Late life-applicable enhancement of longevity and fitness.

Introduction

Aging represents gradual organismal decline driven by the accumulation of cellular and molecular damages, including DNA damage and metabolic failures. At young and middle age, these damages are mitigated by tailored repair systems, such as autophagy and DNA damage response.

Adaptive Stress Responses

The repairs can be triggered through adaptive stress responses induced by anti-aging interventions such as dietary restriction (DR) and DR mimetic metformin. Recently, we found that the loss of metabolic plasticity and repair activities due to aging abrogates the longevity benefits of adaptive stressors at old age.

Limitations of Anti-Aging Treatments

Specifically, we found that aging-linked failures of mitochondria and lipid catabolism limit metformin benefits and confer metformin toxicity in late life. Others have shown comparable limitations for DR and exercise. Our findings demonstrate that anti-aging treatments do lose efficacy in old organisms, and new approaches are required to promote healthy aging in late life.

Research Objectives

Here, we will use multi-omics and functional tests in C. elegans, short-lived killifish, and long-lived mammals to:

1. Probe the origin of aging-linked adaptive failures.
2. Find molecular and therapeutic solutions for overcoming these failures.

Methodology

Omics tests and survival screens will be used to uncover mechanisms of intrinsic resilience against late-life toxicity of metformin and other adaptive stressors in nematodes. Additional omics data will be analyzed to probe the adaptive basis of the exceptional mammalian longevity in naked mole rats (NMR) and whales.

Replication Efforts

This will be followed by an attempted replication of uncovered differences in shorter-lived species (nematodes and fish) through drugs and gene changes, with an outlook of triggering superior stress resilience and metabolic plasticity in late life.

Expertise and Interventions

Our expertise will allow testing late-life responses to diverse adaptive interventions, from moderate genotoxic stress to DR mimetics and microbiome manipulation.

Conclusion

This innovative program will illuminate novel treatments for healthy longevity that are not limited by aging.