CEO and Founder at The Institute for Human Optimization

Dr. Anil Bajnath, MD, IFMCP, ABAARM, is a board-certified family physician who specializes in precision and anti-aging medicine. His practice offers a range of services from conventional preventative screening guidelines to precision personalized healthcare modalities including individualized nutrition, genomic medicine, advanced biomarker testing, microbiome analysis, and biometric lifestyle monitoring.

Dr. Bajnath sees patients in his clinic in Annapolis, Maryland, and also offers telemedicine consultations. To schedule an appointment with Dr. Bajnath or learn more about his research, click here.

Overview | Longevity connection | How they work | Glycation | Blood sugar | Lipids | Senolytics | References

In this long-awaited “berberine vs. metformin” article series, we collaborated with Dr. Anil Bajnath, MD, the founder of the Institute for Human Optimization and an expert in the field of longevity and anti-aging medicine. Dr. Bajnath started with a basic overview of each compound, how they work, and dived right into some exciting evidence and potential benefits of berberine and metformin for longevity.

While both berberine and metformin have various uses, in this article we focus on anti-aging and longevity. For those of you who are interested in berberine as a natural substitute to metformin, make sure to read our second article on this series, as we’ll be diving into some important cautions and potential side effects of berberine along with strategies to mitigate them.

What is metformin?

Metformin is a medication that’s used to help control blood sugar. In fact, it’s the most prescribed medication for type 2 diabetes and has been used since the 1950s. Here are a few things you should know about metformin:

• Millions of people take metformin daily for diabetes or prediabetes^[1].
• Mainstream doctors also prescribe metformin for polycystic ovarian syndrome (PCOS). This is a condition of hormonal imbalance that’s fairly common in women. You can think about PCOS as diabetes of the ovaries, as some of the same biochemical pathways we see in diabetes are involved.
• Because it’s so commonly prescribed, metformin has been widely studied over the course of many years. This means that we have a lot of data on metformin – both on its beneficial effects and its possible side effects. In fact, this huge amount of data is one reason that some people prefer metformin over berberine. You know exactly what to expect with a medication that is so well-studied.

What is berberine?

Berberine is a plant-derived compound that’s been used in traditional Chinese medicine and Ayurvedic medicine for thousands of years.

• Berberine is found in a variety of different plants, including goldenseal, Oregon grape, and barberry.
• In traditional medicine, berberine has a wide variety of uses including treating infections, improving digestive issues, supporting the liver and kidney, and even as a remedy for skin and eye problems^[2].
• Although berberine has not been quite as widely studied as metformin, it has received quite a bit of attention in research studies. Admittedly, the data on berberine is not quite as robust as the data on metformin, we don’t have as many years of research on this compound. Still, we do know quite a bit about berberine, and what we’ve learned so far is intriguing.

The longevity story of metformin and berberine

Because metformin has been so widely prescribed, its effect on mortality has been studied extensively. Initially, the researchers found that diabetic patients who took metformin had a longer lifespan. But was it because metformin was able to reduce the negative side effects of chronic high blood sugar or something else? The researchers started to wonder whether metformin’s ability to extend lifespan might go beyond its ability to help with diabetes, and whether it might promote longevity in people without diabetes too. Since then, we have seen a growing number of studies involving healthy non-diabetic subjects, with promising results.

One landmark study in non-diabetic mice showed that metformin increased mean lifespan by 37.8%, and maximum lifespan by 10.3%^[3]. These are promising results. Interestingly, studies with berberine have shown similar effects. When middle aged mice were given berberine, their overall survival was extended by 16.5%, and their remaining time increased by 80%. Even more, their fitness level and fur density were also improved^[4].

So, we have evidence that both berberine and metformin may extend lifespan and healthspan. We do need to consider, however, that for humans, it’s harder to get reliable data on the effects a compound may have on longevity. You can simply give mice metformin or berberine every day for their whole lives and see what happens, but there are a lot of reasons why this approach won’t work in humans. Our lifespan is much longer. Not to mention, it’s unrealistic to expect people to agree to be randomized to taking a drug or a placebo every day for their entire lives. And even if they did agree, it’s extremely unlikely that they’d all successfully follow through.

Additionally, at this point we don’t yet have data on exactly how much metformin or berberine could increase our lifespan or healthspan. Instead, we can look at surrogate markers for healthy aging, like the formation of advanced glycation end products (AGEs), and various risk factors such as high blood sugar. (We’ll cover more on these in this article as well). The good news here, is that as we speak, researchers continue to dive into the anti-aging activity of berberine and metformin. With studies like the Targeting Aging with Metformin (TAME) trial in progress, we should have much more data soon.

One thing is certain. At this point, we already see the longevity promoting potential of both metformin and berberine.

How berberine and metformin promote longevity

Although berberine and metformin are fairly different chemically, they both activate an important central pathway known as AMPK, that has been shown to play a key role in longevity and aging^[5].

AMPK regulates glucose and lipid metabolism within the cell, causing cells to take up and more effectively use these nutrients. This results in efficient energy production in the cells. Activating AMPK has also been extensively studied as a way to promote autophagy^[6] – the process by which the body gets rid of old or damaged cells. Autophagy can help with longevity and may reduce cancer risk by removing damaged cells before they can become malignant. AMPK can also encourage new cell growth, which may help to maintain healthy functioning tissues.

Because AMPK is involved in so many different processes within the cell, both berberine and metformin have a wide variety of effects on health. Next, we’ll dive into some of the key potential benefits related to longevity.

Glycation and blood sugar control

An emerging body of research suggests that blood sugar control may be very beneficial for our health and longevity. When blood glucose levels rise, the sugar starts reacting with proteins around it, creating a class of harmful compounds called advanced glycation end products, or AGEs. The accumulation of AGEs in various tissues is a known hallmark of aging, and has shown to contribute to many age-related diseases^[7].

You may recognize one type of AGE, hemoglobin A1c (also known as HbA1c or A1c) from the last bloodwork your doctor ordered, as this is the test that measures your average blood sugar levels over the past 3 months.

The higher your blood sugar levels are, the more A1c AGEs are formed. Not surprisingly, higher A1c levels are strongly correlated with increased mortality. Compared with people who have a normal A1c levels (below 5.6), those with an A1c of 6.5 have a 30% greater risk of death within a decade or so^[8]. And if you think this is bad, in those with an A1c of 9.0 or greater, mortality risk is nearly doubled.

Time for some good news. Turns out that both berberine and metformin may be great options to help control blood sugar and glycation:

• Metformin is well-known for this effect as it is such a widely used diabetes drug. To give you an idea, metformin can lower A1c by 1.1 points on average. So, someone whose A1c is 7.5 before taking metformin, can expect to get to about 6.4 with metformin^[9]. That said, the specific results can vary from person to person, and there are many other factors to consider that can affect A1c levels.
• Berberine has also been found to be effective in reducing A1c^[10]. In fact, according to some evidence, berberine may have an edge when it comes to blood sugar control. A recent large meta-analysis of several randomized controlled trials showed that berberine was more effective at improving insulin resistance than metformin^[11].
• Taking metformin with berberine. In some cases, people take both berberine and metformin at the same time, and there’s actually some research showing that this combined approach may be more effective than each compound alone^[12]. I wouldn’t recommend taking them both if you don’t have any issues with your blood sugar control, however, as that may be an overkill. You could potentially lower your blood sugar too much. But if you are struggling with your blood sugar this may be something you and your doctor can consider.

Lipid metabolism

Next to blood glucose control, making sure your blood lipids are optimal is another important anti-aging strategy shown to help with longevity, lifespan, and age‐related disease prevention^[13].

