Big Review paper: Targeting ageing with rapamycin and its derivatives in humans (LancetLongevity)

Big systematic review paper on Rapamycin just published in LancetLongevity

Rapamycin and its derivatives (rapalogs) are inhibitors of mTOR, a major regulator of the ageing process. We aimed to summarise the effects of rapamycin and its derivatives on the severity of ageing-related physiological changes and disease in adults. A search across five databases yielded 18 400 unique articles, resulting in 19 included studies.

Rapamycin and its derivatives improved physiological parameters associated with ageing in the immune, cardiovascular, and integumentary systems of healthy individuals or individuals with ageing-related diseases. Overall, no significant effects on the endocrine, muscular, or neurological systems were found. The effects of rapamycin or its derivatives on the respiratory, digestive, renal, and reproductive systems were not assessed. No serious adverse events attributed to rapamycin and its derivatives were reported in healthy individuals; however, there were increased numbers of infections and increases in total cholesterol, LDL cholesterol, and triglycerides in individuals with ageing-related diseases. Future studies should assess the remaining unexamined systems and test the effects of long-term exposure to rapamycin and its derivatives.

What are people’s thoughts?

https://www.thelancet.com/action/showPdf?pii=S2666-7568(23)00258-1

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Generally - from the diagram - it looks pretty good. Lots of positives in many organs, and partially positives, or no effect.

Rapamycin and its derivatives improved the immune, cardiovascular, and integumentary systems in healthy individuals or individuals with ageing-related diseases. Overall, these drugs had no significant effects on the endocrine, muscular, or neurological systems.

There were no serious adverse events that were related to rapamycin or its derivatives in any studies including healthy individuals.

In addition, in preclinical studies, pharmacological mTOR inhibition reduced age-related cardiac inflammation, fibrosis, hypertrophy, and systolic dysfunction.52 Although improvements in the cardiac index and reductions in both pulmonary vascular resistance and pulmonary arterial pressure have been observed following intervention with everolimus,43 the effects of rapamycin and its derivatives on cardiovascular parameters in humans should be assessed more comprehensively in future studies.

Ah, this paper is from Andrea Maier’s group at NUS. I spoke with her at the Longevity summit in December and she mentioned they were working on a new paper on rapamycin. Their clinical study using rapamycin is starting soon (its been delayed a year from when it was initially planned), largely because of the many questions the IRB had about the study. I suspect this paper may be the response the questions the IRB had regarding the planned clinical trial, and they needed to do a full review of all the existing research to answer the questions and get the IRB approval.

This is a great paper; everyone taking rapamycin (or thinking of taking it) should read it to be fully informed. As a “review” paper, its pretty easy reading, as far as scientific / medical papers go.

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At least five of 12 defined hallmarks of ageing are modulated by the mechanistic target of rapamycin (mTOR) pathway.5–7

The mTOR pathway has been linked by to multiple chronic disease processes, such as declining immune function,8 deteriorating pulmonary function (leading to chronic obstructive pulmonary disease),9 diminishing bone mineral density (leading to osteoporosis),10 development of cancer,11,12 atherosclerosis and cardiac hypertrophy in cardiovascular disease,13–15 and neurodegeneration.16

Animal studies have shown that decreased mTOR signalling extends lifespan by up to 20% in yeast,18,19 19% in worms,20,21 24% in flies,22,23 and 60% in mice.23–25

In humans, randomised controlled trials have shown that the administration of rapamycin derivatives alongside vaccines against seasonal influenza can boost immune response by reversing immunosenescence.26,27

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I appreciate we have limited data, but does this suggest a u-curve for dose-immune function? (The blue circles)

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I would hesitate hard to think that much higher doses might be beneficial without a lot of information and proof.

One of the best quotes I ever found in a novel was something like this…”it isn’t all the little mistakes we make along the way, it’s the one big mistake we make trying to undo all the little ones that does us in.”

I think about this a lot when it comes to longevity.

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Love the quote, if you can remember the source that would be great. It also sums up most political and historical disasters.

My assumption would be that there isn’t a u shaped immunity response curve to rapa, and that this is just an artefact of the limitations of these studies.

I just can’t think how this could possibly be valid

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I believe the quote comes from The Company.

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So, if I’m reading this graphic properly, it’s saying all of the benefits come from 2 mg/day and below? Would it be equivalent to a 12-14 mg weekly dose?

It definitely implies an inverted U-shaped curve for immunity.

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How do we know that? Let me know if I have this backward: it would be an inverted U curve… if so that goes against a lot of the mechanistic understanding of mTOR and logic overall?

Yes, that’s how i interpret it, with the exception of endocrine system benefits. Where you could argue a slightly higher dose (3-4mg/day).

