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Replacement as an aging intervention

Nature Aging volume 5, pages 750–764 (2025)Cite this article

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Abstract

Substantial progress in aging research continues to deepen our understanding of the fundamental mechanisms of aging, yet there is a lack of interventions conclusively shown to attenuate the processes of aging in humans. By contrast, replacement interventions such as joint replacements, pacemaker devices and transplant therapies have a long history of restoring function in injury or disease contexts. Here, we consider biological and synthetic replacement-based strategies as aging interventions. We discuss innovations in tissue engineering, such as the use of scaffolds or bioprinting to generate functional tissues, methods for enhancing donor–recipient compatibility through genetic engineering and recent progress in both cell therapies and xenotransplantation strategies. We explore synthetic approaches including prostheses, external devices and brain–machine interfaces. Additionally, we evaluate the evidence from heterochronic parabiosis experiments in mice and donor–recipient age-mismatched transplants to consider whether systemic benefits could result from personalized replacement approaches. Finally, we outline key challenges and future directions required to advance replacement therapies as viable, scalable and ethical interventions for aging.

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Fig. 1: Overview of approaches for replacement interventions in aging.
Fig. 2: Timeline of milestones in replacement interventions for aging.
Fig. 3: Overview of anatomical systems and potential replacement methods.
Fig. 4: Overview of mechanisms and generation techniques within each category of biological replacement.
Fig. 5: Overview of machines and mechanisms of synthetic replacement from prostheses and external medical devices.
Fig. 6: Overview of devices and interventions in brain–machine interface technology.

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Acknowledgements

Figures 3–6 were created with or modified from BioRender.com. S.L. thanks R. Goodbar, S. Lore, M. van Kooten and A. Colville for their support throughout the preparation of this Perspective. Supported by grants from the National Institute on Aging, the US Department of Health & Human Services (NIH/NIAID grant 1U01AI180158-01) and Hevolution.

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Authors and Affiliations

  1. Buck Institute for Research on Aging, Novato, CA, USA

    Sierra Lore & Eric Verdin

  2. University of Copenhagen, København, Denmark

    Sierra Lore & Morten Scheibye-Knudsen

  3. Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    Jesse R. Poganik, George Church & Vadim N. Gladyshev

  4. Wake Forest Institute for Regenerative Medicine, Winston-Salem, NC, USA

    Anthony Atala

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  1. Sierra Lore
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Contributions

S.L. conceptualized, wrote and revised the Perspective. E.V. and M.S.-K. oversaw the writing and revision of this Perspective. J.R.P., A.A., G.C. and V.N.G. contributed to revising the manuscript and provided critical feedback.

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Correspondence to Eric Verdin.

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Competing interests

G.C. declares potential conflicts of interest related to companies involved in transplantation and aging, including eGenesis, Qihan, GC Therapeutics, Cellino, Rejuvenate Bio and Thymmune (further interests, outside of the scope of the current work, can be found in the Supplementary Note). A.A. declares a potential conflict of interest with Precise Bio, related to the bioprinting of human corneas. S.L., J.R.P., V.N.G., M.S.‑K. and E.V. have no competing interests.

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Nature Aging thanks Marius Wernig, Paolo De Simone, and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Lore, S., Poganik, J.R., Atala, A. et al. Replacement as an aging intervention. Nat Aging 5, 750–764 (2025). https://doi.org/10.1038/s43587-025-00858-6

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