Rapamycin-Based Treatment of Diseases of Aging

Rapamycin-Based Treatment of Diseases of Aging

The Medical Practice of
Alan S. Green, M.D.

The Medical Practice of
Alan S. Green, M.D.

The Medical Practice of
Alan S. Green, M.D.

The Medical Practice of
Alan S. Green, M.D.

The Medical Practice of
Alan S. Green, M.D.

The Medical Practice of
Alan S. Green, M.D.

The Medical Practice of
Alan S. Green, M.D.

The Medical Practice of
Alan S. Green, M.D.

Alan S. Green, M.D.

My Story

I received my MD degree in 1967 when I graduated from SUNY Downstate Medical Center;  I have been a physician for 50 years. 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 proven in the research laboratory.  

I attended college on a tennis scholarship and ran a marathon in just under 4 hours at age 40. But 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. As a trained pathologist I accepted the reality that I was in rather poor shape. My fasting blood sugar was up, my creatinine blood level was elevated indicating renal insufficiency and I couldn't fit into any of my pants. I then began trying to learn about aging. 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 lowly soil bacteria made a poison to target yeast.The chemical target of the poison was the command and control of the yeast cell, which turned out to be the command and control of every cell on planet earth, conserved for 2 billion years of evolution. In 1965 an expedition to the island brought home the soil sample and 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 understanding of cellular biology and disease by about 10 fold. The discovery of how the cell works led to the discovery of how aging works. The discovery of how aging works led to the Koschei formula, with rapamycin as 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 decided to go with aggressive treatment. January 2016, I began the rapamycin-based Koschei formula with intent to take it for one year; in what could euphemistically be called a "proof-of-concept" experiment.  I didn't have to wait one year; by 4 months the results were miraculous. I lost 20 pounds,  my waist-line went from 38 inches to 33. I bought a pair of size 32 jeans and didn't have to wear joggers no more. I could walk 5 miles a day and ride a bike up hills without any hint of angina. Creatinine went from elevated to normal and fasting blood sugar went down. I thought I was Lazarus back from the dead. It's now over 1 year and I feel great. I've also had no mouth sores, the most common clinical side-effect. For me, rapamycin is the world's greatest medicine.  


Blagosklonny TOR Rapamycin

Rapamycin Medicine

 This office practices Rapamycin Medicine. Rapamycin Medicine is an inchoate specialty in the world of Alternative Medicine. It is the application of the theory and research of Mikhail Blagosklonny to clinical medicine. This theory was first articulated in 2006 in "Aging and Immortality: Quasi-programmed Senescence and Its Pharamacologic Inhibition". Clinical treatment is based upon, "Koschei the Immortal and Anti-aging Drugs", 2014. Rapamycin is the cornerstone of treatment.

In order to better explain the practice, I need to define a few terms. I separate aging into "early aging" and "late aging". Early aging is considered a disease which affects people in the 60-99 year age group and late aging is perhaps a "natural process" which effects people in the 100 to 110 age group.  Early aging is driven by TOR and late aging is driven by unknown factors. Lowering TOR is about treatment of "early aging".

The theory of treatment is to slow down aging and thus slow down the development of diseases of aging, in the 60-99 year time frame. In particular, treatment is aimed at specific disease of aging and not at healthy people.

The theory is that diseases of early aging are due to hyperactive TOR and reduction of hyperactive TOR will ameliorate these diseases. In particular, the theory is that in old people, TOR is set at too high a level, a level consistent with "growth and development" appropriate for youth; treatment is to lower TOR to "maintenance" level appropriate for old people. 

In a 2014 paper, it was reported that rapamycin extended median lifespan in mice, 26% females and 23% males. This is equivalent to extending median human lifespan to 100. (Miller, Harrison et. al., "Rapamycin-mediated lifespan increase in mice...", 2014}

Diseases of Aging

In the Speeding car section below we quoted Blagosklonny as saying that smoke was the manifestation of fire the way diseases of aging are the manifestation of aging. The office plan is to slow aging to slow development of diseases of aging. We have 5 disease targets: age-related obesity, atherosclerosis, hypertension, osteoporosis, benign prostate hyperplasia. These diseases are present for a decade or more before the crash; i,e. the heart attack, stroke, onset diabetes, broken bone or need for prostate surgery. These diseases cause symptoms, signs, and laboratory findings which allow us to monitor the effects of treatment. 

