TOR-Driven Aging and Rapamycin

"He not busy being born is busy dying"

"It's Alright Ma", Bob Dylan, 1965


The Blagosklonny theory of TOR-drive aging, [1] is that TOR driven aging is a continuation of TOR driven growth. In the older animal, cells can be blocked from being born [cell cycle, mitosis] and these cell then become senescent cells which promote aging and dying. TOR [Target-of-Rapamycin] was discovered  in 1991 and soon turned out to be one of the greatest discovery in the history of medicine. With the discovery of TOR, scientists had found the holy grail of cellular biology. 


 In an extraordinary leap of genius, Blagosklonny explained how the cell and the organism went from TOR-driven growth to TOR-driven aging. Furthermore, TOR driven aging was the same as TOR-driven age-related disease. All that was needed to slow down aging, slow down development of age-related disease and prolong health and life span was the pharmacologic inhibition of TOR and nobody had to wait for such a magical drug to be discovered; it was a generic drug in clinical practice since 1999 and available at your local drug store. 


All that is necessary to fully understand the Blagosklonny theory of how to slow down aging and prevent age-related disease is the ability look at aging  de novo, free from the barnacles of two thousand years of misconceptions. 


1. Blagosklonny, Aging and Immortality Quasi--Programmed Senescence and its Pharmacologic Inhibition, Cell Cycle. 2006 Sep;5(18):2087-102.



The dawn of the Age of TOR

In 1991, Michael Hall is studying the control mechanism of growth in yeast. He discovers that an obscure  anti-fungal agent called rapamycin can stop growth. Hall concludes that there is something in the yeast cell that is blocked by rapamycin. He calls that substance in the yeast cell, Target of Rapamycin or TOR. Michael Hall had just discovered the holy grail of cellular biology. 


The discovery of TOR in the yeast cell was made possible by the discovery of Rapamycin in the soil of mysterious Easter Island in 1965. Easter Island is primarily barren volcanic rock. Apparently, one strain of soil bacteria, eyeing the neighboring yeast one day, decided that the tiny island was just not big enough for both of them. The bacteria targeted the command and control center of the yeast cell which make the yeast stop growing. The bacteria had targeted what Michael Hall was to call TOR. 


TOR has been conserved through two billion years of evolution. It is the command and control center of every cell, both plant and animal on planet Earth. 


It did not take long for the leading scientists to figure out that what had been discovered was the key to understanding how the cell worked. They had the Control of the cell and they had the Key to the control. The 28 years since the discovery of TOR has ushered in a new Golden Age of discovery in the world of cellular biology and cellular medicine. Scientists have discovered hundred of proteins which are part of various signaling chains that instruct cells how to operate. This world within the cell is a world of extraordinary complexity. Prior to the discovery of TOR, the cell was a Black Box. Twenty eight years after discovery of TOR cell molecular pathways in both health and disease are well defined and better defined every day. For me, this definition of how the cell operates at the molecular level is bigger than everything that went before in 2000 years of medicine.


Disease starts at the cellular level. Understanding a disease is understanding the cellular pathways that have gone awry. Most disease can be seen as a failure to maintain homeostasis at the cellular level. By the time a disease becomes manifest at the tissue and organ level, it is a very advanced disease.


The discovery of TOR and the extraordinary advances that followed have  cracked the code of health and disease at the molecular level. 

Aging comes a cropper

From ancient Greece to Modern times, Aging had remained inscrutable and invincible; until now. Prior to the discovery of TOR in 1991, it was impossible to understanding Aging as TOR is at the center of aging. In 2006, 15 years after the discovery  of TOR, in the seminal paper "Aging and Immortality, Quasi-Programmed Senescence and Its Pharmacologic Inhibition", Mikhail Blagosklonny publishes one of the great original theories in science. It is a radical and entirely  new theory of aging. The paper not only explains the dynamics of aging; but also how to slow aging with a clinically available prescription medication.(1). 


The key concept is that aging is not an abstract thing; TOR-driven aging is the same thing as diseases of aging. The theory is reminiscent  of Einstein's E= MC squared. Aging and diseases of aging are the same matter. 


13 years after the "Aging and Immortality" paper I have a clinical medical practice, now with over 380 patients, using rapamycin to slowing aging in the exact same manner proposed in the 2006 Blagosklonny paper. 

Blagosklonny theory, TOR-driven Aging

The Blagosklonny theory of aging is presented in a large number of papers from 2006 through 2019. Many of these papers are summarized below under the heading "Blagosklonny Literature". In this section, I try to summarize the key concepts from the 2006 paper noted above and the 2009 paper: "TOR-driven aging, Speeding car without brakes." (2)

  1. Aging is not programmed.
  2. Aging is a continuation of growth and development program that is not turned off.  The term quasi-program just means the aimless continuation of the developmental program; but has no further biological purpose and can be harmful.
  3. TOR promotes growth of cells even when cell cycle (mitosis) is blocked. TOR causes the production of SENESCENT CELLS. 
  4. Senescent cells are hyperfunctional and damage tissues and promote diseases of aging.
  5. Aging presents as hyperfunction, hyperplasia, cell hypertrophy.
  6. By analogy, aging can be viewed as a speeding car that lacks brakes and can not slow down when the road requires going slowly and then crashes.
  7. The TOR growth pathway is universal from yeast and worms to humans and plants. TOR is activated by nutrients, Insulin, growth factors. TOR drives growth and aging is a unintended continuation of growth.
  8. "Like crashes at the end of the road, these diseases are late manifestations of aging. From the TOR perspective, death from aging and from diseases of aging has the same meaning, because diseases of aging are just manifestations of aging, like smoke is a manifestation of fire."
  9. According to classic gerontology, non-repaired molecular damage causes aging. In contrast, TOR-driven aging causes damage  (diseases of aging).
  10.  From the classic perspective, nothing can be done to inhibit aging. From the TOR perspective, the pharmacologic brake (rapamycin) will slow down human aging.


2. Blagosklonny, TOR-driven aging Speeding car without brakes, Cell Cycle. 2009 Dec 15;8(24):4055-9.


The Proof is in the Pudding

The following sections will move from theory to the laboratory proof:


  1. Rapamycin Prolongs Lifespan
  2. Rapamycin prevents age-related diseases.
  3. Rapamycin slows production of senescent cells and removal of senescent cells ameliorates disease. 
  4. Rapamycin slows the Epigenetic clock.

