Rapamycin

Many people are now aware that Rapamycin when used correctly could be their answer to slowing down ageing and living a better life in their retirement or working for longer without age related health conditions.

But if your here you most likely are already aware what Rapamycin can do for you.

The two Major influences on using Rapamycin treatment for anti-ageing have been Mikhail Blagosklonny and Dr Alan Green.

Mikhail has published a paper on how Rapamycin prolongs life span and Dr. Green has is own website and Practice in New York where he has many patients using Rapamycin.

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. 

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.

Why Add L-Taurine?

  • Taurine is the most abundant amino acid you’ve never heard of; it is found throughout the body, but especially in tissues containing excitable cells, like nerves and heart muscle.
  • Strong epidemiological evidence suggests that certain groups with the longest life spans consume higher amounts of taurine than those of us in the rest of the world.
  • Taurine supplementation can prevent diabetes and obesity in animal models, and can mitigate the effects of both conditions in humans.
  • Taurine supplementation strengthens heart muscle cells, extends their life spans, and protects them from damage, while reducing many of the factors that produce atherosclerosis and its deadly consequences.
  • Taurine protects retinal and inner ear cells from damage, normalizing the flow of calcium ions they require for proper function.
  • Evidence is growing for taurine’s role in preventing epileptic seizures and liver disease, two conditions that can be attributed to toxic effects on delicate tissue.
  • If you are interested in a longer, healthier, and more active life, consider supplementing with taurine.

Taurine is the most abundant amino acid you’ve never heard of. Strong evidence suggests that groups with the longest life spans consume higher amounts of taurine than those of us in the rest of the world. High intakes of taurine could be the underlying factor in the world’s longest-living populations—and for good reason.

Taurine supplementation can mitigate the damaging effects of fat, glucose, and excess insulin. Taurine strengthens and protects heart muscle cells and the system of blood vessels that supplies blood throughout the body, helping to protect against atherosclerosis, heart attacks, and strokes.

And taurine protects vision and hearing. It can prevent and alleviate seizures, and it has been shown to treat the most common cause of liver disease in the United States.

With epidemiological evidence that it contributes to the longevity of famously long-lived groups, taurine belongs on the short-list of supplements necessary for maintaining optimal health in the face of aging.

  • It increases the action of insulin, improving glucose tolerance, and acting as an antioxidant.
  • It is vital for the proper function of the minerals potassium, calcium, magnesium, and sodium.
  • Taurine regulates heart rhythm, cardiac contraction, blood pressure, and platelet aggregation, and regulates the excitability of neurons.
  • It detoxifies liver cells of various toxins.
  • It helps form bile acids and maintains cell membrane stability.
  • It reduces the synthesis of lipids and cholesterol that are associated with atherosclerosis.