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Distinguishing between driver and passenger mechanisms of aging

Nature Genetics volume 56, pages 204–211 (2024)Cite this article

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Abstract

Understanding why we age is a long-standing question, and many mechanistic theories of aging have been proposed. Owing to limitations in studying the aging process, including a lack of adequate quantitative measurements, its mechanistic basis remains a subject of debate. Here, I explore theories of aging from the perspective of causal relationships. Many aging-related changes have been observed and touted as drivers of aging, including molecular changes in the genome, telomeres, mitochondria, epigenome and proteins and cellular changes affecting stem cells, the immune system and senescent cell buildup. Determining which changes are drivers and not passengers of aging remains a challenge, however, and I discuss how animal models and human genetic studies have been used empirically to infer causality. Overall, our understanding of the drivers of human aging is still inadequate; yet with a global aging population, elucidating the causes of aging has the potential to revolutionize biomedical research.

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Fig. 1: Examples of different types of causal relationship between variables.
Fig. 2: Selection of proposed mechanisms of aging based on age-related changes.
Fig. 3: Major approaches to study the causality of aging mechanisms.

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Acknowledgements

I am grateful to current and past members of the Genomics of Ageing and Rejuvenation Lab for valuable discussions and in particular H. Fitzmaurice, I. Viegas and P. Clark for comments on previous drafts. Work in our laboratory is supported by grants from the Wellcome Trust, Longevity Impetus Grants, LongeCity and the Biotechnology and Biological Sciences Research Council. During the preparation of this work, I used AI-assisted tools, Grammarly, QuillBot and ChatGPT, to improve readability and language. After using these tools, I reviewed and edited the text as needed and take full responsibility for the content of the publication. In trying to cover such a broad topic in a limited amount of space, I apologize to colleagues whose relevant works I was unable to cite.

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  1. Genomics of Ageing and Rejuvenation Lab, Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK

    João Pedro de Magalhães

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  1. João Pedro de Magalhães
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J.P.d.M. conceived and wrote the article.

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Correspondence to João Pedro de Magalhães.

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Competing interests

J.P.d.M. is the CSO of YouthBio Therapeutics, a company developing rejuvenation gene therapies based on partial reprogramming, an advisor or consultant for the Longevity Vision Fund, 199 Biotechnologies and NOVOS and the founder of Magellan Science, a company providing consulting services in longevity science.

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de Magalhães, J.P. Distinguishing between driver and passenger mechanisms of aging. Nat Genet 56, 204–211 (2024). https://doi.org/10.1038/s41588-023-01627-0

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