The usual minimum age of treatment is 60.

Persons with such diseases or conditions which cause elevated mTOR and places person at increased risk of diseases of aging and persons with diseases or conditions for which there is compelling support in medical literature that they would receive substantial benefit from a rapamycin based treatment will also be considered for treatment.

Blagosklonny and Modern Aging Theory

Out of all the known chemical substances in the universe, a single drug has emerged as the most robust in extending lifespan. If fact, it extends lifespan if every living thing tested in the laboratory; yeast, worms, flies, mice; even middle-age mice. That drug is Rapamycin.

2006 was a watershed year in Biology, with the most important paper since 1859 the year Charles Darwin published "On the Origin of Species," That paper was "Aging and Immortality: Quasi-Programmed Senescence and Its Pharmacologic Inhibition" by Mikhaik V. Blagosklonny. In simple terms the idea was aging was a disease process caused by overactive TOR (Target-of-rapamycin). That same disease process was also responsible for most age-related disease. Aging was an unintended program that was a continuation of an essential  growth program. Aging and age-related disease were two sides of the same coin, the same disease process. Furthermore, TOR could be controlled with rapamycin, an approved prescription drug. Therefore, mankind had in their hands the ability to ameliorate aging and age-relate disease; everything from atherosclerosis to Alzheimer's disease. 

Rapamycin was the product of biologic warfare, produced by a chemist far more sophisticated than any human chemist. The chemist who produced rapamycin was a bacteria on Easter Island, one of the most remote and mysterious places on planet earth. The enemy was a yeast and the biologic target was TOR. Blocking TOR was intended to poison the yeast and stop it from growing. By happenstance, the bacteria had targeted the command and control of not just yeast; but every cell of every living thing on planet earth. A substance so important it had been conserved through 2 billion years of evolution. TOR was in essence the secret of how life worked.

For basic understanding any prospective patient should read 4 papers by Blagosklonny; the above paper plus:

 "TOR-driven aging: Speeding car without brakes", 2009.

 "Rejuvenating immunity: "anti-aging drug today" eight years later," 2015.

 "Koschei the immortal and anti-aging drugs", 2014. In Koschei, Blagosklonny creates an anti-aging formula that can be used to ameliorate aging and also almost all age-related disease. All components  of the formula are either free (caloric restriction and physical activity) or inexpensive generic prescription drugs plus aspirin. The 7 components are discussed in detail in later section. 

The following 5 sections each contain a short review of highlights of Blagosklonny papers .[4 noted above] All are "open access" and readers should download and study each paper.

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

"Rejuvenating immunity: "anti-aging drug today" eight years later" 2015; is Blagosklonny's most recent major paper and summarizes the current situation.

The main point is noting the December 2014, Mannick paper, "mTOR inhibition improves immune function in the elderly", which we spend 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 and certainly 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 life time". 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. Fulfilling the Blagosklonny prediction; rapamycin is currently the cornerstone of "anti-aging therapy"; at least for one person.

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:     

                                                                15-Nov    16-Aug    16-Dec    17-Mar
Glucose                                                        89             73           84            86
HgA1c                                                             -                6            6.2          5.9
Insulin with fasting glucose                        -                -               -             6.3
Creatinine                                               1.20H           0.9          0.92        0.94
Cholesterol                                                114           102           140         173
HDL                                                               54             54             52            56
LDL                                                                42             37             78         103
TG                                                                 89              55             49            68
Hemoglobin                                                13L            12.1L       12.5L     12.3L
Hematocrit                                                 39.5            37.4L       37.7L     36.2L
WBC                                                              6.1             6.3           2.6L         4.9
Lymphocytes                                            1129            901          660L        706L    

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. Since rapamycin is clearly the most robust anti-aging drug ever discovered, it does seem a bit odd, that there would be data on only a single person; but it is, what it is.  

