{"id":496,"date":"2016-06-13T17:36:37","date_gmt":"2016-06-13T17:36:37","guid":{"rendered":"http:\/\/joshmitteldorf.peachpuff-wolverine-566518.hostingersite.com\/?p=496"},"modified":"2016-11-18T10:39:49","modified_gmt":"2016-11-18T10:39:49","slug":"rapamycin-redux","status":"publish","type":"post","link":"https:\/\/scienceblog.com\/joshmitteldorf\/2016\/06\/13\/rapamycin-redux\/","title":{"rendered":"Rapamycin Redux"},"content":{"rendered":"

Rapamycin is the best anti-aging treatment yet discovered. \u00a0Most 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<\/a>]. \u00a0It works even when administered late in life, and intermittent dosing works as well or sometimes better than daily dosing.<\/p>\n

Too bad that rapamycin is too dangerous for general human use. \u00a0It is a powerful immune suppressor, used, in fact, to keep kidney transplant patients from rejecting the foreign tissue. \u00a0People who take rapamycin are at elevated risk from infectious disease, and who knows but that the immune suppression might inhibit the body\u2019s ability to detect and eliminate incipient tumors. \u00a0So there\u2019s a search on for safer \u201crapalogs\u201d that work through the same TOR (\u201ctarget of rapamycin\u201d) pathway, but without the side effects, especially with respect to immune suppression.<\/p>\n

But what if rapamycin isn\u2019t dangerous? \u00a0What if people who take rapamycin don\u2019t get sick any more often, and their cancer risk is actually significantly decreased? \u00a0Might rapamycin be a safe and effective anti-aging drug, available now?<\/p>\n

Last month, two encouraging reports came out of the research on rapamycin. \u00a0One short-term test in marmoset monkeys<\/a> seemed to show that \u201cimmune suppression\u201d was a bogeyman. \u00a0There were no adverse effects, even from continuous, long-term administration. \u00a0Daily 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. \u00a0(For organ transplant patients, dosages range from 1 to 5 mg<\/a> per day.) \u00a0Scaling 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.<\/p>\n

Marmosets live about 12 years, and there is not yet any data on whether lifespan is affected by rapamycin.<\/p>\n

Marmoset monkeys weigh less than a pound.<\/figcaption><\/figure>\n

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. \u00a0But the marmosets didn\u2019t have high blood sugar.<\/p>\n

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. \u00a0We don\u2019t know anything about the effect of rapamycin alone in healthy humans. \u00a0Maybe rapamycin enhances the suppression of tissue rejection from other drugs without in itself suppressing the immune system. \u00a0\u00a0This study<\/a> 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. \u00a0Both rapamycin and everolimus act by suppressing the mTOR signal.<\/p>\n

Coming down to earth, this study<\/a> found that in cancer patients treated with everolimus, risk of infection was about double, and in this study<\/a>, mice infected with influenza and treated with an anti-viral agent did a little worse when rapamycin was added to the cocktail. \u00a0But there are other indications that the relationship between TOR and immune response is complex and not yet understood. \u00a0Rapamycin seems to inhibit the age-related reactivation of dormant cyto-megalovirus, though it has no direct action<\/a> against the virus itself.. \u00a0Already in 2009<\/a>, it was seen (in mice) that rapamycin can slow the loss of white blood cells that cripples the immune system with age. \u00a0In this study<\/a>, rapamycin was used successfully to aid in treatment of \u00a0a mouse model of malaria. \u00a0It 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.<\/p>\n

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.<\/p><\/blockquote>\n

 <\/p>\n

Dogs<\/b><\/p>\n

Last month, 40 aging dogs in a limited trial of rapamycin seemed to show improved health without troubling side-effects. \u00a0Some dog owners reported a resurgence of puppy-like activity in older dogs.<\/p>\n

Cautions from the dog study paper:<\/p>\n

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<\/a>; de Oliveira et al. 2011<\/a>).<\/p><\/blockquote>\n

Triglycerides in the blood spike upward when people first take rapamycin. \u00a0Triglyceride 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<\/a>, ref<\/a>]. \u00a0\u201cImpaired glucose homeostasis\u201d 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. \u00a0It\u2019s a big warning sign, and also a paradox. \u00a0At minimum, it suggests that anyone self-experimenting with rapamycin should be taking metformin<\/a> as well. \u00a0Or, maybe the insulin challenge is part of what makes rapamycin work–it wouldn\u2019t be the first time that throwing a challenge at the body<\/a> had the paradoxical effect of extending lifespan.<\/p>\n

