RAPAMYCIN

Can you relate to the following questions?

Many of us have had these questions cross our minds. How do we prevent these types of things from happening? Are these the effects of the normal aging process? Many would argue that these complaints are indeed signs of aging. Are they reversible or treatable?

This last question will lead us to the topic of Rapamycin and mTor, and how to possibly fight back against the effects of aging.

Rapamycin is a natural antibiotic. It is also antifungal and immunosuppressant. mTor stands for “mechanistic target of rapamycin,” and it essentially causes cells to deteriorate and age. 

THE CONNECTION BETWEEN MTOR AND RAPAMYCIN

mTor regulates cell growth and proliferation.

Dr. David Sabatini describes mTOR like this: 

“Pretend your body is an old house. Your oldest cells have all sorts of problems and are implicated in your house falling apart. You couldn’t fully renovate the old house by bringing in only a plumber, or only an electrician, or a roofer, or a drywall guy, you’d need to hire a general contractor, who would hire all those specialists to come fix all those problems. Rapamycin essentially tricks the body into thinking that it’s in a state of calorie deprivation, which is what causes the general contractor to call in all the guys for renovation work. When that happens, the renovation focuses on your oldest and weakest cell parts, including aging cells.”

So, what’s the connection between Rapamycin and mTOR?

Rapamycin inhibits mTOR, which disrupts cell division and cell proliferation — in other words, it inhibits cells from aging. 

There could be benefits beyond anti-aging as well. Disease starts at a cellular level, so those renovated cells could have potentially become even become cancer or other diseases. Understanding a disease is understanding the cellular pathways that have gone bad. Most diseases can be seen as a failure to maintain balance at the cellular level. By the time a disease becomes known at the tissue and organ level, it is very advanced. If Rapamycin helps rejuvenate cells that could turn into disease, there’s a possibility that the bad parts  

RAPAMYCIN AND ANTI-AGING

One of the earliest researchers of Rapamycin, scientist Mikhail Blagosklonny identifies three major criteria for potential anti-aging drugs:

  1. It should prolong the life span in mammals.
  2. It should prevent or delay several age-related diseases in mammals.
  3. It should suppress the formation of aging and deteriorating cells.

Rapamycin in fact meets all three criteria with these benefits:

  • Rapamycin prolongs lifespan
  • Rapamycin prevents age-related diseases and improves cognitive function
  • Rapamycin slows production of aging and deteriorating cells
  • Rapamycin can improve declining immune function
  • Rapamycin can increase autophagy and decrease inflammation
  • Rapamycin slows the epigenetic clock
  • Rapamycin can mimic calorie restriction

Caloric restriction has been shown to delay all diseases of aging and extends life span. One may say that caloric restriction extends life span by delaying disease. Another may say that caloric restriction delays diseases by slowing down aging. Both interpretations are correct. Caloric restriction deactivates the nutrient-sensing pathway, know as TOR. Rapamycin is essentially calorie restriction in pill form. They each target the exact same pathway, TOR. Rapamycin has extended the lifespan of every living thing tested in the laboratory.

During everyday metabolism the cells in your body produce biochemical waste. Cellular components also become damaged over time. Your body naturally cleans up, either eliminating or recycling the waste. As an inhibitor of mTOR, it makes sense that rapamycin would increase autophagy. Cellular waste triggers inflammation, healthy autophagy removes waste and prevents or reduces inflammation. Rapamycin can alleviate system-wide inflammation the same way it improves cellular health, by inhibiting mTOR and promoting autophagy.  

A 2019 study showed that rapamycin induces both microautophagy and macroautophagy. This means that rapamycin is able to increase the recycling of damaged cell components (such as mitochondria) as well as recycle nutrients when fasting.

Studies also show that autophagy decreases as we age. This has been shown in brain aging, osteoarthritis and in declining immune system studies. These studies propose that if we can increase autophagy, it could be a strategy to combat aging and the diseases associated with it. Rapamycin may directly prevent cellular damage by inhibiting other substances that create a toxic environment and trigger aging. 

Evidence also suggests Rapamycin could be the next leading drug to prevent Alzheimer disease. It also prevents osteoarthritis, insulin resistance, metabolic syndrome, osteoporosis and age-related chronic lung disease.

