α level increased in AD mouse model. NAD+ can regulate PGC-1α via SIRT1, which is associated with AD [180, 185, 186]. Reduction of PGC-1α is related to accumulation of amyloid beta in AD. This means that NR may increase the -expression of PGC-1α through upregulation of NAD+, which may reduce the aggregation of amyloid beta and promote synaptic plasticity in AD models [180, 185, 186]. NR also has influence on recovery of cognitive function in mice having cerebral small vessel disease causing AD [187]. Moreover, NR demonstrated neuroprotective effects in PD mice model [182, 188]. NR is also effective in axonal neurodegeneration in mice. Interestingly, the author identified that NR uses same pathway with NAD+ when preventing the neurodegeneration, but the effect of NR is much higher than that of NAD+ alone [189]. The decline of the dopaminergic (DA) neuron and climbing ability induced by human N370S GBA was mitigated by NR in a fruit fly model (Schondorf et al., 2018). In mice, NR upregulated factors related to aging such as NAD+, SIRT1, and PGC-1α [190, 191], while apoptosis and inflammation were downregulated [161, 190–192]. Furthermore, positive cognitive effects such as learning and memory were observed by NR [161, 183, 184, 192].

Table 3

Recent studies regarding the potential benefits of nicotinamide riboside supplementation on brain health.

Animal		Number of animals	Treatment	Dose	Functional outcome	Ref^*
Model type	Sex	Number of animals	Treatment	Dose	Functional outcome	Ref^*
Drosophila	–	~ 50 animals per conditions	Oral gavage	500 mM	– alleviated DA neuron loss and the decline in climbing ability in mutant N370S GBA flies which show increased ER stress, an age-dependent loss of DA neuron	[408]
Mouse	Both	5-17 mice per group	Oral gavage	12 mM	– increased the NAD+/NADH ratio in the cerebral cortex – improved learning ability – alleviated decline of memory and working memory in AD mice – decreased pTau levels and pTau/total Tau ration in AD mice	[184]
	Both	10-16 mice per group	Oral gavage	2.5 g/kg	– decreased the number and total area of Aβ plaques in cortex in AD mice – improved selective cognitive impairment in AD mice – decreased chronic brain neuroinflammation in AD mice	[161]
	Male	8 mice per group	Oral gavage	400 mg/kg	– increased the weights of whole brain by 6 weeks – alleviated the increase of amyloid-concentration by high-fat chow diet in the brain. – improved learning and memory	[183]
	Both	3-17 mice per group	Intraperitoneal injection	200 mg/kg	– increased NAD+ levels – decreased apoptosis in the somatosensory cortex and hippocampus – decreased neuroinflammation	[191]
	Male	4-6 mice per group	Oral gavage	100 μg/kg	– increased NAD+ levels in Gulf War Illness mice model – increased SIRT1 levels in Gulf War Illness mice model – increased PGC-1α levels in Gulf War Illness mice model – increased and acetylated PGC-1α levels in Gulf War Illness mice model – decreased brain inflammation in Gulf War Illness mice model	[190]
	Male	5-7 mice per group	Oral gavage	400 mg/kg	– improved alcohol-induced cognition impairment – decreased alcohol-induced inflammatory cytokines in the brain	[192]

Open in a separate window

^*These references were published from 2018.

Manipulation of NAD+ metabolism is promising therapeutic strategy for the management and treatment of age-related cognitive disorders including AD. There is a growing body of evidence to suggest that raising NAD+ levels using NAD+ precursors may reduce some of pathological hallmarks of AD and improve cognitive performance [161, 168, 170–173, 193, 194]. However, apart from NR (which has 9 clinical papers demonstrating safety), safety data for most NAD+ supplements are not available or have not been collected in a systematic manner [178]. NR (as NR Chloride) has been reviewed and authorized by the four leading authoritative regulatory bodies in the world, including the USFDA, Health Canada, the European Food Safety Authority, and the Therapeutic Goods Administration of Australia. Niagen is the only commercially available NR ingredient that has been twice successfully reviewed under FDA’s new dietary ingredient (NDI) notification [195]. A recent randomized, double-blind, placebo-controlled, parallel-arm study examined the safety of chronic NR supplementation and the dosage required to maintain increases in systemic NAD+ levels. In the study, 132 healthy overweight adults were given either placebo, 100 mg, 300 mg, or 1000 mg of Niagen NR daily for eight weeks. The study reported sustained increases (22%, 51%, and 142%) in whole blood NAD+ at 100, 300, and 1000?mg of NR within two weeks and were maintained throughout the duration of the study. No significant differences in adverse events between the NR and placebo-treated groups or between groups at different NR doses were reported [195]. This suggests that NR is orally bioavailable and well tolerated at once-a-day doses of up to 1 gram per day. However, a 51% increase in whole-blood NAD+ was reported within two weeks of commencing supplementation at the recommended dose of 300 mg daily and was maintained for 8 weeks. Further clinical evidence is necessary to confirm the beneficial effects of NR reported in preclinical animal models for neurodegeneration in humans.

3.3.4 Senolytics

Senolytics are a class of small molecules that remove senescent cells, which are affected in age-related diseases. Elimination of senescent cells using senolytics might have anti-aging benefits in the brain. Senolytic agents currently being investigated include piperlongumine (PL), dasatinib, quercetin, fisetin, FOXO4 peptide, ABT-263 (navitoclax), and ABT-737. Some senolytics may be positively related to brain aging and neurodegenerative disease (Table 4) (Baker and Petersen, 2018; Walton and Andersen, 2019). Among them, a senolytic cocktail of dasatinib plus quercetin (D+Q) have been studies in brain aging. In an AD rat model, quercetin had effects on diminishing cognitive deficits [196]. Treatment with D+Q decreased Tau-containing neurofibrillary tangles (NFTs), which is one of the main pathological hallmarks of AD, in a neurodegenerative mouse model as well as senescence-associated β-galactosidase (SA-βGal) which is associated with amyloid beta plaque in AD [197, 198]. Furthermore, D+Q reduced the accumulation of amyloid beta in an AD mouse model [197]. Acute treatment of D+Q diminished senescent oligodendrocyte progenitor cells (OPCs), is related to amyloid beta, with p16 which induce senescent OPCs [197]. The author assumed that decreased aggregation of amyloid beta by D+Q might recover cognitive dysfunction in AD [197]. Treatment with navitoclax also reduced tau phosphorylation in a mouse model which expresses high levels of human tau in neurons [199] and blunted the senescent cell and performance decline induced by whole brain irradiation [200]. PL is known to have anti-inflammatory and anticancer ability [201, 202]. PL administration also increased the level of NAD+ in vitro assay and attenuated amyloid beta in hippocampal neuron[203]. Moreover, treatment of PL improved adult neurogenesis in the DG and prevented or blocked the decline of cognition in AD mouse model [203, 204]. In mice treated with fisetin, improvement of behavioural performance and cognition and reduction in apoptotic neurodegeneration induced by aluminum chloride were observed [205–207]. A recent study illustrated that fisetin oral administration prevented the decline of recognition with age and increased behavioural performance and memory in the senescence-accelerated mouse prone 8 (SAMP8) model of aging and AD [208]. The other group demonstrated that treatment with fisetin attenuated the impairment of behaviour and increased GSH levels and catalase levels in rotenone induced PD model [209] In AD mouse model, Fisetin showed improvement of learning and memory as well as attenuation in tau phosphorylation [210, 211].

Table 4

Recent studies on the effect of senolytics in the brain.

Animal		Number of animals	Treatment	Dose	Functional outcome	Ref^*
Animal type	Sex	Number of animals	Treatment	Dose	Functional outcome	Ref^*
Mouse	Both	3-5 mice per group	Oral gavage	5 mg/kg dasatinib with 50 mg/kg quercetin	– decreased the number of NFT-containing cortical neurons – decreased gene expression of the NFT-associated senescence genes – improved neurodegeneration in rTg(tauP301L)4510 transgenic mice	[198]
	Both	3-8 mice per group	Oral gavage	50 mg/kg Navitoclax	– attenuated the upregulation of senescence-associated genes in neurodegenerative disease model – attenuated tau phosphorylation in neurodegenerative disease model	[199]
	–	19 mice per group	Oral gavage	50 mg/kg/day PL	– increased the level of NAD+ in vitro assay – attenuated the cytotoxicity of amyloid beta in hippocampal neuron cell – prevented decline of cognition in AD model – attenuated neuroinflammation in the cortex in AD model	[203]
	Female	7-14 mice per group	Oral gavage	50 mg/kg/day PL	– increased adult neurogenesis in the DG of the aged mice	[204]
	Male	5-13 mice per group	Oral gavage	500 ppm (~25 mg/kg/day) fisetin	– prevented the decline of recognition with age in SAMP8 mice – increased behavioural performance and memory in SAMP8 mice	[208]
	Male	5-29 mice per group	Oral gavage	5 mg/kg dasatinib with 50 mg/kg quercetin	– decreased anxiety-behaviour	[409]
	Both	8-16 mice per group	Oral gavage	5 mg/kg dasatinib with 50 mg/kg quercetin	Short term treatment – decreased Aβ-plaque-associated SA-βGal activity in AD model Long term treatment – decreased Aβ-plaque-associated SA-βGal activity in the hippocampus in AD model – decreased Aβ plaque load in the hippocampus in AD model unlike the short-term treatment	[197]
	Male	6 mice per group	Intraperitoneal injection	1.5 mg/kg Navitoclax	– attenuated senescent cells induced by whole brain irradiation – attenuated senescent astrocytes induced by whole brain irradiation – attenuated performance decline induced by whole brain irradiation	[200]
Rat	Male	6 rats per group	Oral gavage	10 mg/kg or 20 mg/kg fisetin	– prevented the behavioural impairment in rotenone induced PD model – increased GSH levels and catalase levels in rotenone induced PD model	[209]

Open in a separate window

^*These references were published from 2018.

The effect of senolytics on senescent cells is dependent on apoptotic pathways such as B-cell lymphoma 2 (Bcl-2) [212] (Fig. 5). PL and Navitoclax are inhibitors of Bcl-2 family proteins which regulate mitochondrial mediated apoptosis, while PL activates autophagy [213, 214]. Fisetin can activate not only the PI3K/Akt/Gsk3β pathway in AD mouse model and Nrf2 but also autophagy [211, 215]. D+Q showed selective elimination of senescent cells in humans and demonstrated little effect on macrophage [216].

Figure 5.

Protective mechanism of senolytics in brain ageing. Piperlongumine, fisetin, dasatinib, quercetin, and navitoclax are included in senolytics. The mechanism of action and effects of senolytics in brain ageing remain obscure. Dasatinib plus Quercetin eliminates senescent OPC. Dasatinib induces apoptosis. Moreover, piperlongumine, fisetin, and navitoclax also induce apoptosis via inhibition of the Bcl-2 family. On the other hand, piperlongumine and fisetin activate autophagy.

While it is anticipated that senolytics are specific to senescent cells, they also have various unwanted side effects since administration is not directed at senescence cells. For example, the release of apoptotic bodies can further stimulate the release of pro-inflammatory proteins that may be cytotoxic to various tissues [217]. More specific side effects such as thrombocytopenia and neutropenia have also been reported following Bcl-2 inhibition [218]. One way to improve the specificity and targeting of senolytics to senescent cells has been through nanocapsulation. These nanocapsules contain enzyme substrates that are overexpressed in senescent cells, allowing the release of senolytics specifically inside senescent cells which then undergo apoptotic cell death. As well, the fate of senescent cells and regenerative processes in the body are nascent in the current literature [219]. Improvement in specificity is important for non-targeted senolytics such as quercetin and fisetin. Moreover, Fisetin higher than effective concentration of senolytic can cause side effects like being cytostatic in proliferating cells [220]. However, the side effects of fisetin are only a little known so far [210]. A recent study illustrated that oral administration of D+Q (D: 100mg/day, Q: 500mg twice daily) for 11 days show no serious side effects [221]. Although these studies can support the safety of senolytic agents, it is not enough to apply to human. The further study what concentration of drugs is effective because the lower concentrations will be ineffective to senolytic and higher concentrations will be toxic.

Although several animal studies have identified beneficial effects and mechanism(s) of action of senolytics, human studies are limited. For example, the effective dosage of senolytics in animal studies may be insufficient to produce desirable effects in humans. While there are several positive findings of using senolytics in animal models, it may be difficult to predict the effects in humans since various interactions can occur in humans. Thus, the studies about adverse effects of senolytics are important.

3.3.5 ‘Young blood’ transfusions

Blood transfusion was considered a means to improve health [222]. The effects of young blood were observed in extending life span and attenuating age-related decline [223, 224]. Blood transfusion was established using two parabiotic parings such as heterochronic parabioses (young and old) and isochronic parabiosis (two young or two old) [225]. Among them, heterochronic parabioses specifically showed positive insights. For example, old mice exposed to young blood showed improvements in learning and memory and showed rejuvenation effects on various tissues including the brain [226, 227], and prevented the decrease in neurogenesis, synaptic plasticity and cognition [228, 229]. Furthermore, young blood plasma transfusion improved memory and cognition in an AD mouse model [230]. Young blood transfusion via heterochronic parabioses are still being studied today (Table 5).

Table 5

Recent studies indicating the potential effect of ‘young blood’ transfusion on brain health.

Cell	Serum	Treatment	Functional outcome	Ref^*
Cell type	Serum	Treatment	Functional outcome	Ref^*
Human neurons from H1 ES cells	15 days or 12 to 15 months old mice	Cultured in the serum	– increased dendritic branch points of neurons – increased dendritic arbor complexity – increased spine-like outgrowths – increased synapse numbers – increased the functional synaptic connectivity	[231]

Open in a separate window

Human		Number of subjects infused	Dose	Functional outcome	Ref^*
Trial type	Sex	Number of subjects infused	Dose	Functional outcome	Ref^*
Randomized, double-blind crossover protocol with 4 once-weekly infusions	Both	9 (Total 18)	1 unit (approximately 250m) plasma from male donors aged 18 to 30 years or 250mL of saline	– adverse events were mild and moderate compare to placebo which means that it is safe, well tolerated, and feasible. – no change in assessments of cognition, mood, functional ability, and default mode network changes	[244]

Open in a separate window

^*These references were published from 2018.

Although the mechanisms behind the success of young blood transfusion are unclear, the beneficial effects may be related to an increase in certain blood-factors such as tissue inhibitor of metalloproteinase 2 (TIMP2), growth differentiation factor 11 (GDF11), C-C motif chemokine 11 (CCL11), thrombospondin-4 (THBS4), and secreted protein acidic and rich in cysteine-like protein 1 (SPARCL1) [227, 231] (Fig. 6). TIMP2 was identified in human umbilical cord plasma [232]. In aged mice, injection of recombinant TIMP2 showed similar effects with injection of umbilical cord plasma to attenuate cognitive decline and TIMP2 knockout mice showed age-related cognitive decline [231, 232]. Secondly, administration of GDF11, which is broadly expressed in the central nervous system (CNS) and detected in human serum [233–235], improved neurogenesis in old mice [236]. Exogenous administered GDF11 (rGDF11) also improved memory and cognition in middle-aged mice [237]. Thirdly, CCL11, which was previously considered to be related to inflammation and immunity [227], increases with age in mice and human [229, 238]. Circulating levels of CCL11 were increased in people with neurodegenerative diseases including AD [239, 240]. Lastly THBS4 and SPARCL1 were enriched in young serum [231]. Both THBS4 and SPARCL1 increase the density of synaptic connectivity, respectively [231].

Figure 6.

Mode of action of ‘young blood’ transfusion in brain ageing. Blood factors which are decreased with ageing including CCL11, GDF11, TIMP2, THBS4, and SPARCL1. Increasing these blood factors through introduction of young blood in the elderly is aimed at improving neurogenesis, cognition, and synaptic connectivity.

Since the understanding of young blood components is unclear, there are some limitations. For example, plasma proteins, leucocytes, red cell antigens, plasma and pathogens may cause side effects [241]. This is why plasma infusions are safer for adverse effects than whole blood infusions [225]. For instance, Allergic reactions from mild reactions to anaphylaxis are major cause for concern [242]. Addition side effects can cause the risk of infection and hemolysis in aged with heart failure [243]. In particularly, whole blood infusion can lead to more side effects than plasma infusion [225]. A recent study reported that young donor plasma infusion to patients with AD showed improvement of daily tasks and safety [244]. This study supports what plasma infusion is known to be safe. Moreover, it is difficult to predict how it works, especially in human and limited to small samples. Therefore, the further studies are needed to identify the specific factors and the effects in human. Recently, parabiosis was used to connect young and old mice. The study found that each mouse had equal parts old blood and young blood circulating through it, the young mouse reported negative effects. Old blood drastically decreased hippocampal neuron generation, learning and agility, and liver regeneration in young mice [228]. However, no significant benefits in cognition, agility, or neurogenesis were reported in old mice exposed to young blood. Therefore, improved brain health may not be related to promotion of rejuvenating factors but rather the inhibition of factors in old blood that promote brain aging [245].

3.3.6 Enhancement of adult neurogenesis

Adult neurogenesis (AN) is a process that involves neural stem cell (NSC) maturation, migration, and addition into previously existing neuronal networks in the adult brain [246]. AN is observed in two niches in the CNS including sub-ventricular zone (SVZ) of the lateral ventricles (LVs) and sub-granular zone (SGZ) of the dentate gyrus (DG) [246]. In these neurogenic niches, AN declines with age mainly due to reduction of NSCs and neural progenitor cells (NPCs) [247–249]. AN was also confirmed in the dentate gyrus (DG) of rodents and humans [250] and is associated with brain function including memory and learning [251]. The decline of AN can cause reduction in proliferation and neuronal production, and the reduction might be associated with age-related plasticity and brain repair capacity [252]. Furthermore, AN is associated with impairment of cognition and aging [253, 254]. The decrease in AN is thought to play a vital role in several degenerative diseases such as AD, PD and HD in murine models as well as ‘normal’ aging in rodents and humans [255]. In human hippocampus, NPCs modulate new neurons by stimulating adult hippocampal neurogenesis (AHN) [256]. Moreover, new neurons derived from NPCs have high degree of synaptic plasticity in both SVZ [257]and SGZ [258]. A recent study suggested that mitochondrial dysfunction is associated with a decline in neurogenesis in the SGZ [259].

Several recent studies have investigated AN as an anti-aging target (Table 6). Mice injected with 2-(2-(5-methoxy-1H-indol-3-yl)ethyl)-5-methyl-1,3,4-oxadiazole (IQM316), which is a melatonin analog, and melatonin showed upregulation of AHN and differentiation of neuronal precursors [260]. Choi et al (2018) [261] illustrated that the AD mouse model injected with aminopropyl carbazole (P7C3) and lentivirus expressing Wnt3 (LV-Wnt3) to induce neurogenesis promoted neurogenesis and improved pattern separation memory in AD male mice. The p38 MAPKs, which are associated with the decline in AN, prevented age-related decline and regulated NPCs in mice [247]. The 3,4,5-tricaffeoylquinic acid (TCQA), a caffeoylquinic acid derivative, increased AN as well as improved spatial learning and memory in SAMP8 mice, a murine model for accelerated aging [262].

Table 6

Recent studies demonstrating the potential effect of modulation of adult neurogenesis on brain function.

Animal		Number of animals	Treatment	Dose	Functional outcome	Ref^*
Animal type	Sex	Number of animals	Treatment	Dose	Functional outcome	Ref^*
Mouse	Male	8 mice per group	Intraperitoneal injection	2 mg/kg IQM316 and melatonin	– promoted AHN by IQM316 and melatonin – induced differentiation of neuronal precursors by IQM316 and melatonin	[260]
	Both	3-12 mice per group	Intraperitoneal injection and hippocampal injection	20 mg/kg P7C3 and 2.0 Pl LV-Wnt3	– promoted AHN by P7C3 and LV-Wnt3 – improved pattern separation memory in male of AD mouse model but not in female of AD mouse model by increasing AHN – no change in other forms of cognition by increasing AHN in AD mouse model – improved pattern separation memory in female of AD mouse model by increasing AHN and BDNF	[261]
	Male	3-6 mice per group	–	–	– decreased p38 expression level with ageing – the reduction of p38 expression is associated with the decline in adult neurogenesis. – prevented the age-related decline in neurogenesis by sustained expression of p38 – regulated neural progenitor cells (NPCs) proliferation in the adult SVZ by p38	[247]
	Male	6-10 mice per group	Mixed with drinking water and then oral gavage	5 mg/kg TCQA	– increased adult neurogenesis in the DG – improved spatial learning and memory in SAMP8 mice	[262]

Open in a separate window

^*These references were published from 2018.

AN is known to be regulated by intracellular, extracellular and environmental factors [246] (Fig. 7). For example, intracellular factors include cell cycle regulators and transcription factors including Wnt/β-catenin pathway, Nrf2, and Notch pathway, while extracellular factors include neurochemical regulators and pharmacological interventions [246]. Among them, the Wnt/β-catenin pathway is a key regulator [246, 263]. The components related to Wnt/β-catenin pathway are expressed in the hippocampal neurogenic niche [264, 265]. Furthermore, Wnt/β-catenin signaling is considered to be linked to pathological conditions, neurodegenerative diseases, and AN and behavioural decline [246]. As well, N-acetyl-5-methoxytryptam (Melatonin), a neuro-hormone, is known to have neurobiological functions including modulation of AN and mitochondrial function [260]. Melatonin not only regulated proliferation and neurogenesis in the DG of rats [266, 267] but also increased cell survival and dendrite maturation of new neurons in the hippocampus of mice [268, 269].

Figure 7.

Mechanism of AN in brain aging. AN can be stimulated by intracellular factors, extracellular factors, and environmental factors. These factors can modulate AN.

Although AN is actively studied, the mechanism is broad and unclear. For example, there are various factors to enhance AN, however the understanding of each factor and their connection is insufficient and yet to be confirmed in human clinical trials. Our understanding of neurogenic mechanisms and factors that influence AN has increased significantly in the last decade. For example, we have an extensive understanding on the importance of vasculature and glial cells on AN and how the vasculature-glial-neuronal crosstalk is influenced by several extrinsic factors such as dietary intake and physical activity. Modulation of AN by regulating transcription factors, cytokine release, neurotransmitters and neuropeptide hormones mediated by maintaining a ‘proneurogenic’ lifestyle could delay the onset and reduce the severity of neurodegenerative diseases and promote ‘healthy’ brain aging [270]. Further studies are necessary to evaluate the clinical utility of well-defined approaches in aging and neurodegenerative conditions.

3.3.7 Stem cell therapy

Cell therapies have emerged as potential treatments for neurological disorders and aging [271–296]. Stem cells can proliferate and differentiate into multiple cellular lineages. There are different classifications of stem cells, which are used therapeutically, including embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs), NSCs, and mesenchymal stem cells (MSCs) [297] (Fig. 8). ESCs, which is pluripotent and self-renewal, can generate neural cells such as neurons, oligodendrocytes and glial cells [298], and has been suggested as a potential therapeutic stem cell [299]. Transplantation of ESCs showed improvement in cognition in rodent models of brain injury [300] and improved behavioural performance in a PD primate model using ESCs derived from both primates and humans [301, 302]. Moreover, transplantation of ESC-derived basal forebrain cholinergic neurons (BFCNs) improved learning and memory in AD mouse model [303].

Figure 8.

Potential role of stem cell therapy in brain ageing. ESC, iPSC can differentiate into various cell types including NSC and MSC since they are pluripotent. Although MSC is mainly differentiated into osteoblasts, chondrocytes, myocytes, and adipocyte, MSC can also differentiate into neurons. Transplantation of neurons derived from NSC or MSC can improve cognition and attenuate degenerative diseases. ESC and iPSC can be directly transplanted for treatment then differentiate into other brain cells such as glial cell.

iPSCs are also potential therapeutic stem cells because of their self-renewal capacity and their ability to differentiate using a 3-phase reprogramming technique including initiation, maturation and stabilization [304, 305]. Transplantation of iPSCs derived from mouse skin fibroblasts induced differentiation into glial cells and improved cognition and decreased plaque depositions in an AD mouse model [306]. iPSC therapy improved behavioural performance in a PD rat model [307] and in PD monkey model [308]. Furthermore, iPSC-derived DA neurons were suggested to be suitable for transplantation because their characteristic is similar to human DA midbrain neurons [309]. NSCs, which can be derived from both ESCs and iPSCs, have the ability of self-renewal and multipotent potential [310]. In AD rodent, NSCs transplantation showed decline in neuro-inflammation, tau and Aβ pathology [311, 312] and improvement in AN, synaptogenesis, and cognition [312–314]. Transplantation of NSCs also improved motor impairment in HD animal models [315].

MSCs not only differentiate into various cells including cartilage cells, muscle cells, fat cells, bone cells, and connective tissue cells but also have low immunogenicity [316]. It is generally accepted that MSCs do not exert their beneficial actions through direct differentiation into neural tissue, but rather by acting as trophic mediators releasing immune modulatory, proangiogenic, and/or pro-neurogenic factors [317]. Additional mechanisms involved in paracrine signalling promoted by MSCs include the secretion of specific cytokines [318] and the transfer of extracellular vehicles (EVs) or even of healthy mitochondria to cells with impaired mitochondrial function [319–321].Recent advances in biomedicine have led to a growing interest in using stem cells as cellular vectors for disease modelling, drug discovery, drug toxicity, and regenerative medicine. Importantly, MSCs have a greater proliferation capacity in vitro with no time limit [322]. They also have immunomodulatory properties, and it was reported recently that they are capable of impairing NK-cells’ function to prevent graft rejection. Transplantation of MSCs reduced tau phosphorylation and improved AN and cognition in vivo [297]. Human MSCs not only attenuated accumulation of amyloid beta but also improved synaptic transmission and memory in an AD mouse model [323, 324]. Moreover, MSCs transplanted showed improvement in locomotion and cognition in aged mice and prevented the accumulation of amyloid beta as well as improved learning and memory in an AD rodent model [325]. Recently, some studies using stem cell therapy in various animal model reported (Table 7). In mice, human NSCs showed improvement of behavioural performance in HD model [326]. Human MSCs improve spatial memory in aged rats [327] and functional neurological recovery in a swine model of traumatic brain injury and hemorrhagic shock [328]. human pathogenetic embryonic stem cells (hPESCs), which is generated from activated oocytes without sperm fertilization, can differentiate DA neuron, and improve locomotive performance in a PD primate model [329].

Table 7

Recent studies utilising stem cell therapy on brain function.

Animal		Number of animals	Cell type	Functional outcome	Ref^*
Animal type	Sex	Number of animals	Cell type	Functional outcome	Ref^*
Mouse	Both	5-8 mice per group	hNSCs	– Improve behavioural performance such as rotarod, pole test, and grip strength in HD model – reduced hyperexcitable input from cortex to striatum after addition of the GABA_A receptor antagonist in HD model – increased BDNF levels in HD model.	[326]
Rat	Female	8 rats per group	hMSCs	– improved spatial memory accuracy in aged rats – increased neuroblasts in aged rats – decreased the number of reactive microglial cells in aged rats – restored presynaptic protein level in aged rats	[327]
Pig	Female	5 pigs per group	hMSCs	– hMSCs derived exosome attenuate neuronal injury in traumatic brain injury and haemorrhagic shock model. – hMSCs derived exosome improve functional neurological recovery in traumatic brain injury and hemorrhagic shock model.	[328]
Monkey	Male	10	hPESCs	– the transplantation of hPESCs derived DA neuron was relatively safe without tumor in PD model. – the transplantation of hPESCs derived DA neuron improved locomotive performance in PD model.	[329]

Open in a separate window

^*These references were published from 2018.

Using neurons derived from the patient’s stem cell can relatively be safe from immunorejection. It was reported recently that MSCs are capable of impairing NK-cells’ function to prevent graft rejection. Despite their long-term survival after transplantation, the MSC are nontumorigenic and are safe and effective for cell-based therapy [322]. However, further investigations are needed to alleviate differentiation of tumors or teratomas. Although stem cells derived from various sources have shown positive effects in cognition and neurodegenerative diseases in animal model, studies in humans are limited, and clinical trials are warranted.

