Next Generation Strategies for Geroprotection via mTORC1 Inhibition

Abstract

Inhibition of mTORC1 (mechanistic Target Of Rapamycin Complex 1) with the pharmaceutical rapamycin prolongs the lifespan and healthspan of model organisms including rodents, with evidence now emerging that rapamycin and its analogs may also have rejuvenative effects in dogs and humans. However, the side effects associated with long-term rapamycin treatment, many of which are due to inhibition of a second mTOR complex, mTORC2, have seemed to preclude the routine use of rapamycin as a therapy for age-related diseases. Here, we discuss recent findings suggesting that strong, chronic inhibition of both mTOR complexes may not be necessary to realize the geroprotective effects of rapamycin. Instead, modestly but specifically inhibiting mTORC1 via a variety of emerging techniques, including intermittent or transient treatment with rapamycin derivatives, or specific dietary regimens, may be sufficient to promote health and longevity with reduced side effects. We will also discuss prospects for the development of new molecules that, by harnessing the detailed molecular understanding of mTORC1 signaling developed over the last decade, will provide new routes to the selective inhibition of mTORC1. We conclude that therapies based on the selective inhibition of mTORC1 may soon permit the safer treatment of diseases of aging.

Effect of rapamycin on aging and age-related diseases—past and future

“…A major advantage of taking rapamycin to the clinic is the large amount of data gathered over the past two decades on the effect of rapamycin and its rapalogs on humans. The side effects of rapamycin in humans are well established, e.g., ulcers of mouth and lips, hyperglycemia/diabetes, hyperlipidemia, and hypercholesterolemia [116][117][118]123]. In addition, the toxicity profile of rapamycin is relatively low in humans [119].…”

“…Transplant patients receiving immunosuppressant regimes containing rapamycin have been reported to become diabetogenic [122] and have increased blood triglyceride levels [47]. However, as Dumas and Lamming (2019) [123] have pointed out, when taking rapamycin to treat human conditions related to aging, the side effects and the risk-benefit trade-off need to be considered. For example, the side effects are viewed as acceptable in treating cancer [124,125] and would be acceptable in treating Alzheimer's disease because there is currently no effective treatment.…”

The mystery of the ketogenic diet: benevolent pseudo-diabetes

“…As recently as 2019, it was warned that "the side effects associated with long-term rapamycin treatment … seemed to preclude the routine use of rapamycin as a therapy for age-related diseases" [51]. I disagree.…”

Hypothalamic mTORC2 is essential for metabolic health and longevity

“…The mTOR protein kinase is found in two distinct protein complexes; mTOR complex 1 (mTORC1) integrates numerous environmental and hormonal cues, including the availability of amino acids (Wolfson & Sabatini, ), to regulate key anabolic processes including ribosomal biogenesis, protein translation, and autophagy, while mTOR complex 2 (mTORC2) plays a role in cytoskeletal organization and is a key effector of insulin/PI3K signaling (Kennedy & Lamming, ; Zhou & Huang, ). The pharmaceutical rapamycin, which acutely and robustly inhibits mTORC1, extends the lifespan in organisms including yeast, worms, flies, and mice, even when begun late in life or when treatment is intermittent (Apelo, Pumper, Baar, Cummings, & Lamming, ; Arriola Apelo & Lamming, ; Bitto et al, ; Bjedov et al, ; Dumas & Lamming, ; Hansen et al, ; Harrison et al, ; Kapahi et al, ; Miller et al, ; Powers, Kaeberlein, Caldwell, Kennedy, & Fields, ; Robida‐Stubbs et al, ; Selman et al, ).…”