Rapamycin Exerts Its Geroprotective Effects in the Ageing Human Immune System by Enhancing Resilience Against DNA Damage
What this study shows
Proposes a geroprotective mechanism for rapamycin that the authors call direct genoprotection. In human T cells exposed to acute genotoxic stress, rapamycin and other mTOR inhibitors suppressed senescence not by slowing protein synthesis, halting cell division, or stimulating autophagy, but by reducing DNA lesion burden and improving cell survival. Ex vivo aged human immune cells showed elevated DNA damage, senescence and mTORC-hyperactivation markers. In a placebo-controlled experimental medicine study, low-dose rapamycin significantly reduced p21 (a DNA-damage-induced senescence marker) in immune cells of older adults versus placebo. Boundary: what was measured is reduced DNA lesion burden under acute genotoxic stress ex vivo, plus one marker (p21) in vivo. 'Genoprotection' as a general property of rapamycin is the authors' interpretation, and no clinical endpoint was measured.
Abstract
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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.
Read the full abstract on PubMed →At a glance
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| Evidence type | H Human study Marked H because it is direct evidence from a human clinical trial or human cohort; the code names the kind of study, not its quality -- a small, well-run trial is still H. |
| Study type | 2 - Human Clinical Trial |
| Model system | Human T cells (ex vivo, genotoxic stress); ex vivo aged human immune cells; placebo-controlled experimental medicine study in older adults (low-dose oral rapamycin, in vivo) |
| Journal | Aging Cell |
| Year | 2026 |
| Peer reviewed | Yes |
| Record last updated | 2026-10-01 |
| Source | DOI 10.1111/acel.70364 · PMID 41524558 · Free full text (PMC12794675) |
Where this study fits
How this study connects to the pathway map, open questions, people and other studies in the Atlas.
Open question
Mechanism-to-outcome gap · H10
How much of rapamycin's healthspan benefit runs through fewer senescent cells?Cited there as evidence. Evidence stands at: Mechanism in cells.
People in the Atlas
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First author identifying a direct genoprotective effect of rapamycin against DNA damage in ageing human immune cells
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Senior author studying autophagy and immune-cell ageing; identified a genoprotective mechanism for rapamycin
More: 7 other authors
No profile yet: Jones EJ, Gharahdaghi N, Wilkinson DJ, Smith K, Atherton PJ, Simon AK, Cox LS
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Topics
Extracted findings
These fields were extracted from the paper with AI assistance and have not been checked against the source. Read them as a pointer into the paper, not as curated claims; where they disagree with the curated summary above, the curated summary stands.
| Intervention | Rapamycin and other mTOR inhibitors (ex vivo); low-dose oral rapamycin vs placebo (older adults) |
| Target | mTOR; DNA damage-induced senescence (p21) |
| Model | Human (T cells ex vivo; older adults in vivo) |
| Effect | mTOR inhibition reduced DNA lesion burden and senescence in T cells, and low-dose rapamycin lowered immune-cell p21 versus placebo. |
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