Rapamycin/TOR Anti-aging Medicine

image1

Rapamycin Prolongs Life Span

From Mikhail Blagosklonny:  


The three major criteria for potential anti-aging drugs are:

  1. A drug that prolongs life span in model organisms preferably mammals.
  2. A drug that prevents or delays several age-related diseases in mammals.
  3. A drug that suppresses cellular geroconversion from quiescence to senescent. [This statement means suppresses the formation of senescent cells. [3]


These criteria overlap each other. If an intervention extends life span, it must delay age-related diseases. Animals die from age-related diseases. For example, caloric restriction (CR) delays all diseases of aging and extends life span. One may say that CR extends life span by delaying disease. One may say that CR delays diseases by slowing down aging, Both interpretations are correct. CR deactivates the nutrient-sensing pathway, know as TOR (Target of Rapamycin). [2]


Rapamycin is essentially CR in a pill. They each target the exact same pathway, TOR.


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


From Matt Kaeberlein: "The drug rapamycin is currently the most effective and reproducible pharmacological approach for directly targeting the aging process to increase life span and health span in laboratory animals. Rapamycin positively impacts most hallmarks of aging and it has been shown to increase lifespan in each major invertebrate model organism and in rodents. Rapamycin increases life span by 10 to 30% in multiple strains of mice." [4] 


Blagosklonny and Kaeberlein are the two foremost experts on the theory and practice of rapamycin.


3. Blagosklonny,  From rapalogs to anti-aging formula, Oncotarget. 2017 May 30; 8(22): 35492–35507.

4. Kaeberlein, Rapamycin and Alzheimer's disease: Time for a clinical trial?,  Sci Transl Med. 2019 Jan 23;11(476).


Rapamycin Prevents Age-Related Disease

From Blagosklonny: "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 cardiomyopathy in rodents. Rapalogs prevent cancer in mice and humans. Rapamycin decreases obesity in mice and humans. As predicted, rapalogs rejuvenate immunity, improve immune response in mice and humans." [3]


From Kaeberlein: "Not only does rapamycin treatment increase life span but it also delays, or even reverses, nearly every age-related disease or decline in function in which tested in mice, rats and companion dogs, including cancer, cardiac dysfunction, kidney disease, obesity, cognitive decline, peridontal disease, macular degeneration, muscle loss, stem cell function, and immune senescence" [4]


The above statements regarding Life span extension and prevention of age-related disease might seem fanciful, overimaginative and unrealistic. However, the quotes come from a 2017 and a 2019 paper prepared by the worlds leading authorities. Furthermore, a review of these two papers will show multiple references to support and document each and every statement.


Not mentioned in above was a very large  body of evidence that rapamycin is the leading drug to prevent Alzheimer's disease. Alzheimer's disease is discussed in following section. 


Rapamycin also prevents insulin resistance, metabolic syndrome, osteoarthritis, osteoporosis and age related chronic lung disease.

Rapamycin Slows Formation of Senescent Cells

Criteria (3) above for potential anti-aging drug was suppressing formation of senescent cells.


In a 2018 paper Blagosklonny states, "It has been calculated than rapamycin slows geroconversion by approximately 3-fold".  This means rapamycin slows formation of senescent cells three-fold. [5]

The Blagosklony theory of aging is that aging is hyperfunctional. 


From Blagosklonny: "Killing senescent cells is beneficial because senescent cells are hyperfunctional. The hypersecretory phenotype or Senescence-Associated Secretory Pheontype (SASP) is the best known example of universal hyperfunction. Most hyperfunctions are tissue-specific. For example, senescent beta cells overproduce insulin and this activate TOR in hepatocytes, adipocytes, and other cells, causing their hyperfunction, which in turn leads to metabolic syndrome (obesity, hypertension, hyperlidemia, and hyperglycemia) and is also a risk factor for cancer. SASP, hyperinsulinemia, obesity, hypertension, hyperlipidemia and hyperglycemia are all examples of absolute hyperfunction (an increase in functionality)." [6]


"Killing senescent cells is beneficial because senescent cells are hyperfunctional." [6]


"Senolytics are drugs that extend life span and delay some age-related diseases by killing senescent cells. Targeting senescent  cells have been shown in animal models to prevent age-related pathologies such as emphysema, lung fibrosis, atherosclerosis, osteoporosis, osteoarthritis, renal disease, intervetebral disc pathology, hepatic steatosis (fatty liver)  and other age-related conditions." [6]


The above list of age-related disease shows why preventing the formation of senescent cells is so important. Senescent cells are extremely harmful and the harm causes by senescent cells can be lowered by preventing their formation in the first place (rapamycin) or killing senescent cells by drugs called senolytics.


These three sections show how rapamycin fulfills the criteria for potential anti-aging drugs.


Nothing in the entire universe of drugs comes close to rapamycin and other rapalogs in fulfilling these three criteria of potential anti-aging drugs.


5. Blagosklonny, Does rapamycin slow down time?, Oncotarget. 2018 Jul 13; 9(54): 30210–30212.

6. Blagosklonny, Paradoxes of senolytics,. Aging (Albany NY). 2018 Dec; 10(12): 4289–4293.


Aging is easily treatable

A recent paper by Blagosklonny has the provocative title: "Disease or not, aging is easily treatable". The first sentence is: "For decades, one of the most debated questions in gerontology was whether aging is a disease or the norm."(7)


In my opinion, this entire debate is obsolete, archaic and medieval. Galen, a philosopher in ancient Greece put forth the idea that aging was not a disease, because everybody got aging and therefore aging was natural. Galen also originated the miasma theory which held that diseases such as cholera and epidemics like the Black Death were due to "bad air." In the second half of 19th century the germ theory of infectious disease exploded Galen's miasma theory. It is also time for Galen's theory of aging to be consigned to the "ash heap of history" 


The answer provided by Blagosklonny is:   "It does not matter because aging is already treated using a combination of several clinically-available drugs, including rapamycin...For treatment purposes, aging is a deadly disease (or more generally, predisease), despite being a normal continuation of normal organismal growth. It must and, importantly, can be successfully treated thereby delaying classic age-related diseases such as cancer, cardiovascular and metabolic diseases, and neurodegeneration." (7)


In my practice, I have treated over 380 patients (Oct 2019) and the one question nobody ever asked was whether aging was a disease or was natural. 


