Epigenetic Alterations and Lifespan

Research led by Juan José Alba-Linares has revealed that changes in epigenetics over time might limit mammalian lifespan[1]. By analyzing 18 mammals, they identified a link between how quickly epigenetic "noise" accumulates and the length of lifespan. Notably, the study estimates that the upper limit for mammalian lifespan could be around 220 years.

Lifespan and Methylation Changes

Species Methylation Rate Average Lifespan
Humans Slow 80-100+ years
Whales Slow 70-200 years
Dogs Intermediate 10-15 years
Mice Fast ~2-3 years

The study shows that species with slower rates of methylation disorganization tend to live longer. In contrast, species with rapid epigenetic changes, like mice, have shorter lifespans.

Why We Age: The Role of Epigenetics

Epigenetic alterations are considered one of the primary mechanisms driving aging. Changes in DNA methylation patterns lead to disruptions in gene expression, which can trigger cellular damage and an increased risk of age-related diseases.

Potential Interventions to Extend Lifespan

The research offers insights into potential strategies to slow down the accumulation of epigenetic noise and extend lifespan:

Approach Mechanism Goal
CRISPR-Based Therapies Editing the genome and epigenome Reverse age-related epigenetic drift
Epigenetic Reprogramming Using reprogramming factors (e.g., Yamanaka factors) Restore youthful gene expression
Senolytics Clearing senescent cells Reduce inflammation and cellular damage
Telomere Extension Activating telomerase to lengthen telomeres Improve genomic stability
NAD+ Restoration Replenishing NAD+ levels Enhance mitochondrial and cellular health
Caloric Restriction Mimetics Mimicking the benefits of caloric restriction Delay age-associated decline

Epigenetic Reprogramming with Yamanaka Factors

Epigenetic reprogramming aims to reset cells to a more youthful state using transcription factors (e.g., Oct4, Sox2, Klf4, c-Myc)[2][3]. If applied safely, this could rejuvenate cells without triggering cancerous changes.

CRISPR-Based Epigenetic Modulation

New therapies are being developed to directly target and modify epigenetic markers through tools like CRISPR. This approach may provide a precise way to reset the biological clock and promote healthier aging[4].

Senolytics and Telomere Maintenance

Senolytics

Senolytics are compounds that target and eliminate senescent cells, which accumulate with age and contribute to tissue inflammation and dysfunction. These drugs, like quercetin and dasatinib, aim to maintain a healthier cellular environment[5][6][7].

Telomere Therapies

Telomere shortening is another hallmark of aging, leading to increased genomic instability. Treatments that extend telomeres, such as telomerase activators, may help prevent cellular senescence and support genome integrity[8][9].

Nutrient-Based Interventions and Caloric Restriction

NAD+ Restoration

As NAD+ levels decline with age, cellular processes like DNA repair are impaired. Interventions like nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN) aim to replenish NAD+ to improve mitochondrial function[10].

Caloric Restriction Mimetics

Compounds like rapamycin, resveratrol, and spermidine mimic the effects of caloric restriction, activating longevity pathways without requiring major dietary changes[11][12][13]. These treatments may help reduce oxidative stress and maintain epigenetic integrity.

Future of Lifespan Extension

While current research suggests a natural cap on mammalian lifespan, advances in biotechnology may extend human healthspan and lifespan. Whether through epigenetic modulation, senescence management, or telomere stabilization, new interventions are being explored to push the boundaries of healthy aging.

References

  1. José, J.; Linares, A.-; Ramón Tejedor, J.; Fernández, A.F.; Pérez, R.F.; Fraga, M.F. A Universal Limit for Mammalian Lifespan Revealed by Epigenetic Entropy. bioRxiv 2024, 2024.09.06.611669. ↩︎
  2. Yamanaka, S. Induced Pluripotent Stem Cells: Past, Present, and Future. Cell Stem Cell 2012. ↩︎
  3. Singh, P.B.; Zhakupova, A. Age Reprogramming: Cell Rejuvenation by Partial Reprogramming. Development (Cambridge) 2022, 149. ↩︎
  4. Fadul, S.M.; Arshad, A.; Mehmood, R. CRISPR-Based Epigenome Editing: Mechanisms and Applications. Epigenomics 2023, 15, 1137–1155. ↩︎
  5. Chaib, S.; Tchkonia, T.; Kirkland, J.L. Cellular Senescence and Senolytics: The Path to the Clinic. Nature Medicine 2022, 28, 1556–1568. ↩︎
  6. Wissler Gerdes, E.O.; Zhu, Y.; Tchkonia, T.; Kirkland, J.L. Discovery, Development, and Future Application of Senolytics: Theories and Predictions. FEBS J 2020, 287, 2418–2427. ↩︎
  7. Nieto, M.; Könisgberg, M.; Silva-Palacios, A. Quercetin and Dasatinib, Two Powerful Senolytics in Age-Related Cardiovascular Disease. Biogerontology 2024, 25, 71–82. ↩︎
  8. Saretzki, G. Role of Telomeres and Telomerase in Cancer and Aging. International Journal of Molecular Sciences 2023, 24, 9932. ↩︎
  9. Rai, R.; Sodeinde, T.; Boston, A.; Chang, S. Telomeres Cooperate with the Nuclear Envelope to Maintain Genome Stability. BioEssays 2024, 46, 2300184. ↩︎
  10. Covarrubias, A.J.; Perrone, R.; Grozio, A.; Verdin, E. NAD+ Metabolism and Its Roles in Cellular Processes during Ageing. Nature Reviews Molecular Cell Biology 2020, 22, 119–141. ↩︎
  11. Panwar, V.; Singh, A.; Bhatt, M.; Tonk, R.K.; Azizov, S.; Raza, A.S.; Sengupta, S.; Kumar, D.; Garg, M. Multifaceted Role of MTOR (Mammalian Target of Rapamycin) Signaling Pathway in Human Health and Disease. Signal Transduction and Targeted Therapy 2023, 8, 1–25. ↩︎
  12. Ni, Y.; Zheng, L.; Zhang, L.; Li, J.; Pan, Y.; Du, H.; Wang, Z.; Fu, Z. Spermidine Activates Adipose Tissue Thermogenesis through Autophagy and Fibroblast Growth Factor 21. J Nutr Biochem 2024, 125, 109569. ↩︎
  13. Pezzuto, J.M. Resveratrol: Twenty Years of Growth, Development and Controversy. Biomol Ther (Seoul) 2019, 27, 1–14. ↩︎