In Mikhail Blagosklonny’s published studies from 2018, “Paradoxes of Senolytics” and “Does Rapamycin slow down time,” he states that “Rapamycin slows geroconversion by approximately 3-fold”. This means Rapamycin slows formation of aging and deteriorating cells, leading to an extended life span and delayed age-related diseases.

In Steve Horvath’s published study from 2019, “Rapamycin retards epigenetic aging of keratinocytes independently of its effects on replicative senescence, proliferation and differentiation,” he shows that Rapamycin suppresses the progression of aging as shown by the Horvath epigenetic clock. Rapamycin in fact reduced biologic aging of growing skin cells in culture. Rapamycin is now the first and only drug shown to slow epigenetic aging. 

BENEFITS OF RAPAMYCIN

Evidence in scientific literature suggests that Rapamycin slows aging, extends life span and delays and decreases the risk of a large number of age-related diseases. Additionally, Rapamycin offers the following:

  • May improve brain function
  • May decrease inflammation
  • Can improve cardiac function: less fatigue and shortness of breath with exercise 
  • May improve atherosclerosis 
  • May enhance muscle strength 
  • May contribute to youthful skin appearance
  • Can improve weight loss ability
  • Can improve declining immune function 
  • May improve kidney function
  • May decrease symptoms of osteoarthritis
  • Can improve prostate and urinary tract function 
RAPAMYCIN POTENTIAL SIDE EFFECTS

The most common side effects are mouth sores (similar to canker sores), increased blood lipids, impaired wound healing, gastrointestinal discomfort, and the potential for an increased risk of infection.

It is important to keep in mind that these side effects have largely been seen in patients who took a higher dose (20mg). The side effects are also dose-dependent and reversible. All side effects were reduced when the dose was reduced to 5 mg/week. 5mg was actually more effective at boosting an immune response. There were no serious adverse side effects from the treatment in human studies. Rapamycin is well tolerated as a monotherapy in elderly people. It should be fairly straightforward to establish a safe weekly dose.

Studies show that rapamycin can reduce both normal aging and Alzheimer’s like disease in preclinical models. Rapamycin is a U.S. Food and Drug Administration–approved drug with known dosing and side effect profiles. There are currently more than 2,000 clinical trials studying rapamycin around the world, nearly 1,000 of them in the United States. 

RESEARCH

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

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

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

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

E. Kraig, L. A. Linehan, H. Liang, T. Q. Romo, Q. Liu, Y. Wu, A. D. Benavides, T. J. Curiel, M. A. Javors, N.Musi, L. Chiodo, W. Koek, J. A. L. Gelfond, D. L. Kellogg Jr., A randomized control trial to establish the feasibility and safety of rapamycin treatment in an older human cohort: Immunological, physical performance, and cognitive effects. Exp. Gerontol. 105, 53–69 (2018)

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

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

Mikhail V Blagosklonny (2010) Calorie restriction: Decelerating mTOR- driven aging from cells to organisms (including humans), Cell Cycle, 9:4, 683-688, DOI: 10.4161/ cc.9.4.10766

Ki Wung Chung, Hae Yung Chung. The Effects of Calorie Restriction on Autophagy: Role on Aging Intervention. Nutrients 2019, 11(12), 2923; https://doi.org/10.3390/nu11122923

Walters HE, Cox LS. mTORC Inhibitors as Broad-Spectrum Therapeutics for Age-Related Diseases. Int J Mol Sci. 2018;19(8):2325. Published 2018 Aug 8. doi:10.3390/ijms19082325

OAN B. MANNICK, MELODY MORRIS, HANS-ULRICH P. HOCKEY, GUGLIELMO ROMA, MARTIN BEIBEL, KENNETH KULMATYCKI, MOLLIE WATKINS, TEA SHAVLAKADZE, WEIHUA ZHOU, DEAN QUINN, DAVID J. GLASS, LLOYD B. KLICKSTEIN. TORC1 inhibition enhances immune function and reduces infections in the elderly. SCIENCE TRANSLATIONAL MEDICINE. 11 JUL 2018

Archana Unnikrishnan, PhD, Kavitha Kurup, PhD, Adam B Salmon, PhD, Arlan Richardson, PhD. Is Rapamycin a Dietary Restriction Mimetic? The Journals of Gerontology: Series A, Volume 75, Issue 1, January 2020, Pages 4–13