Rapamycin exerts its geroprotective effects in the ageing human immune system by enhancing resilience against DNA damage

Kell, Loren; Jones, Eleanor J.; Gharahdaghi, Nima; Wilkinson, Daniel J.; Smith, Kenneth; Atherton, Philip J.; Simon, Anna K.; Cox, Lynne S.; Alsaleh, Ghada

Rapamycin exerts its geroprotective effects in the ageing human immune system by enhancing resilience against DNA damage

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Item Type:	Article
Title:	Rapamycin exerts its geroprotective effects in the ageing human immune system by enhancing resilience against DNA damage
Creators Name:	Kell, Loren, Jones, Eleanor J., Gharahdaghi, Nima, Wilkinson, Daniel J., Smith, Kenneth, Atherton, Philip J., Simon, Anna K., Cox, Lynne S. and Alsaleh, Ghada
Abstract:	mTOR inhibitors such as rapamycin are among the most robust life-extending interventions known, yet the mechanisms un-derlying their geroprotective effects in humans remain incompletely understood. At non-immunosuppressive doses, these drugsare 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 testedwhether mTOR inhibition enhances genome stability. In human T cells exposed to acute genotoxic stress, we found that rapamy-cin and other mTOR inhibitors suppressed senescence not by slowing protein synthesis, halting cell division, or stimulating au-tophagy, but by directly reducing DNA lesional burden and improving cell survival. Ex vivo analysis of aged immune cells fromhealthy donors revealed a stark enrichment of markers for DNA damage, senescence, and mTORC hyperactivation, suggestingthat human immune ageing may be amenable to intervention by low-dose mTOR inhibition. To test this in vivo, we conducteda placebo-controlled experimental medicine study in older adults administered with low-dose rapamycin. p21, a marker of DNAdamage-induced senescence, was significantly reduced in immune cells from the rapamycin compared to placebo group. Thesefindings reveal a previously unrecognised role for mTOR inhibition: direct genoprotection. This mechanism may help explainrapamycin's exceptional geroprotective profile and opens new avenues for its use in contexts where genome instability drivespathology, ranging from healthy ageing, clinical radiation exposure and even the hazards of cosmic radiation in space travel.
Keywords:	Ageing, Cell Senescence, DNA Damage, Genome Stability, Immunosenescence, mTOR, Rapamycin
Source:	Aging Cell
ISSN:	1474-9718
Publisher:	Anatomical Society / Wiley
Volume:	25
Number:	2
Page Range:	e70364
Date:	February 2026
Official Publication:	https://doi.org/10.1111/acel.70364
PubMed:	View item in PubMed

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