The last thing the pharmaceutical industry wants is a proven longevity intervention that is off patent. And it appears that exactly what rapamycin is.
This post is not true. There are a number of reasons:
Here is one:
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I do not accept your criticism of Richard Miller on this point. His arguments were based upon researched facts. It happens to be that I disagree with his analysis, but the claims of side effects that he made are proven.
@John_Hemming, John, you are doing the Lordâs work here. @Bicep thank you for digging up that link, and thank you @dwglinn for bringing this to our attention.
Although I agree with you @dwglinn, that the general safety of rapamycin could use some emphasis (btw. Matt Kaeberlein emphasizes frequently that rapamycin is quite safe), I donât think Richard Miller is being that unreasonably critical of human rapamycin use. Besides, I personally am always very interested in critical views regarding any drugs (or concepts) I use - other perspectives are very valuable, remember what Richard Feynman said âthe first principle is that you must not fool yourself - and you are the easiest person to foolâ, that is something I try to live by, the more enthusiastic I am about something, the more critical views do I seek out.
As to testicular effect of rapamycin itâs entirely unsurprising (after all, note the effect of castration on lifespan, and the long history of fertility vs lifespan trade offs). I personally donât care for myself (no plans to spawn). And I donât especially care about cataracts, as I plan on IOL at some point regardless. If I have any concerns about rapamycin, they center around three things: risk of bacterial infection, interstitial lung disease, and pancreatic beta cell toxicity. And my current use of rapamycin is much more aggressive than John Hemmingâs - I am atm. on an 8 mg once a week protocol. YMMV.
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Abstract
Objective To examine risk of malignancy and death in patients with kidney transplant who receive the immunosuppressive drug sirolimus.
âŚResults The search yielded 2365 unique citations. Patient level data were available from 5876 patients from 21 randomized trials. Sirolimus was associated with a 40% reduction in the risk of malignancy (adjusted hazard ratio 0.60, 95% confidence interval 0.39 to 0.93) and a 56% reduction in the risk of non-melanoma skin cancer (0.44, 0.30 to 0.63) compared with controls. The most pronounced effect was seen in patients who converted to sirolimus from an established immunosuppressive regimen, resulting in a reduction in risk of malignancy (0.34, 0.28 to 0.41), non-melanoma skin cancer (0.32, 0.24 to 0.42), and other cancers (0.52, 0.38 to 0.69). Sirolimus was associated with an increased risk of death (1.43, 1.21 to 1.71) compared with controls.
Conclusions Sirolimus was associated with a reduction in the risk of malignancy and non-melanoma skin cancer in transplant recipients. The benefit was most pronounced in patients who converted from an established immunosuppressive regimen to sirolimus. Given the risk of mortality, however, the use of this drug does not seem warranted for most patients with kidney transplant. Further research is needed to determine if different populations, such as those at high risk of cancer, might benefit from sirolimus.
This is a bit of a surprising result. The increase in mortality seems to be associated with infections and CVD, despite a lower cancer incidence:
There was a higher proportion of death from infection (0.58% v 0.15%) and cardiovascular disease (1.28% v 0.54%) in the sirolimus group compared with the control group.
Patients treated with sirolimus could have had higher net immunosuppression because of the increased risk of acute rejection seen in some of the included trials.20 22 23 This in turn could have contributed to increased infection related mortality. Sirolimus is known to have side effects that are associated with an increased risk of cardiovascular disease, including anemia,20 34 37 proteinuria,37 42 43 hyperglycemia,37 44 and hyperlipidemia.20 34 37 45 Although we did not have relevant individual patient level data, an increase in these known cardiac risk factors might have contributed to the increase in cardiovascular death seen in our analysis.
https://www.bmj.com/content/349/bmj.g6679
But itâs high risk patients on high doses, and no detected increase in mortality in low dose patients. More evidence that rapamycin doesnât protect against CVD on its own.
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And yet none of his criticisms of this drug rise to even moderate safety risks. This intervention has the potential to save thousands of lives and improve the lives of millions. discouraging its use due to testicular shrinking is absurd, considering the population benefiting most from this intervention will be well past the age of reproduction
The CVD risk is slightly surprising, because in animal models (dogs, cats) rapamycin is notably beneficial, even reversing some aspects of aging in the heart. However indeed there may be some effects like elevated glucose and lipids (maybe dose dependent?). This emphasizes something Iâve been convinced of for a long time: concurrent drug use in adjunctive capacity is a must. Itâs not likely that slowing aspects of aging will be down to one drug anyway, and drug combinations with rapamycin in the ITP bear this out. Here, if seems prudent to address lipids through LLT regardless, which should be CVD risk lowering on its own anyway. Same for glucose and proteinuria through an SGLT2i, again regardless of whether one takes rapamycin or not, these are protective not just of glucose regulation, but aspects of CVD and especially kidney health. I would take an SGLT2i regardless, but I think itâs almost mandatory if youâre on rapamycin. Acarbose might be in play too (and seems beneficial in combination per the ITP).
That said, beta cell toxicity is still a concern on its own and also as a possible mechanism of glucose elevation with rapamycin. That is not being addressed by the other drugs in consideration, though perhaps imeglimin might be interesting.
Infection risk is there, but other than vigilance, targeted vaccinations and antibiotics within reach itâs just something that one has to take into the bargain.
Well, the drug does have a âBlack Box Safety Warningâ as part of its FDA approval - so I think that is what most people look at when they develop opinions about safety concerns:
The sirolimus boxed warning has remained structurally identical since 1999. It warns prescribers of three categories of serious risk: increased susceptibility to infection, possible development of lymphoma and other malignancies (particularly of the skin), and the requirement that only physicians experienced in immunosuppressive therapy manage transplant patients on this drug
Source: Rapamycin (Sirolimus) FDA Label Updates: What Changed From 2020 to 2026 | HealthRX.com
So I think there are some reasonable reasons for concerns, at least at the high doses used in organ transplant patients.
For longevity applications we donât see these issues at the doses most of us use.
And slowly the rapamycin reputation is getting better:
Sirolimus â It doesnât deserve its bad Rap(a)
https://www.journal-of-hepatology.eu/article/S0168-8278(11)00515-0/fulltext
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If you have a higher risk for cancer than CVD or infections it might be more favorable if we ignore any mitigations via other medications, although that is a must. High dose patients are often prescribed statins for hyperlipidemia. In Mannickâs study with everolimus hyperlipidemia was rare however (with lower doses).
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Thank you for this post. The association of a disease with a drug does not prove causality. I believe that Mtor2 is being affected. Itâs interesting to note that the preponderance of this affliction was experienced by those using 5 mg of rapamycin daily considering thatâs easily five times what is the standard weekly dosing of off label users.
The anecdotal evidence suggests the older and more you suffer from age related conditions, the greater the effect of rapamycin.
When youâre in your 70s and suffering from multiple age related diseases, your risk reward ratio changes radically.
My personal experience with this drug has been transformational. At some point age brings us all to our knees. I believe rapamycin may be a universal intervention for mankind.
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Yet you make another 10 comments right after the last one LOL. Had to say it. 
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sorry I was waiting for that
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