It has been established that the main tenet for MSCs to exert a dynamic homeostatic response that supports tissue preservation and function recovery is the generation of exosomes [330]. The main mechanism by which MSCs mediate this activity is not through cellular implant and its subsequent differentiation, but the paracrine activity of the secretome [331]. This phenomenon was demonstrated in studies where conditioned medium of MSCs was administered and therapeutic effects similar to those already reported for MSCs were produced in different animal models of diseases [330]. Exosomes encapsulate and transfer several functional molecules including proteins, lipids and regulatory RNA which can modify cell metabolism. More than 730 proteins have been identified in MSC-derived exosome, including specific cell type markers and others that are involved in the regulation of binding and fusion of exosomes with adjacent cells. Additionally, factors that promote the recruitment, proliferation, and differentiation of other cells such as neural stem cells have also been identified. As well, several miRNAs have been found in exosomes, which regulate neural remodeling and angiogenic and neurogenic processes [332]. Therefore, the use of exosomes could be part of a strategy to attenuate irregular pathology and cognitive deficits and promote neural replacement and plasticity in AD with limited adverse effects and immunorejection.

The safety of stem cell therapy is unclear because unwanted and uncontrolled differentiation could be observed. For example, stem cell could differentiate to undesired tissue after transplantation then it may cause tumors [333]. Nevertheless, stem cell therapy still has possibilities to develop as an application for diseases. The adverse effects mentioned above such as development of teratoma could be prevented by screen them for the presence of undifferentiated cells before injection. For example, a study reported that they did not observed teratomas in over 200 animals using the procedure [334]. Furthermore, the other group study showed that serious side effects including adverse proliferation, tumorigenicity, and ectopic tissue formation were not observed after transplantation of ESC-derived retinal pigment epithelial [335]. These studies can support that stem cell therapy can be available with safe under controlled condition. Several studies confirmed the safety of MSC therapy[336–340]. And MSC also showed safety in patients with TBI and neurodegenerative diseases including multi sclerosis and ischemic stroke patients [341–343]. However, it is insufficient data for clinical application. As a result, it will be necessary to further study about safety and efficacy of stem cell therapy.

Table 8

Recent studies about association between vascular factors and brain health.

Animal		Number of animals	Treatments	Functional outcome	Ref^*
Animal type	Sex	Number of animals	Treatments	Functional outcome	Ref^*
Mouse	Male	3-8 mice per group	–	– Increased levels of Aβ in the hippocampus of hypertension mouse model – Increased levels of phosphorylated tau protein in the hippocampus of hypertension mouse model – damaged hippocampus related to learning and memory in hypertension mouse model	[362]
Pig	Male	3-27 pigs per group	–	– Increased levels of Aβ in the hippocampus of hypertension pig model which was induced by abdominal aortic constriction – Increased levels of phosphorylated tau protein in the hippocampus of hypertension porcine model	[362]
Human		Number of subjects	Treatments	Functional outcome
Trial type	Sex	Number of subjects	Treatments	Functional outcome
–	Both	2,004	Antihypertensive Hypoglycemic agents	– showed positive association between antihypertensives and cognition in older adults with hypertension – showed positive association between cognition and dose of antihypertensives and hypoglycemic agents in older adults with both hypertension and diabetes mellitus type II	[364]
–	Both	3201	–	– observed poor global cognitive and memory performances in hypertensive patients compared to non-hypertensive patients	[363]
Retrospective cohort	Both	116	Antihypertensive	– decreased the risks of AD and dementia by combination of statin and an antihypertensive	[365]
Multi-centre cluster randomized controlled	Both	412	Antihypertensive	– improved cognition in people with dementia	[366]

Open in a separate window

^*These references were published from 2018.

3.3.8 Vascular risk reduction

Numerous studies have shown the early role of vascular factors during the prodromal stage of cognitive impairment, parkinsonism. The Vascular hypothesis assumes that vascular risk factors are one of the major considerations for brain aging and neurodegenerative diseases. Many studies have reported that vascular risk factors such as hypertension, hypercholesterolemia, obesity, and diabetes are associated with cognitive dysfunction and dementia including AD [344–346]. For instance, vascular risk factors in mid-life, but not late-life, showed interaction with amyloid deposition [347]. Furthermore, people with diabetes mellitus showed an increase in the risk of cognitive impairment and dementia in the elderly [348]. In particular, the control of blood pressure, which is an important and essential factor for homeostatic control of the living organism, can impact the aging brain such as cognitive impairment [349, 350].

Hypertension has been associated with cognitive impairment or neurodegenerative diseases. Numerous studies reported that hypertension is related to cognitive decline, mild cognitive impairment, dementia, and neurodegenerative diseases such as AD and PD [351–355]. In animal studies, hypertension affected the deposition of brain amyloid, thereby supporting the association between hypertension and brain amyloid [347]. Hypertension is also related to a significant increase in excess ROS [356, 357]. Overall, hypertension may represent a ‘hidden brain risk’ and brain health can be improved by lowering blood pressure.

Nevertheless, the molecular mechanism(s) of how these vascular risk factors impact brain health or neurodegenerative diseases is still unclear. However, there have been some concerted efforts to understand how the vascular risk factors can affect the brain and neurodegenerative diseases (Fig. 9). For instance, cerebrovascular disruption such as blood brain barrier breakdown and resting cerebral blood flow reduction, induced by vascular risk factors, can lead to the accumulation of neurotoxic molecules in the brain [358]. In particular, breakdown of the blood brain barrier, which controls the entry of blood-derived products and pathogens into the brain, is observed in mild cognitive impairment and AD [359, 360]. Moreover, vascular dysfunction can lead to increases in Aβ levels and ROS [356, 357, 361]. A recent study demonstrated increases in the levels of Aβ and damage to the hippocampus associated with learning and memory impairments in a hypertension mouse model. As well, increased levels of Aβ and phosphorylated tau protein were reported in the hippocampus of a hypertension porcine model which is induced by abdominal aortic constriction [362]. In humans, hypertensive patients showed poor global cognitive and memory performance compared to non-hypertensive participants [363]. A strong correlation was observed between cognitive impairment in older adults and incidence of hypertension [364].

Figure 9.

Association between vascular risk factors and cognition as well as neurodegenerative diseases. Vascular risk factors such as hypertension, hyperglycaemia, diabetes, and obesity can increase Aβ and ROS via cerebrovascular disruption. Antihypertensives and cholesterol-lowering medication might improve cognition and prevent neurodegenerative diseases through their effects on vascular risk reduction.

One hot topic in preventing neuro-degenerative diseases such as dementia is optimizing lifestyle and vascular risk factors during middle age, some of which through therapeutic strategies. For instance, pharmacological control of hypertension in middle aged or younger old adults lowered the incidence of dementia in one study [353]. Another study reported reduction in the risks of AD and dementia when antihypertensives were used in combination with statins [365]. Moreover, the treatment of antihypertensive showed improvement in cognition patients with dementia [366]. Recently, the effects of combination of antihypertensive and hypoglycemic agents against cognitive decline has been demonstrated. The study showed a positive correlation with cognition in older patients with both hypertension and diabetes mellitus type II [364].

As well, high levels of cholesterol in plasma is related to risk of AD [367]. In vivo and in vitro studies have demonstrated that high levels of cholesterol in blood may increase the production and deposition of Aβ in AD [368, 369]. Treatment with statins, which are cholesterol-lowering medications, has been reported to reduce the production of Aβ in high cholesterol-fed animal models [370]. Taken together, these results indicate that vascular risk reduction may be an effective therapeutic strategy for the promotion of brain health.

Metformin is a medication originally used for type 2 diabetes. Recent studies have also found that metformin has a positive effect on cardio- vascular protection [8,9,10,11,12]. Metformin also lowers risk factors for cardiovascular disease such as blood fats [13,14,15], body weight and blood pressure. Some experiments have highlighted the possibility of using metformin for anti-aging [72, 73]. Metformin has similar effects to CR regulating pathway and genes related to aging [72–75], However, recent studies reported side effects and sex-dependent variability of metformin [76–78]. Metformin had no effect on female mice with neuropathic pain, whereas it inhibited microglial activation in male mice [78]. Neurogenesis of neuronal precursor cells, an essential factor for repairing brain injury, is improved only in female mice [76]. In humans, diabetic patients with metformin had a higher risk of developing PD and AD than non-metformin treated individuals [79, 80]. On the other hand, metformin has shown positive effects on AD and PD in animal models [74, 81–83]. These results are paradoxical compared to the results in C. elegans and mice.

3.3.9 Non-pharmacological therapies

Non-pharmacological interventions have also been studied to prevent brain aging and neurodegenerative diseases. There are various non-pharmacological interventions such as physical activity and cognitive stimulation. Music therapy is one of the multi-domain cognitive stimulation approaches, which has shown improvement in memory and reduction of negative cognitive symptoms in AD [371]. On the other hand, physical activity is especially considered a common and affordable way to improve neurological health [372]. It has been reported that physical activity can improve cognitive function such as learning and memory and prevent neurological damage in animals and humans [373–376]. Moreover, physical exercise has been proposed as a therapeutic strategy to attenuate age-related neurodegenerative diseases [377, 378]. Physical activity is universal prescription for AD or PD to improve cognitive function and mental health as well as reduce the risk of other degenerative diseases [379, 380]. Among these physical activities, dance therapy and aerobic exercise have shown positive effects. For example, dance therapy, which involves the use of sound and motor movement for cognitive stimulation, had preventive ability in cognitive degradation [371, 381, 382]. In humans, dance therapy showed its potential to use as an intervention for improvement of motor symptoms in PD patients. Furthermore, music therapy improved verbal fluency in mild AD patients as well as psychiatric and behavioural symptoms in patients with severe AD [383, 384]. Aerobic exercise can not only generate structural changes in the brain but also improve cognition [385, 386].

Although the mechanisms to explain how physical activity improves cognition and reduce neurodegenerative disease risk are still unclear, there are many hypotheses (Fig. 10; Table 9). For example, physical activity can affect ROS and redox balance through upregulation of antioxidant and oxidative damage repair enzymes, consequently leading to a reduction in oxidative stress geeration and improvements in brain function [387–389]. In animal and human studies, physical activity also increased the levels and function of several neurotrophic factors such as BDNF, and nerve growth factor (NGF) as well as the expression of IGF-1 and PGC-1α [376, 390]. Furthermore, physical activity has been shown to increase the levels of telomere-stabilizing proteins and reduce the expression of inflammatory cytokines such as IL-1β or TNF-α [391–393]. Overall, physical activity can not only improve redox status increasing neurotrophic factors and enzymes related to antioxidant, but also protect against cellular senescence through telomere-stabilizing proteins. With respect to its effects in AD, physical activity showed enhancement of Aβ degrading enzymes, thereby reducing Aβ plaques [394, 395].

Table 9

Recent studies of non-pharmacological strategies on brain function.

Animal		Number of animals	Intervention	Functional outcome	Ref^*
Animal type	Sex	Number of animals	Intervention	Functional outcome	Ref^*
Mouse	Male	12 mice per group	Treadmill	– decreased Aβ deposition in the hippocampus of AD model – decreased Aβ levels in the hippocampus of AD model – increased autophagy in the hippocampus of AD model	[399]
	–	12 mice per group	Treadmill	– improved learning and memory in AD model – improved mitochondrial fission and fusion balance in AD model – decreased oxidative stress and Aβ levels in the hippocampus of AD model	[400]
	Male	12 mice per group	Treadmill	– attenuated Aβ deposition in the hippocampus of AD model – decreased Aβ levels in the hippocampus of AD model – decreased Aβ production in the hippocampus of AD model	[398]
	Male	25 mice per group	Swimming	– decreased Aβ an P-Tau in the cortex and hippocampus of AD model – attenuated cognitive impairments in AD model	[403]
	Female	10 mice per group	Treadmill	– decreased soluble Aβ levels in the hippocampus of AD model	[397]
	Both	8-10 mice per group	Running wheels	– improved performance in rotarod of AD model – decreased Aβ plaque load in the hippocampus of AD model	[402]
Rat	Female	6-8 rats per group	Running wheels Swimming	– improved locomotion impairment in AD model – improved learning ability in AD model – decreased Aβ level in AD model – prevented the decrease of neurotrophic factors such as NGF and BDNF in AD model – ameliorate oxidative stress in AD model	[401]
	Male	20 rats per group	Environmental enrichment Social enrichment Anaerobic exercise	– prevented impairments in object recognition memory by environmental enrichment and anaerobic exercise – prevented impairments in social recognition memory by each intervention – increased total antioxidant capacity by social enrichment	[404]
	Male	14 rats per group	Treadmill	– prevented Aβ-induced impairment of spatial learning and memory in MWM test – decreased Aβ load and soluble Aβ levels in the hippocampus and plasma of AD model – increased Aβ-degrading enzymes levels in the hippocampus of AD model	[396]
Human		Number of subjects	Intervention	Functional outcome	Ref^*
Trial type	Sex	Number of subjects	Intervention	Functional outcome	Ref^*
Prospective, randomized controlled	Both	13	Dance Therapy	– showed potential to improve motor symptoms in PD patients	[384]
Randomized controlled	Both	288	Music Therapy	– improved verbal fluency test score in mild AD patients – improved psychiatric and behavioural symptoms in severe AD patients	[383]

Open in a separate window

^*These references were published from 2018.

Figure 10.

Positive effects of non-pharmacological strategies in brain health. Among non-pharmacological strategies, physical activity can not only increase antioxidant enzymes, neurotrophic factors, IGF-1, PGC-1α, and telomere-stabilizing proteins but also reduce inflammatory cytokines, which might improve brain health.

Other forms of physical activity have demonstrated positive effects on brain aging and neurodegenerative diseases. For instance, exercise using treadmill showed a significant decline in oxidative stress and Aβ levels in the hippocampus of an AD rodent model [396–400]. Moreover, physical activity also increased autophagy and improved learning and memory in an AD mouse model [399, 400]. Additionally, swimming and running wheels were reported to not only decrease Aβ levels but also improve cognition and motor activity in an AD rodent model [401–403]. Apart from the physical activity, environmental and social enrichment additionally showed improvement in recognition memory in rats [404]. These findings provide insight into the potential mechanisms of physical activity and other non-pharmacological therapies against brain aging and neurodegenerative diseases.

3.4. Anti-aging limitations

The development of anti-aging drugs is an enormous challenge but of great desire to humans. However, there are several limitations to developing anti-aging drugs. One of the challenges is that it takes a considerably long-time to prove aging processes are attenuated in humans and would require several generations of researchers with immense funding working on the project in a large multi-sited population [67]. Moreover, plenty of clinical trials are essential to identify whether data from preclinical animal models can be translated to humans. Traditionally, in vivo studies have been performed using animals with phenotypically accelerated aging or prolonged longevity, transgenic, mutant, and knockout models that focus on a single gene’s role, to generate reproducible results [68, 69]. Due to their short lifespan, inbred laboratory rodents, particularly rats and mice (e.g. senescence accelerated mice – SAM), are used as models to investigate the effects of intrinsic and extrinsic factors on lifespan [69]. However, this is quite limited since these inbred models do not provide significant genetic diversity to be comparable to humans and correlate poorly with human conditions. To date, more than 150 clinical trial candidates to attenuate inflammation in critically ill patients have failed due to over-reliance on inadequate animal models [70]. Another problem is that humans consume various types of food and have different lifestyles, so it is hard to recognize if anti-aging ingredients have synergistic or adverse effects [71]. The aging phenotype is also affected by individual variability i.e., sex, tissues function and socio-economic status [71, 72].

Go to:

4. Conclusion

As the aging population continues to expand, slowing and/or reversing the impact of aging on the brain is becoming important to maintain a good quality life. There are several anti-aging strategies currently under investigation. Some of these strategies have shown considerable promise for improving brain aging. For example, CR is actively studied as an effective intervention, and many studies contribute to understanding the mechanism of CR on the brain. Although the mechanism(s) are still controversial, there are several hypotheses to explain how CR can reduce age-related decline. Moreover, several mechanisms of CR overlap with other strategies including the ketogenic diet and raising NAD+ levels. Pre-clinical studies have shown that elimination of senescent cells using senolytics, transfusion of plasma from young blood, promotion of cellular NAD+ levels using NAD+ precursors such as NR, neurogenesis and BDNF enhancement through specific drugs are promising approaches to prevent age-related neurocognitive disorders. However, these approaches will require critical assessment in clinical trials to determine their long-term efficacy and lack of adverse effects on the function of various tissues and organs. For example, studies exploring KD are largely limited to case studies [151–153, 155]. On the other hand, approaches such as NR treatment are ready for large-scale clinical trials, as it is non-invasive, safe, and orally bioavailable. Stem cell therapy, such as MSCs were able to improve brain function in the aged or AD brain. However, further advances in stem cell therapy are required for promoting successful brain aging. Clinical relevance of stem cells is dependent on further clinical trials to examine the safety and efficacy of stem cell products.

Several dietary interventions have shown promise. A potential naturally occurring phytochemical is resveratrol (RV) [72]. RV is one of the most well-known polyphenols demonstrating anti-aging affects through Caloric restriction (CR) and other mechanisms [84]. In the brain, RV reduces oxidative stress which is a vital factor for brain aging [85]. Moreover, RV has neuroprotective effects in PD rats [86, 87], accelerates recovery of peripheral infection in rats [87, 88], and reduces amyloid beta accumulation in AD patients [89–91]. Although the potential effects of RV for preventing brain aging have been well demonstrated in humans, there are some limitations in humans. It is safe to take up to 5 g a day, however Intake of overly high doses of RV may cause some minor side effects [92]. In addition, the effects of RV are diverse in the human body, but the drug has low bioavailability, whereas designed drugs influence a single target with high affinity. Another challenge is that absorption rate of pure RV is quite lower than naturally occurring RV [67].

As well, NAD+ precursors, including NAM, NA, TRYP, NR and NMN can be obtained from food. NA and NAM are found in eggs, fish, a variety of meats, dairy products, certain vegetables, and whole grains. NR is abundant in milk. Foods that contain NMN include broccoli (0-25-1.12 mg/100 g), avocado (0.36-1.60 mg/100 g), and beef (0.06-0.42 mg/100g) [405]. Ingested NAD+ may be broken down to a number of NAD+ precursors including NR and NMN via the catalytic activity of enzymes in the intestines and/or gut bacterial nicotinamidases [406]. NAD+ precursors can be absorbed from a variety of foods in the diet.

A greater understanding and refinement of pharmacological and non-pharmacological anti-aging strategies to meet individual needs are essential to maintain optimal brain function and extend the health span to promote a global ‘healthy’ aging population.

Go to:

References

[1] Zinger A, Cho WC, Ben-Yehuda A (2017). Cancer and Aging – the Inflammatory Connection. Aging Dis, 8:611-627. [PMC free article] [PubMed] [Google Scholar]

[2] Zamroziewicz MK, Paul EJ, Zwilling CE, Barbey AK (2017). Predictors of Memory in Healthy Aging: Polyunsaturated Fatty Acid Balance and Fornix White Matter Integrity. Aging Dis, 8:372-383. [PMC free article] [PubMed] [Google Scholar]

[3] Xu Z, Feng W, Shen Q, Yu N, Yu K, Wang S, et al. (2017). Rhizoma Coptidis and Berberine as a Natural Drug to Combat Aging and Aging-Related Diseases via Anti-Oxidation and AMPK Activation. Aging Dis, 8:760-777. [PMC free article] [PubMed] [Google Scholar]

[4] Szybinska A, Lesniak W (2017). P53 Dysfunction in Neurodegenerative Diseases – The Cause or Effect of Pathological Changes? Aging Dis, 8:506-518. [PMC free article] [PubMed] [Google Scholar]

[5] Sun N, Youle RJ, Finkel T (2016). The Mitochondrial Basis of Aging. Mol Cell, 61:654-666. [PMC free article] [PubMed] [Google Scholar]

[6] de Magalhaes JP, Stevens M, Thornton D (2017). The Business of Anti-Aging Science. Trends Biotechnol, 35:1062-1073. [PubMed] [Google Scholar]

[7] Aunan JR, Cho WC, Soreide K (2017). The Biology of Aging and Cancer: A Brief Overview of Shared and Divergent Molecular Hallmarks. Aging Dis, 8:628-642. [PMC free article] [PubMed] [Google Scholar]

[8] Panza F, Solfrizzi V, Frisardi V, Maggi S, Sancarlo D, Adante F, et al. (2011). Different models of frailty in predementia and dementia syndromes. J Nutr Health Aging, 15:711-719. [PubMed] [Google Scholar]

[9] Searle SD, Rockwood K (2015). Frailty and the risk of cognitive impairment. Alzheimers Res Ther, 7:54. [PMC free article] [PubMed] [Google Scholar]

[10] Canevelli M, Cesari M (2017). Cognitive Frailty: Far From Clinical and Research Adoption. J Am Med Dir Assoc, 18:816-818. [PubMed] [Google Scholar]

[11] Borges MK, Canevelli M, Cesari M, Aprahamian I (2019). Frailty as a Predictor of Cognitive Disorders: A Systematic Review and Meta-Analysis. Front Med (Lausanne), 6:26. [PMC free article] [PubMed] [Google Scholar]

[12] Brigola AG, Rossetti ES, Dos Santos BR, Neri AL, Zazzetta MS, Inouye K, et al. (2015). Relationship between cognition and frailty in elderly: A systematic review. Dement Neuropsychol, 9:110-119. [PMC free article] [PubMed] [Google Scholar]

[13] Stambler I (2017). Recognizing Degenerative Aging as a Treatable Medical Condition: Methodology and Policy. Aging Dis, 8:583-589. [PMC free article] [PubMed] [Google Scholar]

[14] Konar A, Singh P, Thakur MK (2016). Age-associated Cognitive Decline: Insights into Molecular Switches and Recovery Avenues. Aging Dis, 7:121-129. [PMC free article] [PubMed] [Google Scholar]

[15] Chakrabarti S, Mohanakumar KP (2016). Aging and Neurodegeneration: A Tangle of Models and Mechanisms. Aging Dis, 7:111-113. [PMC free article] [PubMed] [Google Scholar]

[16] Tacutu R, Craig T, Budovsky A, Wuttke D, Lehmann G, Taranukha D, et al. (2013). Human Ageing Genomic Resources: integrated databases and tools for the biology and genetics of ageing. Nucleic Acids Res, 41:D1027-1033. [PMC free article] [PubMed] [Google Scholar]

[17] Kenyon CJ (2010). The genetics of ageing. Nature, 464:504-512. [PubMed] [Google Scholar]

[18] de Magalhaes JP (2012). Programmatic features of aging originating in development: aging mechanisms beyond molecular damage? FASEB J, 26:4821-4826. [PMC free article] [PubMed] [Google Scholar]

[19] Wyss-Coray T (2016). Ageing, neurodegeneration and brain rejuvenation. Nature, 539:180-186. [PMC free article] [PubMed] [Google Scholar]

[20] Jesko H, Wencel P, Strosznajder RP, Strosznajder JB (2017). Sirtuins and Their Roles in Brain Aging and Neurodegenerative Disorders. Neurochem Res, 42:876-890. [PMC free article] [PubMed] [Google Scholar]

[21] Danka Mohammed CP, Park JS, Nam HG, Kim K (2017). MicroRNAs in brain aging. Mech Ageing Dev, 168:3-9. [PubMed] [Google Scholar]

[22] Camandola S, Mattson MP (2017). Brain metabolism in health, aging, and neurodegeneration. EMBO J, 36:1474-1492. [PMC free article] [PubMed] [Google Scholar]

[23] Barter JD, Foster TC (2018). Aging in the Brain: New Roles of Epigenetics in Cognitive Decline. Neuroscientist, 24:516-525. [PubMed] [Google Scholar]

[24] Cobley JN, Fiorello ML, Bailey DM (2018). 13 reasons why the brain is susceptible to oxidative stress. Redox Biol, 15:490-503. [PMC free article] [PubMed] [Google Scholar]

[25] Grimm A, Eckert A (2017). Brain aging and neurodegeneration: from a mitochondrial point of view. J Neurochem, 143:418-431. [PMC free article] [PubMed] [Google Scholar]

[26] Mattson MP, Arumugam TV (2018). Hallmarks of Brain Aging: Adaptive and Pathological Modification by Metabolic States. Cell Metab, 27:1176-1199. [PMC free article] [PubMed] [Google Scholar]

[27] Pandya JD, Grondin R, Yonutas HM, Haghnazar H, Gash DM, Zhang Z, et al. (2015). Decreased mitochondrial bioenergetics and calcium buffering capacity in the basal ganglia correlates with motor deficits in a nonhuman primate model of aging. Neurobiol Aging, 36:1903-1913. [PubMed] [Google Scholar]

[28] Islam MT (2017). Oxidative stress and mitochondrial dysfunction-linked neurodegenerative disorders. Neurol Res, 39:73-82. [PubMed] [Google Scholar]

[29] Tonnies E, Trushina E (2017). Oxidative Stress, Synaptic Dysfunction, and Alzheimer’s Disease. J Alzheimers Dis, 57:1105-1121. [PMC free article] [PubMed] [Google Scholar]

[30] Salim S (2017). Oxidative Stress and the Central Nervous System. J Pharmacol Exp Ther, 360:201-205. [PMC free article] [PubMed] [Google Scholar]

[31] Li J, O W, Li W, Jiang ZG, Ghanbari HA (2013). Oxidative stress and neurodegenerative disorders. Int J Mol Sci, 14:24438-24475. [PMC free article] [PubMed] [Google Scholar]

[32] Kudryavtseva AV, Krasnov GS, Dmitriev AA, Alekseev BY, Kardymon OL, Sadritdinova AF, et al. (2016). Mitochondrial dysfunction and oxidative stress in aging and cancer. Oncotarget, 7:44879-44905. [PMC free article] [PubMed] [Google Scholar]

[33] Cenini G, Lloret A, Cascella R (2019). Oxidative Stress in Neurodegenerative Diseases: From a Mitochondrial Point of View. Oxid Med Cell Longev, 2019:2105607. [PMC free article] [PubMed] [Google Scholar]

[34] Golpich M, Amini E, Mohamed Z, Azman Ali R, Mohamed Ibrahim N, Ahmadiani A (2017). Mitochondrial Dysfunction and Biogenesis in Neurodegenerative diseases: Pathogenesis and Treatment. CNS Neurosci Ther, 23:5-22. [PMC free article] [PubMed] [Google Scholar]

[35] Gauba E, Guo L, Du H (2017). Cyclophilin D Promotes Brain Mitochondrial F1FO ATP Synthase Dysfunction in Aging Mice. J Alzheimers Dis, 55:1351-1362. [PMC free article] [PubMed] [Google Scholar]

[36] Payne BA, Chinnery PF (2015). Mitochondrial dysfunction in aging: Much progress but many unresolved questions. Biochim Biophys Acta, 1847:1347-1353. [PMC free article] [PubMed] [Google Scholar]

[37] Swerdlow RH, Burns JM, Khan SM (2014). The Alzheimer’s disease mitochondrial cascade hypothesis: progress and perspectives. Biochim Biophys Acta, 1842:1219-1231. [PMC free article] [PubMed] [Google Scholar]

[38] Bose A, Beal MF (2016). Mitochondrial dysfunction in Parkinson’s disease. J Neurochem, 139 Suppl 1:216-231. [PubMed] [Google Scholar]

[39] Jardim FR, de Rossi FT, Nascimento MX, da Silva Barros RG, Borges PA, Prescilio IC, et al. (2018). Resveratrol and Brain Mitochondria: a Review. Mol Neurobiol, 55:2085-2101. [PubMed] [Google Scholar]

[40] Chen C, Zhou M, Ge Y, Wang X (2020). SIRT1 and aging related signaling pathways. Mech Ageing Dev, 187:111215. [PubMed] [Google Scholar]

[41] Lee SH, Lee JH, Lee HY, Min KJ (2019). Sirtuin signaling in cellular senescence and aging. BMB Rep, 52:24-34. [PMC free article] [PubMed] [Google Scholar]

[42] Fang EF, Lautrup S, Hou Y, Demarest TG, Croteau DL, Mattson MP, et al. (2017). NAD(+) in Aging: Molecular Mechanisms and Translational Implications. Trends Mol Med, 23:899-916. [PMC free article] [PubMed] [Google Scholar]

