Rapamycin not Dietary Restriction improves resilience against pathogens: a meta-analysis

Dietary Restriction (DR) and rapamycin both increase lifespan across a number of taxa. Despite this positive effect on lifespan and other aspects of health, reductions in some physiological functions have been reported for DR and rapamycin has been used as an immunosuppressant. Perhaps surprisingly, both interventions have been suggested to improve immune function and delay immunosenescence. The immune system is complex and consists of many components. Therefore, arguably, the most holistic measurement of immune function is survival from an acute pathogenic infection. We reanalysed published post-infection short-term survival data of mice (n=1223 from 23 studies comprising 46 effect sizes involving DR (n=17) and rapamycin treatment (n=29) and analysed these results using meta-analysis. Rapamycin treatment significantly increased post infection survival rate (lnHR=-0.72; CI=-1.17, -0.28; p=0.0015). In contrast, DR reduced post-infection survival (lnHR=0.80; CI=0.08, 1.52; p=0.03). Importantly, the overall effect size of rapamycin treatment was significantly lower (P<0.001) than the estimate from DR studies, suggesting opposite effects on immune function. Our results show that immunomodulation caused by rapamycin treatment is beneficial to the survival from acute infection. For DR our results are based on a smaller number of studies, but do warrant caution as they indicate possible immune costs of DR. Our quantitative synthesis suggests that the geroprotective effects of rapamycin extend to the immune system and warrants further clinical trials of rapamycin to boost immunity in humans.

Full Paper below:

2022.10.06.511121v1.full.pdf (1.5 MB)

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This is no small thing as it reinforces the notion of rapamycin, not as an immunosuppressant, but as an immunomodulator. It quells the hyper immune response to organ transplants and autoimmunity, while enhancing it in the face of pathogens. It not only casts doubt on rapamycin predisposing to bacterial infections but makes one wonder if the infections are more a result of a concomitant dietary restriction.

Immunosenescence is the bugaboo of aging, and the evidence for rapamycin improving overall immunity via modulation continues to grow.

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Yes, we already knew rapamycin and everolimus had this effect in the case of CMV

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Yes. I guess the surprising thing is that it also confers protection against bacterial infections. This was also seen in mice.

It’s also surprising that CR had the opposite effect.

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I didn’t look up all those studies but from Longo’s work I recall that the immuno-enhancing effects of CR only came in the refeeding phase, so if the mice where challenged during CR that could explain some of the differences.

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Interesting point. Still, it shows that CR and rapamycin aren’t equivalent in their effects.

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First you have to define what calorie restrictions are you talking about.
Calorie restriction for most people equates to weight loss or maintaining a stable weight. Time-restricted feeding TR also has the same results for most people. On rapamycin + TR, my weight has been stable for months without counting calories. My current BMI is 22.2 and stays consistent.

Yes, Longo says that the immune system is “pruned” during an extended fast (e.g. 3-5 days, full or partial fast), but rapidly expands in a healthier way with refeeding.