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Aging through an epitranscriptomic lens

Abstract

The mechanistic causes of aging, the time-related decline in function and good health that leads to increased mortality, remain poorly understood. Here we propose that age-dependent alteration of the epitranscriptome, encompassing more than 150 chemically distinct post-transcriptional modifications or editing events, warrants exploration as an important modulator of aging. The epitranscriptome is a potent regulator of RNA function, diverse cellular processes and tissue regenerative capacity. To date, only a few studies link alterations in the epitranscriptome to molecular and physiological changes during aging; however, epitranscriptome dysfunction is associated with and underlies several age-associated pathologies, including cancer and neurodegenerative, cardiovascular and autoimmune diseases. For example, changes in RNA modifications (such as N6-methyladenosine and inosine) impact cardiac physiology and are linked to cardiac fibrosis. Although an uncharted research focus, mapping epitranscriptome alterations in the context of aging may elucidate novel predictors of both health and lifespan, and may identify therapeutic targets for attenuating aging and abrogating age-related diseases.

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Fig. 1: Main classes of RNA subject to post-transcriptional editing and modifications.
Fig. 2: Contribution of altered RNA modifications to the various hallmarks of aging.
Fig. 3: Molecular functions of RNA modifications.
Fig. 4: Role of RNA modifications in healthy and pathological tissue regeneration.

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Acknowledgements

We thank J. Kimmel and R. Cohen at Calico Life Sciences LLC as well as D. Fujimori (UCSF) and C. Stumpf (eFFECTOR Therapeutics) for their helpful comments on this article. Figures were created using BioRender.com. M.M. and R.B. have been funded by Calico Life Sciences LLC. C.F. was funded by the NIH/NIDDK (1K08DK119561-01) and the American Society of Hematology (A132428).

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M.M. and R.B. led article conceptualization and writing. M.M., C.F. and R.B. researched data for the article. M.M., C.F. and R.B. discussed the content and contributed to writing and editing of the manuscript before submission.

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Correspondence to Mary McMahon or Rochelle Buffenstein.

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M.M. and R.B. are employees of Calico Life Sciences LLC. C.F. declares no competing interests.

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McMahon, M., Forester, C. & Buffenstein, R. Aging through an epitranscriptomic lens. Nat Aging 1, 335–346 (2021). https://doi.org/10.1038/s43587-021-00058-y

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