[43] Han X, Tai H, Wang X, Wang Z, Zhou J, Wei X, et al. (2016). AMPK activation protects cells from oxidative stress-induced senescence via autophagic flux restoration and intracellular NAD(+) elevation. Aging Cell, 15:416-427. [PMC free article] [PubMed] [Google Scholar]

[44] Weir HJ, Yao P, Huynh FK, Escoubas CC, Goncalves RL, Burkewitz K, et al. (2017). Dietary Restriction and AMPK Increase Lifespan via Mitochondrial Network and Peroxisome Remodeling. Cell Metab, 26:884-896 e885. [PMC free article] [PubMed] [Google Scholar]

[45] Wyse ATS, Grings M, Wajner M, Leipnitz G (2019). The Role of Oxidative Stress and Bioenergetic Dysfunction in Sulfite Oxidase Deficiency: Insights from Animal Models. Neurotox Res, 35:484-494. [PubMed] [Google Scholar]

[46] Toescu EC, Verkhratsky A (2003). Neuronal ageing from an intraneuronal perspective: roles of endoplasmic reticulum and mitochondria. Cell Calcium, 34:311-323. [PubMed] [Google Scholar]

[47] Chandran R, Kumar M, Kesavan L, Jacob RS, Gunasekaran S, Lakshmi S, et al. (2019). Cellular calcium signaling in the aging brain. J Chem Neuroanat, 95:95-114. [PubMed] [Google Scholar]

[48] Lee S, Min KT (2018). The Interface Between ER and Mitochondria: Molecular Compositions and Functions. Mol Cells, 41:1000-1007. [PMC free article] [PubMed] [Google Scholar]

[49] Calvo-Rodriguez M, Hernando-Perez E, Nunez L, Villalobos C (2019). Amyloid beta Oligomers Increase ER-Mitochondria Ca(2+) Cross Talk in Young Hippocampal Neurons and Exacerbate Aging-Induced Intracellular Ca(2+) Remodeling. Front Cell Neurosci, 13:22. [PMC free article] [PubMed] [Google Scholar]

[50] Alzheimer’s Association Calcium Hypothesis W (2017). Calcium Hypothesis of Alzheimer’s disease and brain aging: A framework for integrating new evidence into a comprehensive theory of pathogenesis. Alzheimers Dement, 13:178-182 e117. [PubMed] [Google Scholar]

[51] Kirischuk S, Verkhratsky A (1996). Calcium homeostasis in aged neurones. Life Sci, 59:451-459. [PubMed] [Google Scholar]

[52] Gant JC, Chen KC, Kadish I, Blalock EM, Thibault O, Porter NM, et al. (2015). Reversal of Aging-Related Neuronal Ca2+ Dysregulation and Cognitive Impairment by Delivery of a Transgene Encoding FK506-Binding Protein 12.6/1b to the Hippocampus. J Neurosci, 35:10878-10887. [PMC free article] [PubMed] [Google Scholar]

[53] Jiang Y, Yan F, Feng Z, Lazarovici P, Zheng W (2019). Signaling Network of Forkhead Family of Transcription Factors (FOXO) in Dietary Restriction. Cells, 9. [PMC free article] [PubMed] [Google Scholar]

[54] Bryan MR, Bowman AB (2017). Manganese and the Insulin-IGF Signaling Network in Huntington’s Disease and Other Neurodegenerative Disorders. Adv Neurobiol, 18:113-142. [PMC free article] [PubMed] [Google Scholar]

[55] Ashpole NM, Sanders JE, Hodges EL, Yan H, Sonntag WE (2015). Growth hormone, insulin-like growth factor-1 and the aging brain. Exp Gerontol, 68:76-81. [PMC free article] [PubMed] [Google Scholar]

[56] Kleinridders A, Ferris HA, Cai W, Kahn CR (2014). Insulin action in brain regulates systemic metabolism and brain function. Diabetes, 63:2232-2243. [PMC free article] [PubMed] [Google Scholar]

[57] Piriz J, Muller A, Trejo JL, Torres-Aleman I (2011). IGF-I and the aging mammalian brain. Exp Gerontol, 46:96-99. [PubMed] [Google Scholar]

[58] Farias Quipildor GE, Mao K, Hu Z, Novaj A, Cui MH, Gulinello M, et al. (2019). Central IGF-1 protects against features of cognitive and sensorimotor decline with aging in male mice. Geroscience, 41:185-208. [PMC free article] [PubMed] [Google Scholar]

[59] Denver P, McClean PL (2018). Distinguishing normal brain aging from the development of Alzheimer’s disease: inflammation, insulin signaling and cognition. Neural Regen Res, 13:1719-1730. [PMC free article] [PubMed] [Google Scholar]

[60] Gabuzda D, Yankner BA (2013). Physiology: Inflammation links ageing to the brain. Nature, 497:197-198. [PMC free article] [PubMed] [Google Scholar]

[61] Osborn O, Olefsky JM (2012). The cellular and signaling networks linking the immune system and metabolism in disease. Nat Med, 18:363-374. [PubMed] [Google Scholar]

[62] Stephenson J, Nutma E, van der Valk P, Amor S (2018). Inflammation in CNS neurodegenerative diseases. Immunology, 154:204-219. [PMC free article] [PubMed] [Google Scholar]

[63] Corlier F, Hafzalla G, Faskowitz J, Kuller LH, Becker JT, Lopez OL, et al. (2018). Systemic inflammation as a predictor of brain aging: Contributions of physical activity, metabolic risk, and genetic risk. Neuroimage, 172:118-129. [PMC free article] [PubMed] [Google Scholar]

[64] Di Benedetto S, Muller L, Wenger E, Duzel S, Pawelec G (2017). Contribution of neuroinflammation and immunity to brain aging and the mitigating effects of physical and cognitive interventions. Neurosci Biobehav Rev, 75:114-128. [PubMed] [Google Scholar]

[65] Wu Y, Dissing-Olesen L, MacVicar BA, Stevens B (2015). Microglia: Dynamic Mediators of Synapse Development and Plasticity. Trends Immunol, 36:605-613. [PMC free article] [PubMed] [Google Scholar]

[66] Norden DM, Godbout JP (2013). Review: microglia of the aged brain: primed to be activated and resistant to regulation. Neuropathol Appl Neurobiol, 39:19-34. [PMC free article] [PubMed] [Google Scholar]

[67] Erdogan CS, Vang O (2016). Challenges in Analyzing the Biological Effects of Resveratrol. Nutrients, 8. [PMC free article] [PubMed] [Google Scholar]

[68] Hazzard DG (1991). Relevance of the rodent model to human aging studies. Neurobiol Aging, 12:645-649. [PubMed] [Google Scholar]

[69] Baur JA, Pearson KJ, Price NL, Jamieson HA, Lerin C, Kalra A, et al. (2006). Resveratrol improves health and survival of mice on a high-calorie diet. Nature, 444:337-342. [PMC free article] [PubMed] [Google Scholar]

[70] Seok J, Warren HS, Cuenca AG, Mindrinos MN, Baker HV, Xu W, et al. (2013). Genomic responses in mouse models poorly mimic human inflammatory diseases. Proc Natl Acad Sci U S A. [PMC free article] [PubMed] [Google Scholar]

[71] Corrêa RCG, Peralta RM, Haminiuk CWI, Maciel GM, Bracht A, Ferreira I (2018). New phytochemicals as potential human anti-aging compounds: Reality, promise, and challenges. Crit Rev Food Sci Nutr, 58:942-957. [PubMed] [Google Scholar]

[72] Folch J, Busquets O, Ettcheto M, Sanchez-Lopez E, Pallas M, Beas-Zarate C, et al. (2018). Experimental Models for Aging and their Potential for Novel Drug Discovery. Curr Neuropharmacol, 16:1466-1483. [PMC free article] [PubMed] [Google Scholar]

[73] Liu B, Fan Z, Edgerton SM, Yang X, Lind SE, Thor AD (2011). Potent anti-proliferative effects of metformin on trastuzumab-resistant breast cancer cells via inhibition of erbB2/IGF-1 receptor interactions. Cell Cycle, 10:2959-2966. [PubMed] [Google Scholar]

[74] Saewanee N, Praputpittaya T, Malaiwong N, Chalorak P, Meemon K (2019). Neuroprotective effect of metformin on dopaminergic neurodegeneration and alpha-synuclein aggregation in C. elegans model of Parkinson’s disease. Neurosci Res. [PubMed] [Google Scholar]

[75] Anisimov VN (2010). Metformin for aging and cancer prevention. Aging (Albany NY), 2:760-774. [PMC free article] [PubMed] [Google Scholar]

[76] Ruddy RM, Adams KV, Morshead CM (2019). Age- and sex-dependent effects of metformin on neural precursor cells and cognitive recovery in a model of neonatal stroke. Sci Adv, 5: eaax1912. [PMC free article] [PubMed] [Google Scholar]

[77] Anisimov VN, Popovich IG, Zabezhinski MA, Egormin PA, Yurova MN, Semenchenko AV, et al. (2015). Sex differences in aging, life span and spontaneous tumorigenesis in 129/Sv mice neonatally exposed to metformin. Cell Cycle, 14:46-55. [PMC free article] [PubMed] [Google Scholar]

[78] Inyang KE, Szabo-Pardi T, Wentworth E, McDougal TA, Dussor G, Burton MD, et al. (2019). The antidiabetic drug metformin prevents and reverses neuropathic pain and spinal cord microglial activation in male but not female mice. Pharmacol Res, 139:1-16. [PMC free article] [PubMed] [Google Scholar]

[79] Kuan YC, Huang KW, Lin CL, Hu CJ, Kao CH (2017). Effects of metformin exposure on neurodegenerative diseases in elderly patients with type 2 diabetes mellitus. Prog Neuropsychopharmacol Biol Psychiatry, 79:77-83. [PubMed] [Google Scholar]

[80] Chaudhari K, Reynolds CD, Yang SH (2020). Metformin and cognition from the perspectives of sex, age, and disease. Geroscience, 42:97-116. [PMC free article] [PubMed] [Google Scholar]

[81] Katila N, Bhurtel S, Shadfar S, Srivastav S, Neupane S, Ojha U, et al. (2017). Metformin lowers alpha-synuclein phosphorylation and upregulates neurotrophic factor in the MPTP mouse model of Parkinson’s disease. Neuropharmacology, 125:396-407. [PubMed] [Google Scholar]

[82] Ou Z, Kong X, Sun X, He X, Zhang L, Gong Z, et al. (2018). Metformin treatment prevents amyloid plaque deposition and memory impairment in APP/PS1 mice. Brain Behav Immun, 69:351-363. [PubMed] [Google Scholar]

[83] Ahmad W, Ebert PR (2017). Metformin Attenuates Abeta Pathology Mediated Through Levamisole Sensitive Nicotinic Acetylcholine Receptors in a C. elegans Model of Alzheimer’s Disease. Mol Neurobiol, 54:5427-5439. [PubMed] [Google Scholar]

[84] Springer M, Moco S (2019). Resveratrol and Its Human Metabolites-Effects on Metabolic Health and Obesity. Nutrients, 11. [PMC free article] [PubMed] [Google Scholar]

[85] Sarubbo F, Esteban S, Miralles A, Moranta D (2018). Effects of Resveratrol and other Polyphenols on Sirt1: Relevance to Brain Function During Aging. Curr Neuropharmacol, 16:126-136. [PMC free article] [PubMed] [Google Scholar]

[86] Alvira D, Yeste-Velasco M, Folch J, Verdaguer E, Canudas AM, Pallas M, et al. (2007). Comparative analysis of the effects of resveratrol in two apoptotic models: inhibition of complex I and potassium deprivation in cerebellar neurons. Neuroscience, 147:746-756. [PubMed] [Google Scholar]

[87] Ramis MR, Esteban S, Miralles A, Tan DX, Reiter RJ (2015). Caloric restriction, resveratrol and melatonin: Role of SIRT1 and implications for aging and related-diseases. Mech Ageing Dev, 146-148:28-41. [PubMed] [Google Scholar]

[88] Abraham J, Johnson RW (2009). Consuming a diet supplemented with resveratrol reduced infection-related neuroinflammation and deficits in working memory in aged mice. Rejuvenation Res, 12:445-453. [PMC free article] [PubMed] [Google Scholar]

[89] Fu Z, Aucoin D, Ahmed M, Ziliox M, Van Nostrand WE, Smith SO (2014). Capping of abeta42 oligomers by small molecule inhibitors. Biochemistry, 53:7893-7903. [PMC free article] [PubMed] [Google Scholar]

[90] Turner RS, Thomas RG, Craft S, van Dyck CH, Mintzer J, Reynolds BA, et al. (2015). A randomized, double-blind, placebo-controlled trial of resveratrol for Alzheimer disease. Neurology, 85:1383-1391. [PMC free article] [PubMed] [Google Scholar]

[91] Ahmed T, Javed S, Javed S, Tariq A, Samec D, Tejada S, et al. (2017). Resveratrol and Alzheimer’s Disease: Mechanistic Insights. Mol Neurobiol, 54:2622-2635. [PubMed] [Google Scholar]

[92] Ramirez-Garza SL, Laveriano-Santos EP, Marhuenda-Munoz M, Storniolo CE, Tresserra-Rimbau A, Vallverdu-Queralt A, et al. (2018). Health Effects of Resveratrol: Results from Human Intervention Trials. Nutrients, 10. [Google Scholar]

[93] Mattison JA, Colman RJ, Beasley TM, Allison DB, Kemnitz JW, Roth GS, et al. (2017). Caloric restriction improves health and survival of rhesus monkeys. Nat Commun, 8:14063. [PMC free article] [PubMed] [Google Scholar]

[94] Leonov A, Feldman R, Piano A, Arlia-Ciommo A, Lutchman V, Ahmadi M, et al. (2017). Caloric restriction extends yeast chronological lifespan via a mechanism linking cellular aging to cell cycle regulation, maintenance of a quiescent state, entry into a non-quiescent state and survival in the non-quiescent state. Oncotarget, 8:69328-69350. [PMC free article] [PubMed] [Google Scholar]

[95] Wu D, Rea SL, Cypser JR, Johnson TE (2009). Mortality shifts in Caenorhabditis elegans: remembrance of conditions past. Aging Cell, 8:666-675. [PMC free article] [PubMed] [Google Scholar]

[96] Goldberg EL, Romero-Aleshire MJ, Renkema KR, Ventevogel MS, Chew WM, Uhrlaub JL, et al. (2015). Lifespan-extending caloric restriction or mTOR inhibition impair adaptive immunity of old mice by distinct mechanisms. Aging Cell, 14:130-138. [PMC free article] [PubMed] [Google Scholar]

[97] Wood SH, van Dam S, Craig T, Tacutu R, O’Toole A, Merry BJ, et al. (2015). Transcriptome analysis in calorie-restricted rats implicates epigenetic and post-translational mechanisms in neuroprotection and aging. Genome Biol, 16:285. [PMC free article] [PubMed] [Google Scholar]

[98] Colman RJ, Beasley TM, Kemnitz JW, Johnson SC, Weindruch R, Anderson RM (2014). Caloric restriction reduces age-related and all-cause mortality in rhesus monkeys. Nat Commun, 5:3557. [PMC free article] [PubMed] [Google Scholar]

[99] Schafer MJ, Alldred MJ, Lee SH, Calhoun ME, Petkova E, Mathews PM, et al. (2015). Reduction of beta-amyloid and gamma-secretase by calorie restriction in female Tg2576 mice. Neurobiol Aging, 36:1293-1302. [PMC free article] [PubMed] [Google Scholar]

[100] Gonzalez O, Tobia C, Ebersole J, Novak MJ (2012). Caloric restriction and chronic inflammatory diseases. Oral Dis, 18:16-31. [PMC free article] [PubMed] [Google Scholar]

[101] Most J, Tosti V, Redman LM, Fontana L (2017). Calorie restriction in humans: An update. Ageing Res Rev, 39:36-45. [PMC free article] [PubMed] [Google Scholar]

[102] Fontana L, Partridge L, Longo VD (2010). Extending healthy life span–from yeast to humans. Science, 328:321-326. [PMC free article] [PubMed] [Google Scholar]

[103] Golbidi S, Daiber A, Korac B, Li H, Essop MF, Laher I (2017). Health Benefits of Fasting and Caloric Restriction. Curr Diab Rep, 17:123. [PubMed] [Google Scholar]

[104] Van Cauwenberghe C, Vandendriessche C, Libert C, Vandenbroucke RE (2016). Caloric restriction: beneficial effects on brain aging and Alzheimer’s disease. Mamm Genome, 27:300-319. [PubMed] [Google Scholar]

[105] Zhao G, Guo S, Somel M, Khaitovich P (2014). Evolution of human longevity uncoupled from caloric restriction mechanisms. PLoS One, 9:e84117. [PMC free article] [PubMed] [Google Scholar]

[106] Lee SH, Min KJ (2013). Caloric restriction and its mimetics. BMB Rep, 46:181-187. [PMC free article] [PubMed] [Google Scholar]

[107] Bakker BM, Overkamp KM, van Maris AJ, Kotter P, Luttik MA, van Dijken JP, et al. (2001). Stoichiometry and compartmentation of NADH metabolism in Saccharomyces cerevisiae. FEMS Microbiol Rev, 25:15-37. [PubMed] [Google Scholar]

[108] Guarente L (2000). Sir2 links chromatin silencing, metabolism, and aging. Genes Dev, 14:1021-1026. [PubMed] [Google Scholar]

[109] Anderson RM, Latorre-Esteves M, Neves AR, Lavu S, Medvedik O, Taylor C, et al. (2003). Yeast life-span extension by calorie restriction is independent of NAD fluctuation. Science, 302:2124-2126. [PMC free article] [PubMed] [Google Scholar]

[110] Lin SJ, Ford E, Haigis M, Liszt G, Guarente L (2004). Calorie restriction extends yeast life span by lowering the level of NADH. Genes Dev, 18:12-16. [PMC free article] [PubMed] [Google Scholar]

[111] Li J, Zhang CX, Liu YM, Chen KL, Chen G (2017). A comparative study of anti-aging properties and mechanism: resveratrol and caloric restriction. Oncotarget, 8:65717-65729. [PMC free article] [PubMed] [Google Scholar]

[112] Patel NV, Gordon MN, Connor KE, Good RA, Engelman RW, Mason J, et al. (2005). Caloric restriction attenuates Abeta-deposition in Alzheimer transgenic models. Neurobiol Aging, 26:995-1000. [PubMed] [Google Scholar]

[113] Lin AL, Coman D, Jiang L, Rothman DL, Hyder F (2014). Caloric restriction impedes age-related decline of mitochondrial function and neuronal activity. J Cereb Blood Flow Metab, 34:1440-1443. [PMC free article] [PubMed] [Google Scholar]

[114] Guo J, Bakshi V, Lin AL (2015). Early Shifts of Brain Metabolism by Caloric Restriction Preserve White Matter Integrity and Long-Term Memory in Aging Mice. Front Aging Neurosci, 7:213. [PMC free article] [PubMed] [Google Scholar]

[115] Lopez-Lluch G, Hunt N, Jones B, Zhu M, Jamieson H, Hilmer S, et al. (2006). Calorie restriction induces mitochondrial biogenesis and bioenergetic efficiency. Proc Natl Acad Sci U S A, 103:1768-1773. [PMC free article] [PubMed] [Google Scholar]

[116] Yanckello LM, Young LEA, Hoffman JD, Mohney RP, Keaton MA, Abner E, et al. (2019). Caloric Restriction Alters Postprandial Responses of Essential Brain Metabolites in Young Adult Mice. Front Nutr, 6:90. [PMC free article] [PubMed] [Google Scholar]

[117] Moyse E, Arsenault M, Gaudreau P, Ferland G, Ramassamy C (2019). Brain region-specific effects of long-term caloric restriction on redox balance of the aging rat. Mech Ageing Dev, 179:51-59. [PubMed] [Google Scholar]

[118] Yao M, Zhao Z, Wei L, Zhou D, Xue Z, Ge S (2019). HSF1/HSP pathway in the hippocampus is involved in SIRT1-mediated caloric restriction-induced neuroprotection after surgery in aged mice. Exp Gerontol, 119:184-192. [PubMed] [Google Scholar]

[119] Jenwitheesuk A, Park S, Wongchitrat P, Tocharus J, Mukda S, Shimokawa I, et al. (2018). Comparing the Effects of Melatonin with Caloric Restriction in the Hippocampus of Aging Mice: Involvement of Sirtuin1 and the FOXOs Pathway. Neurochem Res, 43:153-161. [PubMed] [Google Scholar]

[120] Ma L, Wang R, Dong W, Zhao Z (2018). Caloric restriction can improve learning and memory in C57/BL mice probably via regulation of the AMPK signaling pathway. Exp Gerontol, 102:28-35. [PubMed] [Google Scholar]

[121] Wahl D, Solon-Biet SM, Wang QP, Wali JA, Pulpitel T, Clark X, et al. (2018). Comparing the Effects of Low-Protein and High-Carbohydrate Diets and Caloric Restriction on Brain Aging in Mice. Cell Rep, 25:2234-2243 e2236. [PMC free article] [PubMed] [Google Scholar]

[122] Rubovitch V, Pharayra A, Har-Even M, Dvir O, Mattson MP, Pick CG (2019). Dietary Energy Restriction Ameliorates Cognitive Impairment in a Mouse Model of Traumatic Brain Injury. J Mol Neurosci, 67:613-621. [PMC free article] [PubMed] [Google Scholar]

[123] Apple DM, Mahesula S, Fonseca RS, Zhu C, Kokovay E (2019). Calorie restriction protects neural stem cells from age-related deficits in the subventricular zone. Aging (Albany NY), 11:115-126. [PMC free article] [PubMed] [Google Scholar]

[124] Zhang J, Zhang W, Gao X, Zhao Y, Chen D, Xu N, et al. (2019). Preconditioning with partial caloric restriction confers long-term protection against grey and white matter injury after transient focal ischemia. J Cereb Blood Flow Metab, 39:1394-1409. [PMC free article] [PubMed] [Google Scholar]

[125] Smiljanic K, Todorovic S, Mladenovic Djordjevic A, Vanmierlo T, Lutjohann D, Ivkovic S, et al. (2018). Limited daily feeding and intermittent feeding have different effects on regional brain energy homeostasis during aging. Biogerontology, 19:121-132. [PubMed] [Google Scholar]

[126] Yanar K, Simsek B, Cayli N, Ovul Bozkir H, Mengi M, Belce A, et al. (2019). Caloric restriction and redox homeostasis in various regions of aging male rat brain: Is caloric restriction still worth trying even after early-adulthood?: Redox homeostasis and caloric restriction in brain. J Food Biochem, 43:e12740. [PubMed] [Google Scholar]

[127] Rojic-Becker D, Portero-Tresserra M, Marti-Nicolovius M, Vale-Martinez A, Guillazo-Blanch G (2019). Caloric restriction modulates the monoaminergic and glutamatergic systems in the hippocampus, and attenuates age-dependent spatial memory decline. Neurobiol Learn Mem, 166:107107. [PubMed] [Google Scholar]

[128] Huang YJ, Zhang L, Shi LY, Wang YY, Yang YB, Ke B, et al. (2018). Caloric restriction ameliorates acrolein-induced neurotoxicity in rats. Neurotoxicology, 65:44-51. [PubMed] [Google Scholar]

[129] Leclerc E, Trevizol AP, Grigolon RB, Subramaniapillai M, McIntyre RS, Brietzke E, et al. (2020). The effect of caloric restriction on working memory in healthy non-obese adults. CNS Spectr, 25:2-8. [PubMed] [Google Scholar]

[130] Solianik R, Sujeta A, Cekanauskaite A (2018). Effects of 2-day calorie restriction on cardiovascular autonomic response, mood, and cognitive and motor functions in obese young adult women. Exp Brain Res, 236:2299-2308. [PubMed] [Google Scholar]

[131] Martin CK, Bhapkar M, Pittas AG, Pieper CF, Das SK, Williamson DA, et al. (2016). Effect of Calorie Restriction on Mood, Quality of Life, Sleep, and Sexual Function in Healthy Nonobese Adults: The CALERIE 2 Randomized Clinical Trial. JAMA Intern Med, 176:743-752. [PMC free article] [PubMed] [Google Scholar]

[132] Schubel R, Nattenmuller J, Sookthai D, Nonnenmacher T, Graf ME, Riedl L, et al. (2018). Effects of intermittent and continuous calorie restriction on body weight and metabolism over 50 wk: a randomized controlled trial. Am J Clin Nutr, 108:933-945. [PMC free article] [PubMed] [Google Scholar]

[133] Witte AV, Fobker M, Gellner R, Knecht S, Floel A (2009). Caloric restriction improves memory in elderly humans. Proc Natl Acad Sci U S A, 106:1255-1260. [PMC free article] [PubMed] [Google Scholar]

[134] Murphy T, Dias GP, Thuret S (2014). Effects of diet on brain plasticity in animal and human studies: mind the gap. Neural Plast, 2014:563160. [PMC free article] [PubMed] [Google Scholar]

[135] Prehn K, Jumpertz von Schwartzenberg R, Mai K, Zeitz U, Witte AV, Hampel D, et al. (2017). Caloric Restriction in Older Adults-Differential Effects of Weight Loss and Reduced Weight on Brain Structure and Function. Cereb Cortex, 27:1765-1778. [PubMed] [Google Scholar]

[136] Witte AV, Kerti L, Margulies DS, Floel A (2014). Effects of resveratrol on memory performance, hippocampal functional connectivity, and glucose metabolism in healthy older adults. J Neurosci, 34:7862-7870. [PMC free article] [PubMed] [Google Scholar]

[137] Appelhans BM, French SA, Pagoto SL, Sherwood NE (2016). Managing temptation in obesity treatment: A neurobehavioral model of intervention strategies. Appetite, 96:268-279. [PMC free article] [PubMed] [Google Scholar]

[138] Bellush LL, Wright AM, Walker JP, Kopchick J, Colvin RA (1996). Caloric restriction and spatial learning in old mice. Physiol Behav, 60:541-547. [PubMed] [Google Scholar]

[139] Yanai S, Okaichi Y, Okaichi H (2004). Long-term dietary restriction causes negative effects on cognitive functions in rats. Neurobiol Aging, 25:325-332. [PubMed] [Google Scholar]

[140] Wysokinski A, Sobow T, Kloszewska I, Kostka T (2015). Mechanisms of the anorexia of aging-a review. Age (Dordr), 37:9821. [PMC free article] [PubMed] [Google Scholar]

[141] Ravussin E, Redman LM, Rochon J, Das SK, Fontana L, Kraus WE, et al. (2015). A 2-Year Randomized Controlled Trial of Human Caloric Restriction: Feasibility and Effects on Predictors of Health Span and Longevity. J Gerontol A Biol Sci Med Sci, 70:1097-1104. [PMC free article] [PubMed] [Google Scholar]

[142] Rusek M, Pluta R, Ulamek-Koziol M, Czuczwar SJ (2019). Ketogenic Diet in Alzheimer’s Disease. Int J Mol Sci, 20. [Google Scholar]

[143] Newman JC, Covarrubias AJ, Zhao M, Yu X, Gut P, Ng CP, et al. (2017). Ketogenic Diet Reduces Midlife Mortality and Improves Memory in Aging Mice. Cell Metab, 26:547-557 e548. [PMC free article] [PubMed] [Google Scholar]

[144] Hernandez AR, Hernandez CM, Campos K, Truckenbrod L, Federico Q, Moon B, et al. (2018). A Ketogenic Diet Improves Cognition and Has Biochemical Effects in Prefrontal Cortex That Are Dissociable From Hippocampus. Front Aging Neurosci, 10:391. [PMC free article] [PubMed] [Google Scholar]

[145] Mujica-Parodi LR, Amgalan A, Sultan SF, Antal B, Sun X, Skiena S, et al. (2020). Diet modulates brain network stability, a biomarker for brain aging, in young adults. Proc Natl Acad Sci U S A, 117:6170-6177. [PMC free article] [PubMed] [Google Scholar]