Aging should be considered a "term of art".  In my practice aging can have TWO meanings: 

A. "Aging is the sum of all age-related disease."  This means aging is the sum of pre-disease and clinical disease.


 B. Aging is also used as being short for TOR-driven aging as in the title: "TOR -driven aging, Speeding car without brakes" (Blagosklonny, 2009 [2]


Aging mechanisms which is not TOR-driven aging is put in category "post aging syndrome.


Aging must be connected to pre-disease or clinical disease.  Aging is not an abstract concept. Aging is pathology.


"In pre-disease, abnormalities have not reached the arbitrary diagnostic criteria of the disease. So, aging consists of progression from  (pre)-pre-disease (early aging) to disease (late aging associated with functional decline). Aging is NOT a risk factor for these diseases, as aging consists of these diseases: aging and disease are inseparable. [7]


In this paper, Blagosklonny has a very instructive diagram: GROWTH-->AGING. Initially aging is Hyper-functions in the pre-pre-disease and the Pre-disease stages, then aging ends in loss of function and Death.

Caption: Relationship between aging and disease, "When growth is completed. growth-promoting pathways increase cellular and systemic functions and thus drive aging. This is a pre-pre-disease stage, slowly progressing to a pre-disease stage. Eventually, alterations reach clinical disease definitions, associated with organ damage, loss of function (functional decline), rapid deterioration and death."


NORMATIVE AGING

The concept of "normative aging" is where the Blagosklonny concept of aging  splits entirely from conventionally thinking. In conventional thinking normative changes, that which is the norm, is not a disease at all. In the Blagosklonny concept of aging, NORMATIVE AGING is the quintessential disease of aging. Unrelated humans share 99.5% genetic similarity. Therefore, it makes complete sense that something as fundamental as TOR-driven aging should effect everybody. Those changes that effect everybody are the bed rock of the disease. In an extremely important paper discussed below under the topic of normative brain aging; it was shown that rapamycin prevents deterioration of cognitive and vascular decline in the aging rat brain. That paper is the complete vindication of the concept of TOR-driven aging and prevention of pre-disease.


Healthspan. This term refers to the subclinical disease period. "In theory, a treatment that slows aging increases both healthspan (subclinical period) and lifespan. The goal of both anti-aging therapies and preventive medicine is to extend healthspan (by preventing disease), and thus extending total lifespan. 


Preventive Medicine vs Anti-aging medicine

The goal of preventive medicine is to present disease by treating pre-disease. This is the same goal as anti-aging medicine. The difference between classic preventive medicine and anti-aging medicine is the cornerstone of anti-aging medicine is slowing aging.


When you start with preventive medicine and add rapamycin to slow aging, you have transformed preventive medicine into anti-aging medicine.


Conclusion:  "Anti-aging drugs such as rapamycin delay age-relate diseases. In order to extend life span, an anti-aging drug must delay age-related  disease... 


"And this approach is actually being used now to treat aging at Alan Green's clinic in Little Neck, NY."(7)


7. Blagosklonny, Disease or not, aging is easily treatable, Aging (Albany NY). 2018 Nov; 10(11): 3067–3078..

Epigenetic Clock Shows Rapamycin Slows Aging

Recent paper by Steve Horvath shows rapamycin suppresses the progression of aging as shown by the Horvath epigenetic clock. (8)

The Horvath clock is a major achievement in aging research. The Horvath DNA methylation epigenetic clock is an objective way to measure biologic age independently of time. 


In this study Horvath showed that rapamycin reduced biologic aging of growing skin cells in culture. Rapamycin is now the first drug and so far the only drug shown to slow epigenetic aging.


Rapamycin reduced cellular proliferation rate, reduced somatic cell differentiation, REDUCED NUMBER OF SENESCENT CELLS and preserved proliferative capacity, however these specific effects were separate and distinct from slowing of the epigenetic clock. 


The paper concluded: "In summary, the observations above represent the first biologic connection  between epigenetic ageing and rapamycin. 

These results for human cells add to the evidence that extension of life, at least by rapamycin, is indeed accompanied by retardation of ageing.


These observations also suggest that the life-extending property of rapamycin may be a resultant of its multiple actions which include, but not necessarily limited to SUPPRESSION OF CELLULAR SENESCENCE AND EPIGENETIC AGING, WITH THE POSSIBILITY OF AUGMENTATION OF CELLULAR PROLIFERATION POTENTIAL." [8]


This paper is huge. Prior to this paper the evidence that Rapamycin slows aging was the indirect evidence of extension of mouse and other lifespans. 


This study is direct evidence on human cells of rapamycin slowing aging.


8. Horvath. Rapamycin retards epigenetic ageing of keratinocyts independently of its effects on replicative senescence, proliferation and differentiation, Aging (Albany NY). 2019 May 31; 11(10): 3238–3249.

Rapamycin/TOR Anti-aging Medicine

TOR has two components, TOR1 and TOR2. Rapamycin has only one action, it blocks TOR. TOR1 is very sensitive to a single dose of rapamycin and TOR2 is very resistant. Therefore, intermittent use as weekly rapamycin can be used to block TOR1 and not block TOR2. 

 

Rapamycin anti-aging preventive medicine is a combination of Anti-aging Medicine and Preventive Medicine as regards prevention of age-related disease.

Both seek to prevent disease and thus extend health span and prolong life span. Both treat pre-disease to prevent clinical disease. The difference is Preventive medicine uses classic methods to prevent specific age-related diseases. Anti-aging medicine seeks to slow down aging and thus delay all age-related disease. The cornerstone of slowing aging that this office uses is rapamycin. The target is TOR1. The basic concept is TOR1 is driving age-related disease.


The special expertise of this office is knowing how to use rapamycin to lower TOR1; but not lower TOR2


There are no published studies on how to use rapamycin to lower TOR1 and not TOR2 and get a satisfactory result. Knowing how to properly use rapamycin as an anti-aging drug is based upon experience and the art of medicine. 


