Targeting the biology of aging with mTOR inhibitors

Abstract

Inhibition of the protein kinase mechanistic target of rapamycin (mTOR) with the Food and Drug Administration (FDA)-approved therapeutic rapamycin promotes health and longevity in diverse model organisms. More recently, specific inhibition of mTORC1 to treat aging-related conditions has become the goal of basic and translational scientists, clinicians and biotechnology companies. Here, we review the effects of rapamycin on the longevity and survival of both wild-type mice and mouse models of human diseases. We discuss recent clinical trials that have explored whether existing mTOR inhibitors can safely prevent, delay or treat multiple diseases of aging. Finally, we discuss how new molecules may provide routes to the safer and more selective inhibition of mTOR complex 1 (mTORC1) in the decade ahead. We conclude by discussing what work remains to be done and the questions that will need to be addressed to make mTOR inhibitors part of the standard of care for diseases of aging.

Figure 1.. Potential healthspan targets of rapamycin.

Based on studies in rodents and humans, rapamycin and rapalogs may have potential benefits for ameliorating or slowing age-related conditions associated with the brain ^,–, heart ^,,, liver , skeletal muscle , tendons ^,, the immune system ^,–, the skin , and the intestine ^,. Created with BioRender.Com.

Figure 2.. An overview of the mechanistic Target Of Rapamycin Complex 1 (mTORC1) signaling pathway with areas of potential pharmaceutical inhibition highlighted.

Negative regulators (CASTOR1, GATOR1, SAMTOR, Sestrin2, tuberous sclerosis complex [TSC]) and positive regulators (FLCN-FNIP2, GATOR2, KICKSTOR, LRS, RAG GTPases, RAGULATOR, Rheb, SLC38A9, v-ATPase) are shown. Potential mechanisms for the development of mTORC1 specific inhibitors include: A, B, C, D. Identifying small molecules that block the ability of amino acid sensors upstream of mTORC1 to sense the availability of leucine, arginine, or SAM; (E, F, G) developing compounds such as BC-LI-0186 that inhibit the GAP or GEF activities of FLCN-FNIP2, LRS, RAGULATOR or TARS2; (H) Inhibiting the interaction of mTORC1 and Rheb, the mechanism of action of NR1; (I) Identifying small molecules that block the ability of LYCHOS and SLC38A9 to sense the availability of cholesterol; and (J) Identifying rapamycin derivatives such as DL001 that specifically inhibit mTORC1. Select downstream substrates of mTORC1 and processes mediated by them are also show. Figure is adapted from Dumas and Lamming, 2020, JGBS and used with permission.

Figure 3.. The known and unknown effects of rapalog dosing regimens on metabolic health, the immune system, healthspan and longevity in humans and mice.

Chronic (daily) dosing of rapamycin is associated with impaired blood glucose regulation and hyperlipidemia in humans and mice, while everolimus in mice has somewhat reduced effects on glucose homeostasis. Intermittent or low dose regimens of rapamycin or everolimus are associated with reduced side effects, while the mTORC1-selective rapalog DL001 does not impair blood glucose control or alter circulating lipid levels. Green up arrow = improvement, red down arrow = impairment; Dash indicated no change, Question mark indicates unknown.