Longevity Science and Geroscience: Mechanisms of Aging and Pathways for Intervention

Longevity science seeks to extend healthspan, the years lived in good health, while geroscience investigates aging as the primary risk factor for chronic diseases. By targeting fundamental aging processes, geroscience aims to delay multiple age-related conditions simultaneously. This forms the core scientific foundation for advancing therapeutic strategies in aging research.

The Hallmarks of Aging: Cell

Hallmarks of Aging

Aging arises from interconnected molecular and cellular changes. The 2023 updated framework identifies 12 hallmarks:

• Primary (causes): Genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis.

• Antagonistic (responses): Deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence.

• Integrative (consequences): Stem cell exhaustion, altered intercellular communication, chronic inflammation (inflammaging), dysbiosis, disabled macroautophagy.

These hallmarks interact; for example, mitochondrial dysfunction exacerbates genomic instability, while senescence drives inflammaging via the senescence-associated secretory phenotype (SASP).

Key Cellular Pathways in Longevity

Conserved pathways regulate aging by sensing nutrients and stress:

• Insulin/IGF-1 signaling (IIS): Reduced activity promotes longevity by enhancing stress resistance.

• mTOR: Inhibits growth and protein synthesis; inhibition (e.g., by rapamycin) boosts autophagy and extends lifespan in models.

• AMPK: Activated by low energy, opposes mTOR, promotes mitochondrial biogenesis and autophagy.

• Sirtuins: NAD+-dependent deacetylases that enhance DNA repair, metabolism, and stress resistance; link caloric restriction to longevity.

These pathways intersect: AMPK and sirtuins inhibit mTOR, converging on autophagy as a key longevity mechanism.

Interaction between sirtuins, mTOR and IIS signaling. Various points of interaction between these three signaling pathways have been described, some of which are depicted here. See text for details. P-phosphorylation site, Ac-acetylation site.  

Therapeutic Interventions

Interventions target these mechanisms:

• Senolytics (e.g., dasatinib + quercetin): Selectively clear senescent cells, reducing inflammation; early trials show promise for cognition, mobility, and conditions like osteoarthritis and Alzheimer's risk.

• mTOR inhibitors (e.g., rapamycin/rapalogs): Mimic caloric restriction, improving immune function and healthspan.

• NAD+ boosters (e.g., NR, NMN): Restore sirtuin activity and mitochondrial function; combined with senolytics for potential synergy.

• Emerging: Anti-inflammatories, autophagy enhancers, and precision approaches using aging biomarkers like epigenetic clocks.

Clinical trials (over 30 ongoing as of 2025) face challenges in endpoints and regulation, but progress supports targeting aging biology for healthier longevity.

Conclusion

Geroscience's focus on shared aging mechanisms offers transformative potential to compress morbidity and extend vibrant lives. Ongoing research into hallmarks, pathways, and interventions continues to build this essential foundation for conferences and breakthroughs in human health.