At this time (Sept 2019), the office has been treating patients with intermittent rapamycin for over 2 1/2 years and has treated over 350 patients. I have also taken rapamycin myself for close to 4 years. 


The medical literature lists many side-effects from use of rapamycin. Many experts say that rapamycin has too many side-effects to be used for anti-aging medicine. It is true that rapamycin is a potent prescription drug and as is true for all prescription drugs; people who do not know what they are doing should not use or prescribe them. Rapamycin is not for the uninitiated or for those health care providers who lack sufficient expertise required to use rapamycin in a knowing manner. 


COME FOR THE FUTURE, STAY FOR THE PRESENT

The ever expanding evidence in the scientific literature is that rapamycin slows aging, extends life span and delays and decreases risk of a large number of age-related diseases.  


What is not clear from the literature is the effect in the present, not the future. Ameliorating pre-pre disease and pre-disease can have  a dramatic impact on quality of life in three to six month from onset of treatment. One of most noticeable effects is on the brain. Overall mood and feeling of well-being is frequently improved. 


  • Many patients report their brain is sharper, functions better, and processes information better. 
  • Cardiac symptoms of fatigue and shortness of breath with exercise may be significantly improved. This is especially evident if hike or jog or walking up hills.
  • Muscles stay strong. 
  • Skin looks younger.
  • Rapamycin is also the premier weight loss drug. One can get back to the waist size one had when they were twenty-something.
  • Chronic kidney disease improves. Stage 3 chronic kidney disease, as measured by GFR (glomerular filtration rate) can improve to stage 2 and stage 2 to normal.
  • Mild osteoarthritis can improve. 
  • Prostate lower urinary tract symptoms such as  urgency, frequency and nocturia are frequently improved. 


Rapamycin treatment is not about waiting till you are 100 years old and noting all the diseases you dodged; or about a clinical study that follows people for 10 years and does calculations about "Odds ratio" [OR]. 


For many of my patients, slowing aging is about feeling better now [in the present] with life span extension and disease prevention something in the distant future rapamycin provides to boot. 


However, not all patients have pre-clinical disease. Many have serious disease in the present. 


In basic science, rapamycin has emerged as the silver bullet for the treatment of a large number of age-related diseases. However, rapamycin is a generic drug. In the United States, we are not Communists and nobody is expected to spend millions of dollars on clinical studies for which they can not receive any monetary benefit. Therefore, no human clinical studies are anticipated for rapamycin. However, the basic science research suggests that rapamycin is the greatest new drug to emerge since Penicillin, some ninety years ago. This office seeks to accommodate those persons who seek protection from age-related disease in their own lifetime. For this purpose, this office relies heavily upon animal models and basic research.. The  premise underlying treatment is that those of us who need geroprotection now, would most likely be dead before appropriate 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 TOR driven aging and TOR driven 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. 


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


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 encouraged to download and study all references.


CAVEAT:  While I have been on weekly rapamycin for close to 4 years and I am very pleased with the results, and Mikhail Blagosklonny predicts rapamycin will become the standard of care in our lifetime for anti-aging protection; 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/ PREVENTIVE MEDICINE PROGRAM as regards age-related disease.  Furthermore, the majority of physicians do not believe  there is a common underlying cause for diseases of aging or that lowering TOR can prevent such disease.


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.  


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


Disease A:

  • Cancer
  • Atherosclerotic heart Disease
  • Age-associated Cardiomyopathy
  • Obesity
  • Fatty Liver Disease (NAFLD)
  • Osteoarthritis
  • Diabetes type 2, Insulin resistance
  • Hypertension
  • Hearing Loss


Disease B:

  • BPH (Benign prostatic hyperplasia)
  • Osteoporosis
  • Age-related Macular degeneration
  • COPD (Chronic lung disease)
  • Chronic renal disease


Neurodegeneration:

  • Alzheimer's disease (Prevention)
  • Parkinson's disease
  • Tauopathy


In the drop-down section the evidence is primarily from basic science and animal studies. 

Disease A has more evidence and studies than Disease B


APOE4 carriers should consult linked website Alzheimer-prevention.com

Cancer, ASHD, Brain Aging, Alzheimer's Disease

Slow Aging, Prevent Disease

The goal of Rapamycin Medicine is to slow aging, target pre-disease and thus prevent late disease. Here we will look at the 3 major age related diseases plus a condition called normative brain aging.  They are without doubt very different age-related diseases; however, they are all mTOR driven diseases and can be prevented with rapamycin. Of these four conditions; prevention of normative brain aging and cognitive decline may be the most compelling reason to use rapamycin. Even without rapamycin one might live to old age without cancer, atherosclerotc heart disease or Alzheimer's disease; but cognitive decline due to brain vascular deterioration is a "normative change"; so for some people, prevention of cognitive decline may be the most compelling reason for using rapamycin.

Cancer Prevention

"Prevention of cancer by inhibiting aging", 2008, Blagosklonny has an excellent discussion regarding (a) evidence that rapamycin prevents cancer and (b) the mechanism. (9)

A. Evidence rapamycin prevents cancer:

1. Retrospective-analysis of human data; de novo tumors: 

"Retrospective analysis in renal transplant patients has revealed that rapamycin (sirolimus) decreased the frequency of new tumors, [89-94]. In a multicenter study by Mathew at two years after renal transplant, patients receiving rapamycin as base therapy had no malignancies compared with 5% incidence among those receiving cyclosporine."

"In the study that involved 33,000 patients, the incidence rates of patients for any de novo malignancies were 0.6% with rapamycin (rapalogs) and 1.81% with cyclosporine/tacrolimus (not rapalog). There were no de novo solid tumors in patients receiving rapamycin. In contrast 1% of patients receiving cyclosporine had developed de novo solid tumors. Importantly, rapamycin decreased cancer incidence even without the withdrawal of cyclosporine. This indicates that rapamycin decreases cancer incidence."


Rapamycin prevents cancer in very many mouse studies.


Human study: In Phase II study breast cancer, rapalog plus Letrozole was better at preventing breast cancer recurrence than Letrozole alone. 


Caloric restriction, which acts through inhibition of TOR, known to reduce cancer incidence.


