Project description
Understanding ageing, exploring therapeutic solutions
The principal cause of ageing is a gradual decline in cellular and molecular function. As we grow older, our capacity to adapt to stressors and repair our bodies decreases, which limits the effectiveness of anti-ageing treatments such as metformin, dietary restriction and exercise. The ERC-funded LifeLongFit project’s objective is to employ multi-omics and functional tests in various organisms to gain insights into ageing-related issues and investigate potential therapeutic solutions. The project aims to uncover intrinsic resilience mechanisms against late-life toxicity from metformin and adaptive stressors in nematodes. Additionally, the study will investigate the underlying factors contributing to exceptional longevity in mammals like the naked mole-rat and whales through omics data analysis.
Objective
Aging represents gradual organismal decline driven by 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. 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 loss of metabolic plasticity and repair activities due to aging abrogate longevity benefits of adaptive stressors at old age. Specifically, we found that aging-linked failures of mitochondria and lipid catabolism limit metformin benefits and confer metformin toxicity in late life, and others showed 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.
Here, we will use multi-omics, and functional tests in C. elegans, short-lived killifish and long-lived mammals to (a) probe the origin of aging-linked adaptive failures and (b) find molecular and therapeutic solutions for overcoming these failures. 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 adaptive basis of the exceptional mammalian longevity in NMR and whale, followed by attempted replication of uncovered differences in shorter-lived species (nematodes and fish) by drugs and gene changes, with an outlook of triggering superior stress resilience and metabolic plasticity in late life. Our expertise will allow testing late life responses to diverse adaptive interventions from moderate genotoxic stress to DR mimetics and microbiome manipulation. This innovative program will illuminate novel treatments for healthy longevity that are not limited by aging.
Fields of science
Programme(s)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Funding Scheme
HORIZON-ERC - HORIZON ERC GrantsHost institution
07745 Jena
Germany