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mTOR Driven Aging and Rapamycin

Target of Rapamycin or TOR Driven Aging – A New Theory of Aging and it’s Treatment with Rapamycin

Prof Blagosklonny, MD. PhD in 2006 wrote an article “Aging and immortality: quasi-programmed senescence and its pharmacologic inhibition” proposing a new theory of aging centered around the mammalian Target Of Rapamycin or mTOR discovered by Dr. Michael Hall in 1991.

In early life mTOR regulates in a highly programmed manor: cell growth, cell proliferation, cell motility, cell survival, protein synthesis, autophagy, transcription, and other functions.

Dr. Blagosklonny’s theory is that mTOR-driven aging is a continuation of the mTOR driven growth and development program, which has become an obsolete quasi-program causing hyperfunction and age-related disease by middle age.

He also suggests Rapamycin by inhibiting mTOR can slow down development of aging and age-related diseases such as atherosclerosis, hypertension and hyper-coagulation (thus, preventing myocardial infarction and stroke), osteoporosis, cancer, autoimmune diseases and arthritis, obesity, diabetes, macula-degeneration, Alzheimer's and Parkinson's diseases, and prolong lifespan.

Original article in which Prof Mikhail Blagosklonny, MD, PhD, explains his theory of mTOR driven aging:

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

Aging and immortality: quasi-programmed senescence and its pharmacologic inhibition.



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 (target of rapamycin) 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, hyper-function 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 diseases 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.

Discovery of mTOR

In 1991, Michael Hall while studying the control mechanism of growth in yeast discovers that the drug 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 the Target of Rapamycin or TOR.

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. The TOR cellular growth and proliferation control center is the same control center in all plant and animal cells.

Since the discovery of mTOR huge progress is being made in cellular biology and cellular medicine. Scientists have since discovered hundreds of proteins which are involved in cell signaling. Disease starts at the cellular level.

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 very advanced. The discovery of TOR and the extraordinary advances that followed are helping us to understand health and disease at the molecular level.

New Theory of Aging by Mikhail Blagosklonny, MD, PhD

Until the discovery of mTOR in 1991, it was impossible to understanding Aging.

In 2006 in "Aging and Immortality, Quasi-Programmed Senescence and Its Pharmacologic Inhibition", Dr. Blagosklonny explains the mTOR mechanism of aging and how to slow aging with the medication rapamycin.

Blagosklonny theory on mTOR-driven Aging

Aging is not programmed but rather a continuation of growth and development program that is not turned off. The term quasi-program in this case means the continuation of the developmental program that has no further biological purpose and can be harmful.

TOR or mTOR promotes growth of cells even when cell cycle (mitosis) is blocked. In this way TOR causes the production of Senescent cells or Senescence-Associated Secretory Phenotype cells or SASP.

Senescent cells are hyper functional and damage tissues and promote diseases of aging including Atherosclerosis, BPH, Cancer, Cardiomyopathy, Chronic Renal Disease, COPD, Diabetes, Fatty Liver, Hearing Loss, Hypertension, Macular Degeneration, Osteoarthritis, Parkinson’s Disease.

Aging presents as hyperfunction, hyperplasia, cell hypertrophy.

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 an unintended continuation of growth.

According to classic gerontology, non-repaired molecular damage causes aging. In contrast, TOR-driven aging causes damage (diseases of aging).

From the classic perspective, nothing can be done to inhibit aging. From the TOR perspective, the pharmacologic brake (rapamycin) will slow down human aging.

Article Abstract

Dr. Blagosklonny in 2019 in the article "Rapamycin for longevity: opinion article" makes the case for the use of rapamycin for prevention of age related diseases and antiaging.

From the dawn of civilization, humanity has dreamed of immortality. So why didn’t the discovery of the anti-aging properties of mTOR inhibitors change the world forever? I will discuss several reasons, including fear of the actual and fictional side effects of rapamycin, everolimus and other clinically-approved drugs, arguing that no real side effects preclude their use as anti-aging drugs today. Furthermore, the alternative to the reversible (and avoidable) side effects of rapamycin/everolimus are the irreversible (and inevitable) effects of aging: cancer, stroke, infarction, blindness and premature death. I will also discuss why it is more dangerous not to use anti-aging drugs than to use them and how rapamycin-based drug combinations have already been implemented for potential life extension in humans. If you read this article from the very beginning to its end, you may realize that the time is now.




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