But I suspect the underlying studies aren’t compelling.

It would be useful to have a sude effect score for each of the studies too.

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Yes exactly that. But the curve for immunity benefits (the blue circles) does appear to be ushaped. I assume its just an artefact.

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Inverted of what we normally mean by U shape. So it’s the “opposite”. There is not one single, intermediate best point. Rather there are two regions of of it getting better and better with either the lowest doses and better with the highest doses.

Its upside down because generally south on the graph is the good (lowest all cause mortality, etc), but here the good is north on the graph not down.

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I see, yes. This is upside down compared to the usual hazard ratio graph.

This chart, showing better outcomes with either low or high dosing is odd and doesn’t make a lot of sense to me.

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Love to hear everyone’s opinion on this from Lifespan.io.

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@Krister_Kauppi This table of Rapa studies might be useful to you.

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Interesting info. The chart on body part by rapa dose seemed to show Rapa benefit at lower doses but the overall conclusion is negative. It’s no wonder the scientists are so slow to jump on board.

Clearly there are rapa benefits for some people. Perhaps the learning here is that rapa isn’t for everyone. If you don’t seem to get a benefit that is greater than the side effects, don’t push.

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My assumption would be that there isn’t a u shaped immunity response curve to rapa, and that this is just an artefact of the limitations of these studies.

My assumption wouldn’t be…

Because mTOR knock-outs are embryonic lethal, we generated a viable hypomorphic mouse by neo -insertion that partially disrupts mTOR transcription and creates a potential physiologic model of mTORC1/TORC2 inhibition. Homozygous knock-in mice exhibited reductions in body, organ, and cell size. Although reductions in most organ sizes were proportional to decreased body weight, spleens were disproportionately smaller. Decreases in the total number of T cells, particularly memory cells, and reduced responses to chemokines suggested alterations in T-cell homing/homeostasis. T-cell receptor-stimulated T cells proliferated less, produced lower cytokine levels, and expressed FoxP3. Decreased neutrophil numbers were also observed in the spleen, despite normal development and migration in the bone marrow. However, B-cell effects were most pronounced, with a partial block in B-cell development in the bone marrow, altered splenic populations, and decreases in proliferation, antibody production, and migration to chemokines. Moreover, increased AKTSer473 phosphorylation was observed in activated B cells, reminiscent of cancers treated with rapamycin, and was reduced by a DNA-pk inhibitor. Thus, mTOR is required for the maturation and differentiation of multiple immune cell lineages.
Constitutive reductions in mTOR alter cell size, immune cell development, and antibody production

With the caveat that I haven’t read the paper yet and there may be something else I’m still missing:

That’s what you would expect, but the graph as drawn and as (naively?) interpreted shows a true U-shaped curve: benefits at doses up to 1.5 mg/day, neutral at2.9 mg/day, deleterious at 3 or 4.5 mg/day, neutral again at 4.75 or 6 mg/day, and beneficial again at 6 or 10 mg/day.

One thing to remember is that the Mannick papers included daily low-dose and weekly 5 or 20 mg everolimus. Since this graph plots everything in dose/24 hours, 5 mg/week would be .7 mg/24 h, and 20 mg/week would be 2.86 mg/week. That’s consistent with some of the data points attributed to Mannick in the graph, but not the 3 mg/week data point.

Again, I’ve not properly read the paper yet.

Its interesting that this is coming out the same time as the Review Paper by Andrea Maier and her group at the National University of Singapore. I would trust Andrea’s research over that of a journalist (Josh Conway, who seems to have no formal science training that I can see) at lifespan io. I love what Lifespan.io does, but they definitely aren’t experts in the area of rapamycin. It would take a fair amount of work to evaluate and compare the two summaries, and I don’t have time for that right now - but if someone else does, have at it…

I will note that a PubMed search for “rapamycin” returns about 53,900 published papers—including 3,295 clinical trials and 1,991 randomized control trials. Lifespan.IO looked at 19 papers to do their writeup. I wouldn’t be too confident that their summary is representative given the their review of only two dozen papers.

The NUS review at the top of this thread is much, much more in-depth and was produced because they are doing a rapamycin clinical trial soon and needed to summarize the state of the research for their IRB (institutional review board).

Lifespan IO says " Rapamycin and its analogs do not have many large effects on people.". But its still very early in terms of the research of rapamycin use in healthy people, so I wouldn’t put much value in any of the studies done so far (except the Mannick / ResTOR Bio studies, as they were well-funded, large phase 2 and 3 studies - but the phase 3 study had issues because the FDA changed the endpoints between the phase 2 and phase 3 studies).

There are many studies ongoing right now, so we’ll be learning a lot more over the coming 5 years:

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Thank you for that overview and the table of studies. Much appreciated.