Ageing is a complex, multifaceted process leading to widespread functional decline that affects every organ and tissue, but it remains unknown whether ageing has a unifying causal mechanism or is grounded in multiple sources. Phenotypically, the ageing process is associated with a wide variety of features at the molecular, cellular and physiological level—for example, genomic and epigenomic alterations, loss of proteostasis, declining overall cellular and subcellular function and deregulation of signalling systems. However, the relative importance, mechanistic interrelationships and hierarchical order of these features of ageing have not been clarified. Here we synthesize accumulating evidence that DNA damage affects most, if not all, aspects of the ageing phenotype, making it a potentially unifying cause of ageing. Targeting DNA damage and its mechanistic links with the ageing phenotype will provide a logical rationale for developing unified interventions to counteract age-related dysfunction and disease.
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The research was supported by the Deutsche Forschungsgemeinschaft (SCHU 2494/3-1, SCHU 2494/7-1, SCHU 2494/10-1, SCHU 2494/11-1, KFO 286, KFO 329, GRK 2407 to B.S., and CECAD EXC 2030–390661388, SFB 829 to B.S. and J.H.J.H.), Deutsche Krebshilfe (70112899), H2020-MSCA-ITN-2018 (Healthage and ADDRESS ITNs) and John Templeton Foundation Grant (61734) to B.S., NIH grants (PO1 AG017242 to J.V. and J.H., and U19 AG056278, U01 ES029519, P01AG047200, U01HL145560, P30AG038072 to J.V.), European Research Council Advanced Grants DamAge and Dam2Age, ONCODE (Dutch Cancer Society), Memorabel and Chembridge (ZonMW) and BBoL (NWO-ENW) to J.P. and J.H.
J.V. is a co-founder of SingulOmics Corp. The other authors declare no competing interests.
Peer review information Nature thanks Jan van Deursen, John Sedivy and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
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Schumacher, B., Pothof, J., Vijg, J. et al. The central role of DNA damage in the ageing process. Nature 592, 695–703 (2021). https://doi.org/10.1038/s41586-021-03307-7
Ageing Research Reviews (2021)