Fighting the mTOR Syndrome - Rapamycin may delay aging, reduce disease, and increase lifespan

As progress in longevity science continues to accelerate, some researchers have started to investigate three innovative strategies that may be able to delay aging, reduce disease, and increase lifespan.

Rapamycin, mTOR, and Autophagy are at the forefront of the life extension revolution.

Key Points

Rapamycin’s ability to increase median life expectancy in animal models by up to 60% has fascinated the scientific community. The hope is that humans may gain significant improvements in health and increases in lifespan by taking Rapamycin.

In addition, a clinical trial in elderly adults 65 years and older revealed that a once-weekly dosing of everolimus (a rapamycin derivative with properties virtually the same as Rapamycin) strengthened their immune system, evaluated by their enhanced response to influenza vaccine of about 20%.² 

This study is critical because the immune system in all older adults has declined significantly compared to the immune function of healthy adults in their 20s and 30s. The ability of rapamycin-like drugs to enhance the immune system in elderly adults is a significant outcome.

Short read

Rapamycin, also known as sirolimus, is a drug that has various medical applications. It was initially discovered in the 1970s from a bacterium native to Easter Island named Streptomyces hygroscopicus. Critical uses and properties entail:

1. Immunosuppressant: Rapamycin is primarily used as an immunosuppressant. It's often prescribed to prevent organ rejection in transplant patients. Suppressing the immune system reduces the body's natural tendency to reject transplanted organs.

2. mTOR Inhibitor: The drug works by inhibiting the mammalian target of the rapamycin (mTOR) pathway, which is crucial for cell growth and proliferation. This mechanism is also why it's being studied for its potential in cancer treatment, as it can inhibit the growth of cancer cells.

3. Research in Aging and Longevity: Recent research has focused on Rapamycin's potential effects on aging and lifespan extension. Studies, particularly in animals, have shown that it might extend lifespan by delaying specific aging processes, though its effects in humans are still not fully understood.

4. Treatment of Certain Diseases: Besides organ transplantation and cancer, Rapamycin is also investigated for treating other conditions like autoimmune diseases and rare lung diseases like lymphangioleiomyomatosis.

5. Side Effects and Considerations: Like any medication, Rapamycin has side effects. These can include increased susceptibility to infection, elevated cholesterol and triglyceride levels, and other potential issues.

Long read

When rapamycin therapy was initiated in middle-aged mice, median increases in life expectancy of up to 60% were observed.³ 

When rapamycin therapy was initiated in elderly male and female mice that were roughly the equivalent of 60-year-old humans, female mice achieved a 14% increase in lifespan, and males achieved a 9% increase in lifespan.⁴ 

This may equate to an increase of more than seven years of human life.⁵

How does Rapamycin work?

Over the past 25 years, research into Rapamycin’s mechanism of action has discovered a new understanding of cellular biology and the aging process. This research claims that mTOR and Autophagy regulate all living organisms' health and aging processes.

Rapamycin inhibits mTOR and, by this, is supposed to activate the process of Autophagy, which may restore youthful metabolic functions. Research reveals that Rapamycin delays the onset of many age-related diseases that apply to human health.⁶

The mTOR/autophagy aspect may even be more important than Rapamycin itself. Understanding mTOR and Autophagy may ultimately reveal how we can delay the onset of age-related diseases and achieve significant increases in lifespan and healthspan.

 mTOR and Autophagy in detail

When calories are available to a cell, the protein mTOR sends signals that activate cellular metabolism, telling the cell to use the available calories to build new proteins, new enzymes, fat stores, and other cellular components. When mTOR is activated, it initiates anabolic (building) processes of cell growth and proliferation.

Autophagy is the process in which damaged proteins, excess fat, and other worn cellular components are broken down for reuse or elimination. Autophagy can be called the cellular housekeeping process or cellular trash removal. The problem is that chronically activated mTOR - caused, e.g., by relentless calorie ingestion precludes healthy Autophagy.

Why men are not made to eat all the time, and how we can correct this - mTOR Syndrome

Throughout 99.9% of mankind’s evolution, people did not eat three meals per day. However, these days, refrigeration and the widespread availability of processed and packaged foods have always made food readily available. Modern humans spend far more time eating compared to our ancient ancestors.

This results in constant over-activation of mTOR and insufficient functioning of Autophagy. This imbalance may be a significant contributing factor underlying today’s epidemic of health problems, such as cancer,⁷ obesity,⁸ and type II diabetes.⁹ Researchers have chosen to call this condition “mTOR Syndrome.”

Even aggressive fasting does not always induce meaningful reductions in body fat. Many individuals need additional support with compounds that induce beneficial Autophagy. 

Rapamycin is a leading candidate. By inhibiting mTOR, Rapamycin mimics calorie restriction and fasting.

Research indicates that Rapamycin may reduce fat mass and body weight, as seen in cell and animal studies.¹⁰ And favorable findings from pilot studies in older people have prompted formal clinical trials to evaluate the anti-aging effects of Rapamycin, including the ability to improve cardiac function¹¹ and reduce visceral adiposity.¹²

Clinical trials have not yet been completed to determine how effective Rapamycin might be as a drug to induce weight loss in humans.