[146] Morrison SA, Fazeli PL, Gower B, Willig AL, Younger J, Sneed NM, et al. (2019). Cognitive Effects of a Ketogenic Diet on Neurocognitive Impairment in Adults Aging With HIV: A Pilot Study. [J] Assoc Nurses AIDS Care. [PMC free article] [PubMed] [Google Scholar]

[147] Hasan-Olive MM, Lauritzen KH, Ali M, Rasmussen LJ, Storm-Mathisen J, Bergersen LH (2019). A Ketogenic Diet Improves Mitochondrial Biogenesis and Bioenergetics via the PGC1alpha-SIRT3-UCP2 Axis. Neurochem Res, 44:22-37. [PubMed] [Google Scholar]

[148] Ma D, Wang AC, Parikh I, Green SJ, Hoffman JD, Chlipala G, et al. (2018). Ketogenic diet enhances neurovascular function with altered gut microbiome in young healthy mice. Sci Rep, 8:6670. [PMC free article] [PubMed] [Google Scholar]

[149] Elamin M, Ruskin DN, Masino SA, Sacchetti P (2018). Ketogenic Diet Modulates NAD(+)-Dependent Enzymes and Reduces DNA Damage in Hippocampus. Front Cell Neurosci, 12:263. [PMC free article] [PubMed] [Google Scholar]

[150] Gyorkos A, Baker MH, Miutz LN, Lown DA, Jones MA, Houghton-Rahrig LD (2019). Carbohydrate-restricted Diet and Exercise Increase Brain-derived Neurotrophic Factor and Cognitive Function: A Randomized Crossover Trial. Cureus, 11:e5604. [PMC free article] [PubMed] [Google Scholar]

[151] Brown D, Gibas KJ (2018). Metabolic syndrome marks early risk for cognitive decline with APOE4 gene variation: A case study. Diabetes Metab Syndr, 12:823-827. [PubMed] [Google Scholar]

[152] Dahlgren K, Gibas KJ (2018). Ketogenic diet, high intensity interval training (HIIT) and memory training in the treatment of mild cognitive impairment: A case study. Diabetes Metab Syndr, 12:819-822. [PubMed] [Google Scholar]

[153] Stoykovich S, Gibas K (2019). APOE epsilon4, the door to insulin-resistant dyslipidemia and brain fog? A case study. Alzheimers Dement (Amst), 11:264-269. [PMC free article] [PubMed] [Google Scholar]

[154] Morrison SA, Fazeli PL, Gower B, Younger J, Willig A, Sneed NM, et al. (2018). The ketogenic diet as a non-pharmacological treatment for HIV-associated neurocognitive disorder: A descriptive analysis. J Psychiatry Behav Sci, 3. [PMC free article] [PubMed] [Google Scholar]

[155] Morrill SJ, Gibas KJ (2019). Ketogenic diet rescues cognition in ApoE4+ patient with mild Alzheimer’s disease: A case study. Diabetes Metab Syndr, 13:1187-1191. [PubMed] [Google Scholar]

[156] Newman JC, Verdin E (2014). Ketone bodies as signaling metabolites. Trends Endocrinol Metab, 25:42-52. [PMC free article] [PubMed] [Google Scholar]

[157] Masood W, Annamaraju P, Uppaluri KR 2020. Ketogenic Diet. StatPearls Publishing, Treasure Island (FL). [Google Scholar]

[158] Dashti HM, Mathew TC, Hussein T, Asfar SK, Behbahani A, Khoursheed MA, et al. (2004). Long-term effects of a ketogenic diet in obese patients. Exp Clin Cardiol, 9:200-205. [PMC free article] [PubMed] [Google Scholar]

[159] Phillips MCL, Murtagh DKJ, Gilbertson LJ, Asztely FJS, Lynch CDP (2018). Low-fat versus ketogenic diet in Parkinson’s disease: A pilot randomized controlled trial. Mov Disord, 33:1306-1314. [PMC free article] [PubMed] [Google Scholar]

[160] Lautrup S, Sinclair DA, Mattson MP, Fang EF (2019). NAD(+) in Brain Aging and Neurodegenerative Disorders. Cell Metab, 30:630-655. [PMC free article] [PubMed] [Google Scholar]

[161] Xie X, Gao Y, Zeng M, Wang Y, Wei TF, Lu YB, et al. (2019). Nicotinamide ribose ameliorates cognitive impairment of aged and Alzheimer’s disease model mice. Metab Brain Dis, 34:353-366. [PubMed] [Google Scholar]

[162] Mitchell SJ, Madrigal-Matute J, Scheibye-Knudsen M, Fang E, Aon M, Gonzalez-Reyes JA, et al. (2016). Effects of Sex, Strain, and Energy Intake on Hallmarks of Aging in Mice. Cell Metab, 23:1093-1112. [PMC free article] [PubMed] [Google Scholar]

[163] Grant RS, Passey R, Matanovic G, Smythe G, Kapoor V (1999). Evidence for increased de novo synthesis of NAD in immune-activated RAW264.7 macrophages: a self-protective mechanism? Arch Biochem Biophys, 372:1-7. [PubMed] [Google Scholar]

[164] Rahman A, Ting K, Cullen KM, Braidy N, Brew BJ, Guillemin GJ (2009). The excitotoxin quinolinic acid induces tau phosphorylation in human neurons. PLoS One, 4:e6344. [PMC free article] [PubMed] [Google Scholar]

[165] Braidy N, Berg J, Clement J, Khorshidi F, Poljak A, Jayasena T, et al. (2019). Role of Nicotinamide Adenine Dinucleotide and Related Precursors as Therapeutic Targets for Age-Related Degenerative Diseases: Rationale, Biochemistry, Pharmacokinetics, and Outcomes. Antioxid Redox Signal, 30:251-294. [PMC free article] [PubMed] [Google Scholar]

[166] Grant R, Berg J, Mestayer R, Braidy N, Bennett J, Broom S, et al. (2019). A Pilot Study Investigating Changes in the Human Plasma and Urine NAD+ Metabolome During a 6 Hour Intravenous Infusion of NAD. Front Aging Neurosci, 11:257. [PMC free article] [PubMed] [Google Scholar]

[167] Bogan KL, Brenner C (2008). Nicotinic acid, nicotinamide, and nicotinamide riboside: a molecular evaluation of NAD+ precursor vitamins in human nutrition. Annu Rev Nutr, 28:115-130. [PubMed] [Google Scholar]

[168] Hosseini L, Farokhi-Sisakht F, Badalzadeh R, Khabbaz A, Mahmoudi J, Sadigh-Eteghad S (2019). Nicotinamide Mononucleotide and Melatonin Alleviate Aging-induced Cognitive Impairment via Modulation of Mitochondrial Function and Apoptosis in the Prefrontal Cortex and Hippocampus. Neuroscience, 423:29-37. [PubMed] [Google Scholar]

[169] Johnson S, Wozniak DF, Imai S (2018). CA1 Nampt knockdown recapitulates hippocampal cognitive phenotypes in old mice which nicotinamide mononucleotide improves. NPJ Aging Mech Dis, 4:10. [PMC free article] [PubMed] [Google Scholar]

[170] Kiss T, Balasubramanian P, Valcarcel-Ares MN, Tarantini S, Yabluchanskiy A, Csipo T, et al. (2019). Nicotinamide mononucleotide (NMN) treatment attenuates oxidative stress and rescues angiogenic capacity in aged cerebromicrovascular endothelial cells: a potential mechanism for the prevention of vascular cognitive impairment. Geroscience, 41:619-630. [PMC free article] [PubMed] [Google Scholar]

[171] Tarantini S, Valcarcel-Ares MN, Toth P, Yabluchanskiy A, Tucsek Z, Kiss T, et al. (2019). Nicotinamide mononucleotide (NMN) supplementation rescues cerebromicrovascular endothelial function and neurovascular coupling responses and improves cognitive function in aged mice. Redox Biol, 24:101192. [PMC free article] [PubMed] [Google Scholar]

[172] Wang X, Hu X, Yang Y, Takata T, Sakurai T (2016). Nicotinamide mononucleotide protects against beta-amyloid oligomer-induced cognitive impairment and neuronal death. Brain Res, 1643:1-9. [PubMed] [Google Scholar]

[173] Wang X, Hu X, Zhang L, Xu X, Sakurai T (2020). Nicotinamide mononucleotide administration after sever hypoglycemia improves neuronal survival and cognitive function in rats. Brain Res Bull, 160:98-106. [PubMed] [Google Scholar]

[174] Yoshino J, Mills KF, Yoon MJ, Imai S (2011). Nicotinamide mononucleotide, a key NAD(+) intermediate, treats the pathophysiology of diet- and age-induced diabetes in mice. Cell Metab, 14:528-536. [PMC free article] [PubMed] [Google Scholar]

[175] Grozio A, Mills KF, Yoshino J, Bruzzone S, Sociali G, Tokizane K, et al. (2019). Slc12a8 is a nicotinamide mononucleotide transporter. Nat Metab, 1:47-57. [PMC free article] [PubMed] [Google Scholar]

[176] Schmidt MS, Brenner C (2019). Absence of evidence that Slc12a8 encodes a nicoinamide mononucleotide transporter. Nat Metab, 1:660-661. [PubMed] [Google Scholar]

[177] Di Stefano M, Nascimento-Ferreira I, Orsomando G, Mori V, Gilley J, Brown R, et al. (2015). A rise in NAD precursor nicotinamide mononucleotide (NMN) after injury promotes axon degeneration. Cell Death Differ, 22:731-742. [PMC free article] [PubMed] [Google Scholar]

[178] Braidy N, Liu Y (2020). NAD+ therapy in age-related degenerative disorders: A benefit/risk analysis. Exp Gerontol, 132:110831. [PubMed] [Google Scholar]

[179] Johnson S, Imai SI (2018). NAD (+) biosynthesis, aging, and disease. F1000Res, 7:132. [PMC free article] [PubMed] [Google Scholar]

[180] Gong B, Pan Y, Vempati P, Zhao W, Knable L, Ho L, et al. (2013). Nicotinamide riboside restores cognition through an upregulation of proliferator-activated receptor-gamma coactivator 1alpha regulated beta-secretase 1 degradation and mitochondrial gene expression in Alzheimer’s mouse models. Neurobiol Aging, 34:1581-1588. [PMC free article] [PubMed] [Google Scholar]

[181] Belenky P, Racette FG, Bogan KL, McClure JM, Smith JS, Brenner C (2007). Nicotinamide riboside promotes Sir2 silencing and extends lifespan via Nrk and Urh1/Pnp1/Meu1 pathways to NAD+. Cell, 129:473-484. [PubMed] [Google Scholar]

[182] Lloret A, Beal MF (2019). PGC-1alpha, Sirtuins and PARPs in Huntington’s Disease and Other Neurodegenerative Conditions: NAD+ to Rule Them All. Neurochem Res, 44:2423-2434. [PubMed] [Google Scholar]

[183] Lee HJ, Yang SJ (2019). Supplementation with Nicotinamide Riboside Reduces Brain Inflammation and Improves Cognitive Function in Diabetic Mice. Int J Mol Sci, 20. [PMC free article] [PubMed] [Google Scholar]

[184] Lamtai M, Chaibat J, Ouakki S, Zghari O, Mesfioui A, El Hessni A, et al. (2018). Effect of Chronic Administration of Nickel on Affective and Cognitive Behavior in Male and Female Rats: Possible Implication of Oxidative Stress Pathway. Brain Sci, 8. [PMC free article] [PubMed] [Google Scholar]

[185] Qin W, Yang T, Ho L, Zhao Z, Wang J, Chen L, et al. (2006). Neuronal SIRT1 activation as a novel mechanism underlying the prevention of Alzheimer disease amyloid neuropathology by calorie restriction. J Biol Chem, 281:21745-21754. [PubMed] [Google Scholar]

[186] Nemoto S, Fergusson MM, Finkel T (2005). SIRT1 functionally interacts with the metabolic regulator and transcriptional coactivator PGC-1{alpha}. J Biol Chem, 280:16456-16460. [PubMed] [Google Scholar]

[187] Li CC, Chen WX, Wang J, Xia M, Jia ZC, Guo C, et al. (2020). Nicotinamide riboside rescues angiotensin II-induced cerebral small vessel disease in mice. CNS Neurosci Ther, 26:438-447. [PMC free article] [PubMed] [Google Scholar]

[188] Trammell SA, Weidemann BJ, Chadda A, Yorek MS, Holmes A, Coppey LJ, et al. (2016). Nicotinamide Riboside Opposes Type 2 Diabetes and Neuropathy in Mice. Sci Rep, 6:26933. [PMC free article] [PubMed] [Google Scholar]

[189] Vaur P, Brugg B, Mericskay M, Li Z, Schmidt MS, Vivien D, et al. (2017). Nicotinamide riboside, a form of vitamin B3, protects against excitotoxicity-induced axonal degeneration. FASEB J, 31:5440-5452. [PubMed] [Google Scholar]

[190] Joshi U, Evans JE, Pearson A, Saltiel N, Cseresznye A, Darcey T, et al. (2020). Targeting sirtuin activity with nicotinamide riboside reduces neuroinflammation in a GWI mouse model. Neurotoxicology, 79:84-94. [PubMed] [Google Scholar]

[191] Fragola G, Mabb AM, Taylor-Blake B, Niehaus JK, Chronister WD, Mao H, et al. (2020). Deletion of Topoisomerase 1 in excitatory neurons causes genomic instability and early onset neurodegeneration. Nat Commun, 11:1962. [PMC free article] [PubMed] [Google Scholar]

[192] Jiang Y, Liu Y, Gao M, Xue M, Wang Z, Liang H (2020). Nicotinamide riboside alleviates alcohol-induced depression-like behaviours in C57BL/6J mice by altering the intestinal microbiota associated with microglial activation and BDNF expression. Food Funct, 11:378-391. [PubMed] [Google Scholar]

[193] Liu D, Pitta M, Jiang H, Lee JH, Zhang G, Chen X, et al. (2013). Nicotinamide forestalls pathology and cognitive decline in Alzheimer mice: evidence for improved neuronal bioenergetics and autophagy procession. Neurobiol Aging, 34:1564-1580. [PMC free article] [PubMed] [Google Scholar]

[194] Wang Y, Zuo M (2015). Nicotinamide improves sevoflurane-induced cognitive impairment through suppression of inflammation and anti-apoptosis in rat. Int J Clin Exp Med, 8:20079-20085. [PMC free article] [PubMed] [Google Scholar]

[195] Conze D, Brenner C, Kruger CL (2019). Safety and Metabolism of Long-term Administration of NIAGEN (Nicotinamide Riboside Chloride) in a Randomized, Double-Blind, Placebo-controlled Clinical Trial of Healthy Overweight Adults. Sci Rep, 9:9772. [PMC free article] [PubMed] [Google Scholar]

[196] Li Y, Tian Q, Li Z, Dang M, Lin Y, Hou X (2019). Activation of Nrf2 signaling by sitagliptin and quercetin combination against beta-amyloid induced Alzheimer’s disease in rats. Drug Dev Res, 80:837-845. [PubMed] [Google Scholar]

[197] Zhang P, Kishimoto Y, Grammatikakis I, Gottimukkala K, Cutler RG, Zhang S, et al. (2019). Senolytic therapy alleviates Abeta-associated oligodendrocyte progenitor cell senescence and cognitive deficits in an Alzheimer’s disease model. Nat Neurosci, 22:719-728. [PMC free article] [PubMed] [Google Scholar]

[198] Musi N, Valentine JM, Sickora KR, Baeuerle E, Thompson CS, Shen Q, et al. (2018). Tau protein aggregation is associated with cellular senescence in the brain. Aging Cell, 17:e12840. [PMC free article] [PubMed] [Google Scholar]

[199] Bussian TJ, Aziz A, Meyer CF, Swenson BL, van Deursen JM, Baker DJ (2018). Clearance of senescent glial cells prevents tau-dependent pathology and cognitive decline. Nature, 562:578-582. [PMC free article] [PubMed] [Google Scholar]

[200] Yabluchanskiy A, Tarantini S, Balasubramanian P, Kiss T, Csipo T, Fulop GA, et al. (2020). Pharmacological or genetic depletion of senescent astrocytes prevents whole brain irradiation-induced impairment of neurovascular coupling responses protecting cognitive function in mice. Geroscience, 42:409-428. [PMC free article] [PubMed] [Google Scholar]

[201] Raj L, Ide T, Gurkar AU, Foley M, Schenone M, Li X, et al. (2011). Selective killing of cancer cells by a small molecule targeting the stress response to ROS. Nature, 475:231-234. [PMC free article] [PubMed] [Google Scholar] Retracted

[202] Han JG, Gupta SC, Prasad S, Aggarwal BB (2014). Piperlongumine chemosensitizes tumor cells through interaction with cysteine 179 of IkappaBalpha kinase, leading to suppression of NF-kappaB-regulated gene products. Mol Cancer Ther, 13:2422-2435. [PubMed] [Google Scholar]

[203] Go J, Ha TKQ, Seo JY, Park TS, Ryu YK, Park HY, et al. (2018). Piperlongumine activates Sirtuin1 and improves cognitive function in a murine model of Alzheimer’s disease. Journal of Functional Foods, 43:103-111. [Google Scholar]

[204] Go J, Park TS, Han GH, Park HY, Ryu YK, Kim YH, et al. (2018). Piperlongumine decreases cognitive impairment and improves hippocampal function in aged mice. Int J Mol Med, 42:1875-1884. [PMC free article] [PubMed] [Google Scholar]

[205] Maher P, Akaishi T, Abe K (2006). Flavonoid fisetin promotes ERK-dependent long-term potentiation and enhances memory. Proc Natl Acad Sci U S A, 103:16568-16573. [PMC free article] [PubMed] [Google Scholar]

[206] Prakash D, Sudhandiran G (2015). Dietary flavonoid fisetin regulates aluminium chloride-induced neuronal apoptosis in cortex and hippocampus of mice brain. J Nutr Biochem, 26:1527-1539. [PubMed] [Google Scholar]

[207] Prakash D, Gopinath K, Sudhandiran G (2013). Fisetin enhances behavioral performances and attenuates reactive gliosis and inflammation during aluminum chloride-induced neurotoxicity. Neuromolecular Med, 15:192-208. [PubMed] [Google Scholar]

[208] Currais A, Farrokhi C, Dargusch R, Armando A, Quehenberger O, Schubert D, et al. (2018). Fisetin Reduces the Impact of Aging on Behavior and Physiology in the Rapidly Aging SAMP8 Mouse. J Gerontol A Biol Sci Med Sci, 73:299-307. [PMC free article] [PubMed] [Google Scholar]

[209] Alikatte K, Palle S, Rajendra Kumar J, Pathakala N (2020). Fisetin Improved Rotenone-Induced Behavioral Deficits, Oxidative Changes, and Mitochondrial Dysfunctions in Rat Model of Parkinson’s Disease. J Diet Suppl:1-15. [PubMed] [Google Scholar]

[210] Currais A, Prior M, Dargusch R, Armando A, Ehren J, Schubert D, et al. (2014). Modulation of p25 and inflammatory pathways by fisetin maintains cognitive function in Alzheimer’s disease transgenic mice. Aging Cell, 13:379-390. [PMC free article] [PubMed] [Google Scholar]

[211] Ahmad A, Ali T, Park HY, Badshah H, Rehman SU, Kim MO (2017). Neuroprotective Effect of Fisetin Against Amyloid-Beta-Induced Cognitive/Synaptic Dysfunction, Neuroinflammation, and Neurodegeneration in Adult Mice. Mol Neurobiol, 54:2269-2285. [PubMed] [Google Scholar]

[212] Chang J, Wang Y, Shao L, Laberge RM, Demaria M, Campisi J, et al. (2016). Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice. Nat Med, 22:78-83. [PMC free article] [PubMed] [Google Scholar]

[213] Liu J, Liu W, Lu Y, Tian H, Duan C, Lu L, et al. (2018). Piperlongumine restores the balance of autophagy and apoptosis by increasing BCL2 phosphorylation in rotenone-induced Parkinson disease models. Autophagy, 14:845-861. [PMC free article] [PubMed] [Google Scholar]

[214] Zhu Y, Tchkonia T, Fuhrmann-Stroissnigg H, Dai HM, Ling YY, Stout MB, et al. (2016). Identification of a novel senolytic agent, navitoclax, targeting the Bcl-2 family of anti-apoptotic factors. Aging Cell, 15:428-435. [PMC free article] [PubMed] [Google Scholar]

[215] Kim S, Choi KJ, Cho SJ, Yun SM, Jeon JP, Koh YH, et al. (2016). Fisetin stimulates autophagic degradation of phosphorylated tau via the activation of TFEB and Nrf2 transcription factors. Sci Rep, 6:24933. [PMC free article] [PubMed] [Google Scholar]

[216] Xu M, Pirtskhalava T, Farr JN, Weigand BM, Palmer AK, Weivoda MM, et al. (2018). Senolytics improve physical function and increase lifespan in old age. Nat Med, 24:1246-1256. [PMC free article] [PubMed] [Google Scholar]

[217] Munoz-Espin D, Serrano M (2014). Cellular senescence: from physiology to pathology. Nat Rev Mol Cell Biol, 15:482-496. [PubMed] [Google Scholar]

[218] Rudin CM, Hann CL, Garon EB, Ribeiro de Oliveira M, Bonomi PD, Camidge DR, et al. (2012). Phase II study of single-agent navitoclax (ABT-263) and biomarker correlates in patients with relapsed small cell lung cancer. Clin Cancer Res, 18:3163-3169. [PMC free article] [PubMed] [Google Scholar]

[219] Munoz-Espin D, Rovira M, Galiana I, Gimenez C, Lozano-Torres B, Paez-Ribes M, et al. (2018). A versatile drug delivery system targeting senescent cells. EMBO Mol Med, 10. [Google Scholar]

[220] Zhu Y, Doornebal EJ, Pirtskhalava T, Giorgadze N, Wentworth M, Fuhrmann-Stroissnigg H, et al. (2017). New agents that target senescent cells: the flavone, fisetin, and the BCL-X(L) inhibitors, A1331852 and A1155463. Aging (Albany NY), 9:955-963. [PMC free article] [PubMed] [Google Scholar]

[221] Hickson LJ, Langhi Prata LGP, Bobart SA, Evans TK, Giorgadze N, Hashmi SK, et al. (2019). Senolytics decrease senescent cells in humans: Preliminary report from a clinical trial of Dasatinib plus Quercetin in individuals with diabetic kidney disease. EBioMedicine, 47:446-456. [PMC free article] [PubMed] [Google Scholar]

[222] Learoyd P (2012). The history of blood transfusion prior to the 20th century–part 1. Transfus Med, 22:308-314. [PubMed] [Google Scholar]

[223] Conboy IM, Conboy MJ, Wagers AJ, Girma ER, Weissman IL, Rando TA (2005). Rejuvenation of aged progenitor cells by exposure to a young systemic environment. Nature, 433:760-764. [PubMed] [Google Scholar]

[224] Prattichizzo F, Giuliani A, Sabbatinelli J, Mensa E, De Nigris V, La Sala L, et al. (2019). Extracellular vesicles circulating in young organisms promote healthy longevity. J Extracell Vesicles, 8:1656044. [PMC free article] [PubMed] [Google Scholar]

[225] Conese M, Carbone A, Beccia E, Angiolillo A (2017). The Fountain of Youth: A Tale of Parabiosis, Stem Cells, and Rejuvenation. Open Med (Wars), 12:376-383. [PMC free article] [PubMed] [Google Scholar]

[226] Villeda SA, Plambeck KE, Middeldorp J, Castellano JM, Mosher KI, Luo J, et al. (2014). Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice. Nat Med, 20:659-663. [PMC free article] [PubMed] [Google Scholar]

[227] Ma J, Gao B, Zhang K, Zhang Q, Jia G, Li J, et al. (2019). Circulating factors in young blood as potential therapeutic agents for age-related neurodegenerative and neurovascular diseases. Brain Res Bull, 153:15-23. [PubMed] [Google Scholar]

[228] Rebo J, Mehdipour M, Gathwala R, Causey K, Liu Y, Conboy MJ, et al. (2016). A single heterochronic blood exchange reveals rapid inhibition of multiple tissues by old blood. Nat Commun, 7:13363. [PMC free article] [PubMed] [Google Scholar]

[229] Villeda SA, Luo J, Mosher KI, Zou B, Britschgi M, Bieri G, et al. (2011). The ageing systemic milieu negatively regulates neurogenesis and cognitive function. Nature, 477:90-94. [PMC free article] [PubMed] [Google Scholar]

[230] Middeldorp J, Lehallier B, Villeda SA, Miedema SS, Evans E, Czirr E, et al. (2016). Preclinical Assessment of Young Blood Plasma for Alzheimer Disease. JAMA Neurol, 73:1325-1333. [PMC free article] [PubMed] [Google Scholar]

[231] Gan KJ, Sudhof TC (2019). Specific factors in blood from young but not old mice directly promote synapse formation and NMDA-receptor recruitment. Proc Natl Acad Sci U S A, 116:12524-12533. [PMC free article] [PubMed] [Google Scholar]

[232] Castellano JM, Mosher KI, Abbey RJ, McBride AA, James ML, Berdnik D, et al. (2017). Human umbilical cord plasma proteins revitalize hippocampal function in aged mice. Nature, 544:488-492. [PMC free article] [PubMed] [Google Scholar]

[233] Bueno JL, Ynigo M, de Miguel C, Gonzalo-Daganzo RM, Richart A, Vilches C, et al. (2016). Growth differentiation factor 11 (GDF11) – a promising anti-ageing factor – is highly concentrated in platelets. Vox Sang, 111:434-436. [PubMed] [Google Scholar]

[234] Ma J, Zhang L, He G, Tan X, Jin X, Li C (2016). Transcutaneous auricular vagus nerve stimulation regulates expression of growth differentiation factor 11 and activin-like kinase 5 in cerebral ischemia/reperfusion rats. J Neurol Sci, 369:27-35. [PubMed] [Google Scholar]

[235] Hayashi Y, Mikawa S, Masumoto K, Katou F, Sato K (2018). GDF11 expression in the adult rat central nervous system. J Chem Neuroanat, 89:21-36. [PubMed] [Google Scholar]

[236] Katsimpardi L, Litterman NK, Schein PA, Miller CM, Loffredo FS, Wojtkiewicz GR, et al. (2014). Vascular and neurogenic rejuvenation of the aging mouse brain by young systemic factors. Science, 344:630-634. [PMC free article] [PubMed] [Google Scholar]

[237] Zhang M, Jadavji NM, Yoo HS, Smith PD (2018). Recombinant growth differentiation factor 11 influences short-term memory and enhances Sox2 expression in middle-aged mice. Behav Brain Res, 341:45-49. [PubMed] [Google Scholar]

[238] Hoefer J, Luger M, Dal-Pont C, Culig Z, Schennach H, Jochberger S (2017). The “Aging Factor” Eotaxin-1 (CCL11) Is Detectable in Transfusion Blood Products and Increases with the Donor’s Age. Front Aging Neurosci, 9:402. [PMC free article] [PubMed] [Google Scholar]

[239] Huber AK, Giles DA, Segal BM, Irani DN (2018). An emerging role for eotaxins in neurodegenerative disease. Clin Immunol, 189:29-33. [PubMed] [Google Scholar]

[240] Choi C, Jeong JH, Jang JS, Choi K, Lee J, Kwon J, et al. (2008). Multiplex analysis of cytokines in the serum and cerebrospinal fluid of patients with Alzheimer’s disease by color-coded bead technology. J Clin Neurol, 4:84-88. [PMC free article] [PubMed] [Google Scholar]

[241] Basu D, Kulkarni R (2014). Overview of blood components and their preparation. Indian J Anaesth, 58:529-537. [PMC free article] [PubMed] [Google Scholar]

[242] Khoury R, Ghossoub E (2018). Young blood products: emerging treatment for Alzheimer’s disease? Neural Regen Res, 13:624-627. [PMC free article] [PubMed] [Google Scholar]

[243] Aicardi G (2018). Young Blood Plasma Administration to Fight Alzheimer’s Disease? Rejuvenation Res, 21:178-181. [PubMed] [Google Scholar]