Blagosklonny<\/strong><\/p>\n

The Russian-American biochemist Mikhail Blagosklonny is our foremost enthusiast for rapamycin in humans. \u00a0(Read about him in this Bloomsburg article<\/a> from last year.)<\/p>\n

\u201cSome people ask me, is it dangerous to take rapamycin?\u201d Blagosklonny says. \u201cIt\u2019s more dangerous to not take rapamycin than to overeat, smoke, and drive without belt, taken together.\u201d \u00a0Many colleagues have regarded his advocacy as a bit over-the-top.<\/p><\/blockquote>\n

It\u2019s rumored that Blagosklonny takes rapamycin himself, but I couldn\u2019t get him to talk about it. \u00a0(Actually, I agree with him that it\u2019s one thing for him to experiment on himself, another for him to publicly encourage others to do so.) Blagosklonny\u00a0writes<\/a><\/p>\n

\n
    \n
  1. Rapamycin suppresses geroconversion: conversion from cellular quiescence to senescence. Geroconversion is cellular basis of organismal aging.<\/li>\n
  2. Genetic manipulations that inhibit the TOR pathway extend life-span in diverse species from yeast to mammals<\/li>\n
  3. Rapamycin extends lifespan in all species tested<\/li>\n
  4. Calorie restriction, which inhibits MTOR, extends lifespan<\/li>\n
  5. MTOR is involved in diseases of aging and rapamycin prevents these diseases in animal models<\/li>\n<\/ol>\n<\/blockquote>\n

    Caveats and Obstacles<\/b><\/p>\n

    Rapamycin is presently the best candidate we have for a drug to extend life in humans. \u00a0It is expected to extend \u201chealth span\u201d as well as lifespan, lowering incidence of cancer, heart disease and stroke. \u00a0But is it \u201csafe and effective\u201d for use in people? \u00a0We may never know, because its patent has run out, and there is no company motivated to invest the cost of a human trial.<\/p>\n

    Proper dosing for human anti-aging purposes is hard to guess.<\/p>\n

    A short course of Sirolimus (a name brand for rapamycin) can cost thousands of dollars and requires a prescription. \u00a0You can buy rapamycin more cheaply from a number of lab supply houses, but only if you provide a delivery\u00a0address for\u00a0a university lab, and certify that the purchase is for research purposes only. \u00a0It is less pure and quality control is unregulated.<\/p>\n

    Addendum<\/strong><\/p>\n

    In this recent paper<\/a>, D. W. Lamming of UWisconsin suggests that the effects of rapamycin can be divided into inhibition of two complexes, mTORC1 and mTORC2. \u00a0C1, he says, is good for longevity, while C2 is responsible for the side-effects. \u00a0C1 responds quickly, while C2 responds more slowly. \u00a0Hence, he suggests that intermittent\u00a0dosing might be effective at safely increasing life span. \u00a0The definition of “intermittent” remains undefined until a variety of\u00a0schedules can be tested.<\/p>\n","protected":false},"excerpt":{"rendered":"

