Rapamycin

The Rapamycin Story

In the winter of 1972, scientists from Montreal on an expedition to mysterious Easter Island, called Rapa Nui by the local inhabitants, collected soil samples. What they found in the soil was one of the most extraordinary discoveries of the past 100 years. The soil contained a bacteria which made a substance that had an anti-fungal effect. That substance was named Rapamycin.


In 1991, Dr. Michael Hall was studying the growth of yeast in response to nutrients. He discovered that growth of yeast was was blocked by Rapamycin. He called the substance in the yeast that was blocked by Rapamycin, Target of Rapamycin or TOR. Dr. Michael Hall had found the holy grail of cellular biology. Over the next 25 years TOR was to revolutionize our understanding of both basic cellular physiology and disease, especially age-related disease and aging itself. 


The bacteria in the soil of Rapa Nui were engaged in biologic warfare against yeast. This biologic warfare between bacteria and yeast has apparently been going on for countless millions of years. The first sign of this warfare was discovered in 1928 when Alexander Fleming discovered Penicillin, a substance made by yeast to kill bacteria. Rapamycin was the mirror image of Penicillin; a substance made by bacteria to kill yeast. 


What made Rapamycin very special was that by serendipity what the bacteria had targeted was not just the command and control of the yeast cell; it was the command and control of every cell, of every living thing on planet earth. That substance, we now call TOR, has been conserved through two billion years of evolution.  


Within the cell, there is an entire universe of signaling systems, a signaling system that is the product of 2 billion years of evolution. TOR controls this vast array of interrelated functions; most notably control of growth and development. Within the cell, TOR is the leader of the band. 


Rapamycin downregulates TOR. With Rapamycin, man can downregulate the cell control system at the most fundamental molecular level.


The first approved use for rapamycin was essentially as a poison. This was natural as rapamycin was made to be a biologic poison. Rapamycin was approved in 1999 to be used as an immune suppressant; to knock out the immune system to stop rejection and enable organ transplant. 


The first huge discovery that rapamycin might be more than just a biologic poison was that downregulation of TOR increased lifespan. Genetic downregulation of TOR increased the lifespan of everything tested: yeast, flies, worms. For 100 years, there was only one thing that increased lifespan and that was caloric restriction. No pharmaceutical agent had ever increased the lifespan of mammals. 


In 2009, Harrison fed rapamycin to wild-type mice that were 19 months old, the equivalent of 60 years for humans. As a great surprise rapamycin extended the lifespan of both male and female mice, 9% and 14%. (9) A 2014 study using 3 times the original dose increased lifespan of male and female mice 23% and 26%.(10) 


In a very interesting study (41) researchers reduced TOR by genetic modification. The mice had about 25% of TOR activity of both C1 and C2 compared to wild-type mice. The mice were smaller; but demonstrated no metabolic abnormalities and had normal glucose metabolism. The median life span of mice was increased by 20% in both male and female. In old age, the mice were healthier than wild-type mice. They had decreased incidence of cancer. Of significance regarding AD, they had better preserved hippocampal function as demonstrated by spacial learning and memory compared to wild-type mice.


In 2006, Mikhail Blagosklonny, published paper, "Aging and Immortality, Quasi-programmed Senescence and its Pharmacologic Inhibition" (42). In this paper, one of most important papers in biology in 100 years; Blagosklonny put forth a radical new theory of aging and age-related disease. 


The theory was that mTOR was a program to control growth and development in the developing animal. However, in the older animal, the same mTOR program was at too high a level and was driving aging and age-related disease. What was needed was a fix, a mTOR 2.0 program for the older animal.


In the most simple terms, the Blagosklonny theory is explained by the Bob Dylan, lyric  "He not busy being born is busy dying". The Blagosklonny theory is aging is being driven by hyperfunction.  Cells in the older animal that become unable to divide or be born become senescent cells. mTOR in old animals is causing formation of senescent cells. The senescent cell then takes on hyperfunction which drives aging-type pathology. (36, 37,38, 39,40


This is a rather exotic and original theory; but the proof of the pudding is in the eating. In animal models, lowering mTOR extends lifespan and prevents or ameliorates a remarkable number of age-related disease. In animals models lowering mTOR with rapamycin prevents Atherosclerosis, Age-related macular degeneration and Alzheimer's disease, and that it just the As. 


 The facts are that in the laboratory reduction of TOR with rapamycin prevents or ameliorates just about every age-related disease, including cancer.

(42, 43, 44)  


CLINICAL USE OF RAPAMYCIN FOR AGE-RELATED DISEASE


For a discussion of clinical use of rapamycin for prevention of age-related disease see my website, rapamycintherapy.com. 


When rapamycin is administered for the  approved used to prevent organ rejection in transplant medicine, rapamycin is administered as a daily dose. The half-life of rapamycin is @ 60 hours. Administration once a day maintains a continuous high blood level of rapamycin. This continuous high level of rapamycin inhibits both mTORC1 and mTORC2. 


Studies have shown that inhibition of mTORC1 causes lifespan extenson effects and inhibition of mTORC2 is associated with significant side effects. Inhibition of the immune system requires combined inhibition of mTORC1 and mTORC2 and therefore daily dose to reduce activity of mTORC2 is required. 


Daily dose which inhibits both mTORC1 and mTORC2 is associated with significant side-effects. For a review of side-effects associated with daily use of rapamycin, see the large number of reviews of side-effects associated with use of rapamycin for organ transplant.


The daily use of rapamycin is too toxic to be used for prophylactic treatment in healthy persons. While there are innumerable statements in the literature that rapamycin is too toxic for use in healthy persons; there are no studies showing weekly use of rapamycin has unacceptable side-effects in humans.


There has only been a single study done to evaluate the use of a rapalog as an anti-aging drug in which intermittent (weekly) dose was studied. This was Mannick study published December 2014 (49). In the  Mannick study a rapalog was administered as a WEEKLY dose to elderly persons. The weekly dose improved the function of the immune system in contrast to the same drug as daily dose which inhibited the immune system. Furthermore, the weekly dose was noted to have acceptable safety profile and minimal side-effects. 


In anti-aging studies rapamycin is administered to mice in a low dose and lifespan is extended with minimal side-effects. (9.10). 


In the all mouse studies in which rapamycin ameliorated AD-like pathology, rapamycin was administered in the same manner and dose as used in the 2009 Harrison life-extension study. (9).


The effects and side-effects of daily use of rapamycin should not be ascribed to weekly use. On the other hand, experience with weekly use is very limited. While over a million people have used rapamycin as a daily dose for transplant medicine; only a handful have used rapamycin as an intermittent dose to prevent age-related disease. 


I have used weekly rapamycin for 2 years with no significant side-effects. The observed effects have been extremely salutary.