[244] Sha SJ, Deutsch GK, Tian L, Richardson K, Coburn M, Gaudioso JL, et al. (2019). Safety, Tolerability, and Feasibility of Young Plasma Infusion in the Plasma for Alzheimer Symptom Amelioration Study: A Randomized Clinical Trial. JAMA Neurol, 76:35-40. [PMC free article] [PubMed] [Google Scholar]

[245] Pandika M (2019). Looking to Young Blood to Treat the Diseases of Aging. ACS Cent Sci, 5:1481-1484. [PMC free article] [PubMed] [Google Scholar]

[246] Sarubbo F, Moranta D, Pani G (2018). Dietary polyphenols and neurogenesis: Molecular interactions and implication for brain ageing and cognition. Neurosci Biobehav Rev, 90:456-470. [PubMed] [Google Scholar]

[247] Kase Y, Otsu K, Shimazaki T, Okano H (2019). Involvement of p38 in Age-Related Decline in Adult Neurogenesis via Modulation of Wnt Signaling. Stem Cell Reports, 12:1313-1328. [PMC free article] [PubMed] [Google Scholar]

[248] Capilla-Gonzalez V, Herranz-Perez V, Garcia-Verdugo JM (2015). The aged brain: genesis and fate of residual progenitor cells in the subventricular zone. Front Cell Neurosci, 9:365. [PMC free article] [PubMed] [Google Scholar]

[249] Encinas JM, Michurina TV, Peunova N, Park JH, Tordo J, Peterson DA, et al. (2011). Division-coupled astrocytic differentiation and age-related depletion of neural stem cells in the adult hippocampus. Cell Stem Cell, 8:566-579. [PMC free article] [PubMed] [Google Scholar]

[250] Toda T, Gage FH (2018). Review: adult neurogenesis contributes to hippocampal plasticity. Cell Tissue Res, 373:693-709. [PubMed] [Google Scholar]

[251] Gage FH (2000). Mammalian neural stem cells. Science, 287:1433-1438. [PubMed] [Google Scholar]

[252] Apple DM, Solano-Fonseca R, Kokovay E (2017). Neurogenesis in the aging brain. Biochem Pharmacol, 141:77-85. [PubMed] [Google Scholar]

[253] Kron MM, Zhang H, Parent JM (2010). The developmental stage of dentate granule cells dictates their contribution to seizure-induced plasticity. J Neurosci, 30:2051-2059. [PMC free article] [PubMed] [Google Scholar]

[254] Jessberger S, Nakashima K, Clemenson GD Jr, Mejia E, Mathews E, Ure K, et al. (2007). Epigenetic modulation of seizure-induced neurogenesis and cognitive decline. J Neurosci, 27:5967-5975. [PMC free article] [PubMed] [Google Scholar]

[255] Winner B, Kohl Z, Gage FH (2011). Neurodegenerative disease and adult neurogenesis. Eur J Neurosci, 33:1139-1151. [PubMed] [Google Scholar]

[256] Eriksson PS, Perfilieva E, Bjork-Eriksson T, Alborn AM, Nordborg C, Peterson DA, et al. (1998). Neurogenesis in the adult human hippocampus. Nat Med, 4:1313-1317. [PubMed] [Google Scholar]

[257] Jablonska B, Aguirre A, Raymond M, Szabo G, Kitabatake Y, Sailor KA, et al. (2010). Chordin-induced lineage plasticity of adult SVZ neuroblasts after demyelination. Nat Neurosci, 13:541-550. [PMC free article] [PubMed] [Google Scholar]

[258] Jessberger S, Toni N, Clemenson GD Jr, Ray J, Gage FH (2008). Directed differentiation of hippocampal stem/progenitor cells in the adult brain. Nat Neurosci, 11:888-893. [PMC free article] [PubMed] [Google Scholar]

[259] Beckervordersandforth R, Ebert B, Schaffner I, Moss J, Fiebig C, Shin J, et al. (2017). Role of Mitochondrial Metabolism in the Control of Early Lineage Progression and Aging Phenotypes in Adult Hippocampal Neurogenesis. Neuron, 93:1518. [PMC free article] [PubMed] [Google Scholar]

[260] Figueiro-Silva J, Antequera D, Pascual C, de la Fuente Revenga M, Volt H, Acuna-Castroviejo D, et al. (2018). The Melatonin Analog IQM316 May Induce Adult Hippocampal Neurogenesis and Preserve Recognition Memories in Mice. Cell Transplant, 27:423-437. [PMC free article] [PubMed] [Google Scholar]

[261] Choi SH, Bylykbashi E, Chatila ZK, Lee SW, Pulli B, Clemenson GD, et al. (2018). Combined adult neurogenesis and BDNF mimic exercise effects on cognition in an Alzheimer’s mouse model. Science, 361. [PMC free article] [PubMed] [Google Scholar]

[262] Sasaki K, Davies J, Doldan NG, Arao S, Ferdousi F, Szele FG, et al. (2019). 3,4,5-Tricaffeoylquinic acid induces adult neurogenesis and improves deficit of learning and memory in aging model senescence-accelerated prone 8 mice. Aging (Albany NY), 11:401-422. [PMC free article] [PubMed] [Google Scholar]

[263] Qu Q, Sun G, Li W, Yang S, Ye P, Zhao C, et al. (2010). Orphan nuclear receptor TLX activates Wnt/beta-catenin signalling to stimulate neural stem cell proliferation and self-renewal. Nat Cell Biol, 12:31-40; sup pp 31-39. [PMC free article] [PubMed] [Google Scholar]

[264] Marchetti B, Tirolo C, L’Episcopo F, Caniglia S, Testa N, Smith JA, et al. (2020). Parkinson’s disease, aging and adult neurogenesis: Wnt/beta-catenin signalling as the key to unlock the mystery of endogenous brain repair. Aging Cell, 19:e13101. [PMC free article] [PubMed] [Google Scholar]

[265] Inestrosa NC, Arenas E (2010). Emerging roles of Wnts in the adult nervous system. Nat Rev Neurosci, 11:77-86. [PubMed] [Google Scholar]

[266] Rennie K, De Butte M, Pappas BA (2009). Melatonin promotes neurogenesis in dentate gyrus in the pinealectomized rat. J Pineal Res, 47:313-317. [PubMed] [Google Scholar]

[267] Kim MJ, Kim HK, Kim BS, Yim SV (2004). Melatonin increases cell proliferation in the dentate gyrus of maternally separated rats. J Pineal Res, 37:193-197. [PubMed] [Google Scholar]

[268] Ramirez-Rodriguez G, Ortiz-Lopez L, Dominguez-Alonso A, Benitez-King GA, Kempermann G (2011). Chronic treatment with melatonin stimulates dendrite maturation and complexity in adult hippocampal neurogenesis of mice. J Pineal Res, 50:29-37. [PubMed] [Google Scholar]

[269] Ramirez-Rodriguez G, Klempin F, Babu H, Benitez-King G, Kempermann G (2009). Melatonin modulates cell survival of new neurons in the hippocampus of adult mice. Neuropsychopharmacology, 34:2180-2191. [PubMed] [Google Scholar]

[270] Shohayeb B, Diab M, Ahmed M, Ng DCH (2018). Factors that influence adult neurogenesis as potential therapy. Transl Neurodegener, 7:4. [PMC free article] [PubMed] [Google Scholar]

[271] Benhamron S, Nitzan K, Valitsky M, Lax N, Karussis D, Kassis I, et al. (2020). Cerebrospinal Fluid (CSF) Exchange Therapy with Artificial CSF Enriched with Mesenchymal Stem Cell Secretions Ameliorates Cognitive Deficits and Brain Pathology in Alzheimer’s Disease Mice. J Alzheimers Dis, 76:369-385. [PubMed] [Google Scholar]

[272] Bonsack B, Corey S, Shear A, Heyck M, Cozene B, Sadanandan N, et al. (2020). Mesenchymal stem cell therapy alleviates the neuroinflammation associated with acquired brain injury. CNS Neurosci Ther, 26:603-615. [PMC free article] [PubMed] [Google Scholar]

[273] Chu C, Gao Y, Lan X, Lin J, Thomas AM, Li S (2020). Stem-Cell Therapy as a Potential Strategy for Radiation-Induced Brain Injury. Stem Cell Rev Rep. [PubMed] [Google Scholar]

[274] Courtney JM, Sutherland BA (2020). Harnessing the stem cell properties of pericytes to repair the brain. Neural Regen Res, 15:1021-1022. [PMC free article] [PubMed] [Google Scholar]

[275] Di Marco A, Vignone D, Gonzalez Paz O, Fini I, Battista MR, Cellucci A, et al. (2020). Establishment of an in Vitro Human Blood-Brain Barrier Model Derived from Induced Pluripotent Stem Cells and Comparison to a Porcine Cell-Based System. Cells, 9. [PMC free article] [PubMed] [Google Scholar]

[276] Durens M, Nestor J, Williams M, Herold K, Niescier RF, Lunden JW, et al. (2020). High-throughput screening of human induced pluripotent stem cell-derived brain organoids. J Neurosci Methods, 335:108627. [PubMed] [Google Scholar]

[277] Elborai Y, Almutereen M, Maher OM, Hafez H, Lee MA, Lehmann L (2020). Changes in glomerular filtration rate and clinical course after sequential doses of carboplatin in children with embryonal brain tumors undergoing autologous stem cell transplantation. J Egypt Natl Canc Inst, 32:9. [PubMed] [Google Scholar]

[278] Furube E, Ishii H, Nambu Y, Kurganov E, Nagaoka S, Morita M, et al. (2020). Neural stem cell phenotype of tanycyte-like ependymal cells in the circumventricular organs and central canal of adult mouse brain. Sci Rep, 10:2826. [PMC free article] [PubMed] [Google Scholar]

[279] He J, Russell T, Qiu X, Hao F, Kyle M, Chin L, et al. (2020). The contribution of stem cell factor and granulocyte colony-stimulating factor in reducing neurodegeneration and promoting neurostructure network reorganization after traumatic brain injury. Brain Res, 1746:147000. [PubMed] [Google Scholar]

[280] Hou K, Li G, Zhao J, Xu B, Zhang Y, Yu J, et al. (2020). Bone mesenchymal stem cell-derived exosomal microRNA-29b-3p prevents hypoxic-ischemic injury in rat brain by activating the PTEN-mediated Akt signaling pathway. J Neuroinflammation, 17:46. [PMC free article] [PubMed] [Google Scholar] Retracted

[281] Huang L, Reis C, Boling WW, Zhang JH (2020). Stem Cell Therapy in Brain Ischemia: The Role of Mitochondrial Transfer. Stem Cells Dev, 29:555-561. [PubMed] [Google Scholar]

[282] Liu Y, Huber CC, Wang H (2020). Disrupted blood-brain barrier in 5xFAD mouse model of Alzheimer’s disease can be mimicked and repaired in vitro with neural stem cell-derived exosomes. Biochem Biophys Res Commun. [PubMed] [Google Scholar]

[283] Mariottini A, Filippini S, Innocenti C, Forci B, Mechi C, Barilaro A, et al. (2020). Impact of autologous haematopoietic stem cell transplantation on disability and brain atrophy in secondary progressive multiple sclerosis. Mult Scler:1352458520902392. [PubMed] [Google Scholar]

[284] Mayilsamy K, Markoutsa E, Das M, Chopade P, Puro D, Kumar A, et al. (2020). Treatment with shCCL20-CCR6 nanodendriplexes and human mesenchymal stem cell therapy improves pathology in mice with repeated traumatic brain injury. Nanomedicine:102247. [PubMed] [Google Scholar]

[285] Peng X, Song J, Li B, Zhu C, Wang X (2020). Umbilical cord blood stem cell therapy in premature brain injury: Opportunities and challenges. J Neurosci Res, 98:815-825. [PubMed] [Google Scholar]

[286] Pourhassan Shamchi S, Zirakchian Zadeh M, Ostergaard B, Kim J, Raynor WY, Khosravi M, et al. (2020). Brain glucose metabolism in patients with newly diagnosed multiple myeloma significantly decreases after high-dose chemotherapy followed by autologous stem cell transplantation. Nucl Med Commun, 41:288-293. [PubMed] [Google Scholar]

[287] Tang H, Jiang Y, Zhang JH (2020). Stem Cell Therapy for Brain Injury. Stem Cells Dev, 29:177. [PubMed] [Google Scholar]

[288] Willis CM, Nicaise AM, Peruzzotti-Jametti L, Pluchino S (2020). The neural stem cell secretome and its role in brain repair. Brain Res, 1729:146615. [PubMed] [Google Scholar]

[289] Yamashita M, Aoki H, Hashita T, Iwao T, Matsunaga T (2020). Inhibition of transforming growth factor beta signaling pathway promotes differentiation of human induced pluripotent stem cell-derived brain microvascular endothelial-like cells. Fluids Barriers CNS, 17:36. [PMC free article] [PubMed] [Google Scholar]

[290] Yoneda Y, Kawada K, Kuramoto N (2020). Selective Upregulation by Theanine of Slc38a1 Expression in Neural Stem Cell for Brain Wellness. Molecules, 25. [PMC free article] [PubMed] [Google Scholar]

[291] Zajac-Spychala O, Pawlak MA, Karmelita-Katulska K, Pilarczyk J, Jonczyk-Potoczna K, Przepiora A, et al. (2020). Long-term brain status and cognitive impairment in children treated for high-risk acute lymphoblastic leukemia with and without allogeneic hematopoietic stem cell transplantation: A single-center study. Pediatr Blood Cancer, 67:e28224. [PubMed] [Google Scholar]

[292] Zhang G, Ferg M, Lubke L, Takamiya M, Beil T, Gourain V, et al. (2020). Bone morphogenetic protein signaling regulates Id1-mediated neural stem cell quiescence in the adult zebrafish brain via a phylogenetically conserved enhancer module. Stem Cells. [PubMed] [Google Scholar]

[293] Zhang Y, Zhang Y, Chopp M, Zhang ZG, Mahmood A, Xiong Y (2020). Mesenchymal Stem Cell-Derived Exosomes Improve Functional Recovery in Rats After Traumatic Brain Injury: A Dose-Response and Therapeutic Window Study. Neurorehabil Neural Repair, 34:616-626. [PMC free article] [PubMed] [Google Scholar]

[294] Zhao H, Xie L, Clemens JL, Zong L, McLane MW, Arif H, et al. (2020). Mouse Bone Marrow-Derived Mesenchymal Stem Cells Alleviate Perinatal Brain Injury Via a CD8(+) T Cell Mechanism in a Model of Intrauterine Inflammation. Reprod Sci, 27:1465-1476. [PubMed] [Google Scholar]

[295] Zhao M, Chen S, Yang ML, Li SY, Jiang W, Xiao N (2020). Vitamin A regulates neural stem cell proliferation in rats after hypoxic-ischemic brain damage via RARa-mediated modulation of the beta-catenin pathway. Neurosci Lett, 727:134922. [PubMed] [Google Scholar]

[296] Zygogianni O, Kouroupi G, Taoufik E, Matsas R (2020). Engraftable Induced Pluripotent Stem Cell-Derived Neural Precursors for Brain Repair. Methods Mol Biol, 2155:23-39. [PubMed] [Google Scholar]

[297] Vasic V, Barth K, Schmidt MHH (2019). Neurodegeneration and Neuro-Regeneration-Alzheimer’s Disease and Stem Cell Therapy. Int J Mol Sci, 20. [PMC free article] [PubMed] [Google Scholar]

[298] Grochowski C, Radzikowska E, Maciejewski R (2018). Neural stem cell therapy-Brief review. Clin Neurol Neurosurg, 173:8-14. [PubMed] [Google Scholar]

[299] Pera MF, Trounson AO (2004). Human embryonic stem cells: prospects for development. Development, 131:5515-5525. [PubMed] [Google Scholar]

[300] Acharya MM, Christie LA, Lan ML, Donovan PJ, Cotman CW, Fike JR, et al. (2009). Rescue of radiation-induced cognitive impairment through cranial transplantation of human embryonic stem cells. Proc Natl Acad Sci U S A, 106:19150-19155. [PMC free article] [PubMed] [Google Scholar]

[301] Takagi Y, Takahashi J, Saiki H, Morizane A, Hayashi T, Kishi Y, et al. (2005). Dopaminergic neurons generated from monkey embryonic stem cells function in a Parkinson primate model. J Clin Invest, 115:102-109. [PMC free article] [PubMed] [Google Scholar]

[302] Doi D, Morizane A, Kikuchi T, Onoe H, Hayashi T, Kawasaki T, et al. (2012). Prolonged maturation culture favors a reduction in the tumorigenicity and the dopaminergic function of human ESC-derived neural cells in a primate model of Parkinson’s disease. Stem Cells, 30:935-945. [PubMed] [Google Scholar]

[303] Yue W, Li Y, Zhang T, Jiang M, Qian Y, Zhang M, et al. (2015). ESC-Derived Basal Forebrain Cholinergic Neurons Ameliorate the Cognitive Symptoms Associated with Alzheimer’s Disease in Mouse Models. Stem Cell Reports, 5:776-790. [PMC free article] [PubMed] [Google Scholar]

[304] Buganim Y, Faddah DA, Jaenisch R (2013). Mechanisms and models of somatic cell reprogramming. Nat Rev Genet, 14:427-439. [PMC free article] [PubMed] [Google Scholar]

[305] Csobonyeiova M, Polak S, Danisovic L (2020). Recent Overview of the Use of iPSCs Huntington’s Disease Modeling and Therapy. Int J Mol Sci, 21. [PMC free article] [PubMed] [Google Scholar]

[306] Cha MY, Kwon YW, Ahn HS, Jeong H, Lee YY, Moon M, et al. (2017). Protein-Induced Pluripotent Stem Cells Ameliorate Cognitive Dysfunction and Reduce Abeta Deposition in a Mouse Model of Alzheimer’s Disease. Stem Cells Transl Med, 6:293-305. [PMC free article] [PubMed] [Google Scholar]

[307] Kriks S, Shim JW, Piao J, Ganat YM, Wakeman DR, Xie Z, et al. (2011). Dopamine neurons derived from human ES cells efficiently engraft in animal models of Parkinson’s disease. Nature, 480:547-551. [PMC free article] [PubMed] [Google Scholar]

[308] Hallett PJ, Deleidi M, Astradsson A, Smith GA, Cooper O, Osborn TM, et al. (2015). Successful function of autologous iPSC-derived dopamine neurons following transplantation in a non-human primate model of Parkinson’s disease. Cell Stem Cell, 16:269-274. [PMC free article] [PubMed] [Google Scholar]

[309] Rhee YH, Ko JY, Chang MY, Yi SH, Kim D, Kim CH, et al. (2011). Protein-based human iPS cells efficiently generate functional dopamine neurons and can treat a rat model of Parkinson disease. J Clin Invest, 121:2326-2335. [PMC free article] [PubMed] [Google Scholar]

[310] Vogel A, Upadhya R, Shetty AK (2018). Neural stem cell derived extracellular vesicles: Attributes and prospects for treating neurodegenerative disorders. EBioMedicine, 38:273-282. [PMC free article] [PubMed] [Google Scholar]

[311] Lee IS, Jung K, Kim IS, Lee H, Kim M, Yun S, et al. (2015). Human neural stem cells alleviate Alzheimer-like pathology in a mouse model. Mol Neurodegener, 10:38. [PMC free article] [PubMed] [Google Scholar]

[312] Zhang Q, Wu HH, Wang Y, Gu GJ, Zhang W, Xia R (2016). Neural stem cell transplantation decreases neuroinflammation in a transgenic mouse model of Alzheimer’s disease. J Neurochem, 136:815-825. [PubMed] [Google Scholar]

[313] Ager RR, Davis JL, Agazaryan A, Benavente F, Poon WW, LaFerla FM, et al. (2015). Human neural stem cells improve cognition and promote synaptic growth in two complementary transgenic models of Alzheimer’s disease and neuronal loss. Hippocampus, 25:813-826. [PMC free article] [PubMed] [Google Scholar]

[314] Lilja AM, Malmsten L, Rojdner J, Voytenko L, Verkhratsky A, Ogren SO, et al. (2015). Neural Stem Cell Transplant-Induced Effect on Neurogenesis and Cognition in Alzheimer Tg2576 Mice Is Inhibited by Concomitant Treatment with Amyloid-Lowering or Cholinergic alpha7 Nicotinic Receptor Drugs. Neural Plast, 2015:370432. [PMC free article] [PubMed] [Google Scholar]

[315] Choi KA, Choi Y, Hong S (2018). Stem cell transplantation for Huntington’s diseases. Methods, 133:104-112. [PubMed] [Google Scholar]

[316] Lo Furno D, Mannino G, Giuffrida R (2018). Functional role of mesenchymal stem cells in the treatment of chronic neurodegenerative diseases. J Cell Physiol, 233:3982-3999. [PubMed] [Google Scholar]

[317] Sidhu KS, Walke S, Tuch BE (2008). Derivation and propagation of hESC under a therapeutic environment. Curr Protoc Stem Cell Biol, Chapter 1:Unit 1A 4. [PubMed] [Google Scholar]

[318] Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, et al. (2007). Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell, 131:861-872. [PubMed] [Google Scholar]

[319] Hanna J, Saha K, Pando B, van Zon J, Lengner CJ, Creyghton MP, et al. (2009). Direct cell reprogramming is a stochastic process amenable to acceleration. Nature, 462:595-601. [PMC free article] [PubMed] [Google Scholar]

[320] Maherali N, Ahfeldt T, Rigamonti A, Utikal J, Cowan C, Hochedlinger K (2008). A high-efficiency system for the generation and study of human induced pluripotent stem cells. Cell Stem Cell, 3:340-345. [PMC free article] [PubMed] [Google Scholar]

[321] Saha K, Jaenisch R (2009). Technical challenges in using human induced pluripotent stem cells to model disease. Cell Stem Cell, 5:584-595. [PMC free article] [PubMed] [Google Scholar]

[322] Lian Q, Zhang Y, Zhang J, Zhang HK, Wu X, Zhang Y, et al. (2010). Functional mesenchymal stem cells derived from human induced pluripotent stem cells attenuate limb ischemia in mice. Circulation, 121:1113-1123. [PubMed] [Google Scholar]

[323] Bae JS, Jin HK, Lee JK, Richardson JC, Carter JE (2013). Bone marrow-derived mesenchymal stem cells contribute to the reduction of amyloid-beta deposits and the improvement of synaptic transmission in a mouse model of pre-dementia Alzheimer’s disease. Curr Alzheimer Res, 10:524-531. [PubMed] [Google Scholar]

[324] Lee JK, Jin HK, Endo S, Schuchman EH, Carter JE, Bae JS (2010). Intracerebral transplantation of bone marrow-derived mesenchymal stem cells reduces amyloid-beta deposition and rescues memory deficits in Alzheimer’s disease mice by modulation of immune responses. Stem Cells, 28:329-343. [PubMed] [Google Scholar]

[325] Duncan T, Valenzuela M (2017). Alzheimer’s disease, dementia, and stem cell therapy. Stem Cell Res Ther, 8:111. [PMC free article] [PubMed] [Google Scholar]

[326] Reidling JC, Relano-Gines A, Holley SM, Ochaba J, Moore C, Fury B, et al. (2018). Human Neural Stem Cell Transplantation Rescues Functional Deficits in R6/2 and Q140 Huntington’s Disease Mice. Stem Cell Reports, 10:58-72. [PMC free article] [PubMed] [Google Scholar]

[327] Zappa Villar MF, Lehmann M, Garcia MG, Mazzolini G, Morel GR, Console GM, et al. (2019). Mesenchymal stem cell therapy improves spatial memory and hippocampal structure in aging rats. Behav Brain Res, 374:111887. [PubMed] [Google Scholar]

[328] Williams AM, Dennahy IS, Bhatti UF, Halaweish I, Xiong Y, Chang P, et al. (2019). Mesenchymal Stem Cell-Derived Exosomes Provide Neuroprotection and Improve Long-Term Neurologic Outcomes in a Swine Model of Traumatic Brain Injury and Hemorrhagic Shock. J Neurotrauma, 36:54-60. [PubMed] [Google Scholar]

[329] Wang YK, Zhu WW, Wu MH, Wu YH, Liu ZX, Liang LM, et al. (2018). Human Clinical-Grade Parthenogenetic ESC-Derived Dopaminergic Neurons Recover Locomotive Defects of Nonhuman Primate Models of Parkinson’s Disease. Stem Cell Reports, 11:171-182. [PMC free article] [PubMed] [Google Scholar]

[330] Giuliani M, Oudrhiri N, Noman ZM, Vernochet A, Chouaib S, Azzarone B, et al. (2011). Human mesenchymal stem cells derived from induced pluripotent stem cells down-regulate NK-cell cytolytic machinery. Blood, 118:3254-3262. [PubMed] [Google Scholar]

[331] Nakano M, Nagaishi K, Konari N, Saito Y, Chikenji T, Mizue Y, et al. (2016). Bone marrow-derived mesenchymal stem cells improve diabetes-induced cognitive impairment by exosome transfer into damaged neurons and astrocytes. Sci Rep, 6:24805. [PMC free article] [PubMed] [Google Scholar]

[332] Mitsialis SA, Kourembanas S (2016). Stem cell-based therapies for the newborn lung and brain: Possibilities and challenges. Semin Perinatol, 40:138-151. [PMC free article] [PubMed] [Google Scholar]

[333] Wernig M, Zhao JP, Pruszak J, Hedlund E, Fu D, Soldner F, et al. (2008). Neurons derived from reprogrammed fibroblasts functionally integrate into the fetal brain and improve symptoms of rats with Parkinson’s disease. Proc Natl Acad Sci U S A, 105:5856-5861. [PMC free article] [PubMed] [Google Scholar]

[334] Laflamme MA, Gold J, Xu C, Hassanipour M, Rosler E, Police S, et al. (2005). Formation of human myocardium in the rat heart from human embryonic stem cells. Am J Pathol, 167:663-671. [PMC free article] [PubMed] [Google Scholar]

[335] Song WK, Park KM, Kim HJ, Lee JH, Choi J, Chong SY, et al. (2015). Treatment of macular degeneration using embryonic stem cell-derived retinal pigment epithelium: preliminary results in Asian patients. Stem Cell Reports, 4:860-872. [PMC free article] [PubMed] [Google Scholar]

[336] Ciccocioppo R, Bernardo ME, Sgarella A, Maccario R, Avanzini MA, Ubezio C, et al. (2011). Autologous bone marrow-derived mesenchymal stromal cells in the treatment of fistulising Crohn’s disease. Gut, 60:788-798. [PubMed] [Google Scholar]

[337] Molendijk I, Bonsing BA, Roelofs H, Peeters KC, Wasser MN, Dijkstra G, et al. (2015). Allogeneic Bone Marrow-Derived Mesenchymal Stromal Cells Promote Healing of Refractory Perianal Fistulas in Patients With Crohn’s Disease. Gastroenterology, 149:918-927 e916. [PubMed] [Google Scholar]

[338] Lee WY, Park KJ, Cho YB, Yoon SN, Song KH, Kim DS, et al. (2013). Autologous adipose tissue-derived stem cells treatment demonstrated favorable and sustainable therapeutic effect for Crohn’s fistula. Stem Cells, 31:2575-2581. [PubMed] [Google Scholar]

[339] Cho YB, Lee WY, Park KJ, Kim M, Yoo HW, Yu CS (2013). Autologous adipose tissue-derived stem cells for the treatment of Crohn’s fistula: a phase I clinical study. Cell Transplant, 22:279-285. [PubMed] [Google Scholar]

[340] Panes J, Garcia-Olmo D, Van Assche G, Colombel JF, Reinisch W, Baumgart DC, et al. (2016). Expanded allogeneic adipose-derived mesenchymal stem cells (Cx601) for complex perianal fistulas in Crohn’s disease: a phase 3 randomised, double-blind controlled trial. Lancet, 388:1281-1290. [PubMed] [Google Scholar]

[341] Cohen JA, Imrey PB, Planchon SM, Bermel RA, Fisher E, Fox RJ, et al. (2018). Pilot trial of intravenous autologous culture-expanded mesenchymal stem cell transplantation in multiple sclerosis. Mult Scler, 24:501-511. [PMC free article] [PubMed] [Google Scholar]