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.  

Glucose Intolerance, Insulin Sensitivity and "the Grim Reaper"

Both starvation and rapamycin cause glucose intolerance. This is the opposite of glucose intolerance and insulin resistance seen in pre-diabetic persons characterized by overweight or obesity, high fasting insulin levels, high fasting glucose, decrease in insulin sensitivity and high mTOR. This is a very complicated subject and to understand it readers could look at "Koschei the immortal" and  Figure 2  "Insulin-resistance: two opposite conditions. Insulin resistance (IR) can be caused by the activation of mTOR and, paradoxically, by mTOR inhibition. In the first case, IR is detrimental for health, whereas in the second case, it is benevolent. The "x" axis is increasing mTOR activity. There is a U-shaped curve. The left side states  "Low mTOR, Pseudo-diabetes, slows Aging. The right side states, "High mTOR, diabetes type II, Fast aging." For further study, I suggest 2 references by Blagosklonny: 

 "Rapamycin-induced glucose intolerance: hunger or starvation diabetes", 2011;

 "Once again on rapamycin-induced insulin resistance and longevity: despite of or owing to", 2012.

None of this is actually very relevant  to intermittent use of rapamycin as an agent to slow aging. It is brought up because the most common argument against rapamycin is that it causes insulin resistance in high dose organ transplant use and Blagosklonny argues that is "benevolent IR" and related to starvation diabetes. This is a key discussion for daily use of rapamycin.

Intermittent use resembles caloric restriction and the following paper is most relevant: 

"Effects of long-term caloric restriction and endurance exercise on glucose tolerance, insulin action, and adipokine production", 2010, Fontana.

Fontana studied 28 volunteers who had been following severe (about 40%) caloric restriction for average of 7 years, 28 endurance runners (average 50 miles/week)and 28  sedentary controls eating Western diets. Average age 53, each group 24 men, 4 women. Following chart summarizes data:

                                                 CR group                        Runners                           Controls

BMI                                        19.5                                         22.2                                26.0 

Fasting glucose                   83                                            91                                   95 

Fasting insulin                     1.4                                          2.0                                   6.9 

Insulin sensitivity index    18.5                                         20.4                                 7.0 


On testing for glucose tolerance, 40% of CR group had glucose intolerance.  

The 17 in CR group with normal glucose tolerance had IGF-1 (insulin growth factor) of 205 (ng/mL) and the 11 in CR group in glucose intolerance had IGF-1 of 154 (ng/mL) p value 0.01.

In lifespan studies in worms (C. elegans) the DAF-2 gene encodes the IGF-1 gene for worms. Mutatations which knock out DAF-2 double the lifespan of the worms. Cynthia Kenyon, the leading expert, called the DAF-2 gene, "the grim reaper." This is IGF-1 the factor which was low in the CR group who demonstrated "glucose intolerance".

The study showed that "long-term caloric restriction is associated with impaired glucose tolerance in some individuals, presumably because of decreased insulin-mediated glucose disposal. This reduced glucose disposal is associated with lower circulating levels of IGF-1." And this is the very thing associated with increased life-span.   

I suggest that if we asked endocrinologists from Louisiana, the state with 36% obesity, they would say glucose intolerance is "pre-diabetic". On the other hand if we asked endocrinologists from South Sudan, where 42% of population is suffering from severe food shortage what glucose intolerance means, they would probably say, an indication of starvation.   

In the study noted above (Miller, Harrison, 2014) as they increased the dose of rapamycin in mice, they increased lifespan and as they increased lifespan they increased glucose intolerance. In mice, amount of lifespan increase and glucose intolerance were directly connected. Regardless of meaning of glucose intolerance in pre-diabetics;  glucose intolerance is a marker of the changes related to metabolism, which are part of extending lifespan. The controls had "normal" glucose tolerance and the mice with the 26% and 23% median lifespan extension were the mice with the "glucose intolerance". The facts from the research laboratory are that glucose intolerance and lifespan increase are both "abnormal" results which go together.                                            

                                                     

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 included15 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.

