Many experts in the biology of ageing believe that pharmacological interventions to slow ageing are a matter of ‘when’ rather than ‘if’. A leading target for such interventions is the nutrient response pathway defined by the mechanistic target of rapamycin (mTOR). Inhibition of this pathway extends lifespan in model organisms and confers protection against a growing list of age-related pathologies. Characterized inhibitors of this pathway are already clinically approved, and others are under development. Although adverse side effects currently preclude use in otherwise healthy individuals, drugs that target the mTOR pathway could one day become widely used to slow ageing and reduce age-related pathologies in humans.
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The mechanistic target of rapamycin (mTOR) story began in the 1970s when new antifungal activity was discovered in soil samples from the Polynesian island of Rapa Nui (). Thus, the compound, which was isolated from Streptomyces hygroscopicus, was named rapamycin. Also known as sirolimus, rapamycin was widely studied as an immunosuppressant before its mechanism of action was well understood, and in 1999 it was approved for use in post-transplantation therapy. Since then, rapamycin and several derivative compounds (including everolimus, temsirolimus, ridaforolimus, umirolimus and zotarolimus, collectively referred to as ‘rapamycins’ in this Review) have been approved for a variety of uses, including prevention of restenosis following angioplasty and as a treatment for certain forms of cancer.
2012 More than 1,300 clinical trials under way or completed Studies in the budding yeast Saccharomyces cerevisiae first identified the target of rapamycin genes TOR1 and TOR2 as genetic mediators of rapamycin’s growth inhibitory effects, and soon afterwards the mTOR protein was purified from mammalian cells and demonstrated to be the physical target of rapamycin. MTOR is a serine/threonine protein kinase of the phosphatidylinositol-3-OH kinase (PI(3)K)-related family that functions as a master regulator of cellular growth and metabolism in response to nutrient and hormonal cues.
MTOR functions in two distinct complexes: mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2) (). Rapamycins inhibit mTORC1 by binding the FK506-binding protein FKBP12, which then interacts physically with the complex and decreases activity. Although mTORC2 is not directly affected by rapamycin, chronic exposure can sequester mTOR from mTORC2, inhibiting mTORC2 assembly. This effect on mTORC2 is thought to contribute to metabolic complications associated with chronic rapamycin treatment, including glucose intolerance and abnormal lipid profiles (described further later). The two mTOR complexes have distinct constituent proteins and regulate different downstream processes Here (figure represents data from studies in mice) mTORC1 comprises deptor, PRAS40, raptor, mLST8, mTOR and TTI1–TEL2. MTORC2 is comprised of deptor, mLST8, protor, rictor, mSIN1, mTOR and TTI1–TEL2. 