Optimal dose

There may be up to 1,000 mTOR sites within each cell. When Rapamycin is taken, it enters cells and binds to some of the mTOR sites, which results in partial inhibition of mTOR. The degree of mTOR inhibition is dose-dependent. This is a critically important point. Some people may need higher doses of Rapamycin to optimize the effect on mTOR and Autophagy. One clinical trial is studying 5 mg and 10 mg weekly doses of Rapamycin and using imaging scans before and after to measure how much visceral fat may be reduced.¹²

Pioneering physicians are discovering that taking 5-6 mg of Rapamycin once weekly partially inhibits mTOR. This enables Autophagy to be expressed periodically, which provides a wide range of health benefits. When mTOR and Autophagy are optimally balanced, every cell in the body can experience detoxification, renewal, and revitalization. Everything begins to work better.

Taking Rapamycin for life extension is a new field of science, so studies have not been conducted to determine the best dosage and frequency. Many life extension enthusiasts are self-experimenting by taking 5-6 mg once weekly. Eventually, lab tests to determine plasma levels of Rapamycin will be readily available, which will help determine the best dose and frequency of taking Rapamycin for everyone.

At what age?

mTOR is a master regulator of the growth activities in cells. Childhood, adolescence, and even young adulthood are periods of rapid growth. Hence, it would be inappropriate to have young people taking Rapamycin. Although there is no agreed-upon age for people to start taking Rapamycin, people younger than 30 are generally not recommended to take it.

However, as the study of mice showed, the increase in life expectancy was more significant when Rapamycin was initiated in middle-aged mice. While results from ongoing human rapamycin studies are awaited, delays in suppressing excess mTOR and inducing Autophagy may diminish the longevity-enhancing benefits.

Are there natural ways that people can inhibit mTOR and increase the expression of Autophagy?

Autophagy is activated when calories are unavailable. Intermittent fasting and time-restricted eating refer to eating protocols in which all the daily food is consumed within a shorter period. One of the most popular versions is the 16:8 protocol, in which all the food is consumed within eight hours, say from noon to 8 p.m. This leaves 16 hours (from 8 p.m. until noon the following day) of fasting, which enables Autophagy to be activated.

Recent study

Results from a study by Dr. Vera Gorbunova, Co-Director of the Rochester Aging Research Center. Long-lived animals are known to have genes in common that negatively and positively affect lifespan. Dr. Gorbunova examined ten prominent life extension therapies in mice and assessed how each intervention affected the genes associated with maximum lifespan. The interventions evaluated were Rapamycin, 17-alpha-estradiol, pituitary-specific positive transcription Factor 1 (PiT1), growth hormone, rilmenidine, ascorbyl-palmitate, acarbose, calorie restriction, methionine restriction, and protandim.

Rapamycin had the most significant effect in reducing the activity of genes that harm maximum lifespan AND, Rapamycin also had the most significant effect in promoting the activity of genes that have a positive effect on maximum lifespan.

This study may provide some confirmation that Rapamycin is a candidate life-extension drug that is ushering in a revolution in life extension and healthy aging. It is still a bit too early for conclusions.

A book

Ross Pelton, Rapamycin, mTOR, Autophagy & Treating mTOR Syndrome. 

References

1. Available at: https://www.uptodate.com/contents/pharmacology-of-mammalian-mechanistic-target-of-rapamycin-mtor-inhibitors. Accessed March 14, 2022.

2. Mannick JB, Del Giudice G, Lattanzi M, et al. mTOR inhibition improves immune function in older people. Sci Transl Med. 2014 Dec 24;6(268):268ra179.

3. Bitto A, Ito TK, Pineda VV, et al. Transient rapamycin treatment can increase lifespan and healthspan in middle-aged mice. Elife. 2016 Aug 23;5:e16351.

4. Harrison DE, Strong R, Sharp ZD, et al. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature. 2009 Jul 16;460(7253):392-5.

5. Blagosklonny MV. Rapamycin for longevity: opinion article. Aging (Albany, NY). 2019 Oct 4;11(19):8048-67.

6. Selvarani R, Mohammed S, Richardson A. Effect of Rapamycin on aging and age-related diseases-past and future. Geroscience. 2021 Jun;43(3):1135-58.

7. Hua H, Kong Q, Zhang H, et al. Targeting mTOR for cancer therapy. J Hematol Oncol. 2019 Jul 5;12(1):71.

8. Yang SB, Tien AC, Boddupalli G, et al. Rapamycin ameliorates age-dependent obesity associated with increased mTOR signaling in hypothalamic POMC neurons. Neuron. 2012 Aug 9;75(3):425-36.

9. Yang L, Zhang Z, Wang D, et al. Targeting mTOR Signaling in Type 2 Diabetes Mellitus and Diabetes Complications. Curr Drug Targets. 2022 Jan 11.

10. Ro SH, Jang Y, Bae J, et al. Autophagy in Adipocyte Browning: Emerging Drug Target for Intervention in Obesity. Front Physiol. 2019;10:22.

11. Available at: https://clinicaltrials.gov/ct2/show/NCT04996719. It was accessed on March 15, 2022.

12. Available at: https://clinicaltrials.gov/ct2/show/NCT04488601. It was accessed on March 15, 2022.