It is my opinion that this report and Mannick report are only two published reports relevant to expected adverse events in intermittent therapy.

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."



Diseases of Aging (D.O.A.)

Age-related Obesity

Many people successfully fight the "Battle of the Bulge" until they pass age 65 and then begin to loose the battle. Elevated mTOR turns the fight against you. The following from page 2 of Koschei, "Rapamycin prevents Obesity" explains:

1. mTOR decreases lipolysis (hydrolysis of triglycerides) (fatty acids); rapamycin increases lipolysis, releasing fatty acids from the fat tissues.

2. mTOR increases lipogenesis (synthesis of triglycerides; rapamycin blocks lipogenesis. 

3. mTOR promotes adipocyte differentiation and hypertrophy; rapamycin prevents adipocyte differentiation.  

4. Nutrients such as glucose, amino acids, and fats activate mTOR and increase insulin; rapamycin blocks mTOR and decreases insulin secretion and insulin-induced obesity. In a vicious cycle, obesity activates mTOR. 

5. Rapamycin prevents entry of lipoproteins into tissues. This can lead to elevated lipds. This is benign as rapamycin prevents atherosclerosis. However, the elevation of lipids can be blocked by using statins, part of the formula. 

In studies involving mice, rats and humans, rapamycin can decrease weight gain and prevent weight gain with rats on high fat diet. 

Rapamycin doesn't cause automatic weight loss in humans; but makes it much easier to lose weight on weight loss diet with reduced calories.

The decrease of central adipose tissue has very important metabolic impact because of hormone-like substances secreted by adipose tissue called adipokines. Central obesity is belly fat. Belly fat is bad, visceral adipose tissue is bad. However, adipose tissue on butt and extremities appears to be neutral.  

Most adipokines are harmful and increase with central and visceral obesity. Their most common effect is promoting chronic inflammation, which promotes atherosclerosis. 

Adiponectin, another very important adipokine, has beneficial effects; but the level goes down with increase of adipose tissue.

 Creating a better adipokine pattern, as well as reduction of mTOR signaling is main goal of reduction of central obesity.

Atherosclerosis

Animal studies show that rapamycin has great therapeutic potential to inhibit atherosclerosis.  

Frequently, the first sign of cardiovascular disease is sudden death. This is called unheralded myocardial infarction. The problem is sudden "plaque rupture" or destabilization of an asymptomatic atheroma. 650,000 Americans die each year from heart disease: 1.2 million have heart attacks, killing 450,000; 300,000 die suddenly before reaching the hospital and about half had no prior warning. 

Atherosclerosis starts early; but doesn't kill until aging causes destabilization. In Vietnam war, 45% of soldiers who had autopsy examination of coronary arteries had evidence of atherosclerosis. By age 40-49, 70% have coronary artery disease. However, heart attack is mainly a disease of men over 60 and women over 75. Incidence of fatal hart attacks in men and women is: 3%, 2% in age group 44-59; 11%, 4%, in age group 60-79 and 17%, 9% in age group 80+.

1 out of every 3 deaths in U.S. reported in 2015, were caused by cardiovascular disease; so there is clearly no effective treatment.

Research in animal models have shown how rapamycin blocks atherosclerosis on a cellular level. The following 6 papers are selected as examples and the last three (Ma 2007, Zhao 2009, Chen 2008), and are recommended for study.

"Potential therapeutic effects of mTOR inhibition in atherosclerosis", Kurdi, 2015 states, "mTOR has been identified as a pre-eminent factor in the development of atherosclerosis"..."rapalogs have shown undeniable evidence of the value of mTOR inhibition to prevent the development of atherosclerotic plaques in several animal models."

"Everolimus-induced mTOR inhibition selectively depletes macrophages in atherosclerotic plaques by autophagy," Martinet, 2007; "Macrophages ...play a pivotal role in plaque destabilization...macrophages in vascular wall can be cleared via induction of autophagy by mTOR inhibition."

