mTOR Signaling in Growth, Metabolism, and Disease

Summary

This Cell review by Saxton and David Sabatini — Sabatini being one of the original co-discoverers of mTOR — is the most-cited modern synthesis of mTOR signaling biology. The paper traces how mTOR (mechanistic target of rapamycin) integrates four classes of inputs: nutrients (amino acids, especially leucine and arginine), growth factors (insulin, IGF-1), cellular energy state (AMPK senses ATP:AMP), and stress signals. mTOR exists as two complexes: mTORC1, which controls protein synthesis, lipid synthesis, and inhibits autophagy; and mTORC2, which controls cytoskeletal organization and Akt phosphorylation. The review explains how mTORC1 activation drives anabolic programs (cell growth, protein synthesis) while suppressing catabolic programs (autophagy, lipolysis). Conversely, mTORC1 inhibition — by fasting, by rapamycin, by amino acid restriction, or by genetic loss — releases autophagy, increases lipolysis, and engages stress-resistance programs. The paper documents how dysregulated mTOR signaling drives cancer (mTOR is hyperactivated in most tumors), diabetes (mTORC1 contributes to insulin resistance), and aging (mTOR inhibition extends lifespan in every model organism tested). Therapeutic targeting of mTOR is an active drug-development area.