[342] Lee JS, Hong JM, Moon GJ, Lee PH, Ahn YH, Bang OY, et al. (2010). A long-term follow-up study of intravenous autologous mesenchymal stem cell transplantation in patients with ischemic stroke. Stem Cells, 28:1099-1106. [PubMed] [Google Scholar]

[343] Miao X, Wu X, Shi W (2015). Umbilical cord mesenchymal stem cells in neurological disorders: A clinical study. Indian J Biochem Biophys, 52:140-146. [PubMed] [Google Scholar]

[344] van Norden AG, van Dijk EJ, de Laat KF, Scheltens P, Olderikkert MG, de Leeuw FE (2012). Dementia: Alzheimer pathology and vascular factors: from mutually exclusive to interaction. Biochim Biophys Acta, 1822:340-349. [PubMed] [Google Scholar]

[345] Luchsinger JA, Reitz C, Honig LS, Tang MX, Shea S, Mayeux R (2005). Aggregation of vascular risk factors and risk of incident Alzheimer disease. Neurology, 65:545-551. [PMC free article] [PubMed] [Google Scholar]

[346] Kivipelto M, Ngandu T, Laatikainen T, Winblad B, Soininen H, Tuomilehto J (2006). Risk score for the prediction of dementia risk in 20 years among middle aged people: a longitudinal, population-based study. Lancet Neurol, 5:735-741. [PubMed] [Google Scholar]

[347] Gottesman RF, Schneider AL, Zhou Y, Coresh J, Green E, Gupta N, et al. (2017). Association Between Midlife Vascular Risk Factors and Estimated Brain Amyloid Deposition. Jama, 317:1443-1450. [PMC free article] [PubMed] [Google Scholar]

[348] Kalaria RN (2010). Vascular basis for brain degeneration: faltering controls and risk factors for dementia. Nutr Rev, 68 Suppl 2:S74-87. [PMC free article] [PubMed] [Google Scholar]

[349] Iadecola C, Gottesman RF (2019). Neurovascular and Cognitive Dysfunction in Hypertension. Circulation Research, 124:1025-1044. [PMC free article] [PubMed] [Google Scholar]

[350] Wahidi N, Lerner AJ (2019). Blood Pressure Control and Protection of the Aging Brain. Neurotherapeutics, 16:569-579. [PMC free article] [PubMed] [Google Scholar]

[351] Stojkovic T, Stefanova E, Soldatovic I, Markovic V, Stankovic I, Petrovic I, et al. (2018). Exploring the relationship between motor impairment, vascular burden and cognition in Parkinson’s disease. J Neurol, 265:1320-1327. [PubMed] [Google Scholar]

[352] Nicoletti A, Luca A, Baschi R, Cicero CE, Mostile G, Davì M, et al. (2021). Vascular risk factors, white matter lesions and cognitive impairment in Parkinson’s disease: the PACOS longitudinal study. J Neurol, 268:549-558. [PMC free article] [PubMed] [Google Scholar]

[353] Tariq S, Barber PA (2018). Dementia risk and prevention by targeting modifiable vascular risk factors. J Neurochem, 144:565-581. [PubMed] [Google Scholar]

[354] Walker KA, Power MC, Gottesman RF (2017). Defining the Relationship Between Hypertension, Cognitive Decline, and Dementia: a Review. Curr Hypertens Rep, 19:24. [PMC free article] [PubMed] [Google Scholar]

[355] Gottesman RF, Schneider AL, Albert M, Alonso A, Bandeen-Roche K, Coker L, et al. (2014). Midlife hypertension and 20-year cognitive change: the atherosclerosis risk in communities neurocognitive study. JAMA Neurol, 71:1218-1227. [PMC free article] [PubMed] [Google Scholar]

[356] Harrison DG, Gongora MC (2009). Oxidative stress and hypertension. Med Clin North Am, 93:621-635. [PubMed] [Google Scholar]

[357] Montezano AC, Touyz RM (2012). Molecular mechanisms of hypertension–reactive oxygen species and antioxidants: a basic science update for the clinician. Can J Cardiol, 28:288-295. [PubMed] [Google Scholar]

[358] Nelson AR, Sweeney MD, Sagare AP, Zlokovic BV (2016). Neurovascular dysfunction and neurodegeneration in dementia and Alzheimer’s disease. Biochim Biophys Acta, 1862:887-900. [PMC free article] [PubMed] [Google Scholar]

[359] Montagne A, Barnes SR, Sweeney MD, Halliday MR, Sagare AP, Zhao Z, et al. (2015). Blood-brain barrier breakdown in the aging human hippocampus. Neuron, 85:296-302. [PMC free article] [PubMed] [Google Scholar]

[360] Biron KE, Dickstein DL, Gopaul R, Jefferies WA (2011). Amyloid triggers extensive cerebral angiogenesis causing blood brain barrier permeability and hypervascularity in Alzheimer’s disease. PLoS One, 6:e23789. [PMC free article] [PubMed] [Google Scholar]

[361] Ramanathan A, Nelson AR, Sagare AP, Zlokovic BV (2015). Impaired vascular-mediated clearance of brain amyloid beta in Alzheimer’s disease: the role, regulation and restoration of LRP1. Front Aging Neurosci, 7:136. [PMC free article] [PubMed] [Google Scholar]

[362] Shih YH, Wu SY, Yu M, Huang SH, Lee CW, Jiang MJ, et al. (2018). Hypertension Accelerates Alzheimer’s Disease-Related Pathologies in Pigs and 3xTg Mice. Front Aging Neurosci, 10:73. [PMC free article] [PubMed] [Google Scholar]

[363] Rouch L, Cestac P, Hanon O, Ruidavets JB, Ehlinger V, Gentil C, et al. (2019). Blood pressure and cognitive performances in middle-aged adults: the Aging, Health and Work longitudinal study. J Hypertens, 37:1244-1253. [PubMed] [Google Scholar]

[364] Bakouni H, Gentil L, Vasiliadis HM (2019). Cognition and drug adherence to oral hypoglycemic and antihypertensive agents in older adults. Patient Prefer Adherence, 13:891-899. [PMC free article] [PubMed] [Google Scholar]

[365] Barthold D, Joyce G, Diaz Brinton R, Wharton W, Kehoe PG, Zissimopoulos J (2020). Association of combination statin and antihypertensive therapy with reduced Alzheimer’s disease and related dementia risk. PLoS One, 15:e0229541. [PMC free article] [PubMed] [Google Scholar]

[366] de Jong-Schmit BEM, Poortvliet RKE, Böhringer S, Bogaerts JMK, Achterberg WP, Husebo BS (2021). Blood pressure, antihypertensive medication and neuropsychiatric symptoms in older people with dementia: The COSMOS study. Int J Geriatr Psychiatry, 36:46-53. [PMC free article] [PubMed] [Google Scholar]

[367] Loera-Valencia R, Goikolea J, Parrado-Fernandez C, Merino-Serrais P, Maioli S (2019). Alterations in cholesterol metabolism as a risk factor for developing Alzheimer’s disease: Potential novel targets for treatment. J Steroid Biochem Mol Biol, 190:104-114. [PubMed] [Google Scholar]

[368] Wu CW, Liao PC, Lin C, Kuo CJ, Chen ST, Chen HI, et al. (2003). Brain region-dependent increases in beta-amyloid and apolipoprotein E levels in hypercholesterolemic rabbits. J Neural Transm (Vienna), 110:641-649. [PubMed] [Google Scholar]

[369] Daneschvar HL, Aronson MD, Smetana GW (2015). Do statins prevent Alzheimer’s disease? A narrative review. Eur J Intern Med, 26:666-669. [PubMed] [Google Scholar]

[370] Wanamaker BL, Swiger KJ, Blumenthal RS, Martin SS (2015). Cholesterol, statins, and dementia: what the cardiologist should know. Clin Cardiol, 38:243-250. [PMC free article] [PubMed] [Google Scholar]

[371] Nazam F, Shaikh S, Nazam N, Alshahrani AS, Hasan GM, Hassan MI (2021). Mechanistic insights into the pathogenesis of neurodegenerative diseases: towards the development of effective therapy. Mol Cell Biochem. [PubMed] [Google Scholar]

[372] Nay K, Smiles WJ, Kaiser J, McAloon LM, Loh K, Galic S, et al. (2021). Molecular Mechanisms Underlying the Beneficial Effects of Exercise on Brain Function and Neurological Disorders. Int J Mol Sci, 22. [PMC free article] [PubMed] [Google Scholar]

[373] Gomez-Pinilla F, Hillman C (2013). The influence of exercise on cognitive abilities. Compr Physiol, 3:403-428. [PMC free article] [PubMed] [Google Scholar]

[374] Voss MW, Vivar C, Kramer AF, van Praag H (2013). Bridging animal and human models of exercise-induced brain plasticity. Trends Cogn Sci, 17:525-544. [PMC free article] [PubMed] [Google Scholar]

[375] Weuve J, Kang JH, Manson JE, Breteler MM, Ware JH, Grodstein F (2004). Physical activity, including walking, and cognitive function in older women. Jama, 292:1454-1461. [PubMed] [Google Scholar]

[376] Campos C, Rocha NB, Lattari E, Paes F, Nardi AE, Machado S (2016). Exercise-induced neuroprotective effects on neurodegenerative diseases: the key role of trophic factors. Expert Rev Neurother, 16:723-734. [PubMed] [Google Scholar]

[377] Ahlskog JE, Geda YE, Graff-Radford NR, Petersen RC (2011). Physical exercise as a preventive or disease-modifying treatment of dementia and brain aging. Mayo Clin Proc, 86:876-884. [PMC free article] [PubMed] [Google Scholar]

[378] Rolland Y, Abellan van Kan G, Vellas B (2010). Healthy brain aging: role of exercise and physical activity. Clin Geriatr Med, 26:75-87. [PubMed] [Google Scholar]

[379] Alberts JL, Rosenfeldt AB (2020). The Universal Prescription for Parkinson’s Disease: Exercise. J Parkinsons Dis, 10:S21-s27. [PMC free article] [PubMed] [Google Scholar]

[380] Bhatti GK, Reddy AP, Reddy PH, Bhatti JS (2019). Lifestyle Modifications and Nutritional Interventions in Aging-Associated Cognitive Decline and Alzheimer’s Disease. Front Aging Neurosci, 11:369. [PMC free article] [PubMed] [Google Scholar]

[381] Keus SH, Bloem BR, Hendriks EJ, Bredero-Cohen AB, Munneke M (2007). Evidence-based analysis of physical therapy in Parkinson’s disease with recommendations for practice and research. Mov Disord, 22:451-460; quiz 600. [PubMed] [Google Scholar]

[382] Subramanian I (2017). Complementary and Alternative Medicine and Exercise in Nonmotor Symptoms of Parkinson’s Disease. Int Rev Neurobiol, 134:1163-1188. [PubMed] [Google Scholar]

[383] Lyu J, Zhang J, Mu H, Li W, Champ M, Xiong Q, et al. (2018). The Effects of Music Therapy on Cognition, Psychiatric Symptoms, and Activities of Daily Living in Patients with Alzheimer’s Disease. J Alzheimers Dis, 64:1347-1358. [PubMed] [Google Scholar]

[384] Michels K, Dubaz O, Hornthal E, Bega D (2018). “Dance Therapy” as a psychotherapeutic movement intervention in Parkinson’s disease. Complement Ther Med, 40:248-252. [PubMed] [Google Scholar]

[385] Hoffmann K, Sobol NA, Frederiksen KS, Beyer N, Vogel A, Vestergaard K, et al. (2016). Moderate-to-High Intensity Physical Exercise in Patients with Alzheimer’s Disease: A Randomized Controlled Trial. J Alzheimers Dis, 50:443-453. [PubMed] [Google Scholar]

[386] Cotman CW, Berchtold NC, Christie LA (2007). Exercise builds brain health: key roles of growth factor cascades and inflammation. Trends Neurosci, 30:464-472. [PubMed] [Google Scholar]

[387] Gebel K, Ding D, Chey T, Stamatakis E, Brown WJ, Bauman AE (2015). Effect of Moderate to Vigorous Physical Activity on All-Cause Mortality in Middle-aged and Older Australians. JAMA Intern Med, 175:970-977. [PubMed] [Google Scholar]

[388] Verdile G, Keane KN, Cruzat VF, Medic S, Sabale M, Rowles J, et al. (2015). Inflammation and Oxidative Stress: The Molecular Connectivity between Insulin Resistance, Obesity, and Alzheimer’s Disease. Mediators Inflamm, 2015:105828. [PMC free article] [PubMed] [Google Scholar]

[389] Hajjar I, Hayek SS, Goldstein FC, Martin G, Jones DP, Quyyumi A (2018). Oxidative stress predicts cognitive decline with aging in healthy adults: an observational study. J Neuroinflammation, 15:17. [PMC free article] [PubMed] [Google Scholar]

[390] de Oliveira Bristot VJ, de Bem Alves AC, Cardoso LR, da Luz Scheffer D, Aguiar AS Jr, (2019). The Role of PGC-1α/UCP2 Signaling in the Beneficial Effects of Physical Exercise on the Brain. Front Neurosci, 13:292. [PMC free article] [PubMed] [Google Scholar]

[391] Garatachea N, Pareja-Galeano H, Sanchis-Gomar F, Santos-Lozano A, Fiuza-Luces C, Morán M, et al. (2015). Exercise attenuates the major hallmarks of aging. Rejuvenation Res, 18:57-89. [PMC free article] [PubMed] [Google Scholar]

[392] Spielman LJ, Little JP, Klegeris A (2016). Physical activity and exercise attenuate neuroinflammation in neurological diseases. Brain Res Bull, 125:19-29. [PubMed] [Google Scholar]

[393] Mee-Inta O, Zhao ZW, Kuo YM (2019). Physical Exercise Inhibits Inflammation and Microglial Activation. Cells, 8. [PMC free article] [PubMed] [Google Scholar]

[394] Vasconcelos-Filho FSL, da Rocha Oliveira LC, de Freitas TBC, de Pontes P, da Rocha ESRC, Chaves EMC, et al. (2021). Neuroprotective mechanisms of chronic physical exercise via reduction of β-amyloid protein in experimental models of Alzheimer’s disease: A systematic review. Life Sci, 275:119372. [PubMed] [Google Scholar]

[395] López-Ortiz S, Pinto-Fraga J, Valenzuela PL, Martín-Hernández J, Seisdedos MM, García-López O, et al. (2021). Physical Exercise and Alzheimer’s Disease: Effects on Pathophysiological Molecular Pathways of the Disease. Int J Mol Sci, 22. [PMC free article] [PubMed] [Google Scholar]

[396] Khodadadi D, Gharakhanlou R, Naghdi N, Salimi M, Azimi M, Shahed A, et al. (2018). Treadmill Exercise Ameliorates Spatial Learning and Memory Deficits Through Improving the Clearance of Peripheral and Central Amyloid-Beta Levels. Neurochem Res, 43:1561-1574. [PubMed] [Google Scholar]

[397] Zeng B, Zhao G, Liu HL (2020). The Differential Effect of Treadmill Exercise Intensity on Hippocampal Soluble Aβ and Lipid Metabolism in APP/PS1 Mice. Neuroscience, 430:73-81. [PubMed] [Google Scholar]

[398] Xia J, Li B, Yin L, Zhao N, Yan Q, Xu B (2019). Treadmill exercise decreases β-amyloid burden in APP/PS1 transgenic mice involving regulation of the unfolded protein response. Neurosci Lett, 703:125-131. [PubMed] [Google Scholar]

[399] Zhao N, Zhang X, Song C, Yang Y, He B, Xu B (2018). The effects of treadmill exercise on autophagy in hippocampus of APP/PS1 transgenic mice. Neuroreport, 29:819-825. [PMC free article] [PubMed] [Google Scholar]

[400] Li B, Liang F, Ding X, Yan Q, Zhao Y, Zhang X, et al. (2019). Interval and continuous exercise overcome memory deficits related to β-Amyloid accumulation through modulating mitochondrial dynamics. Behav Brain Res, 376:112171. [PubMed] [Google Scholar]

[401] Belviranlı M, Okudan N (2019). Voluntary, involuntary and forced exercises almost equally reverse behavioral impairment by regulating hippocampal neurotrophic factors and oxidative stress in experimental Alzheimer’s disease model. Behav Brain Res, 364:245-255. [PubMed] [Google Scholar]

[402] Francis N, Robison LS, Popescu DL, Michaelos M, Hatfield J, Xu F, et al. (2020). Voluntary Wheel Running Reduces Amyloid-β42 and Rescues Behavior in Aged Tg2576 Mouse Model of Alzheimer’s Disease. J Alzheimers Dis, 73:359-374. [PubMed] [Google Scholar]

[403] Pang R, Wang X, Pei F, Zhang W, Shen J, Gao X, et al. (2019). Regular Exercise Enhances Cognitive Function and Intracephalic GLUT Expression in Alzheimer’s Disease Model Mice. J Alzheimers Dis, 72:83-96. [PubMed] [Google Scholar]

[404] Prado Lima MG, Schimidt HL, Garcia A, Daré LR, Carpes FP, Izquierdo I, et al. (2018). Environmental enrichment and exercise are better than social enrichment to reduce memory deficits in amyloid beta neurotoxicity. Proc Natl Acad Sci U S A, 115:E2403-e2409. [PMC free article] [PubMed] [Google Scholar]

[405] Poddar SK, Sifat AE, Haque S, Nahid NA, Chowdhury S, Mehedi I (2019). Nicotinamide Mononucleotide: Exploration of Diverse Therapeutic Applications of a Potential Molecule. Biomolecules, 9. [PMC free article] [PubMed] [Google Scholar]

[406] Covarrubias AJ, Perrone R, Grozio A, Verdin E (2021). NAD(+) metabolism and its roles in cellular processes during ageing. Nat Rev Mol Cell Biol, 22:119-141. [PMC free article] [PubMed] [Google Scholar]

[407] Hadad N, Unnikrishnan A, Jackson JA, Masser DR, Otalora L, Stanford DR, et al. (2018). Caloric restriction mitigates age-associated hippocampal differential CG and non-CG methylation. Neurobiol Aging, 67:53-66. [PMC free article] [PubMed] [Google Scholar]

[408] Schondorf DC, Ivanyuk D, Baden P, Sanchez-Martinez A, De Cicco S, Yu C, et al. (2018). The NAD+ Precursor Nicotinamide Riboside Rescues Mitochondrial Defects and Neuronal Loss in iPSC and Fly Models of Parkinson’s Disease. Cell Rep, 23:2976-2988. [PubMed] [Google Scholar]

[409] Ogrodnik M, Zhu Y, Langhi LGP, Tchkonia T, Kruger P, Fielder E, et al. (2019). Obesity-Induced Cellular Senescence Drives Anxiety and Impairs Neurogenesis. Cell Metab, 29:1233. [PMC free article] [PubMed] [Google Scholar]

Restore Healthy Stem Cell Function

Blitz Age — Thu, 03 Aug 2023 19:52:53 +0000

Using deep-learning artificial intelligence, scientists have identified three plant-based nutrients that can help reverse age-related damage to our existing pool of stem cells.

Scientifically reviewed by: Dr. Amanda Martin, DC, in May 2022. Written by: Roger Harvey.

The tissues of your body come with a built-in “backup” system known as tissue-specific stem cells.

As functional cells in our tissues grow old, embedded stem cells can replace them by producing new healthy cells.

These fresh functional cells rejuvenate aging tissues.

What few people know is that stem cells have the power to reproduce themselves (self-renew) so they can continue to replace aging functional cells.

So why do our tissues still grow old and lose function as we age?

The problem is that stem cells are also adversely impacted by aging.

Over time, our stem cells accumulate damage just like other cells do. This compromises their ability to keep tissues healthy and fully functional.¹

Scientists at Life Extension^® partnered with a deep-learning AI biotech group called InSilico Medicine. The mission was to discover ways to keep stem cells young and refreshed.

Three plant-based nutrients (garcinol, piceatannol and resveratrol) have been found to promote stem cell health.

Researchers showed that these compounds can help protect and revitalize stem cells.^2-10

What Are Stem Cells?

Most cells in our tissues are specialized for specific functions.

A neuron, for example, is a cell in the nervous system which has been specifically designed to respond to stimuli and conduct electrical impulses. A muscle cell has developed a distinct machinery to enable it to contract—to shorten forcefully to create movement.

These cells, and others throughout the tissues of the body, cannot change types once they mature. A neuron is always a neuron. A muscle cell is always a muscle cell.

In addition, many of these kinds of cells cannot divide to produce more cells. They die off and must be replaced by new cells.

But most tissues also have a small population of stem cells (also referred to as tissue-specific progenitor cells). They are critically important for the maintenance and health of every tissue.

How Do Stem Cells Regenerate?

Stem cells act as a reservoir to replace old, damaged, or dying cells.

When specialized (functional) cells in tissues stop working or are impaired by injury or disease, stem cells have the ability to develop into the needed cell type to replace them.

This helps rejuvenate and repair the tissues themselves.

To work properly, stem cells must perform two basic functions:

Self-renewal. Stem cells continue to divide, forming new stem cells. This maintains the available pool of stem cells and ensures there are enough cells to allow some to develop into specialized cells.
Differentiation. When needed, stem cells transform into specialized functional cell types which replace ones that have been lost or damaged.

When stem cells are working properly, they help maintain tissue and organ function and repair/defend tissues against disease, injury, and aging.

WHAT YOU NEED TO KNOW

Plant-Derived Nutrients Revitalize Stem Cells

Stem cells are found in many organs and tissues in the body. They have the ability to self-reproduce and to develop into specialized tissue cells, replacing dead and damaged cells and keeping tissues youthful.
Stem cells also lose function over time, causing tissues to age and deteriorate.
Scientists have discovered three plant-derived nutrients, garcinol, piceatannol, and resveratrol, that can reverse or repair age-related changes in stem cells.
By keeping stem cells healthy, these nutrients may allow them to rejuvenate their tissues so they can continue functioning optimally.

Stem Cells and Aging

It’s a nearly perfect system—with one huge flaw.

While stem cells are meant to keep tissues young and healthy, advancing age takes its toll on them as well.¹

As this damage accumulates over time, stem cells stop dividing as effectively, lose the ability to replace old and damaged tissue cells, and begin to die.

This causes the entire tissue to age more rapidly and lose its function. Physical frailty advances, cognitive abilities decline, metabolism slows, and the body becomes more susceptible to age-related disease and dysfunction.

Revitalizing Stem Cells

The deterioration of stem cells may seem inevitable. But it’s not.

Scientists have found that there are ways to protect these cells and restore their youthful function:

Activating the enzyme AMPK—considered the “master regulator” of metabolism in the body. This improves energy balance in stem cells and leads to replacement of old, damaged proteins.^11,12
Inhibiting mTOR (an enzyme that regulates protein synthesis and cell growth) and activating FoxO (a protein that regulates the expression of genes). This limits the buildup of toxins and enhances autophagy, cellular “housekeeping” that keeps stem cells running smoothly.^13-15
Activating sirtuins, proteins that regulate cellular health, and protect and repair DNA.^16,17
Blocking the action of enzymes (called histone acetyltransferases) to reduce changes to genetic material that lead to cellular dysfunction.¹⁸

Nutrients That Improve Stem Cell Health

Three nutrients found in plants, garcinol, piceatannol, and resveratrol, have been shown to perform all these stem-cell-protecting actions.

Garcinol

Mangosteen

As stem cells age, their expression of genetic material can be changed by a process known as histone acetylation.

In some cases, histone acetylation can drive up expression of damaging factors which can be very detrimental to the cell. This is one of the main causes of stem cell aging and loss of function and can lead to cellular dysfunction and risk for age-related disease.

An enzyme called histone acetyltransferase (HAT) is required for histone acetylation to occur. If we can block the enzyme, we can stop certain harmful processes and restore youthful stem cell function.

Scientists are looking for synthetic drugs that can inhibit HAT, but there’s already a nutrient that can do it.

Garcinol is a compound extracted from the fruit of the mangosteen tree.¹⁹ Preclinical studies have shown garcinol to be a potent HAT inhibitor. By inhibiting HAT (histone acetyltransferase), it reduces harmful chemical changes that affect gene expression.^7,20

This directly benefits stem cells, promoting the expression of genes involved in self-renewal and suppressing others that restrict it. In an ex vivo study of human blood stem cells, garcinol caused their numbers to increase more than 4.5-fold.⁷

Garcinol may also promote the development of stem cells into specialized tissue cells. For example, garcinol treatment promotes differentiation of rat neural stem cells into neurons.⁹

GARCINOL’S ANTI-CANCER ACTIVITY

Garcinol can stimulate the self-renewal and growth of healthy stem cells.

The activity of cancer stem cells has been linked to drug resistance and tumor relapse.

In one study garcinol treatment inhibited both lung tumor growth and viability of lung cancer stem cells.²⁶

Several preclinical studies have shown that it may suppress the growth of various types of cancers, including cervical, breast, oral, and prostate cancers.^27-30

Piceatannol

Passion fruit

Piceatannol is found in fruits including red and white grapes, passion fruit, and blueberries.²¹

Preclinical studies indicate that it has the ability to stimulate cellular housekeeping and sirtuin function, which has a beneficial impact on stem cells.²²

In a preclinical study, human stem cells isolated from fat tissues were differentiated into mature fat cells in the presence or absence of piceatannol. The cells grown with piceatannol displayed improved fat metabolism and healthier function, as well as reduced uptake of sugar which normally would be converted into fat.³

And in cell culture and adult mice, piceatannol helped neural stem cells differentiate to produce new, specialized brain cells called astrocytes.²

Resveratrol

Grapes

Resveratrol, a nutrient found in the skin of red grapes, has long been known to have a wide range of health benefits.

Several recent studies have shown that it may specifically help restore healthy stem cell function by:

Activating SIRT1. In a study of human stem cells, resveratrol increased activity of SIRT1, a sirtuin protein linked to longevity and anti-aging. This resulted in improved self-renewal of the stem cells as well as differentiation into specialized cells.⁸
Activating AMPK. One recent study showed that resveratrol helps osteogenic stem cell differentiation via AMPK activation.²³
Enhancing mitochondrial function. In aging mice and in cell culture, resveratrol restored healthier cellular metabolism by improving the function of mitochondria.⁶
Inhibiting mTOR. Too much activity of the enzyme mTOR can lead to premature cellular aging.²⁴ Mouse embryonic stem cells treated with resveratrol had decreased mTOR activity, making them more youthful and enhancing their self-renewal ability.⁵

In one recent study, researchers subjected mice to chemotherapy, a harsh treatment that accelerates the aging of ovarian stem cells. But when the animals were treated with resveratrol, the loss of ovarian stem cells was alleviated.¹⁰

Protecting stem cells translates into clear improvements in tissue function. In a rat animal model, scientists created an injury to the aorta, the artery that carries blood from the heart to the rest of the body. In the rats treated with resveratrol, their stem cells were better able to replace the damaged endothelial cells, leading to accelerated healing/repair of the injured artery.⁴

In humans, resveratrol treatment reduced mean fat cells’ size and improved adipogenesis (differentiation of pre-adipocytes into fat cells) related to improved sensitivity of tissues to insulin.²⁵

Resveratrol and piceatannol are both stilbenes, close relatives. In one cell study, resveratrol and piceatannol worked synergistically to enhance each other’s ability to stimulate cellular housekeeping and sirtuin function.²²

Taken together with garcinol, they may provide thorough benefits to stem cells.

Summary

Stem cells are present in many tissues, providing a built-in means to replace dead, dying, and damaged cells, rejuvenating the tissue.

But stem cells are also damaged over time, reducing their ability to function properly.

Scientists have identified three nutrients found in plants that have a powerful impact on stem cell health and functions: garcinol, piceatannol and resveratrol.

Each of these compounds protects and revitalizes stem cells, enhancing their self-renewal and their ability to grow into mature tissue cells.

Maintaining a healthy pool of stem cells can keep tissues functioning optimally, warding off age-related degeneration and loss of function.

If you have any questions on the scientific content of this article, please call a Life Extension^® Wellness Specialist at 1-866-864-3027.

