Introduction to Rapamycin Medicine

Rapamycin and TOR

Of all the known chemical substances in the universe, a single drug has emerged as the most robust in extending lifespan. That drug has extended the lifespan of every living thing tested in the laboratory: yeast, worms, flies, and even middle-aged mice. That drug is Rapamycin. In a recent 2014 paper, it was reported rapamycin extended the median lifespan 23% in male mice and 26% in female mice. 


It has been known since the 1930s that caloric restriction extends lifespan and slows aging. Rapamycin could be characterized as caloric restriction in a pill. In a mouse study discussed in the "Cardiomyopathy" section, rapamycin had similar effect in aged mice as 40% caloric restriction in restoring the dysfunction of old hearts to normal function of young hearts. The effect of caloric restriction is to decrease TOR indirectly, the effect of rapamycin is to  decrease TOR directly.


Aging is defined as an increase in the probability of death. If a drug extends lifespan, that drug is slowing aging. Aging is the main risk factor for age-related disease: heart disease, cancer, Alzheimer's disease, blindness, etc.  Slowing down aging, staying young, is the goal of Rapamycin Medicine.

Rapamycin has only one action; it targets or binds to TOR and thereby lowers TOR activity. TOR stands for Target-Of-Rapamycin. TOR and rapamycin are related as a key to a lock. TOR has been conserved through 2 billion years of evolution. TOR functions as the central hub of the cell signaling system, the command and control center of the cell.


Rapamycin was approved in 1999 as a prescription medicine to be used in high daily dose as an immunosuppressant in transplant medicine. Used in this manner, Rapamycin has very limited benefits aside from use in transplant medicine as it has too many side effects to be of general interest.  Miraculously, when used as a non-immunosupressant, low dose, weekly medication, rapamycin is transformed into a silver bullet, with minimal side effects and extraordinary benefits. For rapamycin, less is more.


Rapamycin, like penicillin, was the product of biologic warfare between bacteria and yeast. Like a mirror image,  penicillin, discovered in 1928, was made by yeast to target bacteria, while Rapamycin, found in the soil of Easter Island in 1965, was made by bacteria to target yeast. The bacteria of Easter Island targeted TOR, the command and control center of the yeast cell. However, TOR, the substance targeted in this never ending war between yeast and bacteria, is the command and control center of not just yeast; but every living thing on planet earth. TOR is in essence, the secret of how life is organized within the cell. 


Rapamycin has another similarity to thediscovery of penicillin. In the "Cancer" section (Ref 7), Mikhail Blagosklonny stated, "Rapamycin could be used for extension of healthy lifespan and prevention of age-related diseases by slowing down the aging process. This may become one of the major breakthroughs in medicine since the discovery of antibiotics."

TOR and Age-Related Disease

TOR is a complex, large protein located in the cytoplasm of the cell, close to the nucleus. TOR operates in close communication with the nucleus of the cell. The nucleus contains the DNA which  is the blueprints for making each individual protein and TOR signals the nucleus which proteins to make. TOR senses what is happening within the cell and then signals the nucleus how to respond. The nucleus then responds by providing the blueprints to make the specific different proteins. 


In the developing and growing animal, TOR functions to near perfection. TOR's primary purpose is growth and development. TOR has been conserved for two billion years for good reason. However, in the older animal, TOR has a dark side. This dark side was first recognized by Mikhail Blagosklonny.

2006 was a watershed year in Biology, with perhaps one of the most important papers since 1859, the year Charles Darwin published, "On the Origin of Species". The 2006 paper was "Aging and Immortality: Quasi-Programmed Senescence and its Pharmacologic Inhibition, by Blagosklonny. In simple terms, Blogosklonny postulates that aging was a disease process caused by overactive TOR. Furthermore, overactive TOR was also responsible for most age-related disease. Aging was merely the accidental result of an intended program (quasi-program) that was the continuation of the essential growth program. Aging and age-related disease are two sides of the same coin, the same disease process. Furthermore, TOR could be controlled with rapamycin. Mankind has in hand, the ability to ameliorate aging and age-related disease.

In summary, the problem for the old animal is TOR is at too high a level after growth and development has stopped. Elevated activity of TOR is at the very center of aging and age-related disease. What the old animal needs is a kind of software update; TOR 2.0 for the older animal. Nature and evolution never provided this fix; but rapamycin is the pharmacologic fix for the older animal. 

Treatment or Prevention, Is Aging a Disease ?

For the past 2000 years, aging has been considered a natural process; not a disease. The reasoning was everybody gets aging and if everybody gets it, then it is natural.  This is the accepted view of orthodox medicine and the position officially endorsed by the FDA. 


Disease is defined as: "A disorder of structure or function in a human, animal, or plant, especially one that produces specific signs or symptoms or that affects a specific location and is not simply a direct result of physical injury." Disease causes pathology.


I consider Aging not just a disease, but "the mother of all disease";  a chronic progressive disease with 100% incidence and 100% fatality.


The general rule in medical treatment is that medicines used to treat a disease that somebody has, i.e. cancer; can have side effects; but a medicine used for prevention should have no side effects.


I consider intermittent rapamycin to have few side effects, a safe drug in the general universe of drugs. However, all drugs have some side effects. If you think aging is not a disease and rapamycin is only for prevention; then you might say rapamycin should not be used. On the other hand, if you have felt the sting of aging and believe rapamycin is treating a disease which you very much already have; then you are far more inclined to think the risk of side effects is justified. 


Aging is not programmed. Aging can be divided into early aging and late aging. 

Early aging includes the pathology in the 50-99 age group and the increasing susceptibility to age-related disease. 

Late aging includes the pathology in the 100-110 age group. Late aging inexorably leads to death. There is no current prevention or treatment for late aging and late aging is outside the scope of my practice.


The use of the term "aging" in this website only refers to "Early Aging". Blagosklony uses the term, "post aging syndrome" to refer to late aging. While I believe that "early aging" is multi-factorial; increased activity of TOR is postulated as a very significant cause of early aging and significant and treatable factor in the cause of the common age-related diseases.


This office treats the disease of increased activity of mTOR.  The objective of such treatment is to ameliorate and prevent of the vast amount of diseases associated with elevated mTOR. Treatment is directed against the disease of aging and age-related diseases are considered to be connected to aging as smoke is to fire. 

ROS Comes of AGE

The Free Radical Theory of Aging also called ROS (reactive oxygen species) was first proposed by Denham Harman in  1956. Since then it has become the most popular explanation of how aging occurs at the molecular level. [mTOR is an explanation of aging at the cellular/signaling level]

The ROS theory is very appealing because it suggests a means for pharmacologic intervention--namely, antioxidants. However, over the next 50 years, hundreds of clinical trials involving over a half million humans failed to show any benefit. Antioxidants (tocopherol, beta-carotine, vitamin E and C, retinol, selenium, folic acid) all failed. They did not show any statistical decrease in age-related disease and/or mortality. In an excellent review in 2008 by Blagosklonny ("ROS or TOR"); he stated, "No disease is treated by antioxidants." He also prophetically noted; "One explanation is that current antioxidants are not good enough". That turned out to exactly the case.


Everything changed in 2005 with the MCAT mouse ("Extension of murine life span by overexpression of catalase targeted to mitochondria). Catalase is part of the body's natural defense against ROS. The Rabinovitch group developed three varieties of transgenic mice; all had increase catalase. One group had increased catalase in the peroxisome (a natural location of ROS), another group of mice had increased catalase in nucleus, the third group of mice had increased catalase in the mitochondria (MCAT mouse). Only the increase in catalase in the mitochondria made a difference and the difference was spectacular.  The MCAT mouse had 20% increase in median lifespan and 10% increase maximum lifespan. The MCAT mouse also has reduced cardiac disease, eye cataracts and reduced hearing loss with aging. The MCAT mouse increased lifespan and prevented certain age-related diseases. 


Reduction of ROS only increased lifespan and prevented certain age-related diseases if and only if; it was targeted to MITOCHONDRIA.


This great new insight led to the rush to develop "smart anti-oxidants" [the biologic equivalent of the smart bomb].