"Autophagy in Atherosclerosis, Martinet, 2009; "Because atherosclerosis is an inflammatory disorder of the arterial intima, pharmacologic approaches could be developed to stabilize vulnerable, rupture-prone lesions through selective induction of macrophage autophagic death."

In promotion of atherosclerosis the main actors are:

1. The vascular smooth muscle cells: Under stimulation mTOR become hyperfunctioning senescent cells with multiple functions that promote atherosclerosis.

2. Monocytes/macrophages: migrate to lesion and promote inflammation; blocked by rapamycin and decreased by autophagy.

3. Lipids: Influx promotes atheroma; rapamycin causes efflux and removal atherosclerosis.

4. Chronic inflammation: ramamycin decreases chronic inflammation by reduction of pro-inflammatory cytokines by blocking their messenger RNA synthesis.

5. Collagen, required for stabilization of plaque; rapamycin increases collagen by decreased catabolism of collagen by reduced expression of metalloproteases (MMP) which dissolve collagen.

"Anti-atherosclerotic effects of sirolimus on human vascular smooth muscle cells", Kun Ma, 2007; Sirolimus prevents lipid accumulation in vascular smooth muscle cells, reduces cytokine production.

"Low-dose oral sirolimus reduces atherogenesis, vascular inflammation and modulates plaque composition in mice lacking LDL receptor", Zhao, 2009; "at low doses, sirolimus was an effective and safe anti-atherogenic agent...it attenuated the progression of atherosclerosis...by reducing the pro-inflammatory vascular response typical of the disease."

"Oral rapamycin attenuates inflammation and enhances stability of atherosclerotic plaques in rabbits independent of serum levels", Chen, 2008; "Oral administration of rapamycin effectively attenuated inflammation, inhibited progression and enhanced stability of atherosclerotic plaques, without altering serum lipid levels. Our findings suggest a novel approach to treatment of atherosclerosis."

In animal studies rapamycin is the most effective drug in preventing progression of atherosclerosis and preventing destabilization of plaque, a major cause of acute myocardiial infarction and sudden death. 



Hypertension

With Hypertension, I become eclectic. Angiotensin II, not mTOR suddenly becomes the main villain; angiotensin II  inhibition is the main treatment and Ariela Benigni is the leading authority on  the multiple effects of angiotensin II. This topic was discussed in the section about angiotensin II inhibition. However, this is not outside the world of Blagosklonny as angiotensin II inhibition is part of the Koschei formula and all our references start with Blogosklonny and Koschei. 

mTOR plays a significant role in hypertension as hyperfunctioning vascular smooth muscle cells and increased inflammation plays a major role. Rapamycin can still be expected to block the increased in proinflammatory substances by decreasing messenger RNA used for their production. Furthermore, hypertension causes cardiac hypertrophy and that hypertrophy is blocked by rapamycin. 

Nevertheless, in hypertension, angiotensin II is the main driving force and blocking angiotensin II is the main treatment. In this way, we are similar to traditional medicine. Millions of people are now treated for hypertension with angiotensin II inhibition. We differ slightly form traditional medicine in a few ways.

 First, we view blocking angiotensin I receptors in the brain of equal importance as treatment of hypertension. Therefore, we only use angiotensin II inhibitors that cross the blood-brain barrier. This is to protect not only cerebral arteries, but the cerebral microcirculation. Protection of the cerebral microcirculation is about increasing Nitric Oxide synthesis. We also want to decrease chronic inflammation in the brain. Studies have shown that only angiotesin inhibitors that cross the blood-brain barrier protect against development of Alzheimer's disease.

 The main drug we like is Candesartan. It crosses the blood-brain barrier, and it doesn't stimulate PPARg, which promotes adipogenesis.

 The second difference from traditional medicine, is that we view blocking angiotensin II as not just treating hypertension, but also as acting as an excellent anti-aging drug. 