Also here, both metformin and berberine have demonstrated efficacy, with berberine performing somewhat better than metformin in some studies. Those who took berberine had slightly lower total cholesterol and LDL, and higher HDL, than those who took metformin^[14]. These differences were not huge, but we can definitely say that berberine was shown to be effective at improving blood lipid levels, at least as well as metformin.

Even more, the lipid-lowering activity of berberine has also been compared to simvastatin, a drug widely prescribed for people with imbalances in blood lipid levels. The efficacy of berberine was found comparable to simvastatin. Much like the results of pairing berberine and metformin for glucose control, combining berberine with simvastatin was more effective in lowering LDL than each alone^[15]. On that note, and similarly to blood glucose, the idea is to reach optimal levels, and not to reduce the levels as low as you can. High levels of circulating LDL are indeed associated with both cardiovascular and all-cause mortality^[16], but very low levels have also been shown to increase mortality risk^[17].

Interestingly, both berberine and metformin regulate lipid metabolism through a variety of mechanisms. One of these is through the inhibition of a protein called PCSK9. This protein can attach itself to LDL receptors, which inhibits the uptake of LDL into the cell, leaving more of it in the blood. By inhibiting PCSK9, the uptake of LDL cholesterol into the cells is enhanced, so that blood levels are then lowered^[18,19,20]. Additionally, through their activation of AMPK, both berberine and metformin are also able to increase the expression of the LDL receptor, which causes more LDL to end up in cells and less of it to circulate in the blood.

Are berberine and metformin senolytics?

If the thought of mutated cells wreaking havoc throughout your entire body sounds like a scene from from a scary sci-fi movie, you may want to sit down before you continue to read, as we are about to share interesting research on cells known in the literature as zombie cells.

For those of you who may not be familiar with senescent cells and their role in aging, here’s a brief summary.

• Senescent cells are damaged aging cells that stop dividing and multiplying but don’t die when they should. Just like zombies, they stick around and cause a whole lot of trouble to nearby healthy cells.
• As a part of the problem they cause, senescent cells release substances that can interfere with the functioning of healthy cells around them. Studies have shown that senescent cells tend to accumulate in aging tissues all over the body and are linked to age-related disease^[21].
• On the flip side, preventing the accumulation of “zombie cells” has shown promise in delaying the onset of certain conditions. You as may expect, cellular senescence is considered by many longevity researchers as a major contributor to the aging process and is a known hallmark of aging^[22].
• Senolytics are agents that cause senescent cells to die off, which could help to slow the process of aging and reduce the risk of age-related diseases. For this reason, senolytics have generated a surge of interest in the anti-aging world, as a potential way to slow aging^[23].

Now, neither berberine nor metformin is technically a senolytic because they don’t directly cause the death of senescent cells. They can, however, help with senescent cells indirectly by promoting autophagy. As the body gets rid of old and tired cells that are no longer functional, this can also mean reducing the senescent cell burden.

On that note, there’s a lot more to be said about senescent cells. If you are looking for ways to help your body remove senescent cells, make sure to subscribe to our longevity newsletter, as we will cover this topic more extensively in the upcoming articles, including natural senolytics, supplements, foods, and other practical evidence-based ways that can help your body get rid of these zombie cells.

Berberine vs. metformin – Final thoughts

As you can see, both berberine and metformin have shown a lot of anti-aging potential. But which one is the right one for you?

While everyone is different, in general, I tend to recommend berberine over metformin for my patients who are interested in longevity. As a natural way to support healthy aging, berberine has shown to be safer, has a wider array of benefits, and according to the data, seems at least as effective as metformin. In fact, there are certain side effects that are more common with metformin that seem to be reduced or absent with berberine.

Additionally, berberine is known to have pleiotropic effects^[24], which means it can act on more than one target in the body. This means you may get several other health benefits when you take berberine.

If you are considering adding berberine to your natural anti-aging or longevity supplement stack, you may want to have a look into our next article titled Is berberine a good natural alternative to metformin? I shared some cautious concerns about berberine and ways to mitigate them.

Despite having different structures, metformin and berberine have many similar activities, making them both potential effective treatments for type 2 diabetes (T2DM), obesity, cardiac disorders, tumors, and inflammation [1].

This article will explore the benefits of berberine vs. metformin for anti-aging effects, diabetes, weight loss, and PCOS. Additionally, we’ll explore the side effects of berberine and metformin.

What is Berberine?

Berberine is a bioactive substance found in a variety of plants, such as the Berberis, which is a group of shrubs [2].

It technically belongs to a group of substances known as alkaloids. It is also a yellow substance that has frequently been used as a dye.

Berberine has been used for centuries in traditional Chinese medicine to treat diseases. In fact, one of berberine’s significant effects is to trigger the cellular enzyme AMP-activated protein kinase (AMPK) [3].

When there is an energy deficit, the AMPK enzyme gets activated to perform its activity. Examples of energy deficits are during fasting or exercise. Thus, activation of the AMPK could reduce fat storage and improve longevity.

Oftentimes, the AMPK enzyme is present in the cells of major organs such as the liver, kidney, heart, brain, and muscle. Aside from activating the AMPK enzyme, berberine is also crucial for controlling metabolism.

What is Metformin?

Metformin is a medication used along with diet to treat type 2 diabetes patients with high blood sugar levels. Basically, metformin reduces the amount of glucose that is absorbed from the intestines, lowers the amount of glucose that is produced in the liver, and increases insulin sensitivity [4].

Furthermore, the drug metformin comes from a plant known as the French Lilac. This plant has been used traditionally since the Middle Ages to treat excessive urination due to diabetes. Initially, the medication was described in 1922, and in 1994 the FDA approved it since then, metformin has served as a medication for diabetes.

Berberine vs. Metformin Benefits

Metformin and berberine have both been used to treat diabetes for a very long time and are both substances that have been around for a while. However, they have only recently been used as a longevity treatment. 

Let’s look at some of the potential health benefits of berberine and metformin.

Berberine vs. Metformin for Diabetes

Research has shown that berberine and metformin showed similar efficacy in improving glucose control, including reducing fasting and post-prandial (after meal) glucose levels and enhancing insulin sensitivity.

Hence, berberine is a potent anti-diabetic agent that has been considered safe and cost-effective. Nonetheless, more research studies are required to confirm its long-term effects and outcomes in diabetes in a larger population [15].

Berberine vs. Metformin for Anti-aging

Supporting the body’s repair process and pursuing a longevity lifestyle can achieve in various ways. Some of them particularly involve dietary and exercise regimens. Furthermore, the body’s healing process may be supported by compounds known as “geroprotectors,” according to anti-aging studies. In particular, berberine, a dietary supplement, and Metformin are two examples of these compounds.

Previously, a study on flies showed that berberine increased their lifespan. This resulted in exploring research on how berberine can fight aging in humans [5 6]. 

Researchers have found that type 2 diabetic patients who use metformin may generally live longer. It is correlated to studies with mice where metformin increased lifespan and overall health [7, 8].

The TAME (Targeting Aging with Metformin) research also examines the possibility of increasing the number of healthy years of life for individuals. [9].

Berberine vs. Metformin for Weight Loss

A study has shown that berberine is significantly better than metformin at reducing the total cholesterol levels and levels of triglycerides, a type of fat found in your blood. Berberine may also reduce weight and hip circumference [15].

Both metformin and berberine can bring about weight loss and may be a safe option for people who have obesity and are looking to lose weight. However, more research needs to compare the efficacy of berberine and metformin for weight loss.

