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Aging by the clock and yet without a program

Nature Aging volume 5, pages 1946–1956 (2025)Cite this article

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An Addendum to this article was published on 15 December 2025

An Addendum to this article was published on 15 December 2025

This article has been updated

Abstract

The mechanisms of aging are becoming increasingly well mapped; however, there remains ongoing debate about the ultimate and proximate causes of aging. The recent development of highly precise aging clocks led to a resurgence of arguments in support of a biological program of aging. However, the declining force of natural selection after the onset of reproduction means that cellular function could deteriorate without requiring a specific program. Here, we argue that aging clocks do not imply an intrinsic program but rather reflect the stochastic accumulation of molecular errors and damage. Damage accumulates due to insufficient maintenance and repair and contributes to system-wide entropy. In support of this, cross-species comparisons indicate that enhanced DNA repair capacity is a key determinant of exceptional longevity in mammals. By better understanding the nature of the stochasticity that governs the aging process, we will have a stronger mechanistic basis for developing geroprotective interventions to promote healthy aging in humans.

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Fig. 1: Molecular mechanisms that are subject to stochasticity.
Fig. 2: Epigenetic changes and transcription.
Fig. 3: Mechanisms of DNA methylation maintenance and sources of variation.

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Acknowledgements

B.S. acknowledges funding from 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, the DFG-ISF project 561031107 and DFG project grants 558166204, 540136447, 496914708, 437825591, 437407415 and 418036758), the Deutsche Krebshilfe (70114555), Deutsche José Carreras Leukämie-Stiftung (DJCLS 04 R/2023), a John Templeton Foundation Grant (61734), the European Research Council (ERC-2023-SyG 101118919) and the Hevolution Foundation (HF-GRO-23-1199212-35). D.H.M. acknowledges funding from the Deutsche Forschungsgemeinschaft (DFG project grant 570621149) and from the Koeln Fortune Program / Faculty of Medicine, University of Cologne. A.A.M. acknowledges funding from the Leverhulme Trust RPG-2023-068 and the Natural Environment Research Council (NE/W001020/1).

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Authors and Affiliations

  1. Institute for Genome Stability in Ageing and Disease, Medical Faculty, University of Cologne, Cologne, Germany

    David H. Meyer & Björn Schumacher

  2. Cologne Excellence Cluster for Cellular Stress Responses in Ageing-Associated Diseases, Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany

    David H. Meyer & Björn Schumacher

  3. School of Biological Sciences, University of East Anglia, Norwich Research Park, Norwich, UK

    Alexei A. Maklakov

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  1. David H. Meyer
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  2. Alexei A. Maklakov
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  3. Björn Schumacher
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Contributions

Conceptualization and writing: D.H.M., A.A.M. and B.S.

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Correspondence to David H. Meyer, Alexei A. Maklakov or Björn Schumacher.

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Nature Aging thanks Steven Cummings, Vera Gorbunova, and Alan Cohen for their contribution to the peer review of this work.

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Meyer, D.H., Maklakov, A.A. & Schumacher, B. Aging by the clock and yet without a program. Nat Aging 5, 1946–1956 (2025). https://doi.org/10.1038/s43587-025-00975-2

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