In another very important paper by Rabinovitch group from Seattle, Washington, "Mitochondria and Cardiovascular disease" in section, "Therapeutic strategies to improve mitochondrial function in aging", the lead section is "Mitochondrial-targeted antioxidants". Here they discuss TPP+(Triphenylphosphonium). They note:  "These mitochondrial targeted drugs can achieve concentrations in the  mitochondrial matrix 100 to 1000- fold higher than those in the cytosol (cell) because of their strong positive charge, as mitochondria have a highly negative membrane potential. "


Two such products, including Mito-Q (TPP plus coenzyme Q) and SkQ1 are now on the market and sold on Amazon as a supplement. [however, only MitoQ is licensed for oral use]


I have further discussion of MitoQ in section on Hearing Loss [Disease A]


In my opinion, mitochondrial-targeted antioxidants, represent a powerful new addition to the anti-aging formula. 


A recent paper entitled, "Is the Oxidative Stress Theory of Aging Dead ?," (2009) by one of the leading anti-aging centers, they conclude that the ROS theory was dead. Of course, I totally disagree with their conclusion; but a statement from their discussion illustrates the critical flaw in their logic and understanding, "Schriner [the MCAT mouse study I discussed] previously reported that the transgenic mice overexpressing catalase showed an ~ 21% increase in lifespan; however, in this study catalase overexpression was targeted to the mitochondria while in our study catalase overexpression occured in the perisomes, where catalase is normally expressed. Moreover, data from the same group  showed that the cytosolic expression of catalase had no effect on lifespan." [Note: All their studies were a complete bust and showed no benefit.]


(Thank you very much, that is the entire point.)


ROS in the cytosol is managed very well and does not cause aging or disease and ROS in peroxisomes is exactly where ROS is supposed to be for essential functions. This explains why 50 years of anti-oxidants had NO BENEFIT. To be effective as an anti-aging agent the drug taken to neutralize ROS must be directed into the mitochondria. Hence the great value of MITOCHONDRIAL-TARGETED ANTIOXIDANTS LIKE MITO-Q.


ROS can cause damage in number of ways. Blagosklonny in above paper, "ROS or TOR" stated ROS can cause aging through signaling pathways. In particular ROS can activate TOR.

In the Hearing Loss section, ROS caused damage to mitochondrial DNA which then signaled apoptosis (through BAK) resulting in death of neurons and hair cells and resulting hearing loss.

With the development of a new generation of mitochondrial-targeted antioxidants, mitochondrial ROS will be shown to be involved in many more age-related diseases by various pathways. 


The combination of anti-mitochondrial ROS plus anti-mTOR with rapamycin is a powerful anti-aging combination.




 


Disease A, Disease B

Disease A is group of diseases for which there is a robust evidence in medical literature indicating major role of elevated mTOR1 in pathology of disease and substantial reason to believe rapamycin will either prevent or  ameliorate disease process. These diseases include:


Cancer*

Atherosclerotic heart disease (CAD)

Age-associated Cardiomyopathy*

Age-related Obesity

Fatty Liver Disease, NAFLD

Osteoarthritis*

Diabetes type 2, Prevention, Insulin resistance

Hypertension (angiotensin 2)

Hearing Loss


Disease B is a group of disease for which there is some evidence in medical literature that rapamycin may prevent or ameliorate disease. These disease include:


BPH (Benign prostatic hyperplasia)

Osteoporosis

Age-related Macular Degeneration 

COPD (chronic obstructive pulmonary disease)***

Chronic renal disease***


Neurodegeneration

Alzheimer's disease (Prevention in APOE4 carriers, Not treatment of AD)

Parkinson Disease*

Tauopathy*


* section incomplete

*** section not yet begun



In the drop-down section the evidence is primarily from  basic science. The evidence for each specific disease comes almost entirely from animal models and animal studies. Evidence from these studies is presented which show the effect of lowering mTOR1 with rapamycin on prevention and amelioration of these diseases. 


APOE4 carriers should consult linked website: www.Alzheimer-prevention.com




Rapamycin Medicine

In the past 10 years, rapamycin has emerged as the silver bullet  for the treatment of aging, in basic science. This office practice is for people who seek protection from age-related disease in their own lifetime. For this purpose, this office relies on what I consider to be the leading basic research. Due to the extremely unfortunate lack of appropriate human clinical trials; this office relies heavily upon animal models. The  premise underlying treatment is that those of us who need geroprotection now, would most likely be dead before such clinical trials are initiated, completed, evaluated and the results incorporated into clinical practice. 


This office practices Rapamycin Medicine. Rapamycin Medicine is the application of the theory and research of Mikhail Blagosklonny to clinical medicine. The Blagosklonny theory of aging and age-related disease is presented below in the following section, Blagosklonny Literature. In short, the theory is elevated TOR causes aging and aging causes age-related disease. Age-related disease and death is a late manifestation of the damage caused on a cellular and molecular level by elevated TOR. 


This office treats elevated mTOR1. To the extent the underlying theory is correct that elevated TOR causes aging and age-related disease, this office is treating those conditions. The cornerstone of treatment is rapamycin.


It is based in very large part on basic science studies involving laboratory animals, such as mice and laboratory models of age-related human disease. Those studies on various age-related disease are presented in great detail in the drop-down sections, Disease.1, Disease. 2 and Neurodegeneration. 


Unfortunately, the benefit of rapamycin lowering TOR in the prevention or amelioration of the various disease of aging in humans has been studied by human clinical trials.


Rapamycin Medicine is the "off-label" use of rapamycin for prevention and amelioration of these diseases. 


It is said that "perfect" is the enemy of "good". Perfect would be human clinical studies to evaluate the safety and efficacy of rapamycin in prevention and amelioration of the various age-related diseases cited above. The apparent problem is that rapamycin is a generic drug and thus there is no commercial interest in use of rapamycin. Therefore, it is expected that human clinical studies on the prevention and amelioration of various age-related diseases by rapamycin will be few and far between. Those of us who need protection now from the ravages of age-related diseases will most likely be long dead before such studies are completed or perhaps even started. Fortunately, there is a very large body of basic science studies available.


This website attempts to present a very large amount of science-based information based upon quoted scientific papers. Almost all papers quoted are "open-label" and readers are strongly encouraged to download and study all references.


The most important part of Website is the drop-down section on specific diseases, especially   Disease A and Neurodegeneration. For a better understanding understanding of the theory of how rapamycin works, the papers presenting the theory of Mikhail Blagosklonny presented below should be reviewed. 



CAVEAT:  While I have been on weekly rapamycin for close to 3 years and I am very pleased with the results, and Mikhail Blagosklonny predicts rapamycin for anti-aging will become the standard of care in our lifetime; nevertheless, to the best of my knowledge, NO OTHER PHYSICIAN IN THE UNITED STATES HAS A SIMILAR PRACTICE USING WEEKLY RAPAMYCIN AS THE CORNERSTONE OF AN ANTI-AGING PROGRAM.  Furthermore, the overwhelming majority of physicians do not believe aging is a disease, or that there is a common underlying cause for diseases of aging or that treatment of aging or the underlying cause for diseases of aging is possible. 


Use of weekly Rapamycin as the cornerstone of an anti-aging formula has not been proven by human clinical trials.  Such treatment is not recognized by the FDA. There is not the safety of many physicians having used a similar weekly rapamycin treatment for many years. 


Furthermore, daily rapamycin, as used by over a million patients, has been clearly shown to have many serious side effects. It  is not widely accepted or believed that weekly rapamycin is different from daily rapamycin.


Therefore, it is essential that all prospective patients, in addition to review of this web site, also take proper note of the opposite opinion of other gerontologist. It will be found that, with the exception of Blagosklonny, almost every other gerontologist states that rapamycin has too many side effects for clinical use for anti-aging purposes.


Consequently, a careful analysis is necessary to make a proper informed decision regarding use of weekly rapamycin.. 




Senescent Cells

SASP (Senescence-associated secretory phenotype)

One of the major recent developments in anti-aging is the recognition of role of senescents cells in age-related disease and frailty.  A hallmark of aging is chronic sterile inflammation. The sterile inflammation is caused by senescent cells which secrete a wide variety of proinflammatory chemicals (cytokines). [SASP] The production of senescent cells is the dark side of cancer prevention mechanisms i.e. damaged cells are not allowed to divide (cell cycle).

Targeting Senescent Cells

There are three potential approaches for targeting senescent cells.

A. Prevent them from arising.

B. Eliminate senescent cells that have already formed. (SENOLYTICS)

C. Blunt the proinflammatory nature of the SASP.


Rapamycin is the most effectve method to prevent the formation of senescent cells.

Rapamycin is the  most effective method to inhibit SASP.

The inhibition of senescent cells is one of major mechanisms by which rapamycin extends lifespan and prevents cancer and other age-related diseases.

Senolytics

The following senolytics are in the news:

A. Desatinib plus Quercetin

B. Fisetin

C. Piperlongumine


A. Desatinib is an extremely expensive brand name anti-leukemia drug with dangerous side effects. Desatinib is very far out of my price range. Quercetin has very little effect by itself.

[Zero plans to use D & Q at this time]


B. Fisetin. Fantastic results in recent paper ("Fisetin is a senotherapeutic that extends health and lifespan", EBioMedicine, Oct 2018.)

Fisetin is supplement, very cheap and very safe. The only reason Fisetin not huge news is cheap supplement.


C. Piperlongumine. Promising supplement


I now take Fisetin.

Working on detailed section on Senescent Cells

Stayed tuned

Bacterial Infections

Major side effect: Neutrophil Dysfunction

After almost 3 years of experience with weekly rapamycin, it has emerged that the major side is increased risk of extracellular bacterial infections. These bacterial infections are mostly skin and subcutaneous tissues. The risk is both increased frequency of bacterial infection and increased severity of bacterial infection 


Some animal studies showed rapamycin caused increased risk of death from pulmonary bacterial infection.


On the other hand, the function of the immune system, involving lymphocytes and antibody production is improved. In a recent study involving humans (Mannick, 2018) the risk of viral infections presenting as URI (upper respiratory infection was decreased.


The increased risk of infection from invading bacteria involves the innate immune system, which includes Neutrophils (also called polys) and macrophages (which engulf bacteria).  Decreasing activity of mTORC1 hinders the function of the innate immune system, especially NEUTROPHILS.


The innate immune system sometimes causes "friendly fire" due to incorrect identification of something as enemy bacteria.  A number of age-related diseases, including atherosclerosis and coronary artery disease are related to this malfunction function of the innate immune system. This results in chronic inflammation, although there are no invading bacteria and no pathogens. One on the ways in which weekly rapamycin therapy ameliorates some age-related disease is by reducing "friendly fire" from the innate immune system.


The cells which compose the innate immune system are controlled by mTORC1. Decreasing mTORC1 activity impairs the function of the innate immune system, including Neutrophils. However, decreasing activity of mTORC1 is the major target of weekly rapamycin therapy.


Since the innate immune system including Neutrophils is the first line of defense against invading bacteria and yeast; decreasing mTORC1 thereby INCREASES the risk of infection from invading bacteria and yeast.


Consequently, In the skin and subcutaneous tissues, any onset of redness, pain, swelling, the cardinal signs of inflammation, should be considered as highly suspicious for bacterial infection.


Whle on rapamycin, anything suspicious for bacterial infection, should be considered as SERIOUS. Bacterial infection is especially serious to persons on rapamycin as there may be a decrease in the function of Neutrophils. ALL BACTERIAL INFECTIONS INVOLVING PERSONS ON RAPAMYCIN SHOULD BE TREATED WITH ANTIBIOTICS. In addition, rapamycin should be stopped until infection is totally eradicated.


(I will write a more scientific discussion of Neutrophil function, mTOR and bacterial infection to be added to drop-down section A.)







My Story

I have been a physician for over 50 years, having received my MD degree in 1967 when I graduated from SUNY Downstate Medical Center.  I also earned a BA degree from George Washington University and a JD degree from Hofstra Law School. I am Board certified in Anatomic, Clinical and Forensic Pathology. I believe in fact-based science.  


When I was young, I attended college on a tennis scholarship and ran a marathon in just under 4 hours at age 40. However, by age 70 my main physical activity was reduced to walking my two Shiba Innu dogs in the park. Then by age 72, I experienced angina and shortness of breath on small hills. I didn't need to be a physician to know I was in bad shape. My fasting blood sugar was high, my creatinine blood level was high [indicating renal insufficiency] and my waistline had expanded too much to fit into any of my pants. I knew I was suffering from aging; but I knew absolutely nothing about aging. Being like most people, and being pretty sure I was dying of aging, I decided to find out what I could. 


 I discovered a story more extraordinary and improbable than anything I had ever encountered in my lifetime. On one of the most remote places on planet earth, a clever soil bacteria decided to use chemical warfare against a bothersome neighbor; so the clever bacteria made a biologic poison to target the pesty yeast.The molecular target of the poison was the command and control of the yeast cell. The substance the bacteria targeted  turned out to be the command and control of not only the yeast cell; but of every cell of every organism on planet earth, a substance so extraordinary it has been conserved through 2 billion years of evolution.


 In 1965 an expedition to that island brought home a soil sample. In the soil sample from Easter Island Rapamycin was discovered and noted to be an anti-fungal agent. In 1991, rapamycin led to the discovery of TOR, target of rapamycin. The discovery of TOR increased our understanding of cellular biology and disease by about 10 fold. 


In 2006 Mikhail Blagosklonny, put all the pieces together and explained aging.  TOR promoted growth and development; but when growth and development stopped; TOR activity continued; but now cells were not busy being born, they were busy dying (conversion to senescent cells). The Blagosklonny answer: reduce activity of TOR and you slow down aging. Blagosklonny created an anti-aging formula (Koschei formula) and rapamycin was the cornerstone of that formula. Based upon "empirical medicine principles", I decided rapamycin 6 mg once a week would be an aggressive treatment and 3 mg once every 10 days would be a conservative treatment. I choose the aggressive treatment. January 2016, I began the rapamycin-based Koschei formula. I considered it a "Hail Mary pass";  a play made in desperation, with only a small chance of success and time running out on the clock.


Four months later, I felt like Archimedes must have felt when he took to the streets of Greece crying "Eureka". Suddenly, I no longer felt old. I felt like a person in good health. I could walk 5 miles without being tired, cycle my bike up hills without a hint of angina, I had no shortness of breath on moderate exertion. I lost 20 pounds, my waist-line went from 38 inches to 33.  Creatinine went from elevated to normal and fasting blood sugar went down.


 It's now over 2 years later, and I feel great. I've had no significant side-effects from rapamycin I believe two things Blagosklonny has said; (a) weekly rapamycin is safer than aspirin and (b) Rapamycin is the most important new drug since antibiotics. Based upon my personal experience with rapamycin and my study of basic research involving rapamycin and age-related diseases, I decided to begin this medical practice.  

Blagosklonny Literature

Quasi-Programmed Senescence

"Aging and Immortality, Quasi-Programmed Senescence and Its Pharmacologic Inhibition", 2006, marks the dawn of anti-aging medicine. The paper presents a radical new theory of aging and a pharmacologic manner to inhibit aging and age-related disease. Its significance for medical treatment is of the same order of importance as the introduction of the germ theory of infectious disease some 150 years earlier. However, the germ theory of disease had to wait 70 years until 1928, for the discovery of Penicillin by Alexander Fleming to have an effective antibiotic; the Blagosklonny theory of aging came with an effective treatment already available as a prescription drug.

Dr. Michael Hall, noted in Acknowledgements, discovered TOR in 1991 and gave it is prophetic name, Target of Rapamycin.

Everybody is advised to study this paper; here I quote Abstract:

     "While ruling out programmed aging, evolutionary theory predicts a quasi-program for aging, a continuation of the developmental program that is not turned off, is constantly on, becoming hyper-functional and damaging, causing diseases of aging. Could it be switched off pharmacologically? This would require identification of a molecular target involved in cell senescence, organism aging and diseases of aging. Notably, cell senescence is associated with activation of the TOR nutrient and mitogen-sensing pathway, which promotes cell growth, even though cell cycle is blocked.

Is TOR involved in organism aging? In fact, in yeast (where the cell is the organism), caloric restriction, rapamycin and mutations that inhibit TOR all slow down aging. In animals from worms to mammals caloric restrictions, life-extending agents, and numerous mutations that increase longevity all converge on the TOR pathway. And in humans, cell hypertrophy, hyperfunction and hyperplasia, typically associated with activation of TOR, contribute to diseases of aging. 

Theoretical and clinical considerations suggest that rapamycin may be effective against atherosclerosis, hypertension and hyper-coagulation (thus preventing myocardial infarction and stroke), osteoporosis, cancer, autoimmune disease, and arthritis, obesity, diabetes, macula-degeneration, Alzheimer's and Parkinson's diseases.

Finally, I discuss that extended life span will reveal new causes for aging (e.g., ROS, "wear and tear", Hayflick limit, stem cell exhaustion) that play a limited role now, when quasi-programmed senescence kills us first."

TOR-driven aging, Speeding Car without Brakes

In the 2009 paper by above title, Blagosklonny discusses the traditional theory of aging and the TOR theory. The traditional belief is that aging is due to "accumulation of molecular damage". According to this theory, aging is a decline, a loss of function, damage caused by wear-and-tear; nothing can be done to stop aging and furthermore, age-related disease all have separate and specific causes distinct from aging.

Blagosklonny uses a speeding car without brakes to analogize his theory of aging and disease of aging. In youth a car is moving at the highest speed on the highway, 80 mph. This is a very dangerous highway due to predators and the program is to drive at top speed. TOR is the program that runs the computer that drives the engine. At a certain point, adulthood, Blagosklonny says a 20 mph section of road is reached. [This is from Blagosklonny's anti-aging viewpoint; to me the wild animal needs to be a super-star athlete to survive and any slowing down will just hasten death from predators.] At any rate, very few animals reach the 20 mph section of road due to external causes of death; furthermore, the car has no brakes and there is no way to slow down from 80 mph. Blagosklonny concludes, "natural selection does not favor brakes." It is only in modern humans and domestic animals, when external causes of death are removed that aging becomes an issue.

The Blagosklonnny theory is that aging is a continuation of growth on a cellular and molecular level. Aging is being driven by TOR just like growth was driven by TOR. Only aging is not programmed but is quasi-program (program-like). "Quasi-program of aging is an aimless continuation of the developmental program that was not switched off. Unlike a program, a quasi-program has no biological purpose and may be harmful. The analogy to the car is that the car crashes (dies) because it doesn't slow down in the 20 mph zone. Speed causes the crash; just like aging causes diseases of aging. In this model, aging and diseases of aging have the same cause, hyperactive TOR, the equivalent of driving 80 mph instead of 20 mph when reaching the 20 mph section of road.

On the molecular level TOR is a growth program. Growth is hypertrophy (increase in size) and hyperplasia (increase in number, mitosis, cell division). In the older animal, many cells are blocked from mitosis by anti-cancer programs. When a cell is directed by TOR to undergo mitosis; but mitosis is blocked by anti-cancer program; that cell becomes a senescent cell. the senecent cell is still able to grow, which is not blocked, and the cell takes on hyperfunction. On the molecular level, hyperfunction of senescent cells is the essence of aging. 

A study of aging shows that before reaching the "end of the road" aging is hyperfunction. "In humans, aging is associated with hyperglycemia and high insulin, increased visceral fat, hyper-immunity, pro-inflammatory states, hyper-coagulation, hypertrophy, hyperplasia, growth of atherosclerotic plaques, proliferating cancer cells. Hyper-active and hypertrophic smooth muscle cell contribute to high blood pressure. Hyperactive osteoclasts cause osteoporosis. Hyper is the key word to describe the onset of aging."

Diseases are like the crashes at the end of the road. The sudden heart attack is the end result of atherosclerosis which has been going on for decades. From the TOR perspective "diseases of aging are just manifestations of aging, like smoke is a manifestation of fire."

To add to the complexity, with age in many ways the speeding car appears to slow down. In some ways it slows to 50 mph and to some "anti-aging specialists" this appears to be the cause of aging and the treatment is hormone supplements to get the car back to 80 mph.

From the TOR perspective, whether the car is going 80 mph or 50 mph it should be going 20 mph. The treatment is to slow the car down. The car has no brakes; but rapamycin is a pharmacologic brake.

The answer of modern medicine is "aging tolerance" Aging tolerance is all the excellent and very expensive modern treatments of diseases of aging.

Blgosklonny concludes: "Medical interventions increase aging tolerance, thus extending average life span despite chronic disease. Yet braking (slowing down)  the aging process itself will prevent or delay diseases themselves. And since a continuation of TOR-driven developmental growth drives the aging process...[this] could be inhibited pharmacologically, thus preventing aging and diseases of aging."

Rapamycin and quasi-programmed aging, 4 years later"

This 2010 paper begins with the statement, "rapamycin is an anti-aging drug that could be used today to slow down aging in humans."

It summarizes the 2006 theory: "Aging is hyper-activation of cellular signaling pathways and cellular function. It is a continuation of developmental growth, a purposeless quasi-program (a continuation of the developmental program that was not switched off after its completion). Figuratively, when TOR cannot drive growth, it drives aging. Age-related disease cannot be dissociated from aging; but it can be prevented by rapamycin.

The main point of this paper is the concept; a theory makes predictions based upon the theory and the verification of a theory is the verification of predictions. Blagosklonny then lists 12 predictions that were verified by new data in the four years after the 2006 paper. Here we look at two predictions:

Prediction 6: Aging is a quasi-program and a quasi-program can be switched off at any age. Administration can be started in aging animals and humans.

"Confirmation: Rapamycin was administered to 600 day old mice and prolonged their lifespan."

Prediction 12: Rapamycin "rejuvenates the immune system,"

Confirmation: "In old mice, rapamycin enabled effective vaccination against a lethal challenge with influenza virus." Note in Mannick paper December 2014, this was verified in humans, rapalog improved immunity.

“Slowing Down Aging"

"Prospective Treatment of Age-Related Disease by Slowing Down Aging, " 2012, in this very short paper Blagosklonny summarizes what I call "Blagosklonny Medicine". The main subject headings are: "mTOR and Geroconversion", "From Gerogenic Cells to Diseases using Atherosclerosis as an Example", "Cancer", Rapamycin for Diverse Disease", "Inhibition of mTOR Extends Life Span", "Caloric Restriction". Here we quote a portion of the Cancer section: 

"Despite the common misconceptions that rapamycin may cause cancer, it has been known for a decade that rapamycin prevents cancers in renal transplant recipients. At 2 years after renal transplantation, patients receiving rapamycin (sirolimus) as a base therapy do not develop any malignancies. In addition rapamycin prevented tumors and cured pre-existing tumors...Rapamycin is also extremely effective in the prevention of cancer in animal models. The cancer preventive effects of rapamycin may be the result  of its anti-aging effect. In fact, caloric restriction that decelerates aging delays cancer. Caloric restriction may slow aging by inhibiting mTOR."

Rejuvenating immunity

In "Rejuvenating immunity: "anti-aging drug today" eight years later" 2015; the focus is the December 2014, Mannick paper, "mTOR inhibition improves immune function in the elderly". [discused in two sections discussing below]. The Abstract states, "The year 2014 ended with celebration: Everolimus, a rapamycin analog, was shown to improve immunity in old humans, heralding "a turning point" in research."

The other major point of this paper is that Blagosklonny states that his hyperfunction theory first presented in 2006 is now accepted. [When he says "accepted" I believe he means accepted by the leading researchers in aging, not accepted by traditional medicine.] 


"INTRODUCTION: "Until recently, aging was believed to be a functional decline caused by accumulation of random molecular damage, which cannot be prevented. Breaking this dogma, hyperfunction theory described aging as a continuation of growth, driven by signaling pathways such as TOR. TOR-centric model predicts that rapamycin (and other rapalogs) can be used in humans to treat aging and prevent diseases, In PROPER DOSES AND SCHEDULES, rapamycin and other rapalogs not only can but also must extend healthy life-span in humans.

This theory was ridiculed by opponents and anonymous peer-reviewers. Yet, it was predicted in 2008 that "five years from now, current opponents will take the TOR-centric model for granted" And this prediction has been fulfilled."


He also notes the 2010 paper we discussed, "By 2010, many predictions of the TOR-centric model have been tested and confirmed. In 2010, one prediction remained: "rapamycin will become the cornerstone of anti-aging therapy in our lifetime". Until December 2014, all gerontological papers on rapamycin stated that current rapalogs are just proof of principle and will not be used due to side effects. Even further, use of anti-aging drugs in our lifetime was called science fiction. For unclear reasons, scientists emphasized that rapamycin and current rapalogs will not be used in aging humans due to imaginary side effects."


