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, i.e. 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 trial 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 rapamycinâs 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.
Hereâs a structured summary of the key points from the paper âRapamycin exerts its geroprotective effects in the ageing human immune system by enhancing resilience against DNA damageâ:
Background
Rapamycin, an mTOR inhibitor, is one of the most consistent lifespan-extending drugs in animals.
At low (non-immunosuppressive) doses, rapamycin reduces cellular senescence but the underlying mechanism in humans was unclear.
DNA damage is a major driver of immune ageing (immunosenescence), which accelerates whole-body ageing.
Main Findings
Rapamycin protects immune cells from DNA damage
In human T cells exposed to genotoxic stress (zeocin, hydrogen peroxide), rapamycin reduced DNA damage markers (ÎłH2AX, p53, p21) and improved cell survival.
This protection was not due to slowing protein synthesis, halting the cell cycle, or increasing autophagy.
Instead, rapamycin directly lowered the DNA lesion burdenâshowing a âgenoprotectiveâ effect.
Mechanism: direct genoprotection
Rapamycin reduced DNA breaks (comet assay) and improved T cell viability after DNA damage.
This effect was independent of classical pathways (autophagy, cell cycle arrest).
Immune ageing is linked to DNA damage + mTOR hyperactivation
Blood samples from older adults showed immune cell subsets (e.g., TEMRA T cells, B cells, monocytes) enriched for DNA damage and senescence markers (p21, p53, p16, ÎłH2AX).
These age-related cells also showed overactive mTOR signalling.
In vivo human trial (pilot study, NCT05414292)
Older men (50â90 years) received 1 mg/day rapamycin or placebo for 4 months.
Rapamycin significantly reduced p21 (DNA damage-induced senescence marker) in immune cells compared to placebo.
Rapamycin also reduced immune exhaustion markers (KLRG1, LAG3, NKG2A) without immunosuppression.
Blood levels of rapamycin were low but within the protective range.
Implications
Rapamycin acts as a genoprotector, a newly recognized mechanism that may explain its strong anti-ageing effects.
Potential applications:
Healthy ageing: slowing immunosenescence.
Medicine: protecting healthy cells from DNA damage during radiation/chemotherapy.
Space travel: mitigating cosmic radiation damage.
Pandemic preparedness: boosting immune resilience in older adults (e.g., against viruses that induce DNA damage).
Cautions
Senescence and DNA damage play physiological roles (e.g., in wound healing, immune clearance of infected cells).
Long-term genoprotection may carry risks such as impaired immune surveillance or delayed tissue repair.
Larger clinical trials are needed before broad use in humans.
Bottom line:
The study demonstrates for the first time that low-dose rapamycin directly protects human immune cells from DNA damage and reduces senescence in vivo, positioning it as a potential therapy to slow immune ageing and enhance resilience in contexts of DNA damage.
Very cool! And I like that it was 4 months, which is a decent length of time. And 1mg/day, though not a âstandard longevityâ weekly dose, is not unreasonably high.
Sample size for the human volunteers was very low though (5 subjects per group)
1 mg / day for months was what was also shown to functionally render apoE4 brain similar to apoe3 so Iâm seeing a lot of backing for this dosage â maybe with a washout period as a safety valve.
Also interesting that mechanistically they couldnât attribute the effects to autophagy or any of the run of the mill mechanisms.
Itâs interesting that the dose is 1mg/day. I have been on that dose for kidney transplant maintenance since 2010. No washout periods were recommended in my case. According to my experience itâs hard to be on this comparatively low dose for a long time bc of side effects.
I suppose no washout would be recommended in your case due to the primary reason for taking it being organ transplant so you canât âaffordâ washout without bringing into the fold some other immunosuppressant.
May I ask 1) why was such a low dose recommended to you â itâs my understanding that for organ transplant the Sirolimus dosage employed is typically much higher 2) what were the side effects for you and how long did it take you to develop them on 1mg/day?
I do not know the reason why I was put on only 1 mg Rapa. Initially it was on combination with a low dose Tacrolimus which I couldnât tolerate so it was dropped. The reasons were based on blood biomarkers Iâm guessing, nearly identical live donor match (my son), overall health. The side effects were the same as described here by many when taken for longevity. No matter whatâs the purpose of taking it (longevity or something else), the sides are the same and point to the overly suppressed immune system (mouth ulcers, skin infections, flu like symptoms, activation of other dormant viruses, like herpes, fatigue, high lipids and glucose, etc.). Rapa accumulates quickly @1mg/day without washouts. I would say that sides appear after 2 weeks. Iâm guessing that 0.5 mg if taken without breaks would work better. We need more research!
It was skin rash like contact dermatitis or eczema that looks like dry scratch-like marks (on shoulders or back), mouth ulcers, skin inflammation (acne-like on scalp), dry lesions after delayed wound healing that would leave a visible red mark for months. Those sides are usually resolved on Rapa breaks.My trough was 3.2-3.5 on 1 mg/day. My nephrologist didnât want it to go lower than 3.
Hi SteveâŠrapamycin was misclassified as an immunosuppressant. It is actually an immunomodulator. When taken episodically, it enhances immune function. Ross
Hi out of interest would LDN work in a similar way but maybe less side effects? âLDN modulates the immune system. It doesnât necessarily boost it, but it doesnât necessarily suppress it to the point where we see issues of recurring infections.â
My current dose regime is 25mg once fortnightly. I combine it with a short fast to maximise autophagy. Looks like I might need to reconsider that approach!
Bottom line:
