Rapalogs and mTOR inhibitors as anti-aging therapeutics

Abstract

Rapamycin, an inhibitor of mechanistic target of rapamycin (mTOR), has the strongest experimental support to date as a potential anti-aging therapeutic in mammals. Unlike many other compounds that have been claimed to influence longevity, rapamycin has been repeatedly tested in long-lived, genetically heterogeneous mice, in which it extends both mean and maximum life spans. However, the mechanism that accounts for these effects is far from clear, and a growing list of side effects make it doubtful that rapamycin would ultimately be beneficial in humans. This Review discusses the prospects for developing newer, safer anti-aging therapies based on analogs of rapamycin (termed rapalogs) or other approaches targeting mTOR signaling.

Figure 1. mTOR signaling.

mTOR is found in two complexes, mTORC1 and mTORC2. mTORC1 is regulated in part via the TSC complex, which normally act as a GTPase-activating protein for Rheb to suppress mTORC1 signaling. mTORC1 is also regulated by amino acids via the Ras-related GTP binding (Rag) family of small GTPases. The Rag proteins activate mTORC1 by localizing mTORC1 to the lysosome via interaction with the ragulator complex (110). mTORC1 promotes growth by enhancing ribosomal biogenesis, translation, and other anabolic processes, while inhibiting autophagy. mTORC1 suppresses insulin/IGF-1 signaling via direct regulation of Grb10 and S6K, which subsequently reduces signaling to mTORC2. AKT, an inhibitor of TSC1/2, is one of several direct substrates of mTORC2. Processes that are upregulated by mTOR signaling are shown in red; those that are downregulated by mTOR signaling are shown in blue.

Figure 2. Chronic rapamycin treatment disrupts mTORC2.

(A) In vivo, nutrients and growth factors drive the activity of mTORC1 and mTORC2, which promote growth, aging, and insulin sensitivity. (B) Acute treatment with rapamycin inhibits mTORC1 signaling, restricting growth and promoting longevity without reducing insulin sensitivity. (C) Chronic treatment with rapamycin inhibits both mTORC1 and mTORC2, restricting growth and impairing insulin signaling, but promoting longevity.

Figure 3. Metformin regulates mTORC1 signaling.

Metformin activates AMPK by inhibiting oxidative phosphorylation, which in turn negatively regulates mTORC1 signaling via activation of TSC2 and inhibitory phosphorylation of raptor. In parallel, metformin inhibits mTORC1 signaling by suppressing the activity of the Rag GTPases and upregulating REDD1.