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

## TL;DR

Rapamycin helps protect the aging human immune system by reducing DNA damage and improving cell survival.

## Contribution

The study reveals that rapamycin protects genome stability in human immune cells by directly reducing DNA damage, a previously unrecognized mechanism.

## Key findings

- Rapamycin reduces DNA damage and improves survival in human T cells under genotoxic stress.
- Low-dose rapamycin significantly reduces p21, a senescence marker, in immune cells of older adults.
- Aged immune cells show signs of DNA damage and mTORC hyperactivation, suggesting potential for mTOR inhibition.

## 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.

Using in vitro DNA damage assays in human T cells, ex vivo profiling of aged immune subsets and a small placebo‐controlled in vivo study, authors show that low‐dose rapamycin, a potent life‐extending mTOR inhibitor, enhances resilience against DNA damage in the human immune system.