For me, the key phrase is "proper doses and schedules". The side-effects weren't imaginary; the problem was a failure of imagination. The failure to imagine what would happen if rapamycin was taken once a week, or once every two weeks and the belief that rapamycin must be taken everyday and have same side-effects as seen in transplant medicine. This was the extreme importance of the Mannick study; demonstration that 5 mg once a week improved immunity with no significant side effects. 


"From Rapalogs to Anti-aging Formula" 2017

Abstract: "Inhibitors of mTOR, including clinically available rapalogs sch as rapaymcin (Sirolimus) and Everolimus are gerosuppressants, which suppress cellular senescence.Rapamycin slows aging and extends life span in a variety of species from worm to mammals. Rapalogs can prevent age-related diseases, including cancer, atherosclerosis,obesity, neurodegeneration and retinopathy and potentially rejuvenate stem cells, immunity and metabolism. Here, I further suggest how rapamycin can be combined with metformin, inhibitors of angiotensin II signaling (Losartan, Lisinopril), statins (simvastatin, atorvastatin [Lipitor]..., aspirn and a PDE5 inhibitor (Cialis). Rational combinations of these drugs with physical exercise and an anti-aging diet (Koschei formula) can maximize their anti-aging effects and decrease side effects".


"Well-tolerated doses with minimal side effects can be deducted based upon clinical use of rapalogs. So optimal anti-aging doses/schedules can be suggested. given that rapamycin consistently extends maximal lifespan in mice, rapamycin will likely allow mankind to beat current record of human longevity, which is 122 years."


"mTOR: from growth to aging"

"It was theoretically predicted that stimulation of mitogenic/growth pathways in arrested or quiescent cells must lead to senescence..Cellular senescece is futile growth, a continuation of cellular growth when actual growth is restricte. Growth-stimulation of arrested cell causes their hypertrophy and hyperfunctions (for example, hypersecretory phenotype or SASP in senescent fibroblasts)."


"This can be applied to organismal aging. When developmental growth is completed, then mTOR and some other signaling pathways drives organismal aging. These pathways stimulate cellular functions, leading to hyperfunctions (for example, hypertension). Secondary, hyperfunctions can lead to loss of function. Hyperfunction theory links growth, aging and age-related diseases. Suppression of aging prevents or delays age-related diseases."


Age-related diseases are manifestations of advanced aging

"Age-related pathologies and conitions include atherosclerosis, hypertension, osteoporosis, obesity, insulin-resistance and type II diabetes, cancer, macular degeneration, Parkinson and alzheimer's diseases as well as menopause in women, and many changes in appearance that are not called diseases (baldness, for example) and presbyopia. Stroke, myocardialinfarction, heart fibrillation, broken hip, renal and other organs failure are consequences of age-related pathology."


In brief, age-related iseases are both manifestations of advanced aging nd causes of death. Aging is the sum of age-related diseases and symptoms from wrinkles and presbyopia to stroke and cancer metastasis. 


Since aging is not programmed, these diseases develop at different speeds..In brief, animals die from ag-related diseases, which are manifestations of advanced aging. 


If a drug delays ALL age-related diseases, it is a classic anti-aging drug becuse it will extend life span by delaying causes of death."


Criteria for potential anti-aging drugs

1. a drug that prolongs life span in model organisms preferably in mammals.

2. A drug that prevents or delays several age-related diseases in mammals.

3. a drug that suppresses cellular geroconversion from quiescence to senescence."


Rapalogs

1. Rapamycin prolongs life span im mice at doses that have no noticeable side effects.

2. Rapalogs prevent age-related diseases in mice as well as in other mammals including non-human primates and humans. As examples rapamycin prevents atherosclerosis, neurodegeneration and retinopathy and cardiopathy in rodents. Rapalogs prevent cancer in mice and humans. Rapamycin decreases obesity in mice and humans. Rapalogs rejunenate immunity, improve immune response in aging mice and humans. 

3. Rapalogs  suppress cellular geroconversion from quiescence to senescence.

4. Rapamycin suppresses aging, age-related pathologies in model organisms: the yeast, the fly and the worm."

[Note: suppress aging in these organism is very significant as these organism do not get cancer; the effect is at the fundamental level of aging]


"According to all criteria, rapalogs are anti-aging drugs. Importantly, rapalogs have minimal side effects."


SIDE-EFFECTS

Rapamycin Side Effects

This section represents what I believe to be just about the total extent of knowledge regarding side-effects from long-term use of weekly rapamycin. The reason for the potential enormous difference between daily side-effects and weekly side-effects is directly related to the half-life of rapamycin. The FDA section on rapamycin says elimination half life is 62+/- 16 hours. Daily dose is every .4 half-lives and weekly is every 2.7 half-lives.Taking a drug once every 0.4 half lives or once every 2.7 half lives can have a profound impact on effects and side-effects. In the paper, "mTOR inhibition improves immune function in the elderly, Joan Mannick, December 2014, writes "adverse events are related to pre-dose (trough) concentrations". Trough concentrations are high after .4 half lives and low after 2.7 half-lives. Transplant medicine needs to prevent low trough concentrations to prevent acute rejection; but anti-aging medicine wants low trough concentrations to prevent side-effects.  

SIDE-EFFECTS RAPAMYCIN WEEKLY 6 MG FOR 14 MONTHS:     

                                             2015-Nov    2016-Aug    2016-Dec      2017-Mar  2017- Aug    2018- March
Glucose                                      89                73                 84                  86                98                 98
HgA1c                                                              6                  6.2                 5.9               6.2               5.6
Insulin                        -                -               -                                               6.3              4.1                4.6
Creatinine                                1.20H            0.9                0.92               0.94            1.20H           1.09
Cholesterol                               114               102               140               173              171               147
HDL                                                               54             54             52            56           60                  60
LDL                                                                42             37             78         103           97                  74
TG                                                                  89             55             49           68          70                   57
Hemoglobin                                                13L            12.1L       12.5L      12.3L     13.0 L        13.0 L
Hematocrit                                                  39.5           37.4L       37.7L      36.2L     39.2           38.8
WBC                                                              6.1             6.3           2.6L         4.9         5.0             5.0
Lymphocytes                                            1129            901          660L        706L      890            1105   

1/1/16: 172 pounds;  3/22/17: 150 pounds.

 Waist/hip ratio start: 38/38 inches; waist/hip ratio 1 year: 33/36 inches.

 Lipitor 80 mg start 10/15 for angina; Stop Lipitor 9/16 causing Gout.

 Analysis: Glucose metabolism: rapamycin caused mild glucose intolerance. Insulin level 3/17 was normal and showed insulin sensitivity. Combination of glucose intolerance and insulin sensitivity is benign and not pre-diabetic. 

Renal: Decrease in creatinine from elevated to normal was extraordinary.

 Lipids: Dramatic results from Lipitor regarding LDL with low of 37 and increase to 103 with stopping lipitor. No apparent effect from rapamycin.

 Blood: Rapamycin increased mild anemia of 13 gm Hemoglobin before to 12.3 gm. Indices normal. Mild anemia is real side-effect. Decrease in absolute lymphocytes.

 Overall: glucose intolerance, insulin sensitivity, improved renal function, mild anemia, decrease lymphocytes.

 Clinical: No mouth sores in 14 months, (apthous stomatitis). No untoward clinical side-effects. 

Subjective impression: Miraculous improvement in health; feeling old to feeling young. 

This is a case report of ONE person, me, taking weekly rapamycin; for 14 months. Until a larger study is reported, I think this is the best source of information regarding expected side-effects from weekly rapamycin.


UPDATE: MARCH 2018.

Now on weekly rapamycin, 6 mg a week for just over 2 years.

Weight 156 pounds. No dieting.

Glucose metabolism seems excellent with Insulin 4.6. Insulin lower August 4.1 probably reflects high level physical activity in Summer and very little physical activity in winter.

Only meds: Rapamycin, Lisinopril.

Lipids good: HDL 60, LDL 74.

(Low Lipids August 2016 on Lipitor stopped due to side-effect from Lipitor.)

Initial mild anemia at 1 year now returned to baseline.

WBC 5.0 low normal associated with longevity.

Creatinine at 2 years at normal level, was initially elevated. Jump creatinine August 2017 probably due to hypotension and dehydration from blood pressure meds. 


