Description du projet
Comprendre le vieillissement, étudier des solutions thérapeutiques
Le déclin progressif des fonctions cellulaires et moléculaires constitue la principale cause du vieillissement. Avec l’âge, notre capacité à nous adapter aux facteurs de stress et à réparer notre corps diminue, ce qui limite l’efficacité des traitements contre le vieillissement tels que la metformine, les régimes alimentaires et l’exercice physique. L’objectif du projet LifeLongFit, financé par le CER, est d’appliquer la multiomique et des tests fonctionnels dans divers organismes afin de mieux comprendre les problèmes liés au vieillissement et d’étudier les potentielles solutions thérapeutiques. Le projet entend mettre en lumière des mécanismes de résilience intrinsèque contre la toxicité tardive de la metformine et les facteurs de stress adaptatifs chez les nématodes. L’étude examinera en outre les facteurs sous-jacents qui contribuent à la longévité exceptionnelle de mammifères tels que le rat-taupe nu et les baleines par l’analyse omique des données.
Objectif
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.
Champ scientifique
Programme(s)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Régime de financement
HORIZON-ERC - HORIZON ERC GrantsInstitution d’accueil
07745 Jena
Allemagne