Reviewers have gone through the latest updates on studies featuring rapamycin and its derivatives in The Lancet Healthy Longevity.
Testing a well-known longevity promoter
Not many compounds actually extend life in healthy animals, but rapamycin is indeed one of them. These researchers report that its mechanism of action, the mechanistic target of rapamycin (mTOR), is linked to five of twelve hallmarks of aging [1]. They give a very long list of the conditions that mTOR affects, including osteoporosis [2], brain degeneration [3], cardiovascular disorders [4], and even cancer [5], a condition for which rapamycin and rapalogs can be prescribed.
Given how central mTOR is to signaling and function, it is no surprise that researchers have homed in on this pathway in an effort to develop potential treatments. These developments have moved beyond the in vitro and animal stage, and there have been enough human studies that this review specifically includes only those that target age-related diseases other than cancer.
After winnowing through ineligible material, 19 articles that reported on a total of 22 human rapamycin studies were included for analysis. 13 of these studies were on healthy participants, while the other 9 focused on people with age-related diseases.
These studies varied widely in composition and analysis, with some only having a handful of participants while others had hundreds. Most, but not all, of these studies were placebo controlled. Rapamycin itself was the most widely tested compound, but the rapalogs RTB101, everolimus, and temsirolimus were also tested. Dosages were also considerably different between these studies.
Some positive effects, but not a panacea
In many of these studies, rapamycin and rapalogs did not have statistically significant results. One milligram of rapamycin did not have any benefits for the brains of healthy people [6], and a different study found that a 2- to 6-milligram does did not help the cognitive function of people with multiple system atrophy either [7].
In two different studies [8, 9], low-dose rapamycin had a few positive results in the treatment of wet age-related macular degeneration (AMD), reducing the key physical effects associated with this gradually blinding disease. However, the side effects were such that rapamycin’s effects were largely negative, and rapamycin was not recommended for further study in this respect.
Everolimus fared better in a study of pulmonary hypertension. While this was an open-label study, and two of the ten patients suffered adverse events, the other patients fared better in pressure measurements. The participants’ hearts had to do less work, and they were able to process more oxygen. However, their cholesterol and triglycerides were also increased [10], and this was corroborated in another study reporting that everolimus reduces rheumatoid arthritis [11].
Rapamycin was found to have no clinically significant effects on glucose or grip strength in healthy older people [12], and, similarly to metformin, it may block rather than promote exercise-induced muscle building [13]. On the other hand, topically administered rapamycin was found to decrease the p16 biomarker of senescence in the skin [14].
Rapamycin and rapalogs had mixed effects on the immune system, with studies disagreeing on its immune effects. One study reported that everolimus improved response to an influenza vaccine in elderly people [15], although another study reported that it increased the inflammatory cytokine TNF-alpha [12].
In total, while rapamycin increases lifespan in mice, its effects in human beings have recently been found to be fairly limited. In the near future, rapamycin and rapalogs are likely to continue to be prescribed for their current purposes and may see use as treatments for rheumatoid arthritis and skin aging.
Literature
[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.
