Descripción del proyecto
Comprender el envejecimiento para investigar soluciones terapéuticas
El declive gradual de la función celular y molecular constituye la principal causa del envejecimiento. A medida que se envejece, disminuye la capacidad de adaptación a los factores estresantes y de reparación del organismo, lo que limita la eficacia de tratamientos antienvejecimiento como, por ejemplo, el uso de la metformina, la dieta y el ejercicio. El proyecto LifeLongFit, financiado por el Consejo Europeo de Investigación, tiene por objeto emplear la multiómica y las pruebas funcionales en diversos organismos para conocer mejor los problemas relacionados con el envejecimiento e investigar posibles soluciones terapéuticas. En este sentido, se pretende dilucidar los mecanismos intrínsecos de resiliencia contra la toxicidad tardía de la metformina y los factores estresantes adaptativos en los nematodos. Además, mediante el análisis de datos ómicos, se investigarán los factores subyacentes que contribuyen a la longevidad excepcional en mamíferos como la rata topo desnuda y las ballenas.
Objetivo
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.
Ámbito científico
Programa(s)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Régimen de financiación
HORIZON-ERC - HORIZON ERC GrantsInstitución de acogida
07745 Jena
Alemania