Blocking Angiotensin I receptors decreases superoxide and increases Nitric oxide. In addition to decreasing hypertension, this has many other beneficial effects including decreasing inflammation, decreasing oxygen free radicals and preserving mitochondria

Atherosclerosis is increasingly seen as part auto-immune disease. Oxidized lipoproteins are misinterpreted by pattern-receptors, part of the innate immune system, as foreign invaders. Oxidized lipoproteins then provoke an intense inflammatory reaction. This inflammatory reaction is driven by Angiotensin I receptors and mediated by superoxide. Blocking angiotensin I receptors blocks this reaction.

In hypertension and atherosclerosis, we are dealing with extremely complex and interrelated pathogenesis with very many moving parts. Prevention of the disease process requires treatment on the molecular and cellular level and requires a package of drugs. Statins, metformin, aspirin all play a role in addition to rapamycin and angiotensin II inhibition.


Osteoporosis

According to current Geriatric theory, Osteoporosis is part of the "normal" aging process. According to the TOR hyperfunction theory of aging, Osteoporosis is caused by over-expression of TOR.

52 million individuals in U.S have low bone mass (9 million osteoporosis). 50% of women and 20% of men will have a fragility fracture (hips, vertebral bodies, wrists).

Bone has two types of cells, the Osteocyte and the Osteoclast. Osteocytes are long lived cells and comprise 90% of all bone cells. They keep bone healthy and make new bone. Osteoclasts are a kind of macrophage, they engulf stuff and they dissolve and break down bone. Osteoporosis is due to excessive bone reabsorption by osteoclasts. These cells operate under control of mTOR within the cell.

 Autophagy and Apoptosis are the two key terms. Apoptosis is self-destruction with loss of cell; autophagy is repair with preservation of cell.

One study in rats showed rapamycin reduced senile osteoporosis by activating osteocyte autophagy and preserving Osteocytes (mTOR reduces autophagy) and by decrease in apoptosis of Osteocytes and decrease in number of Osteoclasts.

Another study with Everolimus (equivalent to rapamycin) in rats showed a decrease of 60% in cancellous bone loss. This was by inhibition of osteoclasts. 

Both studies showed that rapamycin or a rapalog decrease osteoporosis by blocking mTOR and decreasing activity of osteoclasts and preservation of osteocytes by increasing autophagy. 

Benign Prostate Hyperplasia

Benign prostate hyperplasia (BPH) is the most common age-related disease in men. BPH affects 50% of men over 50 and 90% of men over 80. Prostate cancer is the most common cancer in men after skin cancer and the second leading cause of death after lung cancer. Men with BPH have increased risk of prostate cancer. Although BPH does not cause prostate cancer, the fact that both diseases are so common in the same age group suggests that both may have the same underlying basic etiology. In the section on caloric restriction I noted that the Okinawans on caloric restriction diet had 14%  incidence of prostate cancer compared to American men.

 Last May, after 4 months of my rapamycin based treatment, I suddenly realized I no longer had the strong urgency to pass urine in the middle of my 5 mile walk. Surprised, I began searching the internet. I found a 2015 paper by Blagosklonny entitled; "Rapatar a nanoformulation of rapamycin, decreases chemically-induced benign prostate hyperplasia in rats."

In the rat models, BPH was chemically induced in one group of rats by Testosterone and in the other by Prolactin. Prolactin is secreted by Pituitary gland and the prostate has prolactin receptors. While Testosterone levels decrease with age, Prolactin levels go up. Prolactin stimulates mTOR and rapamycin blocks mTOR. Prolactin caused hyperplasia and inflammation of lateral lobes. This action was blocked by rapamycin and normal histology was restored. Lateral lobes are most involved in BPH. Rapamycin also blocked changes caused by Testosterone. This study showed with a reasonable degree of medical certainty, that if you are a rat, rapamycin will prevent BPH.

"Paraphrasing the famous quote, 'Nothing in Biology Makes Sense Except in Light of Evolution, one can say that nothing in aging makes sense except in the light of TOR-driven quasi-programmed aging, a continuation of a developmental growth driven by a growth-promoting pathway."

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. 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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