Berberine vs. Metformin for PCOS

One short research of 89 PCOS patients showed that berberine was superior to metformin at lowering levels of both the waist-to-hip ratio and male hormones [10].

Although the results are intriguing, further studies are still required to determine how berberine may impact weight growth and fat distribution when it comes to larger PCOS groups. 

Berberine vs. Metformin Side Effects

In general, berberine appears to be safe and well-tolerated in most people [11]. But some patients may occasionally experience side effects of berberine on the digestive system, such as gas, diarrhea, and stomach pain [12].

Meanwhile, there are a few typical side effects of metformin. Although they can happen when you first start taking metformin, these often go away with time. Always inform your doctor if these symptoms bother you or are particularly severe.

Metformin adverse effects

When using metformin for the first time, some of the most typical adverse effects are nausea, vomiting, and diarrhea. Usually, these problems lessen with time. And when metformin is taken with a meal, it will relieve these side effects.

In general, your physician may put you on a low dosage of metformin and eventually raise it to reduce your risk of experiencing severe diarrhea.

Berberine and Metformin Together

Although some people might view berberine as a metformin substitute, the two drugs may work better together. For instance, berberine may support normal levels of lactic acid when used with metformin [13]. At least in mice, the combination of berberine and metformin was beneficial.

According to another study, using metformin and berberine together may strengthen its hypoglycemic effects [14]. In other words, the effects of these substances are not simply additive but also synergistic. This means that using metformin and berberine together can potentially increase its efficacy in treating certain conditions.

In some cases, berberine can also increase the intestines’ capacity to tolerate metformin therapy.

Bottomline: Metformin Vs. Berberine Benefits

When comparing berberine to metformin, it becomes clear that while their respective modes of action differ, the two compounds have similar overall effects. Both should be considered in research on human longevity. Further study may also suggest that both can slow down the aging process. 

It is always best to consult with your healthcare provider about consuming berberine supplements and metformin medication in terms of proper dosage and use.

Disclaimer: This article is only a guide. It does not substitute the advice given by your healthcare professional. Before making any health-related decision, consult your healthcare professional.

Editorial References And Fact-Checking 

• Wang H, Zhu C, Ying Y, Luo L, Huang D, Luo Z. Metformin and berberine, two versatile drugs in treatment of common metabolic diseases. Oncotarget. 2017 Sep 11;9(11):10135-10146. doi: 10.18632/oncotarget.20807. PMID: 29515798; PMCID: PMC5839379.
• Clinical Applications for Berberine. (n.d.). Naturalmedicinejournal. https://www.naturalmedicinejournal.com/journal/clinical-applications-berberine
• Yun S. Lee, Woo S. Kim, Kang H. Kim, Myung J. Yoon, Hye J. Cho, Yun Shen, Ji-Ming Ye, Chul H. Lee, Won K. Oh, Chul T. Kim, Cordula Hohnen-Behrens, Alison Gosby, Edward W. Kraegen, David E. James, Jae B. Kim; Berberine, a Natural Plant Product, Activates AMP-Activated Protein Kinase With Beneficial Metabolic Effects in Diabetic and Insulin-Resistant States. Diabetes 1 August 2006; 55 (8): 2256–2264. https://doi.org/10.2337/db06-0006
• Navrotskaya VV, Oxenkrug G, Vorobyova LI, Summergrad P. Berberine Prolongs Life Span and Stimulates Locomotor Activity of Drosophila melanogaster. Am J Plant Sci. 2012 Jul;3(7A):1037-1040. doi: 10.4236/ajps.2012.327123. PMID: 26167392; PMCID: PMC4498586.
• Xu Z, Feng W, Shen Q, Yu N, Yu K, Wang S, Chen Z, Shioda S, Guo Y. Rhizoma Coptidis and Berberine as a Natural Drug to Combat Aging and Aging-Related Diseases via Anti-Oxidation and AMPK Activation. Aging Dis. 2017 Dec 1;8(6):760-777. doi: 10.14336/AD.2016.0620. PMID: 29344415; PMCID: PMC5758350.
• Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998 Sep 12;352(9131):854-65. Erratum in: Lancet 1998 Nov 7;352(9139):1558. PMID: 9742977.
• Martin-Montalvo A, Mercken EM, Mitchell SJ, Palacios HH, Mote PL, Scheibye-Knudsen M, Gomes AP, Ward TM, Minor RK, Blouin MJ, Schwab M, Pollak M, Zhang Y, Yu Y, Becker KG, Bohr VA, Ingram DK, Sinclair DA, Wolf NS, Spindler SR, Bernier M, de Cabo R. Metformin improves healthspan and lifespan in mice. Nat Commun. 2013;4:2192. doi: 10.1038/ncomms3192. PMID: 23900241; PMCID: PMC3736576.
• Clinical Applications for Berberine. (n.d.). Naturalmedicinejournal. https://www.naturalmedicinejournal.com/journal/clinical-applications-berberine
• Targeting the Biology of Aging. Ushering a New Era of Interventions. (n.d.). American Federation for Aging Research. https://www.afar.org/tame-trial
• Wei W, Zhao H, Wang A, Sui M, Liang K, Deng H, Ma Y, Zhang Y, Zhang H, Guan Y. A clinical study on the short-term effect of berberine in comparison to metformin on the metabolic characteristics of women with polycystic ovary syndrome. Eur J Endocrinol. 2012 Jan;166(1):99-105. doi: 10.1530/EJE-11-0616. Epub 2011 Oct 21. PMID: 22019891.
• Zhang Y, Li X, Zou D, Liu W, Yang J, Zhu N, Huo L, Wang M, Hong J, Wu P, Ren G, Ning G. Treatment of type 2 diabetes and dyslipidemia with the natural plant alkaloid berberine. J Clin Endocrinol Metab. 2008 Jul;93(7):2559-65. doi: 10.1210/jc.2007-2404. Epub 2008 Apr 8. PMID: 18397984.
• Yin J, Xing H, Ye J. Efficacy of berberine in patients with type 2 diabetes mellitus. Metabolism. 2008 May;57(5):712-7. doi: 10.1016/j.metabol.2008.01.013. PMID: 18442638; PMCID: PMC2410097.
• Almani SA, Memon IA, Shaikh TZ, Khoharo HK, Ujjan I. Berberine protects against metformin-associated lactic acidosis in induced diabetes mellitus. Iran J Basic Med Sci. 2017 May;20(5):511-515. doi: 10.22038/IJBMS.2017.8675. PMID: 28656086; PMCID: PMC5478779.
• Wang, L. (2021, November 8). Berberine and Metformin in the Treatment of Type 2 Diabetes Mellitus: A Systemic Review and Meta-Analysis of Randomized Clinical Trials. Scientific Research. https://www.scirp.org/journal/paperinformation.aspx?paperid=113351
• Yin, J., Xing, H., & Ye, J. (2008). Efficacy of berberine in patients with type 2 diabetes mellitus. Metabolism: clinical and experimental, 57(5), 712–717. https://doi.org/10.1016/j.metabol.2008.01.013

The supplement berberine has been branded as “nature’s Ozempic” on social media. Ozempic is a type 2 diabetes drug known by the generic name semaglutide that also is used for weight loss. Semaglutide has skyrocketed in popularity as an often effective (albeit sometimes very expensive) weight-loss measure.

Tara A. Schmidt, M.Ed., RDN, LD, a registered dietitian with Mayo Clinic, thinks the term “nature’s Ozempic” for berberine is good marketing — but not necessarily honest or helpful.

Although research suggests some good uses for berberine, it’s not ready for prime time as an obesity treatment. And you should always take a beat to scrutinize a claim that a supplement is “natural,” Schmidt says.

