Rapamycin is the best anti-aging treatment yet discovered. Most treatments that work in flies and worms fail when they get to mammals, but rapamycin has consistently extended lifespan more than 20% in mice [review as or 2014]. It works even when administered late in life, and intermittent dosing works as well or sometimes better than daily dosing.
Too bad that rapamycin is too dangerous for general human use. It is a powerful immune suppressor, used, in fact, to keep kidney transplant patients from rejecting the foreign tissue. People who take rapamycin are at elevated risk from infectious disease, and who knows but that the immune suppression might inhibit the body’s ability to detect and eliminate incipient tumors. So there’s a search on for safer “rapalogs” that work through the same TOR (“target of rapamycin”) pathway, but without the side effects, especially with respect to immune suppression.
But what if rapamycin isn’t dangerous? What if people who take rapamycin don’t get sick any more often, and their cancer risk is actually significantly decreased? Might rapamycin be a safe and effective anti-aging drug, available now?
Last month, two encouraging reports came out of the research on rapamycin. One short-term test in marmoset monkeys seemed to show that “immune suppression” was a bogeyman. There were no adverse effects, even from continuous, long-term administration. Daily dosage in this test was 1mg/kg, which is the same as used in mice, and 50 times larger than typical human dosages, if calculated with strict scaling by body mass. (For organ transplant patients, dosages range from 1 to 5 mg per day.) Scaling of dosage is a not an exact science, and 1 mg per kg of body weight is certainly too large a dosage for our body size.
Marmosets live about 12 years, and there is not yet any data on whether lifespan is affected by rapamycin.
Mice and some people on rapamycin tend to have high blood sugar, which in humans and mice is associated with risk of all age-related disease. But the marmosets didn’t have high blood sugar.
Authors of the marmoset paper note that all studies of rapamycin in humans involve people who are sick enough to need an organ transplant, and are taking many other drugs. We don’t know anything about the effect of rapamycin alone in healthy humans. Maybe rapamycin enhances the suppression of tissue rejection from other drugs without in itself suppressing the immune system. This study claims that everolimus actually enhances immune function in elderly humans. (Everolimus, a.k.a. RAD001, is a chemical cousin of rapamycin, a.k.a. Sirolimus, that is used similarly to prevent tissue rejection by organ transplant patients. Both rapamycin and everolimus act by suppressing the mTOR signal.
Coming down to earth, this study found that in cancer patients treated with everolimus, risk of infection was about double, and in this study, mice infected with influenza and treated with an anti-viral agent did a little worse when rapamycin was added to the cocktail. But there are other indications that the relationship between TOR and immune response is complex and not yet understood. Rapamycin seems to inhibit the age-related reactivation of dormant cyto-megalovirus, though it has no direct action against the virus itself.. Already in 2009, it was seen (in mice) that rapamycin can slow the loss of white blood cells that cripples the immune system with age. In this study, rapamycin was used successfully to aid in treatment of a mouse model of malaria. It is the particular action of inflammation against healthy, native tissues that is arguably the greatest source of metabolic damage in aging, and rapamycin may offer a particular protection against this destruction.
Remarkably, animals were protected against ECM [experimental cerebral malaria] even though rapamycin treatment significantly increased the inflammatory response induced by infection in both the brain and spleen and elevated the levels of peripheral parasitemia.
Last month, 40 aging dogs in a limited trial of rapamycin seemed to show improved health without troubling side-effects. Some dog owners reported a resurgence of puppy-like activity in older dogs.
Cautions from the dog study paper:
The doses used clinically to prevent organ transplant rejection are associated with side effects, such as impaired wound healing, edema, elevated circulating triglycerides, impaired glucose homeostasis, gastrointestinal discomfort, and mouth ulcers (Augustine et al. 2007; de Oliveira et al. 2011).
Triglycerides in the blood spike upward when people first take rapamycin. Triglyceride levels are associated with increased risk of CV disease, and are in fact a better predictor than any of the many measures of cholesterol [ref, ref]. “Impaired glucose homeostasis” means type 2 diabetes, which is tightly correlated with aging, and probably has a causal relationship to many of the losses and risks associated with age. It’s a big warning sign, and also a paradox. At minimum, it suggests that anyone self-experimenting with rapamycin should be taking metformin as well. Or, maybe the insulin challenge is part of what makes rapamycin work–it wouldn’t be the first time that throwing a challenge at the body had the paradoxical effect of extending lifespan.
The Russian-American biochemist Mikhail Blagosklonny is our foremost enthusiast for rapamycin in humans. (Read about him in this Bloomsburg article from last year.)
“Some people ask me, is it dangerous to take rapamycin?” Blagosklonny says. “It’s more dangerous to not take rapamycin than to overeat, smoke, and drive without belt, taken together.” Many colleagues have regarded his advocacy as a bit over-the-top.
It’s rumored that Blagosklonny takes rapamycin himself, but I couldn’t get him to talk about it. (Actually, I agree with him that it’s one thing for him to experiment on himself, another for him to publicly encourage others to do so.) Blagosklonny writes
- Rapamycin suppresses geroconversion: conversion from cellular quiescence to senescence. Geroconversion is cellular basis of organismal aging.
- Genetic manipulations that inhibit the TOR pathway extend life-span in diverse species from yeast to mammals
- Rapamycin extends lifespan in all species tested
- Calorie restriction, which inhibits MTOR, extends lifespan
- MTOR is involved in diseases of aging and rapamycin prevents these diseases in animal models
Caveats and Obstacles
Rapamycin is presently the best candidate we have for a drug to extend life in humans. It is expected to extend “health span” as well as lifespan, lowering incidence of cancer, heart disease and stroke. But is it “safe and effective” for use in people? We may never know, because its patent has run out, and there is no company motivated to invest the cost of a human trial.
Proper dosing for human anti-aging purposes is hard to guess.
A short course of Sirolimus (a name brand for rapamycin) can cost thousands of dollars and requires a prescription. You can buy rapamycin more cheaply from a number of lab supply houses, but only if you provide a delivery address for a university lab, and certify that the purchase is for research purposes only. It is less pure and quality control is unregulated.
In this recent paper, D. W. Lamming of UWisconsin suggests that the effects of rapamycin can be divided into inhibition of two complexes, mTORC1 and mTORC2. C1, he says, is good for longevity, while C2 is responsible for the side-effects. C1 responds quickly, while C2 responds more slowly. Hence, he suggests that intermittent dosing might be effective at safely increasing life span. The definition of “intermittent” remains undefined until a variety of schedules can be tested.