References

Oh J, Lee YD, Wagers AJ. Stem cell aging: mechanisms, regulators and therapeutic opportunities. Nat Med. 2014 Aug;20(8):870-80.
Arai D, Kataoka R, Otsuka S, et al. Piceatannol is superior to resveratrol in promoting neural stem cell differentiation into astrocytes. Food Funct. 2016 Oct 12;7(10):4432-41.
Carpene C, Pejenaute H, Del Moral R, et al. The Dietary Antioxidant Piceatannol Inhibits Adipogenesis of Human Adipose Mesenchymal Stem Cells and Limits Glucose Transport and Lipogenic Activities in Adipocytes. Int J Mol Sci. 2018 Jul 17;19(7).
J G, Cq W, Hh F, et al. Effects of resveratrol on endothelial progenitor cells and their contributions to reendothelialization in intima-injured rats. J Cardiovasc Pharmacol. 2006 May;47(5):711-21.
Li N, Du Z, Shen Q, et al. Resveratrol Enhances Self-Renewal of Mouse Embryonic Stem Cells. J Cell Biochem. 2017 Jul;118(7):1928-35.
Lv YJ, Yang Y, Sui BD, et al. Resveratrol counteracts bone loss via mitofilin-mediated osteogenic improvement of mesenchymal stem cells in senescence-accelerated mice. Theranostics. 2018;8(9):2387-406.
Nishino T, Wang C, Mochizuki-Kashio M, et al. Ex vivo expansion of human hematopoietic stem cells by garcinol, a potent inhibitor of histone acetyltransferase. PLoS One. 2011;6(9):e24298.
Wang X, Ma S, Meng N, et al. Resveratrol Exerts Dosage-Dependent Effects on the Self-Renewal and Neural Differentiation of hUC-MSCs. Mol Cells. 2016 May 31;39(5):418-25.
Weng MS, Liao CH, Yu SY, et al. Garcinol promotes neurogenesis in rat cortical progenitor cells through the duration of extracellular signal-regulated kinase signaling. J Agric Food Chem. 2011 Feb 9;59(3):1031-40.
Wu M, Ma L, Xue L, et al. Resveratrol alleviates chemotherapy-induced oogonial stem cell apoptosis and ovarian aging in mice. Aging (Albany NY). 2019 Feb 14;11(3):1030-44.
Avolio E, Gianfranceschi G, Cesselli D, et al. Ex vivo molecular rejuvenation improves the therapeutic activity of senescent human cardiac stem cells in a mouse model of myocardial infarction. Stem Cells. 2014 Sep;32(9):2373-85.
Burkewitz K, Zhang Y, Mair WB. AMPK at the nexus of energetics and aging. Cell Metab. 2014 Jul 1;20(1):10-25.
Ho TT, Warr MR, Adelman ER, et al. Autophagy maintains the metabolism and function of young and old stem cells. Nature. 2017 Mar 9;543(7644):205-10.
Ito K, Suda T. Metabolic requirements for the maintenance of self-renewing stem cells. Nat Rev Mol Cell Biol. 2014 Apr;15(4):243-56.
Warr MR, Binnewies M, Flach J, et al. FOXO3A directs a protective autophagy program in haematopoietic stem cells. Nature. 2013 Feb 21;494(7437):323-7.
Liu X, Hu D, Zeng Z, et al. SRT1720 promotes survival of aged human mesenchymal stem cells via FAIM: a pharmacological strategy to improve stem cell-based therapy for rat myocardial infarction. Cell Death Dis. 2017 Apr 6;8(4):e2731.
Yuan HF, Zhai C, Yan XL, et al. SIRT1 is required for long-term growth of human mesenchymal stem cells. J Mol Med (Berl). 2012 Apr;90(4):389-400.
Jung JW, Lee S, Seo MS, et al. Histone deacetylase controls adult stem cell aging by balancing the expression of polycomb genes and jumonji domain containing 3. Cell Mol Life Sci. 2010 Apr;67(7):1165-76.
Padhye S, Ahmad A, Oswal N, et al. Emerging role of Garcinol, the antioxidant chalcone from Garcinia indica Choisy and its synthetic analogs. J Hematol Oncol. 2009 Sep 2;2:38.
Balasubramanyam K, Altaf M, Varier RA, et al. Polyisoprenylated benzophenone, garcinol, a natural histone acetyltransferase inhibitor, represses chromatin transcription and alters global gene expression. J Biol Chem. 2004 Aug 6;279(32):33716-26.
Kershaw J, Kim KH. The Therapeutic Potential of Piceatannol, a Natural Stilbene, in Metabolic Diseases: A Review. J Med Food. 2017 May;20(5):427-38.
Pietrocola F, Marino G, Lissa D, et al. Pro-autophagic polyphenols reduce the acetylation of cytoplasmic proteins. Cell Cycle. 2012 Oct 15;11(20):3851-60.
Zhou T, Yan Y, Zhao C, et al. Resveratrol improves osteogenic differentiation of senescent bone mesenchymal stem cells through inhibiting endogenous reactive oxygen species production via AMPK activation. Redox Rep. 2019 Dec;24(1):62-9.
Available at: https://www.leafscience.org/mtor-is-linked-to-diabetes-and-aging/. Accessed November 21, 2019.
Konings E, Timmers S, Boekschoten MV, et al. The effects of 30 days resveratrol supplementation on adipose tissue morphology and gene expression patterns in obese men. Int J Obes (Lond). 2014 Mar;38(3):470-3.
Huang WC, Kuo KT, Adebayo BO, et al. Garcinol inhibits cancer stem cell-like phenotype via suppression of the Wnt/beta-catenin/STAT3 axis signalling pathway in human non-small cell lung carcinomas. J Nutr Biochem. 2018 Apr;54:140-50.
Zhao J, Yang T, Ji J, et al. Garcinol exerts anti-cancer effect in human cervical cancer cells through upregulation of T-cadherin. Biomed Pharmacother. 2018 Nov;107:957-66.
Ye X, Yuan L, Zhang L, et al. Garcinol, an acetyltransferase inhibitor, suppresses proliferation of breast cancer cell line MCF-7 promoted by 17beta-estradiol. Asian Pac J Cancer Prev. 2014;15(12):5001-7.
Aggarwal S, Das SN. Garcinol inhibits tumour cell proliferation, angiogenesis, cell cycle progression and induces apoptosis via NF-kappaB inhibition in oral cancer. Tumour Biol. 2016 Jun;37(6):7175-84.
Wang Y, Tsai ML, Chiou LY, et al. Antitumor Activity of Garcinol in Human Prostate Cancer Cells and Xenograft Mice. J Agric Food Chem. 2015 Oct 21;63(41):9047-52.

Stem cells: What they are and what they doPrint

Blitz Age — Thu, 03 Aug 2023 19:34:42 +0000

Stem cells offer great promise for new medical treatments. Learn about stem cell types, current and possible uses, and the state of research and practice.By Mayo Clinic Staff

You’ve heard about stem cells in the news, and perhaps you’ve wondered if they might help you or a loved one with a serious disease. You may wonder what stem cells are, how they’re being used to treat disease and injury, and why they’re the subject of such vigorous debate.

Here are some answers to frequently asked questions about stem cells.

What are stem cells?

Enlarge image

Stem cells: The body’s master cells

Stem cells are the body’s raw materials — cells from which all other cells with specialized functions are generated. Under the right conditions in the body or a laboratory, stem cells divide to form more cells called daughter cells.

These daughter cells become either new stem cells or specialized cells (differentiation) with a more specific function, such as blood cells, brain cells, heart muscle cells or bone cells. No other cell in the body has the natural ability to generate new cell types.

Why is there such an interest in stem cells?

Researchers hope stem cell studies can help to:

Increase understanding of how diseases occur. By watching stem cells mature into cells in bones, heart muscle, nerves, and other organs and tissue, researchers may better understand how diseases and conditions develop.
Generate healthy cells to replace cells affected by disease (regenerative medicine). Stem cells can be guided into becoming specific cells that can be used in people to regenerate and repair tissues that have been damaged or affected by disease.People who might benefit from stem cell therapies include those with spinal cord injuries, type 1 diabetes, Parkinson’s disease, amyotrophic lateral sclerosis, Alzheimer’s disease, heart disease, stroke, burns, cancer and osteoarthritis.Stem cells may have the potential to be grown to become new tissue for use in transplant and regenerative medicine. Researchers continue to advance the knowledge on stem cells and their applications in transplant and regenerative medicine.
Test new drugs for safety and effectiveness. Before using investigational drugs in people, researchers can use some types of stem cells to test the drugs for safety and quality. This type of testing will most likely first have a direct impact on drug development for cardiac toxicity testing.New areas of study include the effectiveness of using human stem cells that have been programmed into tissue-specific cells to test new drugs. For the testing of new drugs to be accurate, the cells must be programmed to acquire properties of the type of cells targeted by the drug. Techniques to program cells into specific cells are under study.For instance, nerve cells could be generated to test a new drug for a nerve disease. Tests could show whether the new drug had any effect on the cells and whether the cells were harmed.

Where do stem cells come from?

There are several sources of stem cells:

Embryonic stem cells. These stem cells come from embryos that are 3 to 5 days old. At this stage, an embryo is called a blastocyst and has about 150 cells.These are pluripotent (ploo-RIP-uh-tunt) stem cells, meaning they can divide into more stem cells or can become any type of cell in the body. This versatility allows embryonic stem cells to be used to regenerate or repair diseased tissue and organs.
Adult stem cells. These stem cells are found in small numbers in most adult tissues, such as bone marrow or fat. Compared with embryonic stem cells, adult stem cells have a more limited ability to give rise to various cells of the body.Until recently, researchers thought adult stem cells could create only similar types of cells. For instance, researchers thought that stem cells residing in the bone marrow could give rise only to blood cells.However, emerging evidence suggests that adult stem cells may be able to create various types of cells. For instance, bone marrow stem cells may be able to create bone or heart muscle cells.This research has led to early-stage clinical trials to test usefulness and safety in people. For example, adult stem cells are currently being tested in people with neurological or heart disease.
Adult cells altered to have properties of embryonic stem cells. Scientists have successfully transformed regular adult cells into stem cells using genetic reprogramming. By altering the genes in the adult cells, researchers can reprogram the cells to act similarly to embryonic stem cells.This new technique may allow use of reprogrammed cells instead of embryonic stem cells and prevent immune system rejection of the new stem cells. However, scientists don’t yet know whether using altered adult cells will cause adverse effects in humans.Researchers have been able to take regular connective tissue cells and reprogram them to become functional heart cells. In studies, animals with heart failure that were injected with new heart cells experienced improved heart function and survival time.
Perinatal stem cells. Researchers have discovered stem cells in amniotic fluid as well as umbilical cord blood. These stem cells have the ability to change into specialized cells.Amniotic fluid fills the sac that surrounds and protects a developing fetus in the uterus. Researchers have identified stem cells in samples of amniotic fluid drawn from pregnant women for testing or treatment — a procedure called amniocentesis.

Why is there a controversy about using embryonic stem cells?

Embryonic stem cells are obtained from early-stage embryos — a group of cells that forms when eggs are fertilized with sperm at an in vitro fertilization clinic. Because human embryonic stem cells are extracted from human embryos, several questions and issues have been raised about the ethics of embryonic stem cell research.

The National Institutes of Health created guidelines for human stem cell research in 2009. The guidelines define embryonic stem cells and how they may be used in research, and include recommendations for the donation of embryonic stem cells. Also, the guidelines state that embryonic stem cells from embryos created by in vitro fertilization can be used only when the embryo is no longer needed.

Where do these embryos come from?

The embryos being used in embryonic stem cell research come from eggs that were fertilized at in vitro fertilization clinics but never implanted in women’s uteruses. The stem cells are donated with informed consent from donors. The stem cells can live and grow in special solutions in test tubes or petri dishes in laboratories.

Why can’t researchers use adult stem cells instead?

Although research into adult stem cells is promising, adult stem cells may not be as versatile and durable as are embryonic stem cells. Adult stem cells may not be able to be manipulated to produce all cell types, which limits how adult stem cells can be used to treat diseases.

Adult stem cells are also more likely to contain abnormalities due to environmental hazards, such as toxins, or from errors acquired by the cells during replication. However, researchers have found that adult stem cells are more adaptable than was first thought.

What are stem cell lines and why do researchers want to use them?

A stem cell line is a group of cells that all descend from a single original stem cell and are grown in a lab. Cells in a stem cell line keep growing but don’t differentiate into specialized cells. Ideally, they remain free of genetic defects and continue to create more stem cells. Clusters of cells can be taken from a stem cell line and frozen for storage or shared with other researchers.

What is stem cell therapy (regenerative medicine) and how does it work?

Stem cell therapy, also known as regenerative medicine, promotes the repair response of diseased, dysfunctional or injured tissue using stem cells or their derivatives. It is the next chapter in organ transplantation and uses cells instead of donor organs, which are limited in supply.

Researchers grow stem cells in a lab. These stem cells are manipulated to specialize into specific types of cells, such as heart muscle cells, blood cells or nerve cells.

The specialized cells can then be implanted into a person. For example, if the person has heart disease, the cells could be injected into the heart muscle. The healthy transplanted heart muscle cells could then contribute to repairing the injured heart muscle.

Researchers have already shown that adult bone marrow cells guided to become heart-like cells can repair heart tissue in people, and more research is ongoing.

Have stem cells already been used to treat diseases?

Yes. Doctors have performed stem cell transplants, also known as bone marrow transplants. In stem cell transplants, stem cells replace cells damaged by chemotherapy or disease or serve as a way for the donor’s immune system to fight some types of cancer and blood-related diseases, such as leukemia, lymphoma, neuroblastoma and multiple myeloma. These transplants use adult stem cells or umbilical cord blood.

Researchers are testing adult stem cells to treat other conditions, including a number of degenerative diseases such as heart failure.

What are the potential problems with using embryonic stem cells in humans?

For embryonic stem cells to be useful, researchers must be certain that the stem cells will differentiate into the specific cell types desired.

Researchers have discovered ways to direct stem cells to become specific types of cells, such as directing embryonic stem cells to become heart cells. Research is ongoing in this area.

Embryonic stem cells can also grow irregularly or specialize in different cell types spontaneously. Researchers are studying how to control the growth and differentiation of embryonic stem cells.

Embryonic stem cells might also trigger an immune response in which the recipient’s body attacks the stem cells as foreign invaders, or the stem cells might simply fail to function as expected, with unknown consequences. Researchers continue to study how to avoid these possible complications.

What is therapeutic cloning, and what benefits might it offer?

Therapeutic cloning, also called somatic cell nuclear transfer, is a technique to create versatile stem cells independent of fertilized eggs. In this technique, the nucleus is removed from an unfertilized egg. This nucleus contains the genetic material. The nucleus is also removed from the cell of a donor.

This donor nucleus is then injected into the egg, replacing the nucleus that was removed, in a process called nuclear transfer. The egg is allowed to divide and soon forms a blastocyst. This process creates a line of stem cells that is genetically identical to the donor’s cells — in essence, a clone.

Some researchers believe that stem cells derived from therapeutic cloning may offer benefits over those from fertilized eggs because cloned cells are less likely to be rejected once transplanted back into the donor and may allow researchers to see exactly how a disease develops.

Has therapeutic cloning in people been successful?

No. Researchers haven’t been able to successfully perform therapeutic cloning with humans despite success in a number of other species.

However, in recent studies, researchers have created human pluripotent stem cells by modifying the therapeutic cloning process. Researchers continue to study the potential of therapeutic cloning in people.

A Doubled Gene Explains the Bowhead Whale’s Lifespan

Blitz Age — Mon, 31 Jul 2023 15:35:47 +0000

This gene slows down reproduction and protects against cancer.

Peto’s paradox

It would be logical for longer-lived animals to be more susceptible to cancer than shorter-lived animals over time, as they have longer to develop the mutations that lead to cancer. However, this is not the case; there is no correlation between lifespan and cancer. This counterintuitive finding is known as Peto’s paradox, which was originally discovered in 1975 [1] and backed up by studies performed this year [2].

This fact can be explained by genes that increase resilience to genomic instability. Mice that overexpress the tumor suppressor p53 and the cell cycle regulator CDKN2A live longer and are more resistant to cancer [3], despite the fact that CDKN2A is associated with cellular senescence. Increasing the presence of SIRT1, which protects against telomere attrition, protects mice against some aging-associated diseases, including cancer [4].

A whale of a lifespan

Unlike most cetaceans, which normally live between 50 and 70 years, the bowhead whale is estimated to have a lifespan of over two centuries [5]. It is far longer-lived than the right whale, which it diverged from between four and five million years ago. To live this long, it must have some extra resistance to cancer, even beyond the formidable cancer protection of other cetaceans.

Comparing the genes of the bowhead and its nearest relatives, the researchers found that CDKN2C is duplicated in a way that does not occur in related whales. Retrotransposition, a form of genetic mutation, had copied this gene into the cetacean-specific LINE L1 genetic sequence, which drives its substantial expression. Previous research has shown that this gene suppresses cancerous tumors [6].

This abundance of CDKN2C also dramatically slows down the cellular cycle of division and replication. In a way, this is related to the maxim ‘live slow, die old’ in longevity research, but this extra slowdown also gives cells more time to prevent cancerous mutations from occurring. While the researchers have not fully explored the biochemistry involved, they hypothesize that this extra time allows two related genes to do more work: CDKN2A, which inhibits cellular death by apoptosis, and CDKN2D, which enhances DNA repair mechanisms. Apparently, the cells are not just dividing more slowly; they are being more careful in their division.

On the other hand, the researchers also hypothesize that this protection leads to trade-offs in other areas (antagonistic pleiotropy). While it has not been proven, they suggest that this mutation may lead to slow maturation and reduced male fertility in these whales.

Conclusion

It is, of course, completely infeasible to do direct lifespan experiments on whales, even moreso than on humans; any such experiment would take mutliple (current) human lifetimes to complete. However, the gene CDKN2C exists in mice and in people. If this approach can be proven to work through trials, genetic or RNA-based therapies that cause the overexpression of this gene may become part of a near-term approach towards extending human lifespan.

We would like to ask you a small favor. We are a non-profit foundation, and unlike some other organizations, we have no shareholders and no products to sell you. We are committed to responsible journalism, free from commercial or political influence, that allows you to make informed decisions about your future health.

All our news and educational content is free for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, supports independent journalism and sustains our future. You can support us by making a donation or in other ways at no cost to you.

How Metabolic Syndrome Makes Aging Worse

Blitz Age — Mon, 31 Jul 2023 15:11:08 +0000

Metabolic syndrome drives many of the hallmarks of aging, and multiple hallmarks of aging drive metabolic syndrome in a vicious, accelerating cycle.

Central obesity, high triglycerides, low HDL cholesterol, high blood pressure, and elevated fasting glucose comprise a cluster of metabolic disorders that increase the risk of cardiovascular disease and type 2 diabetes and define metabolic syndrome [1].

All of the factors of metabolic syndrome are associated not just with age but with accelerated aging. For example, age-associated inflammation can lead to insulin resistance, impaired glucose metabolism, and dyslipidemia, all of which are components of metabolic syndrome [2].

A healthy lifestyle can reverse or significantly slow the progress of metabolic syndrome in many instances [3, 4]. There are multiple mechanisms linking metabolic syndrome and the primary hallmarks of aging: genomic instability, telomere attrition, epigenetic alterations, altered proteostasis, and disabled macroautophagy [5].

Genomic instability

Metabolic syndrome is linked to an increased risk of genomic instability and thus DNA damage. This, in turn, increases the risk of cancer and other diseases [6, 7].

Factors associated with metabolic syndrome, including insulin resistance, oxidative stress, and chronic inflammation, drive genomic instability. Insulin resistance, for example, can cause increased production of insulin and insulin-like growth factors, which can promote the growth and proliferation of cells and increase the risk of DNA damage [8].

Oxidative stress, which occurs when there is an imbalance between the production of reactive oxygen species (ROS) and the body’s antioxidant defenses, can also contribute to genomic instability. ROS can damage DNA and other cellular components, leading to mutations and other forms of genomic instability [7].

Chronic inflammation, which is a hallmark of metabolic syndrome, can also contribute to genomic instability through the release of cytokines and other molecules that can damage DNA and increase the risk of mutation [9]. Furthermore, oxidative damage is also a product of inflammation [10].

Telomere attrition

Telomeres are the protective caps at the end of chromosomes. They play a critical role in maintaining genomic stability. Telomere attrition, which refers to the gradual shortening of telomeres over time, is a hallmark of aging [11].

Metabolic syndrome has been linked to accelerated telomere attrition through increased oxidative stress, inflammation, and insulin resistance. Oxidative stress can damage telomeric DNA, leading to telomere shortening [12], while inflammation can accelerate telomere attrition by promoting cellular aging and DNA damage. Insulin resistance, which is a hallmark of metabolic syndrome, has also been linked to telomere attrition, likely due to the role of insulin in promoting cell proliferation and DNA replication [13-15].

Epigenetic alterations

Epigenetic alterations are changes in the way that genes are expressed without changing the underlying DNA sequence. These alterations can occur in response to environmental factors such as diet, physical activity, and exposure to toxins. Several studies have suggested that epigenetic alterations play a role in metabolic syndrome and that metabolic syndrome in a vicious cycle drives further alterations in the epigenome.

Additionally, epigenetic changes have been associated with obesity, a key component of metabolic syndrome. Adipose tissue, which is the main place that the body stores fat, has been shown to undergo significant epigenetic changes in response to changes in nutrient availability and metabolic stress. These changes can contribute to insulin resistance and other metabolic abnormalities [16, 17]. For example, high-fat diets have been shown to induce changes in DNA methylation patterns that lead to altered gene expression in a way that favors metabolic syndrome [18].

Loss of proteostasis

Proteostasis refers to the maintenance of protein homeostasis, which is essential for cellular and organismal health. The loss of proteostasis, which can occur due to genetic and environmental factors, is associated with several age-related diseases, including metabolic syndrome [19].

Several mechanisms have been proposed to explain the relationship between the loss of proteostasis and metabolic syndrome. For example, the accumulation of misfolded or aggregated proteins can activate stress response pathways, such as the unfolded protein response (UPR), which can lead to insulin resistance and other metabolic abnormalities [20].

Furthermore, proteostasis is closely linked to mitochondrial function, which is essential for cellular energy metabolism. Mitochondrial dysfunction, which can result from impaired proteostasis, can contribute to metabolic abnormalities by reducing cellular energy production and increasing oxidative stress [21].

Finally, the loss of proteostasis can also contribute to chronic inflammation, which is a hallmark of metabolic syndrome. Misfolded or damaged proteins can activate the immune system and induce the release of inflammatory cytokines, which can contribute to insulin resistance and other metabolic abnormalities [22]. Conversely, metabolic syndrome can aggravate faltering proteostasis through several mechanisms.

Metabolic syndrome often leads to increased oxidative stress, which can damage proteins and make them misfold. This misfolding disrupts proteostasis and can lead to the formation of protein aggregates, which are harmful to cells [23].

Chronic inflammation, a common symptom of metabolic syndrome, can also disrupt proteostasis. Inflammation can lead to the production of cytokines that interfere with the normal functioning of the proteostasis network. For example, inflammation can affect the function of the endoplasmic reticulum, a cellular organelle involved in protein folding [24].

Insulin resistance can also disrupt proteostasis. Insulin signaling is crucial for many aspects of cellular function, including protein synthesis. Therefore, insulin resistance can lead to the overproduction or underproduction of certain proteins, disrupting the balance of the proteostasis network [25].

High levels of lipids, a common characteristic of metabolic syndrome, can cause lipotoxicity, leading to the impairment of various cellular processes, including proteostasis. High lipid levels can induce endoplasmic reticulum stress and initiate the unfolded protein response pathway, which can ultimately disrupt the balance of protein synthesis, folding, and degradation [26].

Lastly, prolonged high blood sugar levels can lead to the formation of advanced glycation end-products (AGEs). These AGEs can alter protein structure and function, thus contributing to impaired proteostasis [27].

Disabled autophagy

Autophagy is a process by which cells break down and recycle damaged or dysfunctional cellular components. Autophagy is essential for maintaining cellular homeostasis and is involved in a wide range of physiological processes, including nutrient metabolism, inflammation, and cellular stress response [28].

Disabled autophagy has been implicated in the development of metabolic syndrome. Several studies have shown that impaired autophagy is associated with insulin resistance, dyslipidemia, and other metabolic abnormalities [28, 29].

One potential mechanism by which impaired autophagy contributes to metabolic syndrome is through the accumulation of damaged organelles, such as mitochondria, which can lead to increased oxidative stress and inflammation [30].

Furthermore, autophagy plays a crucial role in the regulation of lipid metabolism. Impaired autophagy has been shown to result in the accumulation of lipids in cells and tissues, which can lead to dyslipidemia and non-alcoholic fatty liver disease (NAFLD), a common complication of metabolic syndrome [29].

Finally, autophagy is involved in the regulation of energy metabolism and glucose homeostasis. Impaired autophagy can lead to the accumulation of misfolded proteins and other cellular components, which can activate stress response pathways, such as the UPR, and lead to insulin resistance and impaired glucose metabolism [22].

Antagonistic and integrative hallmarks of aging

The integrative and antagonistic hallmarks of aging, which are interconnected and influence each other, are also affected by metabolic syndrome. They collectively contribute to the aging phenotype and age-related diseases. They include deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, altered intercellular communication, chronic inflammation and dysbiosis [31].

Deregulated nutrient sensing

Nutrient sensing is the ability of cells to sense and respond to changes in nutrient availability. This process plays a crucial role in the regulation of energy metabolism and is essential for maintaining metabolic homeostasis. Deregulated nutrient sensing, which can occur due to genetic and environmental factors, may lead to metabolic syndrome [32].

One way in which deregulated nutrient sensing can contribute to metabolic syndrome is through insulin resistance [33]. Insulin is a hormone that regulates glucose and lipid metabolism. Deregulated nutrient sensing can disrupt insulin signaling pathways, leading to impaired glucose and lipid metabolism along with insulin resistance [34].

Furthermore, deregulated nutrient sensing can lead to the accumulation of excess nutrients, such as glucose and fatty acids, in cells and tissues [35]. This can promote lipotoxicity, a condition in which excess lipids accumulate in tissues and lead to cellular dysfunction and inflammation. Lipotoxicity can contribute to insulin resistance and other metabolic abnormalities [36, 37].

Additionally, deregulated nutrient sensing can lead to chronic low-grade inflammation (inflammaging) [38], which is a hallmark of metabolic syndrome. Excess nutrient availability can activate immune cells and promote cytokine release [39].

Finally, deregulated nutrient sensing can contribute to NAFLD. Excess nutrient availability can lead to the accumulation of lipids in liver cells, leading to hepatic steatosis and NAFLD [40].

Mitochondrial dysfunction

Mitochondria are organelles within cells that play a critical role in energy production and metabolism. Mitochondrial dysfunction, which refers to impaired mitochondrial function, has been implicated in metabolic syndrome [41].

Mitochondrial dysfunction can contribute to metabolic syndrome through several mechanisms. For example, impaired mitochondrial function can lead to reduced energy production, which can impair glucose and lipid metabolism and contribute to insulin resistance and other metabolic abnormalities [42]. Mitochondrial dysfunction can also lead to the accumulation of ROS, can contribute to NAFLD [43], and can contribute to inflammation through immune cell and cytokine activation [44].

Cellular senescence

Cellular senescence is a process in which cells stop dividing and enter a state of irreversible growth arrest. Cellular senescence plays a crucial role in aging and is associated with several age-related diseases, including metabolic syndrome [45]. The inflammaging associated with metabolic syndrome also increases the risk of cellular senescence [46].

Furthermore, metabolic syndrome is associated with oxidative stress, which can contribute to cellular senescence by inducing DNA damage and other forms of cellular stress. Oxidative stress can activate stress response pathways, such as the p53 pathway, which can induce cellular senescence [47]. Telomere attrition can also contribute to cellular senescence by activating stress response pathways and inducing cellular damage [48].