“If you are looking at something that’s being considered a ‘natural’ version of a medication, it can look really appealing,” says Schmidt. But the natural label does not guarantee a pure and unprocessed substance, and consumers may not realize that a supplement can seriously interfere with other medications they are taking.

And even if a supplement truly comes from natural sources, it’s still unlikely to provide a quick and easy fix for health conditions such as obesity.

“With weight loss and with diabetes management, even when (we offer) a prescription medication, we always, always, always also combine it with lifestyle interventions,” she says. “So when people get excited about supplements out there, even if there is some evidence, we can’t just assume that it’s magic — even Ozempic’s not magic in itself.”

What is the supplement berberine?

Berberine is a type of plant substance known as an alkaloid, and is found in a variety of plants, including barberry, goldenseal, Oregon grapes and coptis. These plants have long been used in traditional medicines — including Native American and Chinese practices — to treat a wide variety of illnesses, including eye conditions, diarrhea, jaundice and acne.

Today, berberine is available in supplement form and taken orally, though it is sometimes delivered intravenously or topically.

What is berberine used for?

According to TikTok, a whole lot. Alongside first-person online testimonials about weight loss, skim through social media and you’ll find people who are using berberine for ailments like high cholesterol, insulin resistance and polycystic ovary syndrome (PCOS).

While such a wide array of benefits seems too good to be true, a look at the research shows that berberine is indeed ripe with possibility. Researchers are exploring many possible uses of berberine including as a treatment for diabetes, obesity, cancer, PCOS, high cholesterol and more.

However, research is still limited, especially as some of the studies done thus far were small or performed on animals, Schmidt says. Even so, some of the most encouraging results for berberine thus far are for:

• Lowering cholesterol. Studies have demonstrated that berberine may reduce low-density lipoprotein (LDL, or “bad”) cholesterol, total cholesterol and triglycerides.
• Diabetes. Berberine may improve blood sugar measures such as fasting glucose and hemoglobin A1c (HbA1c) in those with type 2 diabetes, and by some measures may work about as well as the commonly prescribed oral diabetes medication metformin.
• PCOS with insulin resistance. Berberine supplements may lower testosterone levels, improve cholesterol, lower fasting blood sugar levels and decrease measures of insulin resistance in people with PCOS and insulin resistance.

You may notice that obesity didn’t make the shortlist. That’s because there aren’t enough high-quality studies on the subject, though there has been some research showing that berberine supplementation may help reduce weight.

What are the risks of berberine?

Berberine may be safe when taken in recommended amounts — with the exceptions that it should not be used by children or people who are pregnant or breastfeeding.

The main side effects are gastrointestinal (GI) and include nausea, constipation, diarrhea, gas and vomiting. But Schmidt sees a much more pressing potential risk than GI symptoms.

“The scary thing is that it interacts with a ton of medications. There is a very long list of meds that could possibly interact with the berberine,” Schmidt says. “Don’t take this unless you speak to your medical provider first.’”

Possible interactive medications include anti-clotting drugs, sedating medications such as zolpidem (Ambien, Edluar) and diabetes drugs including metformin.

How does berberine work?

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It potentially works in a bunch of different ways. It’s considered antimicrobial and may alter the bacteria in your gut. In addition, berberine may affect a wide variety of body functions, and is thought to act as an anti-inflammatory, antioxidant and anti-cancer substance.

Berberine’s effects on insulin and gut microbiota may be partially responsible for potential weight loss, Schmidt says. And one animal study showed that it affected glucagon-like peptide 1 (GLP-1) — a hormone involved in insulin secretion — which semaglutide also affects.

Some people on social media are claiming that the supplement berberine is helping them lose weight by lessening their appetite.

“One week in. 3 pounds down. All the snack chatter in my head has disappeared,” one TikTok commenter wrote. Another chimed in, “Same thing happened to me! Food noise gone and hunger really reduced.”

Better blood sugar regulation may explain a more regulated appetite, Schmidt says.

“If you’re not having those highs and lows in your blood sugar, you might not feel that more extreme hunger,” she says.

It’s also possible that some people experience a reduced appetite due to berberine’s possible GI side effects such as nausea, she says. This can lead to the question, “Did the side effects impact my hunger, or is the supplement actually regulating my appetite?”

How much berberine should I take?

As with any supplement, it’s best not to take any berberine until you’ve talked with a member of your health care team, especially as berberine may interact with other medications or supplements. Definitely don’t drop a prescription drug such as metformin in favor of berberine without talking to your prescribing doctor or a pharmacist.

It’s thought that taking 1.5 grams of berberine every day — sometimes split into multiple doses — for six months or less is safe. The six-month limit is due to a lack of longer term data, Schmidt says.

The ‘natural’ dilemma

Berberine shares some issues with all other supplements, Schmidt says. Supplements are not subject to the more-rigorous regulation that the U.S. Food and Drug Administration (FDA) applies to medications, and they are not proved to be safe or effective.

Because of this, medical professionals may shy away from taking a stand on a supplement, citing lack of research, Schmidt says. People looking for alternative solutions — maybe because they can’t afford prescription medications, maybe because they are looking for alternative solutions after being ignored or failed by the medical system — may then turn elsewhere for insight.

“We get TikTokkers — who are not physicians, who are not pharmacists, who are not registered dietitians — giving advice, and now we have consumers listening to people who are outside of the medical industry, because no one in the medical industry is comfortable enough to endorse it or not,” Schmidt says.

“We just have to wait sometimes for research to catch up. But research requires money. And research requires time.”

While research plays catch-up, there are many pharmaceutical and lifestyle evidence-based interventions backed up by years of research to help address the same issues berberine may help with, including gut health, blood sugar problems and weight loss, Schmidt says.

And although many supplements are touted as a natural solution, this is not always an accurate representation — whether due to manufacturer malfeasance (such as weight-loss supplements found to contain unlisted prescription drugs) or the realities of processing the supplement.

“(For example), people aren’t eating stevia leaves. Stevia is still an artificial sweetener unless you’re putting the leaf in your coffee. So natural or not, these are still processed supplements; they come out of a factory,” Schmidt says.

Finally, just because something is naturally occurring or seems beneficial does not necessarily mean consuming it in supplement form will be helpful. For example, it’s possible that supplemental vitamin E increases the risk of prostate cancer.

“(The assumption is) taking more vitamin E is going to be a good thing, right? It’s a vitamin,” Schmidt says. “You can’t assume anything is going to be beneficial until it’s studied.”

CEO and Founder at The Institute for Human Optimization

Dr. Anil Bajnath, MD, IFMCP, ABAARM, is a board-certified family physician who specializes in precision and anti-aging medicine. His practice offers a range of services from conventional preventative screening guidelines to precision personalized healthcare modalities including individualized nutrition, genomic medicine, advanced biomarker testing, microbiome analysis, and biometric lifestyle monitoring.

Dr. Bajnath sees patients in his clinic in Annapolis, Maryland, and also offers telemedicine consultations. To schedule an appointment with Dr. Bajnath or learn more about his research, click here.Epigenetics | Precision medicine | Omega 3-6 ratio | Omega index | Fasting | Anti-aging goals | References

So many people are looking for the “perfect” recipe for longevity or anti-aging, that magical formula for longer and healthier life.

You might have attempted to discover the ultimate anti-aging diet, the perfect exercise routine for longevity, or the best supplements to activate longevity genes, the potential methods are endless!

But the more we learn about genetics, aging, and lifestyle, it becomes clear that the universal “perfect” fountain of youth blueprint doesn’t really exist. That’s because there’s no one-size-fits-all longevity plan.

