Age-related diseases are a major healthcare issue for older populations, burdening personal relationships, healthcare systems and economies1. Incidence of cancer, cardiovascular, pulmonary, kidney, neurodegenerative, metabolic, mobility, and immune disorders rises with longer lifespans. With 93% of adults over 65 suffering from at least one age-related disease, and 79% from two or more2, there is an urgent need for interventions that delay the onset of multiple morbidities. Because every tissue undergoes damage and functional decline during aging, healthcare faces the challenge of which diseases to treat and with what strategies. Beyond disease-specific therapies, gerotherapies targeting the fundamental biology of aging offer the potential to extend healthspan acting across the tissues on the inter-organ deficits and metabolic homeostasis1. A key research focus is slowing cellular damage to delay the aging clock3. Targeting the aging clock by interventions on metabolic rate and fate presents major opportunities for prevention and treatment of age-related diseases in our LIFT-AGE research proposal. In this research proposal, we will study a newly established in vivo model of accelerated aging, in which one single metabolic perturbation of the lipid fate triggers a severe senescence response across tissues. Genetic screens combined with metabolomics will identify the molecular mechanisms of the coordinated organ failure. Both phenotypic and in silico screens of chemical compounds will reveal lead molecules in drug discovery, that will be tested in vivo for their efficacy counteracting age-related diseases in multiple tissues.