Metformin, which reduced TOR throught AMPK pathway, shown to reduce cancer incidence in diabetic patients.


"Cancer is Age-related disease:"

"The incidence of cancer is lowest at age 20 and then increases exponentially, doubling every eight years." "Cancer disproportionately strikes individuals of ages 65 and older. median ages of cancer patients at death for major tumors ranges from 71 to 77 years. median age prostate cancer  is 79 years."


"Why common cancer is an age-related disease:"

  1. Mutations accumulate with age.
  2. Aging, per se renders an organism cancer-prone as aging process promotes cancer. 


Tumor Regression in Young Animals:

In certain animal models, tumors preferentially grow in old animals. Hepatic tumor cells transplanted into liver of young animals regressed, while grow in old animals.

Tumor cells injected into lungs of old animals grow but not in young animals.


Latent versus Clinical Cancer:

"After age 50 years, both incidence and mortality rates from prostate cancer increase at a nearly exponential rate. Autopsy study data from many countries  demonstate that 15% to 30% of men older than 50 years have histological evidence of latent prostate cancer. The presence of latent cancer increases with age so that by age 80 approximately 60% to 70% of men have evidence of histological cancinoma at autopsy. Yet, wth similar incidence of histological cancer, clinical cancer is 10-20 times less frequent in Japan than in the USA and prostate cancer mortality is low in Japan." Thus prevention of cancer progression (from latent to clinical) is very important.


Senescent Stroma may Promote Cancer:

"Stromal cells affect cancer growth. In some experiments, cancer-associated stroma, but not normal stroma, promoted cancer growth. Carcinoma-associated fibroblast can direct tumor progression of and initiated prostate epithelial cell changes in the tissue milieu, such as those that accompany normal aging, may determine the ability of a genetically aberrant cell to produce a tumor."

"By altering the tissue microenviornment, senescent cells may contribute to the rise in cancer that occurs with age..senescent stromal cells can stimulate neighboring premalignant or dormant cells to form tumors. Senescent cells produce enzymes, growth factors and inflammatory cytokines. Human fibroblasts that have undergone senescence increase the growth of co-transplanted cancer cells in mice. These senescent cells seem to promote cancer growth both by direct mitogenic effects and by indirect effect via tissue damage. Senescent fibroblasts promote tumor growth. Stromal fibroblasts adjacent to human ovarian cancer cells are senescent. 

"Aging of stromal-derived human breast fibroblasts can contribute to breast cancer progression due to secretion cytokines including MMP...Senescent cells secrete MMP, which are major mediators of basement membranes degradation, angiogenesis, tumor invasion and metastasis. Thus senescent human fibroblasts increase the early growth of tumors via MMP secretion. Noteworthy, TOR induces MMP synthesis, which is inhibited by rapamycin. 


Summary:

Rapamycin does not prevent the mutations and DNA damage which causes cancers. Rapamycin in low dose used for anti-aging does not have a strong direct effect on cancer cells. Rapamycin slows aging. Slows the formation of senescent cells. Slows the formation of the permissive enviornment which promotes cancer growth.


Rapamycin prevents latent cancers from becoming clinical cancers. By slowing aging, rapamycin has a very powerful effect on delay of clinical cancer.


9. Blagosklonny, Prevention of cancer by inhibiting aging, Cancer Biol Ther. 2008 Oct;7(10):1520-4. Epub 2008 Oct 21.

Atherosclerotic Heart Disease

There is very large body of evidence that shows long-term caloric restriction is highly effective in reducing risk for atherosclerosis in humans. There also is abundance of evidence that caloric restriction works through reducing the TOR pathway. In heart transplant recipients rapamycin prevents coronary artery disease. In various animal models, rapamycin prevents progression of atherosclerosis. This section looks at the mechanism by which reducing the TOR pathway with rapamycin prevents atherosclerosis. 


In the paper "Prospective Treatment of Age-related diseases by slowing down Aging" (10) atherosclerosis is used as model for how TOR drives age-related diseases. 

Step 1: Cellular Geroconversion from resting cell to Senescent cell. "When cell cycle is blocked, active growth promoting pathways as TOR cause irreversible conversion to cellular senescence characterized by cellular hypertrophy, hyperfunction, hypersecretory and pro-inflammatory phenotype. Rapamycin decelerates or suppresses geroconversion. 


Atherosclerosis depends on hyperfunctions of local cells: endothelial cells, smooth muscle cells (SMCs)  and macrophages. The development of atherosclerotic plaque involves endothelial activation, hypertrophy and hyperpasia of SMCs, monocyte migration, macrophage activation, uptake of lipids by activated cells, accumulation of fat and formation of foam cells.  In one study rapamycin was shown to inhibit monocyte/macrophage migration and their accumulation in carotid lesions in cholesterol fed rabbits. (10)


The best study to demonstrate the mechanism of atherosclerosis is:

Senescent intimal foam cells are deleterious at all stages of atherosclerosis". (11) 

In this study they demonstrated that atherosclerotic lesions contain senescent cells. They identified 3 types of senescent cells:

a. Macrophage/monocytes

b. Endothelial cells

c. Vascular smooth muscle cells.


In early lesions senescent foamy macophages accumulate in the subendothelial space at the onset of atherosclerosis, where they drive pathology by increasing the expression of key atherogenic and inflammatory cytokines and chemokines.

In advanced lesions, senescent cells promote features of plaque instability, including elastic fiber degradation and fibrous cap thinning, by heightening metalloprotease (MMP) production. 


"Together, these results demonstrate that senescent cells are key drivers of atheroma formation and maturation."


Fig 1: Senescent cells drive formation of atherosclerotic plaque.

Fig 2: Intimal senescent foamy macrophages form during early atherogenesis and foster production of proatherogenic factors.

Fig 3: Removal senescent cells reverses proatherogenic microenvironment

Fig 4: Senescent cells promote plaque instability by elevating metalloprotease (MMP)  production.