In this article series, we collaborated with Dr. Anil Bajnath, MD, a pioneer in precision and anti-aging medicine. Dr. Bajnath shared some of the core principles of his personalized approach to aging and why it may revolutionize our ability to extend our lifespan and healthspan.

We are all unique

Every one of us has a unique genetic makeup which we inherited from our parents. This influences how our body responds to various inputs from our environment.

We’re also learning more and more about epigenetics – the relationship between environment and genes. This is what determines which genes will be expressed and which will not. Or, in other words, when genes will be turned on or off.

Even though our genes can’t be changed, epigenetics gives us the capacity to change our health outcomes by influencing the expression of individual genes. Our lifestyle choices and behaviors can change how our genes will be expressed.

And what we have learned is that similarly to your unique genetic makeup, your (epigenetics) gene expression is also completely individual.

So, the only way to create an ideal longevity “recipe” is to have your genes expressed in the way that best supports your health according to your genetic and epigenetic makeup, not someone else’s. This means your journey will involve discovering the variables that improve your individual health. I believe that personalized medicine is the future of anti-aging medicine and healthcare. And the future, to some degree, is already here.

While this area of study is incredibly exciting, what does the research say?

How good science may obscure individual differences

Think about a large research study, in which researchers are asking whether a particular intervention increases people’s longevity. This could be a dietary pattern, a supplement, an exercise program, a drug – anything. To know whether the intervention is beneficial, we often look at a large group of people, some of whom got the intervention while others didn’t. (There are a lot of different ways to create, or find, these two groups, but this is the basic idea.)

These types of studies are the most accepted way that we can start to figure out what really works and what doesn’t. However, it’s important to recognize that when we look at a large group of people and just take the average, we’re obscuring a lot of individual differences. We might find that a certain supplement or drug is beneficial overall – but maybe a few people in the group were actually harmed by it, while others experienced a significant benefit. Also, how do we know this intervention is the optimal one for each person?

The “N of 1” precision medicine approach to aging

When you’re considering how you’re going to optimize your own health and longevity, it’s important to recognize that you’re not the average of a large group. You’re a unique individual, and it’s likely that you have some significant differences from the average.

My colleagues and I sometimes refer to this as an “N of 1” approach. “N” is a commonly used notation for the number of subjects in a scientific study. However, because you’re unique, you’re the only subject in the study of your own health. You’re an individual – an N of 1.

The best way to optimize your health is to take note of the impacts of various interventions on how you feel and how your body reacts. A big part of this approach includes testing various biomarkers of longevity to get a good idea if a certain practice is helping or harming you. Then you can adjust as needed to get the results that you’re looking for. You can still use large studies as a starting point for deciding what to try because they certainly do have value. You just need to keep your awareness on what’s working and what’s not.

This approach is sometimes known as precision medicine. The goal is to precisely tailor medical care to the needs of a particular individual. We can use this type of approach to help us personalize a lifestyle plan to best support longevity and healthspan.

Let’s take a look at a few examples of precision medicine in action.

The omega-3 to 6 ratio and healthspan

You may have heard that the balance between omega-3 and omega-6 fatty acids is essential for good health. A higher ratio of omega-6/omega-3 was associated with a higher risk of many chronic diseases, while a lower ratio seems to decrease the risk^[1].

Even more, omega-3 fatty acids have demonstrated potent anti-inflammatory properties in several studies showing potential in helping reduce symptoms of inflammatory conditions such as rheumatoid arthritis, psoriasis, asthma, and inflammatory bowel disorders^[2].

Now, with chronic inflammation playing such a key role in ageing, shouldn’t we all just mega dose omega 3’s to increase our longevity?

Well, before you go to the store and start ordering fish oil supplements in bulk, there’s something you should know about omega-3 to 6 ratio. It’s called the omega 3 index.

Omega 3 index and longevity

Recently, we’ve discovered the importance of a test called the omega-3 index. This is a simple lab test that many doctors aren’t even aware of yet, that can have a significant influence for promoting longevity in an individual.

The omega-3 index is a measurement of the ratio of omega-3 fatty acids (specifically EPA and DHA) to other fatty acids in the cell membranes of your red blood cells. Red blood cells are used because they’re the most accessible type of cell and they’re likely a good representation of what your cell membranes are generally made of. The test measures what percentage of the fatty acids in your cell membranes are omega-3s.

A study published last year in the prestigious American Journal of Clinical Nutrition (AJCN), showed that people with an omega-3 index of 6.7% or greater had a life expectancy that was extended by 4.8 years^[3]. This is similar to the life extension that can be achieved by quitting smoking, so we know that the omega index is a powerful predictor of longevity.

The exciting news here is that this test is highly actionable. Measuring your omega-3 index is an effective way to determine whether you’re optimizing your intake of essential fatty acids:

• If you have a high omega-3 index, then your diet is working well for you. Therefore, it might not make sense for you to add a supplement with extra omega-3s.
• If your omega-3 index is low, you might want to focus on including more omega-3s in your diet or supplementing to bring your levels up.

Why optimal balance is key

The omega-3 index is a great example of how we can use a single test to carefully tailor the approach to an individual and optimize the outcomes.

Now, you may be wondering after reading all these omega 3 benefits, couldn’t we just take a large amount every day?

Turns out, more is not better, even in the case of omega 3’s.

There are some studies on omega-3 supplementation that I think really illustrate how important it is to consider the individual balance, rather than the more is better approach.

In the last two years, a few studies linked high intake of omega-3s to atrial fibrillation, which is an abnormal heart rhythm that can lead to issues like strokes^[4]. If you look at these studies, they used incredibly high doses of omega-3s. This isn’t the tablespoon of cod liver oil that your grandma fed to you.

These products have been developed by pharmaceutical companies and I believe that the problem is that the dosage they use is far too high. The companies jumped on the idea of omega-3s being beneficial, and developed products with such high dosage, that they may cause health problems.

This doesn’t mean that omega-3 fatty acids are not beneficial if they’re consumed at the right dose by the right person. These negative outcomes could have been avoided with a precision medicine approach. In the omega 3 case, with just one test- the omega-3 index.

How long should I fast for longevity?

Another common example that is very popular in the anti-aging and longevity circles is fasting. By now, the potential of fasting to extend lifespan and healthspan is well established. But which fasting protocol is the best? How long should one fast for best results? Clearly, more fasting is not always better.

I find that this is another area where people may differ from each other. While many studies have demonstrated that fasting has beneficial effects overall^[5], the optimal length of a fast depends not only on a person’s physiology, but also on their own circumstances and what they are trying to achieve.

For instance, I’m sometimes very busy in my professional life. If I need to do quite a bit of teaching and presenting at conferences during a particular week, then I wouldn’t choose that week to do an extended fast. It would impair my ability to perform cognitively at my highest level.

As another example, many of my patients are competitive athletes. While they’re in training, a fast may not be beneficial for them because they’re expending a lot of energy and need to replenish those resources.

It’s also important to remember that there are a variety of different reasons that someone may be fasting. For example, some people fast for spiritual purposes – it’s common to experience a sense of clarity, peace, and connection during an extended fast. Fasting is an important part of many spiritual traditions. If this is your goal, then you may need to fast for a longer time to cultivate this state of consciousness.

By contrast, someone who’s fasting for the purposes of improving physical health may do well with a shorter fast, which they may perform more frequently to stimulate processes like autophagy.

Be mindful of your individual anti-aging goals

I find that any conversation about anti-aging and longevity should always consider the deeper individual meaning of “anti-aging”.

We all appreciate longevity, especially a greater health span, which gives us the ability to have more years that are free of pain and disability. However, what’s a longer healthy life means, may differ between individuals.

