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.

A central aspect in aging concerns the extent to which early-in-life events can determine the aging process. For instance, stress-inducing conditions during development can positively impact healthspan and lifespan. However, the location, timing and cellular effects of such events are largely unknown. The coordinator wishes to build on previous knowledge on signaling functions of Reactive Oxygen Species (ROS) which, when activated during early life stages, have protective effects. By partnering with two prominent Centers in Aging Research, we plan to identify the critical time window and specific mechanisms which are triggered in response to stressors to contribute to lifespan determination and apply this knowledge to prolong life and protect against age-related pathologies. This Twinning action will also enable the University of Crete to establish comprehensive training for its young scientists, strengthen the research management and organizational skills of its staff and the capacity to commercially exploit research outputs. Though this partnership University of Crete will establish the first excellence hub in Research, Training and Innovation in the Biology of Aging in Greece and will converge with the most advanced institutions in terms of the quality of scientific data it produces, the amount of funding it secures, the supportive research culture and career prospects for its young scientists and the way it communicates research results and converts them to tangible outcomes for the society.

Europe’s ageing population is characterized by an increasing gap between the ‘successful agers’ and the less successful ones, resulting in a significant fraction of the population suffering multiple diseases and disabilities. For the foreseeable future, interventions that increase healthy ageing bear the most promising potential to relieve individual suffering as well as the enormous strain on public finances. RESETageing project aims at enhancing the scientific and innovation competences of University of Coimbra (UC), Portugal, a low-performing partner, in the area of cardiovascular ageing, with three high-performing partners, University of Newcastle upon Tyne (UNEW), United Kingdom (ageing biology), the University of Maastricht (UM), Netherlands (cardiovascular biology) and the Leibniz Institute on Aging– Fritz Lipmann Institute (LIA), Germany (cardiovascular ageing). To accomplish this goal, the project is divided in 6 work packages that will: (i) stimulate research excellence in the aging and age-related cardiovascular diseases, (ii) train and give institutional exposure of UC researchers in the area of ageing mechanisms and new tools in age-related diseases (omics, system biology and animal models), and (iii) build an innovation and entrepreneurship environment at UC by nurturing an entrepreneurial and risk-taking spirit among UC students and researchers.