Understanding the mechanisms that regulate lifespan and aging is a critical area of research in biology. Lifespan varies widely both within and across mammalian species, driven by a combination of genetic, environmental, and evolutionary factors. This article discusses a comprehensive study that investigates the gene expression signatures associated with longevity across 41 mammalian species and examines how these signatures interact with aging and lifespan-extending interventions.
Key Findings
- The study identified distinct molecular mechanisms that control lifespan both within and across species. This includes the downregulation of the insulin-like growth factor 1 (Igf1) and the upregulation of genes involved in mitochondrial translation.
- Shared features across long-lived species include the regulation of the innate immune response and cellular respiration, which were found to be distinct from the changes observed within a single species undergoing lifespan extension.
- Longevity and Aging Biomarkers:
- Aging-related changes in gene expression were positively correlated across different tissues and species, suggesting common molecular mechanisms underlying aging.
- Long-lived species exhibited gene expression profiles that were also enriched for genes involved in proteolysis and PI3K-Akt signaling pathways, indicating that these pathways play a role in lifespan regulation.
- Impact of Lifespan-Extending Interventions:
- Lifespan-extending interventions, such as calorie restriction and growth hormone receptor knockout (GHRKO), showed a counteractive effect on aging patterns. These interventions targeted younger, more mutable genes, predominantly affecting energy metabolism.
- The study also discovered new potential geroprotectors, including the compound KU0063794, which extended the lifespan and healthspan in mice.
Methodology
The research utilized multi-tissue RNA-seq analysis across 41 mammalian species, identifying gene expression signatures associated with longevity. The study included an integrative analysis combining these signatures with known biomarkers of aging and transcriptomic data from lifespan-extending interventions.
Results
- Gene Expression Analysis:
- RNA-seq data from various tissues (brain, kidney, liver, cerebellum, heart, and testis) revealed that gene expression profiles were significantly influenced by both organ type and species.
- Long-lived species like the naked mole rat, Brandt’s bat, and bowhead whale showed unique gene expression patterns compared to shorter-lived species.
- Elastic Net Linear Regression Model:
- A predictive model based on tissue gene expression successfully captured 78% of the total variation in lifespan across species, significantly outperforming predictions based solely on body mass.
- Functional Enrichment Analysis:
- Genes associated with translation, base excision repair, and mitochondrial function were upregulated in long-lived species.
- Genes involved in ubiquitin-mediated proteolysis and the TCA cycle were downregulated, indicating reduced metabolic activity and proteolysis in longer-lived species.
Discussion
The study highlights the complexity of lifespan regulation, revealing that while some molecular mechanisms of longevity are shared across species, others are unique to specific lineages. The findings suggest that certain pathways, such as those involving Igf1 and mitochondrial function, play a critical role in promoting longevity both within and across species.
Moreover, the identification of gene expression biomarkers common to both aging and lifespan-extending interventions provides a valuable tool for discovering new geroprotectors. The compound KU0063794, identified through these biomarkers, successfully extended the lifespan and healthspan of mice, demonstrating the potential of this approach in developing anti-aging therapies.
Conclusion
This research provides significant insights into the molecular mechanisms that regulate lifespan across mammals. By identifying both universal and species-specific longevity signatures, the study offers new avenues for the development of interventions aimed at extending healthspan and lifespan in humans and other animals. The discovery of compounds like KU0063794 underscores the potential for targeted therapies that leverage these molecular insights to promote longevity.
References
- Tyshkovskiy, A., Ma, S., Shindyapina, A. V., et al. (2023). Distinct longevity mechanisms across and within species and their association with aging. Cell, 186(2929-2949). https://doi.org/10.1016/j.cell.2023.05.002
Source: https://www.cell.com/cell/fulltext/S0092-8674(23)00476-2