"Advanced plaques contain three distinct senescent cell types that not only drive lesion maturation through inflammation and monocyte chemotaxis but also promote extracellular matrix degradation. Clearing senescent cells from lesion inhibits both plaque growth and maladaptive plaque remodeling processes associated with plaque rupture, including fibrous cap thinning and elastic fiber degeneration. Furthermore, senescent cells in lesions show heightened expression of key SASP factors and effectors of inflammation. These data suggest that senescent cells can directly influence core proatherogenic processes through specific secreted factors."(11)


This paper directly shows the key role of senescent cells in the pathogenesis of atherosclerosis. At this point in time, senolytics to remove these senescent cells are slowly becoming clinically available. Rapamycin decreases the production three fold of all types of senescent cells  by inhibiting TOR. 


10. Blagosklonny, Prospective Treatment of Age-Related Diseases by Slowing Aging. Am J Pathol. 2012 Oct;181(4):1142-6..

11. Childs, Senescent intimal foam cells are deleterious at all stages of atherosclerosis. Science. 2016 Oct 28;354(6311):472-477.

Prevention of Normative Brain Aging

Normative brain aging refers to the mental decline which is considered the norm for older persons. This includes cognitive decline, impairment of memory and leaning ability; not quite dementia; just becoming a little bit stupid. An extraordianary study published November 2019, by the Veronica Galvan group in San Antonio, Texas, shows rapamycin has the extraordinary ability to prevent this normative brain aging in elderly rats. Rats started at 19 months (equivalent to middle age) and maintained on low dose rapamycin to 34-months old (maximum age for rats) were free of any evidence of age-related vascular deterioration and were as "smart" as 16 month old adult rats as regards memory and learning ability. 

Results:

1. Rapamycin restores cortical microvascular density. Untreated old rats had reduced microvascular density in cortex and hippocampus. Rapamycin treated 34 month old rats had microvascular density indistinguishable from young 16 month old mice. 

2. Rapamycin restores cerebral blood flow. The old rats had decreased cerebral blood flow that was global, cortical and hippocampal. The rapamycin treated 34 month old rats had blood flow same as 16 month old rats.

3. Rapamycin prevents loss of pre-synaptic density. Presynaptic density is a measure of neuronal integrity. It is required for learning and memory.

4. Rapamycin preserves functional hyperemia.  When area of brain is stimulated to perform specific function, that area lights up with increased blood supply. This is a complex mechanism called neurovascular coupling. This is lost during aging; but preserved in old rats on rapamycin.

5. Rapamycin preserves hippocampal learning and memory. The net result of all the above is loss of learning abilty and memory in old rats; however, this was preserved to levels indistinguishable from young rats in rapamycin treated 34 month old rats. 


Cerebrovascular dysfunction and cognitive decline are highly prevalent and considered the norm in aging. This study showed these changes can be prevented with low dose rapamycin. This is of extreme importance in and of itself. However, these vascular changes are the precursors for dementia and can be considered the early pre-disease state of Alzheimer's disease. 


12. Van Skike, mTOR drives cerebrovascular, synaptic, and cognitive dysfunction in normative aging, Aging Cell. 2019, Nov 6.  

Alzheimer's Disease

In 2019, there was a very excellent paper by Matt Kaeberlein and Veronica Galvan. (4) Matt Kaeberlein was noted above and Veronica Galvan is one of the world's leading research scientists in prevention of Alzheimer's disease (AD) with rapamycin. In 2010, she was first to demonstrate that rapamycin could prevent AD in a transgenetic mouse model of AD. The paper includes one paragraph which summarized the body of research of the past 10 years regarding rapamycin and prevention of AD. I suggest that anybody interested in this topic download this open access paper and review references 13-24.


"In addition to its robust effects at attenuation normative aging, rapamycin has also been shown to have beneficial effects in several different mouse models of AD that exhibit amyloidosis alone, or amyloidosis plus tauopathy, or primary tauopathy. Indeed, the breath and depth of positive preclinical data for rapamycin are perhaps greater than for any other potential AD therapy at this time. Such beneficial effects of rapamycin include:

  1. Reducing amyloid B deposition,
  2. Reducing pathogenic tau phosphorylation and abundance of misfolded tau species including neurofibrillary tangles,
  3. Restoring cerebral blood flow and cerebrovascular density,
  4. Preserving blood-brain barrier integrity,
  5. Preventing human tau-induced neuronal loss, and
  6. Improving cognitive function.


Beneficial outcomes have been seen in several different mouse models of AD including:

a. 3X transgenic mice [3 human AD genes]

b. P3015 mice

c. hAPP mice

d. transgenic 2576 mice

e. APP/PS1 mice

f. ApoE4 transgenic mice [Mice with human ApoE4 gene]

g. A viral vector-based mouse model of AD in which tau P301L is expressed in layer II of the lateral entorhinal cortex of the mouse brain.


Improvement after rapamycin treatment have been observed in these animal models when initiated either before the onset of disease symptoms or after symptoms and pathology are already present.

In addition to studies with rapamycin, genetic inhibition of mTOR rescued memory deficits, improved cognitive function and decreased tau and AB deposits.

The rapamycin derivative temsirolimus also improved special learning and memory and prevented apoptosis [cell death] in the hippocampus of AD mouse models."


This extraordinary paragraph summarized 10 years of very compelling evidence.


Everybody has the ApoE gene. 20% of persons have the ApoE4 allele, while 75% have ApoE3. 


The ApoE4 allele increased the risk of AD 3 fold and lowers the median age of onset from 85 for non-ApoE4 carriers to to age 75 for those with 1 E4 allele. I suggest that anybody with a family history of AD, especially if onset 80 years or younger have genetic testing for presence of ApoE4 allele. (23&Me does test)


My linked website, www.Alzheimer-prevention.com is directed at ApoE4 carriers who need protection against risk of AD.


My opinion, based upon the very extensive literature, is that rapamycin will provide excellent protection for both ApoE4 carriers and non-carriers prior to the onset of symptoms (the pre-disease stage).


The above paper suggests rapamycin treatment for early onset AD diagnosed as MCI (mild cognitive impairment stage).(4)


As is true for almost all the age-related diseases, rapamycin is best for pre-disease. However, for persons with onset of AD in the MCI stage; rapamycin is best hope to stop or slow progression.

The Usual Suspects, MMP

In the discussion of the above three disease there are the usual suspects. The main suspect is senescent cells. However, a particular enzyme keeps appearing as one of the usual suspects. This is Matrix metalloprotinase (MMP), which is an enzyme that breaks down proteins such as collagen which are usually found in the spaces between cells.  TOR increases MMP and rapamycin blocks the production of MMP.


