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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, 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 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.

https://www.biorxiv.org/content/10.1101/2025.08.15.670559v1?ct=

ChatGPT summary

Here’s a structured summary of the key points from the paper “Rapamycin exerts its geroprotective effects in the ageing human immune system by enhancing resilience against DNA damage”:

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

  1. 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 burden—showing a “genoprotective” effect.

  2. 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).
    • Suggests rapamycin enhances genome stability itself.

  3. 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.

  4. In vivo human trial (pilot study, NCT05414292)

    • Older men (50–90 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.

:white_check_mark: 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.

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mTOR inhibitors and the Blood Brain Barrier
#2

Very cool! And I like that it was 4 months, which is a decent length of time. And 1mg/day, though not a “standard longevity” weekly dose, is not unreasonably high.

Sample size for the human volunteers was very low though (5 subjects per group)

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#3

Very very nice paper. Oxford, so quite good. @John_Hemming you’ll like it!

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#4

1 mg / day for months was what was also shown to functionally render apoE4 brain similar to apoe3 so I’m seeing a lot of backing for this dosage — maybe with a washout period as a safety valve.

Also interesting that mechanistically they couldn’t attribute the effects to autophagy or any of the run of the mill mechanisms.

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#5

It’s 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 it’s hard to be on this comparatively low dose for a long time bc of side effects.

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#6

FWIW, I used to get a cold almost every winter. Been taking rapamycin 3 years. Haven’t had a cold since 2021.

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#7

I suppose no washout would be recommended in your case due to the primary reason for taking it being organ transplant so you can’t “afford” washout without bringing into the fold some other immunosuppressant.

May I ask 1) why was such a low dose recommended to you — it’s 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?

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#8

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 couldn’t tolerate so it was dropped. The reasons were based on blood biomarkers I’m 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 what’s 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. I’m guessing that 0.5 mg if taken without breaks would work better. We need more research!

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#9

Lara, what side effects have you seen consistently over the years that you think are due to rapamycin? (at the 1mg/day dosing level).

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#10

What is “Blood levels of rapamycin were low but within the protective range.”?

#11

In the rapamycin cohort of this study, the blood concentration of rapamycin reached an average of 3.24 Âą 1.81 nM after 8 weeks of intervention.

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#12

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 didn’t want it to go lower than 3.

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#13

When I was on rapa, I found that the side effects ceased when I added metformin.

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#14

Did you have similar side effects before the metformin?

The skin ones sound mostly accountable for by delayed epithelial cell turnover.

#15

Its interesting… there are quite a few studies showing rapamycin reducing rates of DNA damage in different scenarios:

Rapamycin improves the quality and developmental competence of mice oocytes by promoting DNA damage repair during in vitro maturation

mTOR Inhibition Prevents Epithelial Stem Cell Senescence and Protects from Radiation-Induced Mucositis

https://www.sciencedirect.com/science/article/pii/S1934590912003694

Autophagy confers DNA damage repair pathways to protect the hematopoietic system from nuclear radiation injury

https://www.nature.com/articles/srep12362

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#16

Hi Steve…rapamycin was misclassified as an immunosuppressant. It is actually an immunomodulator. When taken episodically, it enhances immune function. Ross

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#17

Hi out of interest would LDN work in a similar way but maybe less side effects? ‘LDN modulates the immune system. It doesn’t necessarily boost it, but it doesn’t necessarily suppress it to the point where we see issues of recurring infections.’

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#18

I’ve just switched to this protocol and will do it 3 weeks a month, use the 4th week as my trough.

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#19

Keep us posted pls about side effects if any. It’s odd that they included 50-60 yo men in the same group as 90 yo.

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#20

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! :slight_smile:

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