The above laboratory results suggest that all the "experts" who say can't take rapamycin long-term to prevent diseases of aging are MISINFORMED.  There is extreme difference between DAILY VERSUS WEEKLY. 


My experience is that weekly rapamycin has an acceptable safety profile in contrast to daily rapamycin which I consider toxic.


HOMA Score

Homa score is calculated from glucose and insulin levels and shows insulin resistance. [See HOMA IR resistance calculator on line]

Rapamycin treatment started Jan 2016

HOMA score:

3/17  1.3

8/17  1.1

3/18   1.1

Healthy range: 0.5-1.4

Above 1.9 early insulin resistance

Above 2.9 significant insulin resistance

{Note: without insulin level can not calculate degree of insulin resistance and without knowing insulin resistance, don't know anything about glucose homeostasis.]

mTOR inhibition Improves Immune Function

"mTOR inhibition improves immune function in the elderly", a Novartis sponsored paper by Joan Mannick, December 2014, was a watershed moment in clinical anti-aging medicine. It was the first and ONLY study involving humans and a rapalog used in a manner relevant to anti-aging medicine. In a March, 2015 paper, "Rejuvenating Immunity..."Blagosklonny quotes Nir Barzilai, "it sets the stage for using this drug to target aging, to improve everything about aging...turning point in research".

 2009 was a big year for rapamycin. In the Harrison experiment, rapamycin was shown to significantly extend the lifespan of middle-age mice and Rapamycin became an FDA approved drug for use to prevent organ rejection in transplant medicine. The problem was rapamycin became the Dr. Jekyll and Mr. Hyde of medicine. In animal studies rapamycin looks like the best drug in the world; it ameliorates atherosclerosis  and prevents development of Alzheimer's disease in mice and everything imaginable in between in  regard to amelioraton of age-related disease. However, in transplant medicine involving humans, just about everything rapamycin does is bad; unless you think knocking out the immune system is good. The paradox was how could rapamycin be so good in animal studies in the laboratory and so bad for humans in transplant medicine.

 For the answer, one must go back 500 years to Paracelsus, the father of Toxicology. Born in the year 1493, he expounded the concept of dose response, "Solely the dose determines that a thing is not a poison," In the 500 years since Paracelsus, the importance of dose was lost.

 In the Mannick study, they used a different interval and gave Everolimus once a week instead of every 12 hours as everolimus is used in transplant medicine and lo and behold, Everolimus improved immune function instead of knocking out immune function.  This study involved 218 elderly volunteers over age 65. They were divided into 4 groups. One group took 0.5 mg once a day, one group 5 mg once a week, one group 20 mg once a week, and a control group. They took Everolimus for 6 weeks, stopped for 2 weeks and then were given a flu shot. The Everolimus treated group had a 20% enhancement response to the flu shot. Novartis has a drug which was approved to enhance immune response which had a 20% level of enhancement; so 20% enhancement is clinically significant and good enough for FDA approval.

 The explanation of the mystery is as follows: Mannick states, "many of the adverse events are related to the pre-dose (trough) concentration". Mannick meant this to refer to "side-effects"; but on the molecular level, the little molecules do not know the difference between an effect, a side-effect and an adverse event.

 A little arithmetic makes it all clear. The average dose of Everolimus in transplant medicine is 1 mg every 12 hours. The half-life of Everolimus is 30 hours. I calculated the following table to show the trough level in total milligrams of Everolimus remaining before the next dose when reach steady state.                           

                Dose                                             Half-lives                   Trough level in stead-state                                                  

1 mg every 12 hours                                     0.4                                      4.8 mg                                                                        

0.5 mg every 24 hours                                0.8                                        0.8 mg                                                                        

5 mg every 168 hours                                5.6                                         0.1 mg                                                                        

20 mg every 168 hours                             5.6                                          0.4 mg                                                                        

 The chart explains the mystery. The trough level when Everolimus used in transplant medicine is 50 times higher than when given 5 mg once a week. That 50 fold difference in trough level is highly significant.  Everolimus is a poison when give 1 mg every 12 hours; but Everolimus is not a poison when give 5 mg once a week. Rapamycin is a poison when given 2 mg or 5 mg once a day; but not a poison at 3 mg or 6 mg once a week. Rapamycin was designed to be a poison. Its use in transplant medicine is consistent with the original purpose; poison the TOR control system. But by changing the interval between doses, rapamycin is a medication that can ameliorate disease; not knock-out the immune system.

Conclusions from Mannick study

1. The effects of rapamycin as used in transplant medicine should not be extrapolated to use of rapamycin in anti-aging medicine. The two uses have different aims and extreme differences in trough level which causes entirely different effects.

 2. Animal studies can be very relevant to anti-aging medicine. In discussion, Mannick states that in a study of elderly mice, treatment with rapamycin for 6 weeks enhanced the response to influenza vaccination; therefore they tried it in human study and got the same results. Animals studies; but not results fom transplant medicine, correctly predicted the outcome of the study.

 3. A rapalog can be used in elderly humans to improve immune response. Mannick notes immunosenescence is a decline in immune function that occurs in the elderly, leading to an increased susceptibility in infection and decreased response to vaccination as compared to younger adults. Adults 65 years and older account for 90% of influenza related deaths. In this study, Everolimus enhanced immune response to flu shot by 20%. In humans and mice, Rapalogs improved immune response in fundamental ways on the cellular level. Everolimus reduced the percent of CD4 and CD8 T lymphocytes expressing programmed death-1 (PD-1) receptor, which inhibits T cell signaling and is more highly expressed with age. Mannick also noted that "in elderly mice 6 weeks treatment with rapamycin rejuvenated HSC (hematopoietic stem cells) function, leading to increased production of naive lymphocytes and improved response to vaccination. 

 4. Proper anti-aging dose need not cause toxicity to be effective. The "sine qua non" of rapalog toxicity is the canker sore, also called aphthous ulcer. In the study the 5 mg a week dose was no less effective than 20 mg weekly. The following is chart of incidence of canker sores in 4 groups:  

                                 0.5 mg daily                  5 mg weekly              20 mg weekly         Placebo

 Mouth ulcer             6 (11%)                           2  (4%)                         9 (17%)               3 (5%)                     

Note: The 5 mg weekly dose, which had excellent results, also had less incidence of canker sores than the control. This dose also had a much lower trough levels than .5 mg daily and 20 mg weekly.  

Low Dose Sirolimus study

"The efficacy and safety of low-dose sirolimus for treatment of lymphangioleiomyomatosis" [LAM], Andoa, 2012, is the only paper reporting a series of patients on low dose Sirolimus. The study included 15 patients, average age 40, duration of treatment 17 months. They were under treatment for LAD, a rare condition caused by elevation of mTOR due to defect in gene that control TSC complex, which inhibits mTOR. 

In renal transplant patients with dose of 2 mg daily mean trough level is  8.5 ng/mL and with 5 mg a day mean trough level is 17 ng/mL. 

In this study 11 patients took 1 mg a day and 4 patients took 2 mg a day. The mean trough level was 2.16 ng/mL. In addition, they didn't take any other potent medications. Therefore, their reported adverse events are closer to what would be expected on sirolimus therapy for disease of aging prevention with intermittent dose aimed at low trough level. Following chart was reported:

                                                   Adverse events related to Sirolimus therapy

                                                                 Total            Grade 1-2        Grade 3

Upper respiratory infection                   5                       5                      0

Fungal Infection                                     1                       0                      1

Hypercholesterolemia                          0                        0                     0

Diarrhea                                                  6                        6                     0

Stomach discomfort                            2                        2                     0

Stomatitis                                              9 (60%)             8                     1

Discussion of Adverse events: One patient developed an Aspergillus infection in the third year of mTOR inhibition treatment, in which severe parenchymal damage due to underlying disease had created a cavity. 

"The most common adverse events related to low-dose sirolimus were stomatitis (canker sore) (9 patients), gastrointestinal episodes (8 patients) including diarrhea and stomach discomfort (2 patients) and upper respiratory infection, usually not severe, except one patient with Aspergillus infection in cavity-like area of lung. Stomatitis was usually not severe.  Elevated cholesterol was not observed.

