COLORADO AGELESS INSTITUTE
Anti-aging strategies to optimize health and vigor
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HOW IS RAPAMYCIN USED IN AGE REVERSAL MEDICINE?
The mainstream medical community may view the use of Rapamycin in age reversal medicine as new, controversial, and unnecessary. Age reversal strategies are not commonly used in conventional medicine, given it doesn’t fit the disease management paradigm. Aging itself is considered a modifiable disease risk. Though intensely science-based, the anti-aging use of Rapamycin is based to a considerable degree upon animal studies, not human clinical studies. Rapamycin is a prescription drug approved by the FDA for a different indication and has been in clinical use for over twenty years. This review summarizes the re-purposing of this drug for its age-reversal effect. Therefore this is an “off-label” use, namely attempting to slow down aging at the cellular level. “Off-label use” means an FDA-approved drug is used in therapies and treatments for which the drug was not explicitly approved. As much as forty-six percent (46%) of certain classes of prescriptions commonly used by most physicians are for off-label use of FDA-approved drugs.
Human clinical trials have not proved weekly Rapamycin as the cornerstone of an anti-aging formula. There is no safety in having many physicians use a similar weekly Rapamycin treatment in patients over many years.
The premise underlying this proposed use of Rapamycin is that those who need or desire age reversal benefits now don’t have the luxury of waiting decades before definitive clinical trials are initiated, completed, evaluated, and the results incorporated into clinical practice.
WHAT IS THE HISTORY OF RAPAMYCIN?
Rapamycin (Sirolimus) was initially discovered in 1965 as an antifungal metabolite produced by Streptomyces hygroscopicus from a soil sample from Easter Island. In 1991, Rapamycin was found to stop growth in yeast and subsequently found to possess immunosuppressive and anti-proliferative properties in mammalian cells due to its ability to inhibit the primary cellular mechanism of growth named TOR (Target of Rapamycin). TOR has been conserved through two billion years of evolution. It is the command and control center of every cell on Earth, both plant and animal. Since the discovery of TOR, there has been an explosion in cellular medicine knowledge, thus allowing for potential disease modification and prevention interventions.
In 2006, a new theory of aging based on TOR-driven aging explained the dynamics of aging and how to slow aging with a clinically available prescription medication Rapamycin. The key concept is that TOR-driven aging is the same thing as diseases of aging. Addressing one affects the other.
TOR has been implicated in many aging processes, including cellular senescence, immunosenescence, cell stem dysregulation, reduced autophagy, mitochondrial dysfunction, and impaired protein homeostasis (proteostasis). Furthermore, Rapamycin’s inhibition of TOR has been shown to mitigate cell senescence, thus reducing the age-related loss of function. Mitigation then improves physiological function and extends longevity.
If an intervention extends life span, it must delay age-related diseases, which usually cause death (trauma being one exception). For example, caloric restriction (CR) delays all diseases of aging and extends life span by delaying disease onset via slowing down aging itself. CR does this by deactivating the nutrient-sensing pathway TOR. Rapamycin is essentially CR in a pill. They each target the same pathway, TOR.
Rapamycin is a potent inhibitor of antigen-induced proliferation of T cells, B cells, and antibody production at higher doses. Interest in sirolimus as immunosuppressive therapy in organ transplantation derives from its unique mechanism of action, unique side-effect profile, and ability to synergize with other immunosuppressive agents. This uniqueness leads to its use in preventing organ transplant rejection following FDA approval.
In 2006, the concept of aging due to cellular hyperfunction, epitomized by senescent cells, was recognized as a driving force in aging. So central to aging and age-related diseases are senescent cells that aging could be renamed “senescent cell disease.” Senescent cells were first described by Hayflick in 1961, initially referring to a cell that had reached its maximum number of divisions (40) and then could no longer divide due to the shortening of the telomeres or the coating at the ends of the chromosomes. However, the role of senescent cells in aging was not delineated until 2011. Someone recognized that senescent cells transform into senescent-associated secretory phenotype (SASP) or “Zombie cells” that not only accelerate aging but also infect surrounding cells to convert to SASPs via cell to cell communication (inflammatory cytokines).
Rapamycin has extended the lifespan by 10-30% of every living thing tested in the laboratory: yeast, worms, flies, and even middle-aged mice. Upregulated TOR causes TOR-driven aging, and TOR-driven aging causes age-related disease. The evidence suggests that inhibition of TOR with Rapamycin will impair TOR-driven aging and related age-related diseases, promoting longevity.
WHAT IS RAPAMYCIN'S MECHANISM OF ACTION (MOA)?
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Downregulate cellular TOR activity resulting in:
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The reduction of TOR-induced cell cycle arrest is the mechanism by which senescent cells form. Senescent cells accelerate the aging process, and reducing their formation will slow aging at the cellular level.
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The upregulation of autophagy (cellular regeneration) promotes longevity
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The reversal of mitochondrial dysfunction (improving cellular efficiency)
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The reversal of immunosenescence (reduce risk of infections and cancer)
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The maintenance of stem cell viability (promoting cellular and organ vitality)
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Acting as a senolytic, it induces posttranslational modifications of histones and DNA, changing phenotypic expression. Or stated differently, it reverses epigenetic aging, which results in a more youthful expression of one’s genetic code.