In cancer MMP degrades the basement membranes and promotes tumor invasion. 


In ASHD, MMP destroys the collagen support for the fibrous cap which causes the plaque to become unstable, break down, bleed and result in occlusion of blood vessel and myocardial infarction.  


In Alzheimer's disease, MMP breaks down the blood brain barrier and causes damage to the cerebral microcirculation; a critical early step in pathogenesis of AD.


These are very different diseases; but at the cellular and molecular level; you find the usual suspects.  

Bacterial Infections (FEVER) Require Antibiotics

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.


The most serious infection is PNEUMONIA. Any onset of fever (100.0)  should be aggressively treated with antibiotics. If had a "cold" followed by fever, treat with antibiotics. If fever persists go to E.R. for possible pneumonia. 

The mTOR and Alcohol Connection

It is widely know that moderate alcohol drinkers live longer that teetolers. However, the mechanism was not understood until revealed by David Foster. Alcohol is involved with the mTOR pathway. mTOR, raptor and phosphatidic acid (PA) are combined to build mTORC1 while mTOR, rictor and phosphatidic acid (PA) are combined to build mTORC2. 


Alcohol interacts with PA and reduces its availability.

 

The net results is a small amount of alcohol lowers mTOR1; while a large amount of alcohol lowers both mTOR1 and mTOR2.


For this reason, moderate alcohol consumption has an anti-aging health benefit; but heavy alcohol consumption has negative health consequences. 


Alcohol is far from an ideal anti-aging drug because the safety margin between good and bad effects is fairly narrow. However, for people who do drink, it is good to be aware that moderate drinking may lower mTOR1 and be good; but too much will lower mTOR2 and be harmful.


The health benefits of moderate alcohol consumption of reduced cancer risk, reduced risk of cardiovascular disease and reduced mortality is through reduced mTORC1.

 

Foster, DA ,"Reduced mortality and moderate alcohol consumption: The phospholipase mTOR connection. Cell Cycle. 2010 Apr 1;9(7):1291-4.


Rapamycin and Gout

Rapamycin increases the risk of Gout. Rapamycin decreases innate immune system. One effect of this is to decrease the action of macrophages. Macrophages remove urate acid crystals which provoke gout attacks. Allopuriinol can be used to reduce Uric acid and prevent Gout if have episodes of Gout while taking rapamycin.

My Story, January 2016

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 pesky 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.


Update, January 2018

 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.  


Update, August 2019

I recently had a cardiology evaluation with an echocardiogram. I discovered,  much to my great surprise, that I was NOT suffering from "aging" in 2015 when had marked failing health. I was suffering from heart failure due to a very serious inherited autosomal dominant CARDIOMYOPATHY, specifically "apical hypertrophic cardiomyopathy". If I had seen a cardiologist I would have been told that there was no treatment except a heart transplant when I reach end stage heart failure.  While my diagnosis was wrong, the treatment was right. I had an excellent clinical response with rapamycin as described above. At my current age of 76, 6 years after onset of first symptoms and after 3 1/2 years of rapamycin weekly treatment, I am doing very well. I feel great, walk 5 miles a day, weigh 145 pounds and feel totally asymptomatic. Technically, I was not treating aging; but rather unknowingly treating a very specific genetic disease. However, although, the heart condition was inherited, elevated TOR played a major role in progression of the disease and lowering TOR provided excellent symptomatic improvement.   


 But aging is driven by TOR and the hypertrophic cardiomyopathy also appears to be driven by TOR. Although I clearly had the genetic disorder all my life, it presented as a pre-disease at age 55 with atrial fibrillation and 18 years later at age 73 with early heart failure.   


Whether I was suffering from an inherited disease or an age-related disease or an inherited disease that presents with aging may be a distinction without a difference.


The one thing I am rather sure about is that without Mikhail Blagosklonny and rapamycin, I would probably not be alive today.


Update, November 2019

Tried Dasatinib and Quercetin, 100 mg Dasatinib and 1000 mg of Quercetin daily  for 3 days. My impression is side-effects were similar to a flu shot and quite mild. Cost of treatment was $30.00. Datasinib obtained with prescription sent to a Kentucky compounding pharmacy. 

Blagosklonny Literature

Quasi-Programmed Senescence

My prediction is 50 years from today, the Blagosklonny theory of TOR-driven aging  will form the foundation of primary medical care for older person, the prevention of age-related disease. I consider these to be the major papers. 


"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.


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."

Koschei the immortal and the anti-aging drugs

In this classic paper, Blagosklonny first presents the idea of an anti-aging formula. This formula was expanded in the 2017 paper discussed below and forms the basis of the treatment plan used by this office.

The paper has excellent discussion of How Rapamycin Prevents Obesity

1. Rapamycin increases lipolysis, releasing fatty acids from fat tissue.

2. Rapamycin prevents entry of lipoproteins into the tissues.

3. Rapamycin decreases insulin secretion, therefore, preventing insulin-induced obesity.

4. Rapamycin prevents adipocyte differentiation.


Prevention of cancer by inhibiting Aging. This paper is discussed above.


TOR-centric view on insulin resistance and diabetic complications: perspective for endocrinologists and gerontologists.

This paper presents a radical new concept for understanding diabetic complications such as blindness, cardiovascular disease, kidney disease.

Glucose and insulin activate the mTOR pathway.

Overactivation of mTOR pathway causes insulin resistance.

mTOR is involved in diabetic complications.

mTOR is involved in aging and age-related disease.


This paper forms the basis of one of main tenets of anti-aging medicine: the promotion of insulin sensitivity which then lowers mTOR.



“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."


"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."


 "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. 


In this paper, Blagosklonny discusses, "Post-Aging syndrome". This is idea that today most people die from TOR-driven aging; but when TOR-driven aging is defeated, many new causes of death from aging will be revealed.

"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. 
  3. Rapalogs prevent cancer in mice and humans. 
  4. Rapamycin decreases obesity in mice and humans. 
  5. Rapalogs rejunenate immunity, improve immune response in aging mice and humans. 
  6. Rapalogs  suppress cellular geroconversion from quiescence to senescence.
  7. 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."


