Projektbeschreibung
Erforschung des Alterns und therapeutischer Lösungen
Die Hauptursache des Alterns ist ein allmählicher Rückgang der zellulären und molekularen Funktionen. Mit zunehmendem Alter nimmt die Fähigkeit des Körpers ab, sich an Stressfaktoren anzupassen und zu reparieren, was die Wirksamkeit von Anti-Aging-Behandlungen wie Metformin, Diät und Sport einschränkt. Ziel des vom Europäischen Forschungsrat finanzierten Projekts LifeLongFit ist es, mithilfe von Multiomik und funktionellen Tests in verschiedenen Organismen Erkenntnisse über altersbedingte Probleme zu gewinnen und mögliche therapeutische Lösungen zu untersuchen. Das Projektteam will intrinsische Resilienzmechanismen gegen die späte Toxizität von Metformin und adaptive Stressfaktoren in Nematoden aufdecken. Darüber hinaus sollen im Rahmen der Studie mit Omik-Datenanalysen die Faktoren untersucht werden, die für die außergewöhnliche Langlebigkeit von Säugetieren wie Nacktmullen und Walen verantwortlich sind.
Ziel
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.
Wissenschaftliches Gebiet
Schlüsselbegriffe
Programm/Programme
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Thema/Themen
Finanzierungsplan
HORIZON-ERC - HORIZON ERC GrantsGastgebende Einrichtung
07745 Jena
Deutschland