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Upregulating the p53 suppressor gene determines the cell growth cycle between cell division and cell growth cycle arrest, which triages the cell for either autophagy (rejuvenation) in the former or senescence in the latter. Epigenetic aging and associated p53 gene inhibition results in cell arrest and subsequent development of senescent cells. These, in turn, progress to Senescent Associated Secretory Phenotype (SASP), which accelerates aging in all tissues in which they reside.
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Generally, a programmed cell death cascade occurs after a cell’s life cycle, resulting in apoptosis and cell removal. Cell cycle arrest diverts the cell into senescence and ultimately a SASP or “Zombie” cell that won’t die and becomes a vehicle of accelerated aging.
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SASP is a TOR state, with proliferative cellular arrest, but is productive of pro-inflammatory cytokines that recruit neighboring cells to convert to senescence as well (thus the term “Zombie cell” as they “infect” neighboring cells to also become “Zombie” cells.)
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Suppress the progression of aging as shown by the Horvath epigenetic clock. The Horvath clock is a significant achievement in aging research. The Horvath DNA methylation epigenetic clock is an objective way to measure biological age independently of time.
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Rapamycin does not prevent the mutations and DNA damage that causes cancers. Rapamycin in the low dose used for anti-aging does not have a substantial direct effect on cancer cells. Rapamycin slows aging and slows the formation of senescent cells, thereby slowing the formation of the permissive environment, promoting cancer growth.
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To provide a scientifically based, modifiable, quantifiable corrective action plan to optimize the above issues risk-free.
BASED PRIMARILY ON ANIMAL STUDIES, WHAT ARE THE POTENTIAL BENEFITS?
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Slow down and reverse aging at the cellular level with the ultimate goal of increased longevity and reduced disease states
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Prevent age-related diseases including cancer, atherosclerosis, obesity, neurodegeneration, cardiomyopathy, arthritis, frailty, skin aging, and retinopathy
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Reverse epigenetic aging
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Reverse immunological senescence by reducing TOR, and senescent cell formation, thereby reducing susceptibility to infection and optimizing response to vaccination (i.e., flu, Covid-19)
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Often results in a “feeling of well being” and feeling “younger” (anecdotal human clinical experience)
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Optimize cellular metabolism, including reversing insulin resistance
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Weight loss, including visceral abdominal fat, due to the reduction in senescent cells. Obesity and especially visceral abdominal fat accelerate aging by promoting insulin resistance and senescent cell formation.
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Neuroprotective effects, particularly in the pre-disease stage:
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Improve cerebral blood flow, helps maintain neuronal connections, preserve hippocampal memory and learning
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Reverse the preconditions for the development of dementia by
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Reducing amyloid B deposition,
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Reducing pathogenic tau phosphorylation and abundance of misfolded tau species, including neurofibrillary tangles,
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Restoring cerebral blood flow and cerebrovascular density,
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Preserving blood-brain barrier integrity,
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Preventing human tau-induced neuronal loss, and improving cognitive function.
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WHAT ARE THE POTENTIAL SIDE EFFECTS AND CONTRAINDICATIONS?
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In transplant medicine, Rapamycin is dosed higher to be an immunosuppressant. At this dosage, it is pro-aging, shortens lifespan, and is not suitable for age reversal purposes.
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Rapamycin (called Everolimus or Rapamune) is dosed at 1 mg every 12 hours in transplant medicine. Given that the half-life of Everolimus is 30 hours, it is dosed every 0.4 half-lives resulting in a steady-state serum trough level of 4.8 mg. In age reversal medicine, it is dosed at 5 mg weekly (every 168 hours), which is every 5.6 half-lives, and the trough steady-state serum levels are 0.1 mg or 50 times lower than used in transplant medicine.
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There is no scientific evidence that low dose weekly or intermittently dosed Rapamycin, compared to high doses as used in transplant medicine, causes unacceptable side effects that would preclude its use in age reversal medicine. Side effects listed for Rapamycin dosed daily as an immunosuppressant are generally not seen when dosed weekly for age reversal intent. Those side effects include infections such as pneumonia, stomatitis, or mucositis (ulcers in the mouth and GI tract), fever, flu-like symptoms, muscle pains, diarrhea, constipation, nausea, vomiting, joint pain, rash, acne, headaches, dizziness, insomnia, vision changes, increase in urination, fatigue, palpitations, ankle swelling, increase in triglycerides or cholesterol.
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Studies on Rapamycin have shown an occasional increase in insulin resistance similar to caloric restriction associated with a decrease in IGF-1 and the associated increase in longevity. The increase reflects a metabolic bio-resilience to maintain serum blood sugar levels in low caloric states to maintain adequate brain function via a compensatory increase in insulin resistance. Therefore, this is not a concern in using Rapamycin at age reversal doses.
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Rapamycin increases the risk of Gout. Rapamycin decreases the innate immune system, one effect of which is to decrease the action of macrophages. Macrophages remove urate acid crystals which provoke gout attacks if they accumulate. Allopurinol can reduce uric acid and prevent Gout if you have Gout episodes while taking Rapamycin.
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Rapamycin should be held until any infection is completely eradicated.