Rapamycin Research in Humans (15 Longevity Studies)

The Benefits of Rapamycin: An Overview of Research and Implications

Rapamycin stands out as one of the few compounds proven to extend life in healthy animals. Its mechanism of action, involving the mechanistic target of rapamycin (mTOR), has been linked to five of the twelve hallmarks of aging. This makes it a key area of focus for researchers investigating treatments for age-related conditions. mTOR is implicated in a wide range of health conditions, including osteoporosis, brain degeneration, cardiovascular disorders, and even cancer, for which rapamycin and its derivatives, known as rapalogs, can already be prescribed.

mTOR: A Central Target for Aging Research

Given the central role of mTOR in cellular signaling and function, it is unsurprising that it has become a prime target for potential treatments. Research has progressed beyond laboratory and animal studies to include human trials. A review of existing studies analyzed 19 articles covering 22 human studies on rapamycin and rapalogs, focusing specifically on age-related diseases excluding cancer.

Study Design and Findings

Of the 22 studies analyzed, 13 involved healthy participants, while 9 targeted individuals with age-related diseases. These studies varied significantly in size, with some involving just a few participants and others including hundreds. While most studies were placebo-controlled, the findings were often mixed, with outcomes differing based on dosage, participant health, and the specific compound tested.

For example, one milligram of rapamycin showed no benefits for brain function in healthy individuals. Similarly, doses ranging from 2 to 6 milligrams did not improve cognitive function in people with multiple system atrophy. However, low-dose rapamycin demonstrated some success in treating wet age-related macular degeneration (AMD), reducing key physical effects associated with the condition. Unfortunately, the side effects outweighed the benefits, leading researchers to recommend against further study in this area.

Rapalogs and Their Effects

Rapalogs such as everolimus showed more promise in certain areas. For instance, an open-label study of everolimus in patients with pulmonary hypertension reported improved heart efficiency and oxygen processing. However, adverse effects were noted in some participants, and cholesterol and triglyceride levels were elevated. Everolimus also showed potential in reducing symptoms of rheumatoid arthritis, although its overall effects were mixed.

Immune System and Other Observations

Rapamycin and rapalogs had varied impacts on the immune system. One study found that everolimus enhanced the response to an influenza vaccine in elderly participants. However, another study reported increased levels of the inflammatory cytokine TNF-alpha, highlighting the complexity of its effects. Topically applied rapamycin reduced the p16 biomarker of senescence in the skin, suggesting some potential for skin health and anti-aging applications. On the other hand, rapamycin showed no clinically significant effects on glucose levels or grip strength in older adults and, like metformin, may inhibit exercise-induced muscle building.

Conclusion and Perspectives

The findings from these studies highlight the complexity and variability of rapamycin’s effects. While some results are promising, many are inconclusive or come with significant side effects. As researchers and enthusiasts such as Brian Johnson and David Sinclair continue to explore rapamycin, the consensus remains that more research is needed to fully understand its potential benefits and risks. For now, rapamycin represents a fascinating area of study rather than a definitive solution for aging or age-related diseases.

My YouTube Channel: https://www.youtube.com/@MyLongevityExperiment

Study Links:

[1] Papadopoli, D., Boulay, K., Kazak, L., Pollak, M., Mallette, F. A., Topisirovic, I., & Hulea, L. (2019). mTOR as a central regulator of lifespan and aging. F1000Research, 8.

[2] Lin, Y., Chen, T., Chen, J., Fang, Y., & Zeng, C. (2021). Endogenous Aβ induces osteoporosis through an mTOR-dependent inhibition of autophagy in bone marrow mesenchymal stem cells (BMSCs). Annals of Translational Medicine, 9(24).

[3] Querfurth, H., & Lee, H. K. (2021). Mammalian/mechanistic target of rapamycin (mTOR) complexes in neurodegeneration. Molecular neurodegeneration, 16(1), 44.

[4] Sciarretta, S., Forte, M., Frati, G., & Sadoshima, J. (2018). New insights into the role of mTOR signaling in the cardiovascular system. Circulation research, 122(3), 489-505.

[5] Sabatini, D. M. (2006). mTOR and cancer: insights into a complex relationship. Nature Reviews Cancer, 6(9), 729-734.

[6] Kraig, E., Linehan, L. A., Liang, H., Romo, T. Q., Liu, Q., Wu, Y., … & Kellogg Jr, D. L. (2018). A randomized control trial to establish the feasibility and safety of rapamycin treatment in an older human cohort: Immunological, physical performance, and cognitive effects. Experimental gerontology, 105, 53-69.

[7] Palma, J. A., Martinez, J., Millar Vernetti, P., Ma, T., Perez, M. A., Zhong, J., … & Kaufmann, H. (2022). mTOR inhibition with Sirolimus in multiple system atrophy: a randomized, double‐blind, placebo‐controlled futility trial and 1‐year biomarker longitudinal analysis. Movement Disorders, 37(4), 778-789.

[8] Minturn, R. J., Bracha, P., Klein, M. J., Chhablani, J., Harless, A. M., & Maturi, R. K. (2021). Intravitreal sirolimus for persistent, exudative age-related macular degeneration: a Pilot Study. International Journal of Retina and Vitreous, 7, 1-10.

[9] Petrou, P. A., Cunningham, D., Shimel, K., Harrington, M., Hammel, K., Cukras, C. A., … & Wong, W. T. (2015). Intravitreal sirolimus for the treatment of geographic atrophy: results of a phase I/II clinical trial. Investigative ophthalmology & visual science, 56(1), 330-338.

[10] Seyfarth, H. J., Hammerschmidt, S., Halank, M., Neuhaus, P., & Wirtz, H. R. (2013). Everolimus in patients with severe pulmonary hypertension: a safety and efficacy pilot trial. Pulmonary circulation, 3(3), 632-638.

[11] Bruyn, G. A., Tate, G., Caeiro, F., Maldonado-Cocco, J., Westhovens, R., Tannenbaum, H., … & RADD Study Group. (2008). Everolimus in patients with rheumatoid arthritis receiving concomitant methotrexate: a 3-month, double-blind, randomised, placebo-controlled, parallel-group, proof-of-concept study. Annals of the rheumatic diseases, 67(8), 1090-1095.

[12] Kraig, E., Linehan, L. A., Liang, H., Romo, T. Q., Liu, Q., Wu, Y., … & Kellogg Jr, D. L. (2018). A randomized control trial to establish the feasibility and safety of rapamycin treatment in an older human cohort: Immunological, physical performance, and cognitive effects. Experimental gerontology, 105, 53-69.

[13] Drummond, M. J., Fry, C. S., Glynn, E. L., Dreyer, H. C., Dhanani, S., Timmerman, K. L., … & Rasmussen, B. B. (2009). Rapamycin administration in humans blocks the contraction‐induced increase in skeletal muscle protein synthesis. The Journal of physiology, 587(7), 1535-1546.

[14] Chung, C. L., Lawrence, I., Hoffman, M., Elgindi, D., Nadhan, K., Potnis, M., … & Sell, C. (2019). Topical rapamycin reduces markers of senescence and aging in human skin: an exploratory, prospective, randomized trial. Geroscience, 41(6), 861-869.

[15] Mannick, J. B., Del Giudice, G., Lattanzi, M., Valiante, N. M., Praestgaard, J., Huang, B., … & Klickstein, L. B. (2014). mTOR inhibition improves immune function in the elderly. Science translational medicine, 6(268), 268ra179-268ra179.