For example, for me, I love training Brazilian jiu jitsu. This is a practice that lights me up and makes me feel great. I want to be able to do it for as many years as I possibly can. So, as I age, I want to maintain the ability to do some intense physical training and to avoid becoming fragile and easily injured.

When you are trying to discover your longevity blueprint take some time to get clear on what your values are and what’s important to you as you age. What makes your life worth living? What is your purpose? What are your priorities? These questions are fundamental to creating your own longevity plan.

Where do we go from here?

The field of precision medicine is vast and is changing every day as new research is emerging. There are thousands of tests available now, looking at various gene polymorphisms and biomarkers that can be used to assess individual health and genetics. Some of these tests such as the omega-3 index are very useful and actionable, while others aren’t there yet. In fact, in some cases, the companies that sell these tests tend to over promise or misrepresent the research.

I find that working with the right health practitioner in anti-aging and precision medicine is key, especially since a lot of the data is constantly evolving. Not all medical professionals are up to date with the latest longevity research or anti-aging tests, so they can offer the best options for each individual.

Published online 2014 Dec 18. doi: 10.4161/auto.36413

PMCID: PMC4502795

PMID: 25484097

Caloric restriction mimetics: natural/physiological pharmacological autophagy inducers

Guillermo Mariño,^1,2 Federico Pietrocola,^1,3 Frank Madeo,^4,* and Guido Kroemer^1,2,5,6,*

Author information Article notes Copyright and License information PMC Disclaimer

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Abstract

Nutrient depletion, which is one of the physiological triggers of autophagy, results in the depletion of intracellular acetyl coenzyme A (AcCoA) coupled to the deacetylation of cellular proteins. We surmise that there are 3 possibilities to mimic these effects, namely (i) the depletion of cytosolic AcCoA by interfering with its biosynthesis, (ii) the inhibition of acetyltransferases, which are enzymes that transfer acetyl groups from AcCoA to other molecules, mostly leucine residues in cellular proteins, or (iii) the stimulation of deacetylases, which catalyze the removal of acetyl groups from leucine residues. There are several examples of rather nontoxic natural compounds that act as AcCoA depleting agents (e.g., hydroxycitrate), acetyltransferase inhibitors (e.g., anacardic acid, curcumin, epigallocatechin-3-gallate, garcinol, spermidine) or deacetylase activators (e.g., nicotinamide, resveratrol), and that are highly efficient inducers of autophagy in vitro and in vivo, in rodents. Another common characteristic of these agents is their capacity to reduce aging-associated diseases and to confer protective responses against ischemia-induced organ damage. Hence, we classify them as “caloric restriction mimetics” (CRM). Here, we speculate that CRM may mediate their broad health-improving effects by triggering the same molecular pathways that usually are elicited by long-term caloric restriction or short-term starvation and that imply the induction of autophagy as an obligatory event conferring organismal, organ- or cytoprotection.

Keywords: acetyl-coenzyme A, acetyl transferase, acetylation, deacetylase, deacetylation

Abbreviations: AcCoA, acetyl coenzyme A; CRM, caloric restriction mimetics; EGCG, epigallocatechin-3-gallate

Macronutrient scarcity constitutes one the most common inducers of macroautophagy (to which we refer as autophagy). In teleological terms, the prime finality of autophagy is the mobilization of the cell’s reserves and hence the conversion of macromolecules into energy-rich substrates that are required for maintaining essential functions, the avoidance of cell death, and the adaptation to stress.^1,2 Starvation of human cells (by their culturing in nutrient-free medium) or starvation of mice (by removing food from the cages for 24 h, granting access only to water) results in the preponderant depletion of 1 intracellular metabolite, acetyl coenzyme A. Kinetic experiments performed in vitro, on human cell lines cultured in the absence of nutrients indicate that depletion of the nucleocytosolic pool of AcCoA occurs before ATP is reduced, NADH is oxidized, and amino acids are depleted from the intracellular metabolome, at the same time as autophagy becomes detectable.³ Specific depletion of cytosolic AcCoA pools by inhibition of its mitochondrial synthesis (from pyruvate, branched amino acids or lipid ß-oxidation) or its transfer from the mitochondrial matrix to the cytosol (which requires the conversion of AcCoA to citrate in the matrix, the export of citrate by the citrate carrier, and final conversion of citrate to AcCoA by ACLY [ATP citrate lyase]) is sufficient to induce autophagy even in conditions in which ATP and NADH levels are normal.³ Moreover, external provision of AcCoA (e.g., by microinjection of the metabolite into the cytoplasm) is sufficient to prevent starvation-induced autophagy.³

Altogether, these observations point to the idea that starvation causes autophagy because it results in the early depletion of AcCoA.^3,4 This adds to other mechanisms through which caloric restriction or starvation can stimulate autophagy, namely the induction of the deacetylase activity of sirtuins (as a result of changing NADH/NAD⁺ ratios and increased SIRT1 expression),⁵ the activation of AMPK activity (as a result of changing ATP/ADP ratios),⁶ and the inhibition of MTORC1 (as a result of amino acid depletion).⁷ The available evidence indicates that the principal acetylransferase that is required for the AcCoA-mediated repression of autophagy is EP300,³ an acetyltransferase that can transfer acetyl groups from AcCoA to autophagy core proteins including ATG5, ATG7, ATG12, and LC3, thus inhibiting their pro-autophagic activity.⁸ Specific AcCoA depletion or direct inhibition of EP300 by genetic or pharmacological methods causes the rapid activation of AMPK and the inactivation of MTORC1, suggesting that these nutrient sensors are functionally connected to each other.³

The aforementioned results suggest a strategy for the identification of drugs that mimic the effects of starvation with regard to the depletion of AcCoA and the consequent deacetylation of cellular proteins. Within this framework, there would be 3 categories of “caloric restriction mimetics” (CRMs): (i) agents that reduce the concentration of cytosolic AcCoA; (ii) inhibitors of autophagy-repressive acetyltransferases including EP300; and (iii) activators of autophagy-stimulatory deacetylases including SIRT1.⁹ It is reasonable to expect that CRMs falling in one of these 3 categories would elicit the same biochemical pathways that are usually stimulated by starvation and hence induce an autophagic response that is exempt from major toxicological side effects (Fig. 1).

Figure 1.

Caloric restriction and its pharmacological mimetics. (A) General outline of the mechanisms of health improvement by caloric restriction (CR). (B) Molecular mechanism of autophagy induction by CR. (C) Mechanism of action of caloric restriction mimetics (CRMs). (D) Hypothetical mechanisms of anti-aging effects of CR and CRMs.

