DNA, which has a double-helix structure, can have many genetic mutations and variations. Credit: NIH

University of Oxford-led research finds low-dose rapamycin functions as a genomic protector in aging human immune cells, lowering DNA damage.

The mechanistic target of rapamycin (mTOR) is a central signaling pathway that regulates and coordinates cell growth, metabolism, and survival in response to environmental cues. It helps cells integrate signals from growth factors, nutrients, and stress to control whether they are in an anabolic (building up) or catabolic (breaking down) state.

Aging immune systems accumulate DNA damage linked to immunosenescence. Rapamycin is a drug that inhibits the mTOR pathway. Originally developed for organ transplantation to prevent immune rejection, previous research has found that, at non-immunosuppressive doses, rapamycin can mitigate cellular senescence.

In the study, "Rapamycin exerts its geroprotective effects in the ageing human immune system by enhancing resilience against DNA damage, " published on the bioRxiv pre-print server, researchers combined in vitro DNA damage assays in human T cells, ex vivo profiling of age-related immune subsets, and a single-blind, placebo-controlled trial in older adults to test whether low-dose mTOR inhibition enhances genome stability and limits DNA damage–induced senescence.

Nine older male participants (65–75 years) were randomized in a single-blind, placebo-controlled trial to receive 1 mg/day rapamycin (n=4) or placebo (n=5) for four months, with peripheral blood mononuclear cells (PBMCs) sampled across multiple time points.

Researchers activated human PBMCs with anti-CD3 and anti-CD28 for three days, induced acute DNA damage with zeocin for two hours or hydrogen peroxide for 15 minutes, and assessed recovery at four and 24 hours. PBMC cultures received low-dose rapamycin 10 nM before, during, and after genotoxin exposure, with parallel controls.

DNA-damage pulled human T cells to DNA damage signals that peaked at four hours and eased by 24 hours, alongside rises in checkpoint alarms and stress proteins p53 and p21 (a p53-controlled cyclin-kinase inhibitor and a sign of DNA damage-induced senescence).

Rapamycin and a second mTOR blocker dialed down the main damage signal and the pathway readout signal, with rapamycin cutting p53 and p21 at four hours and more by 24 hours. Given before, during, or after zeocin exposure (the DNA-damaging treatment), rapamycin reduced the damage signal (γH2AX) in CD4 T cells.

Zeocin nudged cells out of DNA-copying mode toward division prep. Rapamycin did not affect this phase mix among damaged cells. Short protein production did not fall with rapamycin during or after damage.

Cells carrying more damage showed less autophagy, a protective recycling process, and blocking autophagy raised damage signals further. Rapamycin cut these signals even under blockade and also increased autophagy.

A DNA break test showed fewer breaks with rapamycin from 0 to 24 hours after damage. Survival improved with about 20% alive with zeocin exposure alone vs. over 60% with rapamycin at 24 hours. After four months on rapamycin, p21 dropped across most immune subsets while p53 rose, and inhibitory markers KLRG1, NKG2A, and LAG3 decreased, with PD-1 unchanged.

Authors conclude that rapamycin provides direct genomic protection in human immune cells and may support healthy aging, offer benefits after clinical radiation exposure, and could even address risks from cosmic radiation during extended space travel.

Written for you by our author Justin Jackson, edited by Sadie Harley, and fact-checked and reviewed by Robert Egan—this article is the result of careful human work. We rely on readers like you to keep independent science journalism alive. If this reporting matters to you, please consider a donation (especially monthly). You'll get an ad-free account as a thank-you.

More information: Loren Kell et al, Rapamycin exerts its geroprotective effects in the ageing human immune system by enhancing resilience against DNA damage, biorxiv (2025). DOI: 10.1101/2025.08.15.670559  Journal information: bioRxiv

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