This was total adverse events reported in 15 patients with mean of 17 months. As shown by Mannick study, fewer adverse events can be expected on weekly therapy than low-dose daily therapy. In particular in Mannick study fewer mouth sores were reported in 5 mg a week group than in control. Although this was only 6 weeks, mouth sores and various adverse events are more common in first few weeks of treatment.

High Weekly dose of 6 mg once a week has lower trough than 1 mg daily. My experience has much less mouth sores. Some patients do have stomach discomfort and diarrhea.

"It's the half-life, stupid"

The rapamycin half-life for humans is 62 hours. The rapamycin half life for mice is 6.4 hours. 


In 2007 Granville paper (Ref 5 Cancer) "A Highly Effective Rapamycin Schedule" they used rapamycin to reduce size and number of tobacco carcinogen-induced mouse lung tumors. They found 3 injections a week of 1.5 mg/kg was extremely effective and better than every day for 5 days a week. They determined 4.5 mg/week  was better than 7.5 mg/week. As discussed in Cancer section, prevention of cancer requires the same mechanism as extension of lifespan and prevention of other age-related diseases.


In mice, every other day is once every 7.5 half lives.

In humans a daily dose is once every 0.4 half lives.

In humans, a weekly dose is once every 2.7 half lives. 


An excellent paper, "The Enigma of Rapamycin Dosage", Mukhopadhyay, 2016, sheds much light. 


For an anti-aging effect must reduce mTOR1; but not mTOR2. 


Rapamycin as used as an immunosuppressant is NOT an anti-aging drug and shortens lifespan.


Formed mTOR1 is very sensitive to rapamycin in contrast to formed mTOR2 which is very resistance to rapamycin. 


The mTOR1 complex consists of mTOR +Raptor +PA (phosphatidic acid.

The mTOR2 complex consists of mTOR+ RIctor + PA.

Rapamycin competes with PA.

Nano-molar doses of Rapamycin can  dislocate  PA from mTORC1 and  partially dislodge Raptor and thus cause inactivation of mTORC1.

mTOR-Rictor+PA is very stable and only micro-molar doses of rapamycin could dislocate Rictor and inactivate mTORC2.


 mTORC2 deteriorates over time and more mTORC2 must be synthesized.


 Rapamycin in nano-molar doses can bind to newly synthesized mTOR before it binds to Rictor and thus prevent formation of mTORC2.


Therefore must allow sufficient time for rapamycin to be reduced to low enough level so that doesn't prevent synthesis of new mTOR2.


This requires sufficient time between doses, based on half-life of rapamycin to not block formation of new mTORC2.


However, when rapamycin is used as immunosuppressant must maintain high nadir dose of rapamycin to prevent formation of new mTORC2; therefore use daily dose, 0.4 half lives.


When rapamycin used as anti-aging drug must not inhibit mTORC2 and therefore must have low nadir level before new dose and therefore use weekly dose, once every 2.7 half lives.





Koschei Anti-Aging Formula

Rapamycin

In "Koschei the Immortal and Anti-aging Drugs", 2014, Blogosklonny, sets forth an anti-aging formula. Rapamycin is the cornerstone of that formula. Rapamycin was approved in 2009 for use in transplant medicine. For that purpose it has been used in over a million people with good results with foreign organ retention for many years. Rapamycin is generally well tolerated with only mild to moderate side-effects. I stipulate that the dose and manner of use of Rapamycin in transplant medicine is hazardous to your health and certainly that manner of use is in no way suitable for anti-aging medicine.  

In transplant medicine they start with somebody with a normal level of mTOR function and use rapamycin to knock mTOR activity down to almost zero level of activity. Then they keep mTOR at this very low level. The goal is to totally disrupt normal mTOR function and signaling. This complete disruption of normal mTOR function causes a severe disruption of lymphocyte function. The net result is you can put a foreign organ into a person and not get an immediate violent rejection and infarction of the transplanted organ. This is how the body is supposed to react. However, as long as mTOR is kept continuously depressed, the immune system will not function properly and orchestrate rejection of the foreign organ. This is great medicine and saves lives. The extraordinary thing is the "experts" who ascribe the same side-effects seen in transplant medicine to the effects they claim would be seen if   rapamycin was used in anti-aging medicine.

 It was well known in medicine 500 years ago that whether a drug is poison or safe is a matter of dose. Indeed, consuming 4 liters of water quickly is fatal 50% of time [LD 50] due to sudden hyponatremia and brain swelling and edema. Nobody says water is too dangerous to drink.

In anti-aging medicine, Blagosklonny  recommends intermittent or pulse treatment and also suggested weakly dosage.Rapamycin has a half-life of @ 62 hours. That means daily use is once every 0.4 half-lives while weekly use is once every 2.7 half lives. For that reason, only data regarding using rapamycin once a week is applicable to side-effects expected from once a week use and side-effects from daily use are not applicable. 

In my practice, I consider the proper anti-aging dose of rapamycin to be 2-6 mg, and the proper interval 1-3 weeks. So the most conservative anti-aging dose would be 2 mg once every 3 weeks.

I would certainly welcome formal research studies on the best dose and best interval and I expect to see those results in about 50 years from now.  

Caloric Restriction

  Caloric restriction is major component of Koschei formula. Caloric restriction has been known to extend life span in numerous species from worms to mice for 100 years. Caloric restriction prevents age-related diseases including cancer and atherosclerotic heart disease. Interestingly, caloric restriction ameliorates sarcopenia. While caloric restriction increases insulin sensitivity, severe caloric restriction produces a glucose intolerance picture which is benign in significance.  A 2015 study in mice showed mechanism of action of caloric restriction was inhibition or TOR and increase in SIRT1. Thus caloric restriction is different from rapamycin alone which only inhibits TOR.

 In a very important study in humans, there was 25% caloric restriction in one group and 12.5% caloric restriction in another group combined with 12.5% increase in energy use through exercise. Compared to control group the caloric restriction group and the caloric restriction group plus exercise had similar results. There was a 20 pound weight loss, mostly body fat. Fasting glucose remained about the same; but fasting insulin levels went down 33%. Adiponectin showed 17% increase. SIRT1 level increase 3 fold. There was indication of decease in oxygen free radicals in muscle by 22%. Most important was the effect on mitochondria. Mitochondria increased in number and became more efficient. The increased efficiency of mitochondria was shown by reduced basal energy use at rest and less production of free radicals. 

 The best natural experiment showing what caloric restriction can do to a human population is the traditional Okinawan diet in the years 1950 to 1995. These people were farmers who worked very hard and as a matter of culture consumed less food. Studies calculated that they took in 8% less calories than their requirements. They had a remarkable decrease in age-related disease.  Compared with Americans, men had 17% incidence of coronary heart disease and women 8%. Men had 50% incidence of colon cancer and women 30%. Men had 14% incidence of prostate cancer and women 9% incidence of breast cancer. As regards average life span, it was 5 years longer than Americans. The oldest 1% lived to 105 compared to 101 for oldest 1% of Americans. For the last 20 years, Okinawans have switched to a more traditional Japanese caloric intake and they no longer show any health benefits. The Okinawan experience shows that an 8% caloric restriction less than required can achieve excellent results.

 Most people notice that after a period of time on a caloric restriction diet they stop losing weight. They then get discouraged and go off the diet. In the Koschei formula, the purpose of a diet is not to loose weight; but rather maintain weight on less calories. It is not the weight loss; but the caloric restriction itself which results in the health benefits. 

Physical Activity

Physical activity is a very important part of the Koschei formula. Blagosklonny states, "chronic physical exercise inhibits mTOR and increases insulin sensitivity." 

For an excellent study on the cellular mechanisms and signaling pathways through which physical activity decreases insulin resistance, see 2008 paper by Erin Glynn entitled, "A chronic increase in physical activity inhibits the fed-state mTOR/S6K1 signaling and reduced IRS-1 serine phosphorylation in rat skeletal muscle." The very short explanation is physical activity causes activation of AMPK energy sensing pathway, which leads to a decrease in insulin resistance in skeletal muscle. Muscle is the major regulator of insulin resistance as skeletal muscle is responsible for up to 75% of insulin dependent glucose disposal in humans.