Indeed there is a vast literature showing that there are multiple CRMs that can be used in humans. As an example, hydroxycitrate, an inhibitor of ACLY that causes cytosolic AcCoA depletion, protein deacetylation, and massive autophagy in all studied organs in mice,³ is also an over-the-counter weight loss agent commercialized in the US.¹⁰ A variety of agents known to inhibit EP300 are being used in traditional medicine or are obtainable without a prescription. This applies to anacardic acid (6-pentadecyl-salicylic acid from the nutshell of the cashew, Anacardium occidentale),¹¹ curcumin (from the South Asian spice turmeric, Curcuma longa, one of the principal ingredients of curry powder),¹² and garcinol (from the fruit of the Kokum tree, Garcina indica).¹³ All these agents are also potent inducers of protein deacetylation and autophagy when added to cultured human cells.³ Similarly, epigallocatechin-3-gallate (EGCG, one of the major active compounds contained in green tea) can inhibit a range of acetyltransferases¹⁴ including EP300.¹⁵ Spermidine (a polyamine contained in all organisms, but found at particular high concentrations in some health-related products such as durian fruit, fermented soybeans, and wheat germs) was first characterized as a histone acetyl transferase inhibitor.¹⁶ Spermidine potently induces protein deacetylation and autophagy in vivo, in mice or in cultured human cells.¹⁷ Finally, resveratrol exemplifies a widely used over-the-counter drug that can stimulate the deacetylase activity of SIRT1, thereby causing general protein deacetylation and autophagy.^17-19 Nicotinamide is another potential SIRT1 activator that is sold over the counter in the US²⁰ and that induces autophagy in rodents.²¹

What could be the therapeutic indications for the use of such CRMs? CR or intermittent fasting are known for their wide life-span-extending and health-improving effects that can be measured in an objective fashion in multiple model organisms including rodents²² and primates.²³ Beyond their capacity to reduce aging and aging-associated pathologies (such as neurodegeneration, type-2 diabetes, and cancer), fasting also has an important preconditioning effect, protecting different organs from ischemic insult. This applies to the heart^24,25 brain,²⁶ liver,²⁷ and kidney.²⁸ There is emerging evidence that autophagy is involved in starvation-mediated organ protection.^25,28 Moreover, fasting can reduce the subjective and objective toxicity of cytotoxic anticancer chemotherapies, both in humans and in mouse models, at the same time that it improves treatment outcome in mice.^29,30 It is tempting to speculate that CRMs could be used for the same therapeutic indications in which fasting has proven to be useful. In accord with this idea, several CRMs can increase the health span and life span of rodents (as demonstrated for EGCG, spermidine and resveratrol),^31-33 reducing the advancement of neurodegenerative diseases (as shown for spermidine, nicotinamide and resveratrol), likely through their capacity to induce autophagy.^34,35 Moreover, several CRMs (including EGCG and resveratrol) have potent preconditioning effects in ischemia,^36,37 which, at least on theoretical grounds, might be due to the induction of cytoprotective autophagy.³⁸

Future studies should address the following major questions:

• Do all beneficial effects of CRMs result from the induction of autophagy, or are there any autophagy-independent effects? This question should be addressed in suitable mouse models in which autophagy can be genetically inhibited in a spatially- and temporarily-controlled fashion.
• Which are the CRMs that are optimally suitable for a precise indication (anti-aging effects, neuro-, cardio-, hepatoprotection, adjuvant treatment of anticancer chermotherapy), comparing them in preclinical tests to their positive control, that is fasting or caloric restriction? Ideally, this problem should be addressed in a systematic fashion involving the simultaneous comparison of multiple CRMs.
• Is it possible to develop more specific CRMs, such as inhibitors of EP300 that fail to affect other acetyltransferases or truly specific inhibitors of ACLY, with the scope of optimizing their efficacy?
• Is it possible to combine several mechanistically distinct CRMs (such as those depleting AcCoA, inhibiting acetyltransferases, or activating deacetylases) to obtain synergistic effects for maximal induction of therapy-relevant autophagy?

We surmise that responding to these questions will boost the rational development of new indications for old drugs, as well as the development of novel CRMs with a broad therapeutic potential.

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Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

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Funding

GK is supported by the Ligue contre le Cancer (équipe labelisée); Agence Nationale de la Recherche (ANR); Association pour la recherche sur le cancer (ARC); Cancéropôle Ile-de-France; Institut National du Cancer (INCa); Fondation Bettencourt-Schueller; Fondation de France; Fondation pour la Recherche Médicale (FRM); the European Commission (ArtForce); the European Research Council (ERC); the LabEx Immuno-Oncology; the SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE); the SIRIC Cancer Research and Personalized Medicine (CARPEM); and the Paris Alliance of Cancer Research Institutes (PACRI). FM is supported by FWF grants LIPOTOX, P23490-B12, I1000 and P24381-B20.

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Calorie Restriction Mimetics (CRMs) are compounds that can induce the same mechanisms as eating less, without having to actually eat less. R

In this, post we will discuss how to have your cake (food) and eat it too.. 

Contents:

1. Basics
2. Benefits Of CRMs/Fasting Mimetics
3. Real Life Examples Of Fasting
4. List Of Caloric Restriction Mimetics
5. What Goes Well With Calorie Restriction Mimetics?
6. Mechanism Of Action

Basics

What Defines A CRM?

CRMs should: R

1. Mimic the metabolic, hormonal and physiological effects of CR
2. Don’t significantly decrease long-term food intake
3. Activate stress–response pathways, as observed in CR, and protect against a variety of stressors
4. Reduce inflammation and autoimmunity. 

Benefits Of CRMs/Fasting Mimetics

Mimicking CR/Fasting may improve:

1. Adaptability to Stress (CR acts on hormesis via NRF2) R R R
2. Autophagy (improve stem cells) R R R R
3. Body Fat Mass R R
4. Cardiovasuclar Function R R R 
5. Eyesight/Ocular Health R R
6. Healthspan R R
7. Immune Function R
8. Insulin Sensitivity R R
9. Kidney Function R
10. Leptin Sensitivity R
11. Lifespan R
12. Liver Function R
13. Memory (is Alzheimer’s) R
14. Metabolism (may help with hypoxia) R R
15. Mitochondrial Function R
16. Muscle R
17. NAD levels R R
18. Neurogenesis R
19. Prevention of Cancer and Anti-tumor Efficacy (of chemotherapy) R R R R
20. Skin and Wound Healing R

Some CRM’s can mimic exercise or even synergize well with exercise and improve muscle function. R R

Real Life Examples Of Caloric Restriction

Compared to the rest of the Japanese population, inhabitants of Okinawa who followed a low-calorie diet over a prolonged period of time show to have a longer lifespan and an increased healthspan. R

They eat a mildly caloric restricted diet (10-15%) and high consumption of foods that may mimic the biological effects of caloric restriction, including sweet potatoes, marine-based carotenoid-rich foods, and turmeric. R

List Of Calorie Restriction Mimetics

buy on amazon

These CRMs work on the mechanisms of calorie restriction.

Dietary/Mechanical Strategies (that aren’t calorie restriction):

• Amino Acid Restriction R
• Avocado (Mannoheptulose) R
• Bariatric Surgery R
• Cinnamon (Methylhydroxychalones) R
• Coffee R
• Intermittent Fasting/Feeding R
• Olive Oil (Tyrosol) R
• Rosemary (Rosmarinic Acid) R
• Sesame (Sesamin) R
• Tomatoes (Tomatidine) R
• Turmeric (Curcumin) R

Supplements:

• Allantoin R
• Allulose R
• Ashwaganda (Withaferin A) R
• Astaxanthin R
• BCAAs (Leucine can increase mitochondrial mass in human muscle cells) R R
• Caffeic acid R
• Caffeine R
• Carnitine R
• Chitosan (Inhibiting Nutrient Absorption) R
• EGCG R R
• Fisetin R R
• Ginseng (Ginsenosides) R
• Glucosamine R
• Gymnema R
• Gynostemma (jiaogulan)
• Hesperidin R
• Kaempferol R
• Ketones R
• Kokum (Garcinia Indica) R
• Lactoferrin R
• Licorice (isoliquiritigenin) R 
• Lipoic Acid (weak) R
• Mannan Oligosaccharides (Inhibiting Nutrient Absorption) R
• MitoQ R
• NAC R
• Naringenin R
• Nicotinamide Riboside R
• Olestra R
• Polydatin R
• Quercetin R
• Resveratrol R
• Thundergod Vine (Celastrol) R
• Ursolic acid (ie holy basil, thyme, rosemary) R

Hormones:

• Adiponectin (binding to AdipoR1 and AdipoR2)
• Irisin R
• Leptin (possibly lower) R
• Melatonin R
• Meteorin-like R
• NPY R
• Resistin (lower levels) R

Drugs:

• Acarbose (Inhibiting Nutrient Absorption) R
• Allantoin R
• AICAR R
• Aspirin R
• Bezafibrate R
• Dapsone R
• Epitalon R
• Exanadin
• GW1516 R
• Hydroxycitrate (citric acid) R
• LY‐294002 R
• Metformin R R
• Olbetam (niacin derivative)
• Orlistat (Inhibiting Nutrient Absorption) R
• Oxaloacetic acid R
• Pioglitazone R
• Rapamycin R
• Rimonabant
• Rosiglitazone (modulation PPARs leptin/adiponectin)
• SARMs (some) R
• Sodium phenylbutyrate
• Spermidine R
• SRT1720 R
• Trichostatin A (TSA) R

What Goes Well With Calorie Restriction Mimetics?

