Abstract
Ageing is the most important risk factor for many common human diseases, including cancer, diabetes, neurodegeneration and cardiovascular disease. Consequently, combating ageing itself has emerged as a rational strategy for addressing age-related multimorbidity. Over the past three decades, multiple genetic and pharmacologic interventions have led to substantial extension of lifespan and healthspan in model organisms. However, it is unclear whether these interventions target the causal mechanisms of ageing or downstream consequences. Ample evidence suggests that DNA damage to the somatic genome is a major causal mechanism of ageing, which compromises essential cellular functions such as transcription and replication, and leads to cellular senescence, apoptosis and mutations. Recently, new concepts have emerged to target the main consequences of DNA damage and enhance DNA repair capacities, thereby extending maintenance of the genome. Here, we review advances in this field and discuss approaches to pharmacologically mitigate the adverse effects of DNA damage to delay ageing, prevent mutation-driven cancer and mitigate age-related degenerative diseases.
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Acknowledgements
G.A.G. and B.S. acknowledge funding from the Hevolution Foundation (HF-GRO-23-1199212-35) and the ERA Chair Program (101176529). J.V. acknowledges support from NIH grants (P01 AG017242, P01 AG047200, P30 AG038072, U01 ES029519, U01 HL145560, and U19 AG056278). P.D.R. acknowledges grants R01 AG069819, P01 AG043376, U19 AG056278, P01 AG062413, U54 AG079754, U54 AG076041, P01 AI172501, R01 AG076515, R01 AG081293, R01 AG069819 from the National Institutes of Health and the Aligning Science Across Parkinson’s (ASAP-000592) grant administered through the Michael J. Fox Foundation for Parkinson’s Research (MJFF). B.S. acknowledges funding from the European Research Council (ERC-2023-SyG, 101118919), the Deutsche Forschungsgemeinschaft (Reinhart Koselleck-Project 524088035, FOR 5504 project 496650118, FOR 5762 project 531902955, SFB 1678, SFB 1607, CECAD EXC 2030 – 390661388, ANR-DFG project 545378328, and the DFG project grants 558166204, 540136447, 496914708, 437825591, 437407415, 418036758), the José Carreras Leukaemia Foundation, DJCLS 04 R/2023, the Deutsche Krebshilfe (70114555) and the John Templeton Foundation Grant (61734). Figures were generated using Biorender.
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J.V. is co-founder of Singulomics Inc. and Mutagentech Inc, and P.D.R. is co-founder of Genascence and Itasca Therapeutics. The other authors declare no competing interests.
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Bujarrabal-Dueso, A., Garinis, G.A., Robbins, P.D. et al. Targeting DNA damage in ageing: towards supercharging DNA repair. Nat Rev Drug Discov 24, 785–807 (2025). https://doi.org/10.1038/s41573-025-01212-6
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DOI: https://doi.org/10.1038/s41573-025-01212-6
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