Rapamycin and Longevity: A Few Thoughts On Dosing

Note: This article on rapamycin and longevity is a guest post from friend-of-the-site Nils Osmar while Rachel is out on maternity leave (baby and mother are doing just great!). Nils runs one of our favorite longevity Facebook groups, and is also the proprietor of the New Life Longevity website where he shares his own longevity protocol, as well as lots of well-researched articles on the newest in anti-aging science. And we’ve interviewed him before about his longevity diet. Make sure to check him out!

For those interested in achieving extreme longevity, it can be helpful to understand a few basics about a protein kinase called mTOR (short for mammalian target of rapamycin) and AMPK, two enzymes that respond to levels of nutrients and other growth signals by regulating cell growth and survival.

AMPK supports catabolism and suppresses anabolic (growth) pathways); mTOR supports anabolism, controlling protein synthesis and regulating cell growth in response to our intake of nutrients.  (We’ve looked into the role of mTOR and growth in our earlier article on protein and longevity -J.P.)

mTOR actually has two complexes, mTORC1 and mTORC2. Both are necessary metabolic pathways. But inhibiting mTORC1, at least periodically, can have benefits for both health and longevity. 

mTOR inhibition increases longevity

Interventions such as taking a drug called rapamycin, or eating a calorie-restricted diet, both of which inhibit mTORC1, have been found in animal studies both to slow aging while extending lifespan, and to slow the progression of age-related diseases such as cancer (see study: Regulation and metabolic functions of mTORC1 and mTORC2).

When mTORC1 is inhibited, mice exposed to carcinogens can still get cancer but the cancers grow slowly. In one study, two groups of mice were given rapamycin then exposed to carcinogens. The controls died of cancer. The mice that had been treated with rapamycin went on living in apparent good health for weeks after the controls had died. When the treated mice were dissected at the end of the experiment, it was found that they did have tumors, but the tumors were small and had not killed them (see study: Dysregulation of the mTOR pathway in p53-deficient mice).

So if our goal is to live long, healthy lives — and perhaps even reach longevity escape velocity, the point at which medical interventions can repair the damage done by the aging process faster than it’s occurring, which would in theory eliminate aging as a cause of death — it may be wise to take breaks from the activation of mTORC1.

Inhibiting the other mTOR complex — mTORC2 — a regulator of immune cell metabolism — can be more problematic.

The rapamycin longevity wrinkle: mTORC2

When mTORC2 is activated, under most circumstances, we live longer. 

This isn’t always true. There are conditions under which mTORC2 can support the growth of cancer (see study: mTORC2 in the center of cancer metabolic reprogramming).

But in general, activating mTORC2 appears to be beneficial for those whose goal is anti-aging. When it’s inhibited, the result can be impaired glucose metabolism and poor immune functioning, which could in theory lead to a shorter life. 

Many interventions associated with improved all cause mortality, including taking drugs such as rapamycin, as well as fasting and exercise, selectively inhibit mTORC1 while supporting the activation of mTORC2 and also activating AMPK.  AMPK itself can also activate mTORC2 and promote cell survival under conditions of energetic stress (see studies: AMPK directly activates mTORC2 to promote cell survival during acute energetic stress and Mammalian target of rapamycin complex 2 regulates muscle glucose uptake during exercise in mice).

It’s worth noting that mTORC2 is not directly inhibited by rapamycin under most circumstances, but can be under some. Some studies have found that after prolonged use, rapamycin can also begin inhibiting mTORC2 (see study: Alternative rapamycin treatment regimens mitigate the impact of rapamycin on glucose homeostasis and the immune system).  

So taking breaks from rapamycin may also be beneficial.

Optimal rapamycin dosing for life extension

Could taking some time off undermine rapamycin’s anti-aging benefits? It’s hard to know for sure, because people are so long-lived there’s no way to test its effects on human aging directly.  But in mice, at least, it’s been found that administering rapamycin for two weeks out of every four can still significantly extend lifespan (see study: Alternative rapamycin treatment regimens mitigate the impact of rapamycin on glucose homeostasis and the immune system). 

Note that one week, for a mouse, is the equivalent of 100 days in humans. So our equivalent of a two week break would be over six months long.

This suggests that if our goal is life extension, we might not want or need to take rapaymycin endlessly.

Most people taking rapamycin for longevity purposes take a bolus dose of rapamycin once a week or so, then take several days off while the amount gradually decreases in our bloodstream. So in a sense, short breaks are factored into our dosing schedules. But if our goal is to maintain a baseline of health while also angling for extreme longevity, it may also be beneficial, or at least not be detrimental, to take longer breaks once in a while.

Guest Author: Nils Osmar

Nils has had a lifelong interest in life extension. He is the Director of Rekindle School, an independent educational program. He is the Administrator of a Facebook group called “Life Extension and Anti-Aging” and of several Youtube channels including “Pathways to Longevity.”

J.P.

I’m the co-founder of Longevity Advice and have been passionate about radical life extension ever since I was a teenager. Formerly I was a content marketing director in the B2B software space. I’m also a sci-fi novelist, wargame rules writer, and enthusiast for cooking things in bacon fat. My sister once called me “King of the Nerds” and it’s a title I’ve been trying to live up to ever since.