Exercise Mimetics may go well with CRMs. 

Mechanism Of Action

Some Mechanisms / Pathways Of CR Mimetics

Working on these mechanisms may also help mimic CR:

• Increasing AMPK R R
• Increasing cAMP R
• Increasing ERRγ R
• Increasing FGF21 R R
• Increasing FOXO R
• Increasing HSF1 R
• Increasing LKB1 R
• Increasing NO -> HSP R
• Increasing NRF1 R
• Increasing NRF2 R
• Increasing NR3C4 R
• Increasing PNC-1 R
• Increasing PPARβ/δ R R
• Increasing PGC-1α R
• Increasing REV-ERBα R
• Increasing SIRTs (and other STACs, ie fisetin) R R
• Increasing SOD R
• Increasing UCP2 and UCP3 R
• Inhibiting ActRIIB R
• Inhibiting DPP-4
• Inhibiting Glycolysis R
• Inhibiting HDACs 1 and 2 R
• Inhibiting mTOR R R
• Inhibiting Myostatin R
• Reduces AGEs R
• Reduces FAO R
• Reduces GH R
• Reduces HMG-Co-A reductase R
• Reduces IGF1 R

Advanced:

• Nutrient depletion, which is one of the physiological triggers of autophagy, results in the depletion of intracellular acetyl coenzyme A (AcCoA) coupled to the deacetylation of cellular proteins (3 ways). RR
  1. The depletion of cytosolic AcCoA by interfering with its biosynthesis
  2. The inhibition of acetyltransferases, which are enzymes that transfer acetyl groups from AcCoA to other molecules, mostly leucine residues in cellular proteins
  3. The stimulation of deacetylases, which catalyze the removal of acetyl groups from leucine residues. 
• CRMs deplete regulatory T Cells from tumor bed and trigger an autophagy-dependent anticancer immune response. R
• In the liver, AdipoR1 activates the AMPK pathways and AdipoR2 activates PPARα pathways. R
• AMPK enhances SIRT1 activity by increasing cellular NAD+ levels, resulting in the deacetylation and modulation of the activity of downstream SIRT1 targets such as PPARγ coactivator 1α (PGC-1α) and forkhead box O1 (FoxO1), and is regulated by adiponectin–adipoR1 system. R
• CR induces the function of the pyrazinamidase/nicotinamidase 1 (PNC-1) enzyme which deaminates and depletes nicotinamide. R

Living to 100 today is not unheard of, but is still rare. In America and Britain centenarians make up around 0.03% of the population. Should the latest efforts to prolong life reach their potential, living to see your 100th birthday could become the norm; making it to 120 could become a perfectly reasonable aspiration.

Abstract

Hundreds of millions of people now die over the age of 80 years primarily due to twentieth century progress in hygiene, chemotherapy, and immunology. With a longer average lifespan, the need to improve quality of life during the latter decades is more compelling. “Aging — The Epidemic of the New Millenium,” a recent international conference (Monte Carlo, June 17–18, 2000), showed with peculiar clarity that a safe and efficient drug strategy to slow the age‐related decay of brain performance is still missing. This review summarizes the physiologic and pharmacologic arguments in favor of a peculiar lifelong prophylactic medication with reasonable chances to keep in check brain aging and decrease the precipitation of age‐related neurological diseases.

SUMMARY AND CONCLUSIONS

The specific brain activation mechanism (“drive”) that ensures that living beings surmount every obstacle to reach a goal, even if life is in the balance, roots in the existence of “enhancer‐sensitive” neurons in the brain that are ready to increase their activity with lightning speed in response to endogenous “enhancer” substances, of which phenylethylamine (PEA) and tryptamine are the presently known examples. PEA and tryptamine enhance the impulse‐propagation‐mediated release of catecholamines and serotonin in the brain (CAE/SAE effect). This is the best model for studying the enhancer regulation in the mammalian brain, which starts working at the discontinuation of breast feeding. Weaning is the beginning of the developmental (“uphill”) period of life and is characterized by significantly higher brain activity levels that last until the sexual hormones dampen this regulation, thereby terminating the uphill period. This is the prelude of the postdevelopmental (“downhill”) phase of life and the beginning of the slow brain aging process from which there is no escape until natural death.

It has been proposed that enhancer compounds can delay the natural age‐related deterioration of brain performance and keep the brain on a higher activity level during postdevelopment longevity. PEA, a substrate of MAO‐B, and tryptamine, a substrate of MAO‐A, are rapidly metabolized, short‐acting endogenous enhancer compounds. PEA and its long‐acting derivatives, amphetamine and methamphetamine, which are not metabolized by MAO, are enhancer substances at low concentrations but also potent releasers of catecholamines and serotonin from their pools at higher concentrations. The catecholamine‐releasing effect masked for decades the enhancer property of these compounds.

(‐)Deprenyl (selegiline) is the first PEA derivative free of the catecholamine‐releasing property and made possible the discovery of the enhancer regulation in the brain. This drug is presently the only clinically used enhancer compound. (‐)Deprenyl is also a highly potent, selective inhibitor of MAO‐B and is metabolized to amphetamines. Tryptamine is an endogenous enhancer substance free of the catecholamine/serotonin‐releasing property. The newly developed tryptamine derivative (‐)BPAP is the first highly selective enhancer substance. It is also much more potent than (‐)deprenyl.

Enhancer substances that keep the enhancer‐sensitive neurons on a higher activity level slow the age‐related deterioration of the mammalian brain. Maintenance of rats on (‐)deprenyl during post‐developmental longevity slows the age‐related decline of sexual and learning performances and prolongs life significantly. Patients with early Parkinson’s disease who are maintained on (‐)deprenyl need levodopa significantly later than their placebo‐treated peers and they live significantly longer when on levodopa plus (‐)deprenyl than patients on levodopa alone. In patients with moderately severe impairment from Alzheimer’s disease, treatment with (‐)deprenyl slows the progression of the disease.

(‐)BPAP is an especially promising prophylactic antiaging compound that may provide the opportunity to shift the functional constellation of the brain during postdevelopmental longevity towards the one characteristic to the uphill period of life. According to the available experimental and clinical data, it is reasonable to expect that daily administration of an enhancer drug [e.g., (‐)deprenyl 1 mg or (‐)BPAP 0.1 mg] from sexual maturity until death will improve quality of life in the latter decades, shift the time of natural death, decrease the precipitation of age‐related depression, and reduce the prevalence of Parkinson’s disease and Alzheimer’s disease.

Keywords: Selegiline, Deprenyl, Antiaging drugs, BPAP

Full Text

The Full Text of this article is available as a PDF (542K).

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