1. Aging and Immortality, 2006 (above Ref 1)

2. TOR-driven aging, Speeding car without brakes (above Ref 2)

3. Koschei the immortal and anti-aging formula

4. Prevention of cancer by inhibiting aging  (above Ref 9)

5. TOR-centric view of insulin resistance and diabetic complications

6. Prospectve Treatment of Age-related Diseases by Slowing Down Aging (above Ref 10)

7. Rejuvenating immunity: "anti-aging today" eight years later

8. From rapalogs to anti-aging formula  (above Ref 3)

2018 Papers:

9. Disease of not, aging is easily treatable (above Ref 7)

10. Does rapamycin slow down time? (above Ref 5)

11. Paradoxes of senolytics (above Ref 6)

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

image2

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 lose 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."

Toxins In Our Foods (A.G.E.s)

Introduction to A.G.E.s

Toxins in our most common and most loved foods, called Advanced Glycation End Products, acronyn A.G.E.s, have emerged in the past 20 years as something of great importance. However, A.G.E.s and their dangers and origins remain unknown to most health care professionals and most people. These toxins are not directly related to mTOR or treatment with rapamycin. They are toxins that work downstream to action of mTOR and rapamycin. The connection is Preventive Medicine. For people taking rapamycin to try to maintain good health; it does not seem like a good idea to be simultaneously poisoned by high levels of toxins in our diet. Especially, since these toxins can be reduced to safe level with no  cost, no risk, no caloric restriction, no  medication. All that is required is information about the risk and a practical guide showing how to lower A.G.E.s. in our diet.

How It All Began

Dr. Helen Vlassara arrived at Rockerfeller University, a leading world center for medical research in NYC, in the summer of 1974 as a newly minted medical school graduate. Over the next 20 years her group studied diabetes. Over the next 20 years her group became more and more impressed with the role of A.G.E.s in the pathogenesis of all diabetic complications, including those involving the eye, brain, heart, kidney, nerves, circulatory system. They noted that diabetes resembled accelerated aging. They considered A.G.E.s a strictly endogenous problem, produced in the body.


A.G.E.s had been described by a French chemist Louis Maillard in 1912 as a complex chemical reaction between amino acids and sugars during cooking. They were then called "browning products" for the brown color they gave food as oven-baked bread. Everybody is very well acquainted with these brown substances as they impart the enticing aroma, flavor and taste to our favorite foods, including roast chicken, grilled steak, fried bacon, pizza from the oven and grilled burgers and fries. 

"Look at all those A.G.E.s !!"

Until 1995 it was assumed that there was no connection between the delicious A.G.E.s in foods and the very bad A.G.E.s causing havoc in the body of diabetics. One day in 1995, Dr. Vlassara was the guest speaker at an international diabetes conference and was attending a spectacular  banquet reception. As she looked out at the stunning display of food she exclaimed, "Look at all  those A.G.E.s at a diabetes event !". Her colleague responded, "Why not, We don't absorb A.G.E.s from food." 

However, by this time, Dr. Vlassara's lab had the newly developed the technical ability to measure A.G.E.s in blood. The next day the colleague cooked up a delicious meringue of egg whites and table sugar, loaded with A.G.E.s. The colleague gave a blood sample before and after eating the meringue. The results showed the the A.G.E.s in his blood skyrocketed within minutes after he ate the meal. Two years later they published the ground breaking paper; "Orally absorbed reactive glycation products (glycotoxins): an enviornmental risk factor in diabetic nephropathy", Koschinsky...Vlassara, 1997. 


The science of the toxic effect of A.G.E.s in foods was off and running.  

Firsthand look

Dr. Vlassara was at the center and leading researcher in the development of this story. She has published over a hundred scientific papers. In 2017, she published an excellent book on this subject; Dr. Vlassara A.G.E Less Diet. The book is highly authoritative and gives a first hand account of how field developed

Toxin in Our Foods

Most of the A.G.E.s in the body come from our diet, in particular, a relatively small number of very high A.G.E. foods. The toxins are produced by exposing animal products, meat, fish, dairy, to high dry heat as in broiling, grilling, frying and baking. The average NYC diet has 16,000 KU quantity of A.G.E.s. The body can handle about 5000-8000 A.G.E.s. Most people consume 2-3 times more A.G.E.s than their body can handle. The kidneys remove the A.G.E.s and when kidney function decreases with age and disease, the ability to handle A.G.E.s becomes much less. Excess A.G.E. accumulate in the body and cause havoc. The following sections will discuss the havoc caused by an excess of these toxins.

Caloric Restriction Is Not Caloric Restriction

Feeding mice 40% less standard mouse chow is called 40% caloric restriction.  Standard mouse chow is commercially heat processed for longer shelf life and is very high in AGEs. Mouse chow provides mice with a higher relative AGE diet than typical standard Western diet. Therefore,  feeding mice 40% less standard mouse chow is 40% less AGEs  PLUS 40 percent less calories. As will see in later discussion, feeding mice same amount of chow with same calories; but with AGEs reduced 40% results in substantial improvement in lifespan and health span. In many studies, what is called 40% caloric restriction has superior results to oral rapamycin. In my opinion, the superior results of 40% caloric restriction over oral rapamycin is the combined synergistic effect of reduction in both AGEs and a separate effect from reduction in calories. It is also my opinion, that the combination of oral rapamycin combined with substantial reduction in AGEs can achieve all the benefits of caloric restriction.

CAVEAT

The theory and praxis of my system is not CONVENTIIONAL MEDICINE and it is NOT based upon accepted STANDARD OF CARE. It is based upon the theory of mTOR driven aging first presented by Mikhail Blagosklonny in 2006 paper cited above. While the practice is intensely science -based; it is based to a very large degree upon animal studies; not human clinical studies. Almost all treatments are prescription generic drugs which have been in clinical use for twenty years or more; but the drugs are re-purposed for anti-aging. This is "off-label" medicine. Furthermore, the very thing this office purports to treat, TOR-DRIVEN AGING, is not recognized as a disease by conventional medicine.


  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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Rapamycin-Based Prevention of Diseases of Aging

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Treatment is off-label and experimental and not covered by insurance or 3rd party payors.


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