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Rapamycin Exerts Its Geroprotective Effects in the Ageing Human Immune System by Enhancing Resilience Against DNA Damage.

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Affiliations

  • 1. Department of Biochemistry, University of Oxford, Oxford, UK.
      Authors
    • Kell L 1, 3, 4
    • Cox LS 1
    (2 authors)
  • 2. MRC-Versus Arthritis Centre for Musculoskeletal Ageing Research, Centre of Metabolism, Ageing and Physiology (COMAP), Academic Unit of Injury, Recovery and Inflammation Sciences (IRIS), School of Medicine, University of Nottingham, Royal Derby Hospital, Derby, UK.
      Authors
    • Jones EJ 2
    • Gharahdaghi N 2
    • Wilkinson DJ 2
    • Smith K 2
    • Atherton PJ 2
    (5 authors)
  • 3. The Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences (NDORMS), University of Oxford, Oxford, UK.
      Authors
    • Kell L 1, 3, 4
    • Simon AK 3
    • Alsaleh G 3, 4
    (3 authors)
  • 4. Botnar Institute for Musculoskeletal Sciences, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences (NDORMS), University of Oxford, Oxford, UK.
      Authors
    • Kell L 1, 3, 4
    • Alsaleh G 3, 4
    (2 authors)

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Aging Cell, 01 Feb 2026, 25(2):e70364
https://doi.org/10.1111/acel.70364 PMID: 41524558 PMCID: PMC12794675

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Abstract 

mTOR inhibitors such as rapamycin are among the most robust life-extending interventions known, yet the mechanisms underlying their geroprotective effects in humans remain incompletely understood. At non-immunosuppressive doses, these drugs are senomorphic, that is, they mitigate cellular senescence, but whether they protect genome stability itself has been unclear. Given that DNA damage is a major driver of immune ageing, and immune decline accelerates whole-organism ageing, we tested whether mTOR inhibition enhances genome stability. In human T cells exposed to acute genotoxic stress, we found that rapamycin and other mTOR inhibitors suppressed senescence not by slowing protein synthesis, halting cell division, or stimulating autophagy, but by directly reducing DNA lesional burden and improving cell survival. Ex vivo analysis of aged immune cells from healthy donors revealed a stark enrichment of markers for DNA damage, senescence, and mTORC hyperactivation, suggesting that human immune ageing may be amenable to intervention by low-dose mTOR inhibition. To test this in vivo, we conducted a placebo-controlled experimental medicine study in older adults administered with low-dose rapamycin. p21, a marker of DNA damage-induced senescence, was significantly reduced in immune cells from the rapamycin compared to placebo group. These findings reveal a previously unrecognised role for mTOR inhibition: direct genoprotection. This mechanism may help explain rapamycin's exceptional geroprotective profile and opens new avenues for its use in contexts where genome instability drives pathology, ranging from healthy ageing, clinical radiation exposure and even the hazards of cosmic radiation in space travel.

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    Funding 

    Funders who supported this work.

    Biotechnology and Biological Sciences Research Council (1)

    • Grant ID: BB/W01825X/1

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    Diabetes UK/BIRAX

      Helmholtz Association

        Medical Research Council (1)

        • Grant ID: MR/P021220/1

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        Mellon Longevity Graduate Programme at Oriel College, University of Oxford

          Public Health England

            UK SPINE (Research England)

              Versus Arthritis (1)

              • Grant ID: 22617

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              Wellcome Trust

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