 In the book, "Autobiography of Geronimo", it was stated that Apaches could travel 70 miles a day on foot. There are ultra-marathon runners who train for runs of 50-100 miles. If they ever see a doctor, it is about running related injuries as they have very low level of age-related disease. The major negative effect of civilization on human health is that civilization caused a decrease use of leg muscles. Humans are by nature, the greatest long-distance runners of the animal world.

 The question is: "what is the minimum level of physical activity needed"? The minimum requirement seems to be burning 1000 calories a week; the equivalent to walking 10 miles. One study showed that moderate physical activity is associated  with 50% reduction in cardiovascular disease in over-65s. Another study had shown that moderate physical activity of walking 4 hours a week had a 54% reduction in cardiovascular mortality and a high level which was described as jogging 3 hours a week, had a 66% reduction.Note that the difference between moderate and high was small; but the difference between moderate and low activity was dramatic.The conclusion of the study was that older adults who are physically active have a lower risk of coronary heart disease, stroke, and death from cardiovascular disease. 

The main point is that physical activity, like walking or jogging, causes a decrease in insulin resistance in leg muscles. A decrease in insulin resistance causes a decrease in insulin levels which causes a decrease in mTOR. 

Metformin

Metformin is part of our anti-aging formula. In a 2014 UK paper metformin monotherapy had a 15% longer survival than non-diabetic control subjects. Survival of diabetic patients not on Metformin had a survival 23% lower than non-diabetic subjects, which reflects expected results. 

 In a NIA (National Institute of Aging) 2016 study, metformin used alone had a modest increase in life spanbut only in male mice.When metformin was combined with rapamycin there was a very dramatic increase in one of two strains of mice. Male and female mice had a 24% increase in median life span and 10% and 17% increase in maximum life span. This was an impressive increase over rapamycin alone.

 Metformin has been shown to reduce cancer in a great majority of animal studies and many human studies, especially liver and pancreas.  Metformin acts through very interesting pathways which include activation of LKB1 (a tumor suppressor) and then stimulation of AMPK pathway which inhibits TOR. 

For such an excellent drug, the question is why Metformin doesn't get more attention. A leading researcher on Metformin,  explained, "The problem with Metformin is it's cheap, it's widely available, it has a great safety profile, and anyone can use it." 

Metformin is also excellent to combine with rapamycin as the two agents have many opposite side effects, which can cancel each other's negative side effects.

Angiotensin II disruption

Angiotensin II disruption is an extremely important part of the anti-aging formula. In clinical medicine today, there are two ways to disrupt angiotensin II, angiotensin-converting enzyme inhibitors (ACEIs, [Lisinopril, enalapril] and angiotensin II receptor blackers (ARBs, (Losartan, Candesartan). [We only use those that cross the blood-brain barrier]. These drugs are the most popular drugs used for the therapy for hypertension and are used by millions for that purpose. However, angiotensin II is involved in far more than just hypertension.

 Two great parallel systems on the cellular level are the TOR system and the angiotensin system. The TOR system is 2 billion years old and the angiotensin system is 500 million years old. The evolution of the angiotensin system was essential for the development of a circulatory system, which was required for animals to get bigger than a few millimeters, the distance for effective diffusion. 

There are two main theories of aging. The hyperactive TOR theory first presented  in 2006, and the ROS theory (reactive oxygen species) first presented in 1956. The hyperactive TOR theory is about early aging and diseases of aging related to hyperactive TOR, and the ROS theory relates more to late aging. [see first section Blagosklonny Medicine] The current major focus of the ROS theory is on mitochondria, the major source of oxygen free radicals. Angiotensin is intimately involved with mitochondria and oxygen free radicals. While TOR is strictly organic chemistry, in the angiotensin system, the most important components are small molecules, superoxide and Nitric oxide. 

Disruption of angiotensin II, prolongs lifespan of mammals. In hypertensive rats, treatment with angiotensin II inhibition with ACEIs or ARBs ameliorated the harmful vascular effects of hypertension and doubled the rats lifespan. In a study of normal rats without hypertension, Enalapril, an ACEi prolonged lifespan by 21.4% and Losartan, an ARB, increased lifespan 12.5%.

 In an extremely important study by Begnigni, 2009, "Disruption of the Ang II type 1 receptor promotes longevity in mice", they created homozygous mice with knock-out of the Ang type 1 receptor. The knock-out mice lived a remarkable 26% longer than the controls. The knock-out mice showed protection from atherosclerosis and vascular damage. The knock-out mice also showed reduced age-induced mitochondrial loss. The conclusion was that reduction in oxidative stress ameliorated mitochondrial loss. They also showed an increase in genes for Nampt and SIRT3. Caloric restriction also has this effect, but not rapamycin, which only extends lifespan by inhibition of TOR. This study showed that knock-out Ang II receptor increased lifespan dramatically, but it seemed through a separate system than inhibition of TOR. Caloric restriction appears to have one foot in each system.

 In a separate study of genes associated with extreme human longevity, Begnigni showed that  genes with variations in angiotensin II receptor, which decreased function, were associated with extreme longevity. 

Another study in humans showed treatment with angiotensin II inhibitors reduced risk of cancer, hazard ratio of 0.66.

 For an understanding of the extraordinary roles of angiotensin II on age-related disease, I recommend reading, "Angiotensin II revisited: new roles in inflammation, immunology and aging", by Ariela Benigni, 2010. For the role of angiotensin II regarding mitochondria, I recommend "Renin-angiotensin system inhibitors protect against age-related changes in rat liver mitochondrial DNA content and gene expression", Elena de Cavanagh, 2008. 

Aspirin and Statins

Aspirin is the only "anti-aging" drug recommended by the US Preventive Task force. The recommendation is for men 45-79 and  women 55-79 to prevent cardiovascular disease and colorectal cancer. They did not specify 81 mg or 325 mg. I recommend 81 mg to decrease risk of upper gastrointestinal bleed.

 I agree with evidence showing aspirin has a very beneficial effect on health of endothelial cells. The effect is mediated through both inhibition of platelets and decrease in chronic inflammation of endothelial cells. Part of the protective effect of Aspirin on endothelial cells is through blocking an inhibitor of NO synthase and increasing production of Nitric oxide. The increase in Nitric oxide causes a decrease in vasoconstriction and is similar to pathway of Ang II inhibitors who's main action is to increase Nitric Oxide.

 I also agree with data that aspirin decreases risk of colon cancer.

One important study (Wan, 2013), established aspirin as a true anti-aging drug. The study was "Aspirin extends the lifespan of C.elegans via AMPK and DAF-16/FOXO in dietary restriction pathway." In this study aspirin was shown to activate LKB1. LKB1 is a very important tumor suppressor. LKBI then activates AMPK which in addition to many other beneficial effects also inhibits mTOR. This puts aspirin in same pathway as metformin with activation of LKB1 and AMPK. In contrast to Rapamycin, which  has a single action; the direct inhibition of mTOR; Aspirin and Metformin are indirect inhibitors of mTOR and also involved in many other pathways.  


Statins are included in our anti-aging formula. In addition to usual reasons for using statin; rapamycin can cause elevation of lipids. This elevation is a result of beneficial effect in that rapamycin prevents lipids from entering tissues and rapamycin has a robust anti-atherogenic effect regardless of elevated lipids. However, lowering serum lipids with statins through decreased production in liver is beneficial and synergistic with the rapamycin effect of removing lipids from atheroma.

In the 2013 Cochrane report, which reviewed 19 trials involving 60,000 patients with mean age 57, statins reduced all cause mortality (OR 0.86). In a VA study, all cause mortality was also decreased (OR 0.54) and the conclusion was "statins showed a highly significant negative association with death."

CAVEAT

The theory and praxis of my system of using the Koschei formula to prevent and treat D.O.A by slowing aging is ALTERNATIVE MEDICINE.  Use of Rapamycin is "off-label". Use  of metformin is "off-label". Traditional medicine doesn't accept the Blagosklonny hyperfunction theory of aging which forms the theoretical basis for treatment.Traditional medicine doesn't accept that reduction of activity of mTOR slows aging or that slowing aging prevents age-related disease or that age-related disease and aging have a common etiology and are in effect one and the same. Traditional medicine does not accept that intermittent rapamycin has a different side-effects profile than daily use or that intermittent rapamycin can be used safely. Therefore, all prospective patients are advised to use due diligence and investigate opinions of many other experts before seeking treatment. DUE DILIGENCE is required to make a proper informed consent to treatment.

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