Finally, metabolic syndrome is associated with impaired proteostasis, which can contribute to cellular senescence by inducing the accumulation of misfolded or damaged proteins, leading to the activation of stress response pathways and other forms of cellular stress [49].

Stem cell exhaustion

Stem cell exhaustion refers to the depletion of the pool of stem cells in tissues due to aging or other factors. Stem cells play a crucial role in tissue regeneration and repair, and their exhaustion has been implicated in the development of several age-related diseases, including metabolic syndrome [41].

Metabolic syndrome is associated with the accumulation of cellular damage and stress, which can contribute to the depletion of stem cells. Inflammaging, oxidative stress, and impaired proteostasis can all induce cellular damage and stress and contribute to stem cell exhaustion [50].

Furthermore, metabolic syndrome is associated with impaired tissue regeneration and repair, which can be attributed, at least in part, to the depletion of stem cells. Impaired tissue regeneration and repair can lead to the accumulation of damage and stress, contributing to metabolic abnormalities [50, 51].

In addition, metabolic syndrome has been associated with impaired angiogenesis, which is the process by which new blood vessels form from pre-existing ones. Angiogenesis is essential for tissue regeneration and repair, and its impairment can alsocontribute to metabolic abnormalities [52].

Finally, metabolic syndrome is associated with insulin resistance, which can impair the function of stem cells through reactive oxygen species production, activation of inflammatory pathways, and disruption of the insulin/IGF signaling pathway. Insulin resistance can contribute to the depletion of stem cells and impair tissue regeneration and repair [34, 53, 54].

Altered intercellular communication and metabolic syndrome

Intercellular communication refers to the exchange of information between cells, which is essential for maintaining cellular homeostasis and physiological function. Alterations in intercellular communication have been implicated in the development of metabolic syndrome [41], and the inflammaging associated with metabolic syndrome can lead to intercellular communication disruption [55, 56].

Furthermore, altered intercellular communication can impair the function of adipose tissue, which plays a crucial role in energy metabolism and is dysregulated in metabolic syndrome. Adipose tissue communicates with other tissues through the release of adipokines, which can influence glucose and lipid metabolism [57]. Alterations in adipokine secretion can contribute to insulin resistance and other metabolic abnormalities [58].

In addition, altered intercellular communication can impair the function of the gut microbiota, which plays a critical role in nutrient metabolism and the regulation of inflammation. The gut microbiota communicates with host cells through the release of metabolites and other molecules, which can influence energy metabolism and immune function. Alterations in the gut microbiota can contribute to insulin resistance and other metabolic abnormalities [59]. Finally, altered intercellular communication can contribute to NAFLD as well [60, 61].

Inflammaging

Inflammaging, which is a common link between metabolic syndrome and other hallmarks of aging, is associated with insulin resistance, dyslipidemia, and hypertension [62]. Several factors can contribute to this, including excessive nutrients leading to immune activation [63]. Metabolic stress, such as that caused by insulin resistance, can also activate immune cells and promote inflammation [64].

Another factor that can contribute to chronic inflammation in metabolic syndrome is the accumulation of visceral adipose tissue. Adipose tissue produces pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6), which can contribute to insulin resistance and other metabolic abnormalities [65].

Furthermore, chronic inflammation can lead to the activation of stress response pathways, such as the UPR [66]. Chronic inflammation can also contribute to NAFLD [60].

Dysbiosis

Dysbiosis refers to an imbalance in the gut microbiota, the complex community of microorganisms that inhabit the gastrointestinal tract. Dysbiosis has been implicated in the development of several diseases, including metabolic syndrome [67].

The gut microbiota plays a critical role in nutrient metabolism and the regulation of inflammation. Dysbiosis can impair the function of the gut microbiota and contribute to metabolic abnormalities [67].

One of these pathways is insulin resistance [68, 69]. Dysbiosis can lead to the production of lipopolysaccharides (LPS), a molecule found in the outer membrane of certain bacteria, which can induce low-grade inflammation and contribute to insulin resistance [70]. Dysbiosis is linked to inflammaging [71] and NAFLD [72] as well.

Finally, dysbiosis can contribute to obesity, a key component of metabolic syndrome. Dysbiosis can alter the production of hormones and other molecules that regulate appetite and energy metabolism, leading to increased caloric intake and decreased energy expenditure [68].

Current and emerging strategies for managing metabolic syndrome

Given the multifaceted nature of metabolic syndrome and its association with the hallmarks of aging, the steps to mitigate its development should also be multi-targeted. There are potential steps that may influence metabolic syndrome and its effects on the hallmarks.

Regular physical activity and a balanced diet rich in fruits, vegetables, lean proteins, and whole grains can help maintain metabolic homeostasis, regulate nutrient sensing, and reduce excess nutrient accumulation in tissues. This can also help reduce obesity [73-75].

Anti-inflammatory diets that are rich in antioxidants and omega-3 fatty acids, or anti-inflammatory medications may help mitigate inflammaging [76]. Metformin and other glucose-lowering drugs can be beneficial in managing deregulated nutrient sensing and improving insulin sensitivity when used under medical supervision [77].

Supplements and interventions that support mitochondrial health, such as Coenzyme Q10 and PQQ, can potentially offset the mitochondrial dysfunction associated with metabolic syndrome [78]. Drugs like senolytics, which selectively remove senescent cells, could be helpful in managing metabolic syndrome [79].

Probiotics, prebiotics, and a diet promoting a healthy gut microbiome can address dysbiosis and reduce its contribution to metabolic syndrome [80]. Although this is a newer area of research, stem cell therapy could potentially help replenish the exhausted stem cell pool and support tissue regeneration and repair [81].

In conclusion, metabolic syndrome significantly intersects with the hallmarks of aging, and studies suggest that metabolic syndrome can accelerate aging by exacerbating these hallmarks.

Effective management and prevention of metabolic syndrome, therefore, could serve as a strategy for promoting healthy aging and delaying the onset of age-related diseases. This underscores the importance of early intervention and the adoption of healthy lifestyles, including a balanced diet and regular physical activity. Future research should continue exploring these critical interactions, ultimately leading to improved therapeutic approaches that address the multifaceted nature of aging and metabolic health.

Literature

[1] A. Tchernof and J. P. Després, “Pathophysiology of human visceral obesity: an update,” Physiol Rev, vol. 93, no. 1, pp. 359–404, Jan. 2013

[2] F. Bonomini, L. F. Rodella, and R. Rezzani, “Metabolic syndrome, aging and involvement of oxidative stress,” Aging Dis, vol. 6, no. 2, pp. 109–120, 2015

[3] N. J. Stone, “Successful control of dyslipidemia in patients with metabolic syndrome: focus on lifestyle changes,” Clin Cornerstone, vol. 8, no. SUPPL. 1, 2006

[4] P. M. Nilsson, J. Tuomilehto, and L. Rydén, “The metabolic syndrome – What is it and how should it be managed?,” Eur J Prev Cardiol, vol. 26, no. 2_suppl, pp. 33–46, Dec. 2019

[5] C. López-Otín, M. A. Blasco, L. Partridge, M. Serrano, and G. Kroemer, “Hallmarks of aging: An expanding universe,” Cell, vol. 186, no. 2, pp. 243–278, Jan. 2023

[6] S. Furukawa et al., “Increased oxidative stress in obesity and its impact on metabolic syndrome,” J Clin Invest, vol. 114, no. 12, pp. 1752–1761, May 2017

[7] M. Wlodarczyk and G. Nowicka, “Obesity, DNA Damage, and Development of Obesity-Related Diseases,” International Journal of Molecular Sciences 2019, Vol. 20, Page 1146, vol. 20, no. 5, p. 1146, Mar. 2019

[8] M. S. Lewitt, M. S. Dent, and K. Hall, “The Insulin-Like Growth Factor System in Obesity, Insulin Resistance and Type 2 Diabetes Mellitus,” Journal of Clinical Medicine 2014, Vol. 3, Pages 1561-1574, vol. 3, no. 4, pp. 1561–1574, Dec. 2014

[9] L. M. Coussens and Z. Werb, “Inflammation and cancer,” Nature 2002 420:6917, vol. 420, no. 6917, pp. 860–867, Dec. 2002

[10] M. Mittal, M. R. Siddiqui, K. Tran, S. P. Reddy, and A. B. Malik, “Reactive oxygen species in inflammation and tissue injury,” Antioxid Redox Signal, vol. 20, no. 7, pp. 1126–1167, Mar. 2014

[11] C. López-Otín, M. A. Blasco, L. Partridge, M. Serrano, and G. Kroemer, “The hallmarks of aging,” Cell, vol. 153, no. 6, p. 1194, Jun. 2013

[12] R. P. Barnes, E. Fouquerel, and P. L. Opresko, “The impact of oxidative DNA damage and stress on telomere homeostasis,” Mech Ageing Dev, vol. 177, pp. 37–45, Jan. 2019

[13] D. Révész et al., “Associations between cellular aging markers and metabolic syndrome: Findings from the cardia study,” Journal of Clinical Endocrinology and Metabolism, vol. 103, no. 1, pp. 148–157, 2018

[14] D. Révész, Y. Milaneschi, J. E. Verhoeven, and B. W. J. H. Penninx, “Telomere length as a marker of cellular aging is associated with prevalence and progression of metabolic syndrome,” Journal of Clinical Endocrinology and Metabolism, vol. 99, no. 12, pp. 4607–4615, Dec. 2014

[15] D. Révész, Y. Milaneschi, J. E. Verhoeven, J. Lin, and B. W. J. H. Penninx, “Longitudinal Associations Between Metabolic Syndrome Components and Telomere Shortening,” J Clin Endocrinol Metab, vol. 100, no. 8, pp. 3050–3059, Aug. 2015

[16] O. Ramos-Lopez, J. I. Riezu-Boj, and F. I. Milagro, “Genetic and epigenetic nutritional interactions influencing obesity risk and adiposity outcomes,” Curr Opin Clin Nutr Metab Care, vol. 25, no. 4, pp. 235–240, Jul. 2022

[17] P. Cordero, J. Li, and J. A. Oben, “Epigenetics of obesity: Beyond the genome sequence,” Curr Opin Clin Nutr Metab Care, vol. 18, no. 4, pp. 361–366, Jul. 2015

[18] R. S. Strakovsky, X. Zhang, D. Zhou, and Y. X. Pan, “Gestational high fat diet programs hepatic phosphoenolpyruvate carboxykinase gene expression and histone modification in neonatal offspring rats,” J Physiol, vol. 589, no. Pt 11, pp. 2707–2717, Jun. 2011

[19] F. Ottens, A. Franz, and T. Hoppe, “Build-UPS and break-downs: metabolism impacts on proteostasis and aging,” Cell Death Differ, vol. 28, no. 2, p. 505, Feb. 2021

[20] U. Özcan et al., “Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes,” Science, vol. 306, no. 5695, pp. 457–461, Oct. 2004

[21] B. Lu and S. Guo, “Mechanisms Linking Mitochondrial Dysfunction and Proteostasis Failure,” Trends Cell Biol, vol. 30, no. 4, pp. 317–328, Apr. 2020

[22] G. S. Hotamisligil, “Endoplasmic reticulum stress and the inflammatory basis of metabolic disease,” Cell, vol. 140, no. 6, pp. 900–917, 2010

[23] N. Gregersen and P. Bross, “Protein misfolding and cellular stress: An overview,” Methods in Molecular Biology, vol. 648, pp. 3–23, 2010

[24] S. Z. Hasnain, R. Lourie, I. Das, A. C. H. Chen, and M. A. McGuckin, “The interplay between endoplasmic reticulum stress and inflammation,” Immunol Cell Biol, vol. 90, no. 3, pp. 260–270, Mar. 2012

[25] H. A. James, B. T. O’Neill, and K. S. Nair, “Insulin Regulation of Proteostasis and Clinical Implications,” Cell Metab, vol. 26, no. 2, p. 310, Aug. 2017

[26] N. Ho, C. Xu, and G. Thibault, “From the unfolded protein response to metabolic diseases – Lipids under the spotlight,” J Cell Sci, vol. 131, no. 3, Feb. 2018

[27] J. Chaudhuri et al., “The role of advanced glycation end products in aging and metabolic diseases: bridging association and causality,” Cell Metab, vol. 28, no. 3, p. 337, Sep. 2018

[28] N. Mizushima, T. Yoshimori, and Y. Ohsumi, “The Role of Atg Proteins in Autophagosome Formation,” Annual review of cell and developmental biology, vol. 27, pp. 107–132, Oct. 2011

[29] R. Singh et al., “Autophagy regulates lipid metabolism,” Nature, vol. 458, no. 7242, pp. 1131–1135, Apr. 2009

[30] G. Ashrafi and T. L. Schwarz, “The pathways of mitophagy for quality control and clearance of mitochondria,” Cell Death Differ., vol. 20, no. 1, pp. 31–42, Jan. 2013

[31] C. López-Otín, M. A. Blasco, L. Partridge, M. Serrano, and G. Kroemer, “Hallmarks of aging: An expanding universe,” Cell, vol. 186, no. 2, pp. 243–278, Jan. 2023.

[32] M. Laplante and D. M. Sabatini, “mTOR signaling in growth control and disease,” Cell, vol. 149, no. 2, pp. 274–293, Apr. 2012

[33] V. T. Samuel and G. I. Shulman, “Mechanisms for insulin resistance: Common threads and missing links,” Cell, vol. 148, no. 5, pp. 852–871, Mar. 2012

[34] V. T. Samuel and G. I. Shulman, “The pathogenesis of insulin resistance: integrating signaling pathways and substrate flux,” J Clin Invest, vol. 126, no. 1, pp. 12–22, Jan. 2016

[35] C. B. Newgard, “Interplay between lipids and branched-chain amino acids in development of insulin resistance,” Cell Metab, vol. 15, no. 5, pp. 606–614, May 2012

[36] R. Stinkens, G. H. Goossens, J. W. E. Jocken, and E. E. Blaak, “Targeting fatty acid metabolism to improve glucose metabolism,” Obesity Reviews, vol. 16, no. 9, pp. 715–757, Sep. 2015

[37] R. C. R. Meex, E. E. Blaak, and L. J. C. van Loon, “Lipotoxicity plays a key role in the development of both insulin resistance and muscle atrophy in patients with type 2 diabetes,” Obes Rev, vol. 20, no. 9, pp. 1205–1217, 2019

[38] G. S. Hotamisligil, “Inflammation and metabolic disorders,” Nature 2006 444:7121, vol. 444, no. 7121, pp. 860–867, Dec. 2006

[39] Y. Alwarawrah, K. Kiernan, and N. J. MacIver, “Changes in nutritional status impact immune cell metabolism and function,” Front Immunol, vol. 9, no. MAY, p. 1055, May 2018

[40] B. Khambu, S. Yan, N. Huda, G. Liu, and X. M. Yin, “Autophagy in non-alcoholic fatty liver disease and alcoholic liver disease,” Liver Res, vol. 2, no. 3, pp. 112–119, Sep. 2018

[41] C. López-Otín, M. A. Blasco, L. Partridge, M. Serrano, and G. Kroemer, “The hallmarks of aging,” Cell, vol. 153, no. 6, p. 1194, Jun. 2013.

[42] K. Kolczynska, A. Loza-Valdes, I. Hawro, and G. Sumara, “Diacylglycerol-evoked activation of PKC and PKD isoforms in regulation of glucose and lipid metabolism: a review,” Lipids in Health and Disease 2020 19:1, vol. 19, no. 1, pp. 1–15, May 2020

[43] R. J. Mailloux, “An Update on Mitochondrial Reactive Oxygen Species Production,” Antioxidants 2020, Vol. 9, Page 472, vol. 9, no. 6, p. 472, Jun. 2020

[44] M. J. López-Armada, R. R. Riveiro-Naveira, C. Vaamonde-García, and M. N. Valcárcel-Ares, “Mitochondrial dysfunction and the inflammatory response,” Mitochondrion, vol. 13, no. 2, pp. 106–118, Mar. 2013

[45] D. Muñoz-Espín and M. Serrano, “Cellular senescence: From physiology to pathology,” Nat Rev Mol Cell Biol, vol. 15, no. 7, pp. 482–496, 2014

[46] R. Spinelli et al., “Increased cell senescence in human metabolic disorders,” J Clin Invest, vol. 133, no. 12, 2023

[47] M. Monserrat-Mesquida et al., “Metabolic Syndrome Is Associated with Oxidative Stress and Proinflammatory State,” Antioxidants 2020, Vol. 9, Page 236, vol. 9, no. 3, p. 236, Mar. 2020

[48] D. Révész, Y. Milaneschi, J. E. Verhoeven, J. Lin, and B. W. J. H. Penninx, “Longitudinal Associations Between Metabolic Syndrome Components and Telomere Shortening,” J Clin Endocrinol Metab, vol. 100, no. 8, pp. 3050–3059, Aug. 2015

[49] N. Gregersen and P. Bross, “Protein misfolding and cellular stress: An overview,” Methods in Molecular Biology, vol. 648, pp. 3–23, 2010

[50] K. S. Rajagopalan et al., “Metabolic Syndrome Induces Epigenetic Alterations in Mitochondria-Related Genes in Swine Mesenchymal Stem Cells,” Cells, vol. 12, no. 9, p. 1274, May 2023

[51] E. Mansilla et al., “Could metabolic syndrome, lipodystrophy, and aging be mesenchymal stem cell exhaustion syndromes?,” Stem Cells Int, 2011

[52] R. Soares, “Angiogenesis in the metabolic syndrome,” Oxidative Stress, Inflammation and Angiogenesis in the Metabolic Syndrome, pp. 85–99, 2009

[53] A. Salminen, K. Kaarniranta, and A. Kauppinen, “Insulin/IGF-1 signaling promotes immunosuppression via the STAT3 pathway: impact on the aging process and age-related diseases,” Inflammation Research, vol. 70, no. 10–12, pp. 1043–1061, 2021

[54] S. Hurrle and W. H. Hsu, “The etiology of oxidative stress in insulin resistance,” Biomed J, vol. 40, no. 5, pp. 257–262, Oct. 2017

[55] K. Esposito and D. Giugliano, “The metabolic syndrome and inflammation: association or causation?,” Nutrition, Metabolism and Cardiovascular Diseases, vol. 14, no. 5, pp. 228–232, Oct. 2004

[56] M. Kabátková et al., “Interactive effects of inflammatory cytokine and abundant low-molecular-weight PAHs on inhibition of gap junctional intercellular communication, disruption of cell proliferation control, and the AhR-dependent transcription,” Toxicol Lett, vol. 232, no. 1, pp. 113–121, Jan. 2015

[57] B. B. BRANDAO, E. ALTINDIS, R. GARCIA MARTIN, and C. R. KAHN, “Serum Exosomal Proteins—A New Component of Intercellular Communication in Metabolism,” Diabetes, vol. 67, no. Supplement_1, Jul. 2018

[58] P. Trayhurn, B. Wang, and I. S. Wood, “Hypoxia in adipose tissue: a basis for the dysregulation of tissue function in obesity?,” Br J Nutr, vol. 100, no. 2, pp. 227–235, 2008

[59] P. X. Wang, X. R. Deng, C. H. Zhang, and H. J. Yuan, “Gut microbiota and metabolic syndrome,” Chin Med J (Engl), vol. 133, no. 7, p. 808, Apr. 2020

[60] M. Arrese, D. Cabrera, A. M. Kalergis, and A. E. Feldstein, “Innate Immunity and Inflammation in NAFLD/NASH,” Dig Dis Sci, vol. 61, no. 5, pp. 1294–1303, May 2016

[61] M. M. Yeh and E. M. Brunt, “Pathological features of fatty liver disease,” Gastroenterology, vol. 147, no. 4, pp. 754–764, Oct. 2014

[62] V. Guarner and M. E. Rubio-Ruiz, “Low-Grade Systemic Inflammation Connects Aging, Metabolic Syndrome and Cardiovascular Disease,” Interdiscip Top Gerontol, vol. 40, pp. 99–106, Oct. 2014

[63] T. Caputo, F. Gilardi, and B. Desvergne, “From chronic overnutrition to metaflammation and insulin resistance: adipose tissue and liver contributions,” FEBS Lett, vol. 591, no. 19, pp. 3061–3088, Oct. 2017

[64] Q. Yuan, Z. L. Zeng, S. Yang, A. Li, X. Zu, and J. Liu, “Mitochondrial Stress in Metabolic Inflammation: Modest Benefits and Full Losses,” Oxid Med Cell Longev, vol. 2022, 2022

[65] K. Rabe, M. Lehrke, K. G. Parhofer, and U. C. Broedl, “Adipokines and Insulin Resistance,” Molecular Medicine 2008 14:11, vol. 14, no. 11, pp. 741–751, Nov. 2008

[66] J. Grootjans, A. Kaser, R. J. Kaufman, and R. S. Blumberg, “The unfolded protein response in immunity and inflammation,” Nature Reviews Immunology 2016 16:8, vol. 16, no. 8, pp. 469–484, Jun. 2016

[67] S. Carding, K. Verbeke, D. T. Vipond, B. M. Corfe, and L. J. Owen, “Dysbiosis of the gut microbiota in disease,” Microb Ecol Health Dis, vol. 26, no. 0, Feb. 2015

[68] E. Amabebe, F. O. Robert, T. Agbalalah, and E. S. F. Orubu, “Microbial dysbiosis-induced obesity: role of gut microbiota in homoeostasis of energy metabolism,” British Journal of Nutrition, vol. 123, no. 10, pp. 1127–1137, May 2020

[69] E. Lazar, A. Sherzai, J. Adeghate, and D. Sherzai, “Gut dysbiosis, insulin resistance and Alzheimer’s disease: Review of a novel approach to neurodegeneration,” Frontiers in Bioscience – Scholar, vol. 13, no. 1, pp. 17–29, Jun. 2021

[70] M. V. Salguero, M. A. I. Al-Obaide, R. Singh, T. Siepmann, and T. L. Vasylyeva, “Dysbiosis of Gram-negative gut microbiota and the associated serum lipopolysaccharide exacerbates inflammation in type 2 diabetic patients with chronic kidney disease,” Exp Ther Med, vol. 18, no. 5, pp. 3461–3469, Nov. 2019

[71] R. Tyszkowski and R. Mehrzad, “Inflammation: A multifaceted and omnipresent phenomenon,” Inflammation and Obesity: A New and Novel Approach to Manage Obesity and its Consequences, pp. 19–30, Jan. 2023

[72] C. O. M. Jasirwan, C. R. A. Lesmana, I. Hasan, A. S. Sulaiman, and R. A. Gani, “The role of gut microbiota in non-alcoholic fatty liver disease: pathways of mechanisms,” Biosci Microbiota Food Health, vol. 38, no. 3, p. 81, 2019

[73] J. Myers, P. Kokkinos, and E. Nyelin, “Physical Activity, Cardiorespiratory Fitness, and the Metabolic Syndrome,” Nutrients 2019, Vol. 11, Page 1652, vol. 11, no. 7, p. 1652, Jul. 2019

[74] I. Hoyas and M. Leon-Sanz, “Nutritional Challenges in Metabolic Syndrome,” Journal of Clinical Medicine 2019, Vol. 8, Page 1301, vol. 8, no. 9, p. 1301, Aug. 2019

[75] S. M. Grundy et al., “Diagnosis and management of the metabolic syndrome: An American Heart Association/National Heart, Lung, and Blood Institute scientific statement,” Circulation, vol. 112, no. 17, pp. 2735–2752, Oct. 2005

[76] J. Wärnberg, S. Gomez-Martinez, J. Romeo, L. E. Díaz, and A. Marcos, “Nutrition, Inflammation, and Cognitive Function,” Ann N Y Acad Sci, vol. 1153, no. 1, pp. 164–175, Feb. 2009

[77] Z. Lv and Y. Guo, “Metformin and Its Benefits for Various Diseases,” Front Endocrinol (Lausanne), vol. 11, p. 191, Apr. 2020

[78] T. Pham et al., “MitoQ and CoQ10 supplementation mildly suppresses skeletal muscle mitochondrial hydrogen peroxide levels without impacting mitochondrial function in middle-aged men,” European Journal of Applied Physiology 2020 120:7, vol. 120, no. 7, pp. 1657–1669, May 2020

[79] E. O. Wissler Gerdes, Y. Zhu, T. Tchkonia, and J. L. Kirkland, “Discovery, development, and future application of senolytics: theories and predictions,” FEBS J, vol. 287, no. 12, pp. 2418–2427, Jun. 2020

[80] R. Kumar, U. Sood, V. Gupta, M. Singh, J. Scaria, and R. Lal, “Recent Advancements in the Development of Modern Probiotics for Restoring Human Gut Microbiome Dysbiosis,” Indian Journal of Microbiology 2019 60:1, vol. 60, no. 1, pp. 12–25, May 2019

[81] W. Zakrzewski, M. Dobrzynski, M. Szymonowicz, and Z. Rybak, “Stem cells: Past, present, and future,” Stem Cell Res Ther, vol. 10, no. 1, pp. 1–22, Feb. 2019

Life extension – Blitz Age

Unveiling the mTOR Pathway – A Gateway to Life Extension and Immune Modulation

The mTOR Pathway: A Master Regulator of Cellular Processes

Rapamycin and Rapalogs: Targeting mTOR for Health and Longevity

Rapamycin in Autoimmune Disease Management:

Rapamycin and Longevity:

Rapalogs: Enhancing the Benefits of mTOR Inhibition:

Comparing mTOR Inhibitors with Other Therapeutic Agents

Calcineurin Inhibitors (e.g., Tacrolimus):

Metformin:

Integrating mTOR Inhibition into a Comprehensive Life Extension Strategy

The Future of mTOR Modulation in Life Extension

Unlocking the Future of Life Extension: The Power of Organ Regeneration and Genetic Innovation

The Crucial Role of Organ Regeneration in Life Extension

Genetic Innovation: The Blueprint for Longevity

Broader Applications: Beyond Human Health

The Path Forward: Encouraging Research and Investment

Conclusion: A New Era of Longevity

Comprehensive Analysis: Peroxisomes, PPARs, AMPK, and Life Extension

Recent Advancements in Aging Research

Mitochondrial Function and Aging

Peroxisomes and Their Functions

Key Functions of Peroxisomes:

Roles of PPARs

Role of AMPK

Pharmacological Interventions and Longevity

Pharmaceutical Development and Peroxisome-Related Drugs

Latest Research in Life Extension

Proteomics and Genomics

Novel Pharmacological Agents

Lifestyle Interventions

Practical Examples of Dual PPAR Agonists

Expanded Content on Life Extension and Related Areas

Plasmalogens and Lipid Rafts

Advanced Pharmaceutical Development

Development of Antioxidant Therapies

Gene Therapy and Life Extension

Innovative Drug Development

Decrease Oxygen to Boost Longevity?

RELATED STORIES

Unraveling the Mysteries of Aging

Loss of Epigenetic Information Can Drive Aging, Restoration Can Reverse It

Defining Aging

Aging Connection

Life Extension Treatments: A New Era in Anti-Aging

What is Life Extension?

The Science Behind Life Extension

The Current Role of Drugs in Life Extension

The Power of Vitamin D3

The Impact of Technology on Lifespan

Stem Cell Therapy: A Promising Future

The Future of Life Extension with Mesenchymal Stem Cells

Rejuvenation Strategies

Rejuvenation and Regeneration of Aged Cells

Tissue Repair and Regeneration

Benefits of Stem Cells in Anti-aging Treatments

Discover the potential of stem cells for yourself!

The Benefits of Life Extension

Economic and Societal Implications

The Controversy Surrounding Life Extension

Critics’ Arguments

Future Studies and Developments

The Possibility of an Indefinite Lifespan

The Impact of Diet and Physical Activity

The Role of Weight Management

Life Extension with Stem Cells

Uncover the Cost of Stem Cell Therapy Now!

The Future of Life Extension: Radical Approaches and Ethical Considerations

Ethical Considerations and Future Developments

Find out if you are a candidate.

Frequently Asked Questions

What is the maximum human lifespan?

Can we live up to 200 years?

What is the cure for aging in 2023?

What are the benefits of extending the human lifespan?

What are the ethical considerations of life extension?

References

Recent Neurotherapeutic Strategies to Promote Healthy Brain Aging: Are we there yet?

Abstract

1.Introduction