Ask the Author: Rapamycin’s Role in Fighting Aging

Some of the most promising advances in anti-aging science involve the drug rapamycin and its effects on a cellular protein called mTOR and the process of autophagy, or "cellular housekeeping."¹

In this interview, Life Extension discusses the latest research with pharmacist Ross Pelton, who recently published the second edition of his book, Rapamycin, mTOR, Autophagy & Treating mTOR Syndrome.

Life Extension: Can you explain what mTOR and autophagy are?

Ross Pelton: mTOR and autophagy are the yin and yang of cellular metabolism. mTOR is a protein that initiates growth signals in cells when nutrients are available. When nutrients are not available, autophagy is activated. Autophagy breaks down and removes old or damaged cellular components, which is critical for rebuilding and renewal of the body.^1,2

LE: In the new edition of your book, you propose the mTOR/Autophagy Theory of Aging. What is that?

Pelton: For millions of years of human evolution, the mTOR/autophagy ratio was about 1:4. That means mTOR was activated approximately 20% of the time while autophagy was activated about 80% of the time.

These days, the ratio is reversed. Most people have mTOR activated about 80% each day and only about 20% autophagy. This reversal is largely due to drastic changes in the amount of time modern humans spend consuming calories every day compared to our ancestors.

This mTOR/autophagy imbalance is associated with common diseases including cancer, Alzheimer's and Parkinson's diseases, obesity and diabetes, and cardiovascular disease.3 Recent studies confirm that under-activation of autophagy is a fundamental cause of metabolic dysfunction and accelerated biological aging.⁴

LE: How can we correct the under-activation of autophagy?

Pelton: Rapamycin is a drug approved by the FDA to treat some cancers and prevent organ transplant rejection.⁵  Its ability to activate autophagy is a major aspect of its ability to increase healthspan and lifespan.⁶

LE: Are there specific conditions rapamycin can help prevent?

Pelton: I wrote a chapter in the second edition of my book on sarcopenia, the loss of muscle mass and strength in older adults. Sarcopenia results in loss of function and greater risk of falls, fractures, hospitalizations, and death. Three interventions that have been shown to delay the onset of sarcopenia are strength training, dietary protein, and rapamycin.

Strength training helps build muscle mass and delay the onset of physical disability.⁷ Dietary protein is required for muscle protein synthesis. By activating autophagy, rapamycin clears out old, damaged proteins, setting the stage for new muscle protein synthesis when mTOR is reactivated.

LE: Does rapamycin have other anti-aging benefits?

Pelton: A paper published in 2021 documented that rapamycin reduces translation errors in protein synthesis. Increased fidelity of protein synthesis extends lifespan in several animal models. This represents another way rapamycin improves health and extends lifespan, independent of its effect on mTOR and autophagy.⁶

LE: Is there additional evidence supporting the use of rapamycin to extend lifespan?

Pelton: I reported on a study conducted by Vera Gorbunova, PhD, co-director of the Rochester Aging Research Center. Her research focuses on the genomes of exceptionally long-lived mammals, which have many genes in common that affect lifespan.⁸

Dr. Gorbunova examined 10 prominent life extension therapies in mice and assessed how each affected the genes associated with maximum lifespan.⁹

Of the 10, rapamycin had the greatest effect on activation of genes associated with maximum lifespan. It also had the lowest effect on activation of genes that negatively affect lifespan.

This study provides strong support for the claim that rapamycin is an effective life extension drug.

LE: Who can benefit from rapamycin?

Pelton: I think most adults aged 50 and older can gain significant health benefits from taking rapamycin. Individuals with certain medical conditions such as type II diabetes or obesity might benefit by starting at a younger age, but these decisions need to be made with a physician. Pregnant women should not take rapamycin.

LE: What motivated you to write a second edition of your first Rapamycin book?

Pelton: I was pleasantly surprised by the continuing number of published studies that corroborate what I wrote just a few years prior about rapamycin, mTOR, and autophagy. What inspired me the most are newly identified mechanisms of action to explain the ability of rapamycin to extend life span while combating the most prevalent diseases afflicted aging humans.

LE: Do you have any final thoughts you’d like to share with our readers?

Pelton: When something is broken, you have to remove the damaged or broken part before you can replace it with a new part. In your body, old damaged cellular components (mostly proteins and enzymes) cause varying degrees of malfunction. Autophagy removes these damaged cellular components so they are replaced by healthy new ones. Autophagy is the constant process of rebuilding and renewing your body. Under-activation of autophagy is one of the most serious causes of accelerated biological aging. Rapamycin inhibits mTOR and activates autophagy, which increases lifespan and healthspan.

If you have any questions on the scientific content of this article, please call a Life Extension Wellness Specialist at 1-866-864-3027.

References

1. Saxton RA, Sabatini DM. mTOR Signaling in Growth, Metabolism, and Disease. Cell.2017Mar 9;168(6):960-76.
2. González A, Hall MN, Lin S-C, et al. AMPK and TOR: The Yin and Yang of Cellular Nutrient Sensing and Growth Control. Cell Metabolism. 20202020/03/03/;31(3):472-92.
3. Lu G, Wang Y, Shi Y, et al. Autophagy in health and disease: From molecular mechanisms to therapeutic target. MedComm.2022;3(3):e150.
4. Kaushik S, Tasset I, Arias E, et al. Autophagy and the hallmarks of aging. Ageing Res Rev.2021Dec;72:101468.
5. Blagosklonny MV. Rapamycin for longevity: opinion article. Aging (Albany NY). 2019Oct 4;11(19):8048-67.
6. Martinez-Miguel VE, Lujan C, Espie-Caullet T, et al. Increased fidelity of protein synthesis extends lifespan. Cell Metab.2021Nov 2;33(11):2288-300 e12.
7. Roth SM, Ferrell RF, Hurley BF. Strength training for the prevention and treatment of sarcopenia. J Nutr Health Aging.2000;4(3):143-55.
8. Lu JY, Simon M, Zhao Y, et al. Comparative transcriptomics reveals circadian and pluripotency networks as two pillars of longevity regulation. Cell Metab.2022Jun 7;34(6):836-56 e5.
9. Available at: https://www.youtube.com/watch?v=q0ZYfVoV0s0 . Accessed June 13, 2023.