    Rapamycin is the best anti-aging treatment yet discovered. \u00a0Most 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]. \u00a0It works even when administered late in life, and intermittent dosing works as well or sometimes better than … Read more<\/a><\/p>\n","protected":false},"author":65,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"jetpack_post_was_ever_published":false,"_jetpack_newsletter_access":"","_jetpack_dont_email_post_to_subs":true,"_jetpack_newsletter_tier_id":0,"_jetpack_memberships_contains_paywalled_content":false,"_jetpack_memberships_contains_paid_content":false,"footnotes":""},"categories":[1],"tags":[],"class_list":["post-496","post","type-post","status-publish","format-standard","hentry","category-uncategorized"],"yoast_head":"\nRapamycin Redux - Josh Mitteldorf<\/title>\n<meta name=\"robots\" content=\"index, follow, max-snippet:-1, max-image-preview:large, max-video-preview:-1\" \/>\n<link rel=\"canonical\" href=\"https:\/\/scienceblog.com\/joshmitteldorf\/2016\/06\/13\/rapamycin-redux\/\" \/>\n<meta property=\"og:locale\" content=\"en_US\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"Rapamycin Redux\" \/>\n<meta property=\"og:description\" content=\"Rapamycin is the best anti-aging treatment yet discovered. \u00a0Most 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]. \u00a0It works even when administered late in life, and intermittent dosing works as well or sometimes better than ... 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The surprising fact that our bodies are genetically programmed to age and to die offers an enormous opportunity for medical intervention. It may be that therapies to slow the progress of aging need not repair or regenerate anything, but only need to interfere with an existing program of self-destruction. Mitteldorf has taught a weekly yoga class for thirty years. He is an advocate for vigorous self care, including exercise, meditation and caloric restriction. After earning a PhD in astrophysicist, Mitteldorf moved to evolutionary biology as a primary field in 1996. He has taught at Harvard, Berkeley, Bryn Mawr, LaSalle and Temple University. He is presently affiliated with MIT as a visiting scholar. In private life, Mitteldorf is an advocate for election integrity as well as public health. He is an avid amateur musician, playing piano in chamber groups, French horn in community orchestras. His two daughters are among the first children adopted from China in the mid-1980s. Much to the surprise of evolutionary biologists, genetic experiments indicate that aging has been selected as an adaptation for its own sake. This poses a conundrum: the impact of aging on individual fitness is wholly negative, so aging must be regarded as a kind of evolutionary altruism. Unlike other forms of evolutionary altruism, aging offers benefits to the community that are weak, and not well focussed on near kin of the altruist. This makes the mechanism challenging to understand and to model. more at http:\\\/\\\/mathforum.org\\\/~josh\",\"sameAs\":[\"http:\\\/\\\/AgingAdvice.org\"],\"url\":\"https:\\\/\\\/scienceblog.com\\\/joshmitteldorf\\\/author\\\/joshmitteldorf\\\/\"}]}<\/script>\n<!-- \/ Yoast SEO Premium plugin. -->","yoast_head_json":{"title":"Rapamycin Redux - Josh Mitteldorf","robots":{"index":"index","follow":"follow","max-snippet":"max-snippet:-1","max-image-preview":"max-image-preview:large","max-video-preview":"max-video-preview:-1"},"canonical":"https:\/\/scienceblog.com\/joshmitteldorf\/2016\/06\/13\/rapamycin-redux\/","og_locale":"en_US","og_type":"article","og_title":"Rapamycin Redux","og_description":"Rapamycin is the best anti-aging treatment yet discovered. \u00a0Most 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]. \u00a0It works even when administered late in life, and intermittent dosing works as well or sometimes better than ... 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The surprising fact that our bodies are genetically programmed to age and to die offers an enormous opportunity for medical intervention. It may be that therapies to slow the progress of aging need not repair or regenerate anything, but only need to interfere with an existing program of self-destruction. Mitteldorf has taught a weekly yoga class for thirty years. He is an advocate for vigorous self care, including exercise, meditation and caloric restriction. After earning a PhD in astrophysicist, Mitteldorf moved to evolutionary biology as a primary field in 1996. He has taught at Harvard, Berkeley, Bryn Mawr, LaSalle and Temple University. He is presently affiliated with MIT as a visiting scholar. In private life, Mitteldorf is an advocate for election integrity as well as public health. He is an avid amateur musician, playing piano in chamber groups, French horn in community orchestras. His two daughters are among the first children adopted from China in the mid-1980s. Much to the surprise of evolutionary biologists, genetic experiments indicate that aging has been selected as an adaptation for its own sake. This poses a conundrum: the impact of aging on individual fitness is wholly negative, so aging must be regarded as a kind of evolutionary altruism. Unlike other forms of evolutionary altruism, aging offers benefits to the community that are weak, and not well focussed on near kin of the altruist. This makes the mechanism challenging to understand and to model. more at http:\/\/mathforum.org\/~josh","sameAs":["http:\/\/AgingAdvice.org"],"url":"https:\/\/scienceblog.com\/joshmitteldorf\/author\/joshmitteldorf\/"}]}},"jetpack_featured_media_url":"","jetpack_shortlink":"https:\/\/wp.me\/pgtN8h-80","jetpack_sharing_enabled":true,"_links":{"self":[{"href":"https:\/\/scienceblog.com\/joshmitteldorf\/wp-json\/wp\/v2\/posts\/496","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/scienceblog.com\/joshmitteldorf\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/scienceblog.com\/joshmitteldorf\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/scienceblog.com\/joshmitteldorf\/wp-json\/wp\/v2\/users\/65"}],"replies":[{"embeddable":true,"href":"https:\/\/scienceblog.com\/joshmitteldorf\/wp-json\/wp\/v2\/comments?post=496"}],"version-history":[{"count":0,"href":"https:\/\/scienceblog.com\/joshmitteldorf\/wp-json\/wp\/v2\/posts\/496\/revisions"}],"wp:attachment":[{"href":"https:\/\/scienceblog.com\/joshmitteldorf\/wp-json\/wp\/v2\/media?parent=496"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/scienceblog.com\/joshmitteldorf\/wp-json\/wp\/v2\/categories?post=496"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/scienceblog.com\/joshmitteldorf\/wp-json\/wp\/v2\/tags?post=496"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}