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.

Alternative rapamycin treatment regimens mitigate the impact of rapamycin on glucose homeostasis and the immune system

“…Chronic rapamycin results in fasting hyperglycemia in both humans and mice (Lamming et al ., 2013b). After 5 weeks of treatment, mice treated daily with rapamycin, but not mice treated intermittently, showed fasting hyperglycemia and hyperinsulinemia (Fig.…”

“…The immunosuppressive effects of rapamycin are a potential barrier to widespread use of rapamycin as a therapy for age‐related diseases (Lamming et al ., 2013b), although the dosing strategy utilized may be of major importance. The true impact of rapamycin on the immune system is still unclear, and rapamycin may not be generally immunosuppressive—indeed, rapamycin treatment improves survival in mouse models of infection (Hinojosa et al ., 2012; Hasty et al ., 2014) and improves the response to vaccines in both nonhuman primates (Turner et al ., 2011) and elderly humans (Mannick et al ., 2014).…”

“…These rapalogs, which include everolimus and temsirolimus, were developed in part to improve the pharmacokinetics of sirolimus. For example, everolimus has an approximately 50% shorter blood half‐life than sirolimus in humans (Formica et al ., 2004), while in vitro sirolimus has a slightly lower IC 50 against mTORC1 (Lamming et al ., 2013b). While comparing side effects across clinical trials is difficult, it has been suggested that the side effect profiles of rapalogs in humans may differ (Sankhala et al ., 2009).…”

“…Unfortunately, the potential for serious side effects in humans, including immunosuppression and glucose intolerance, may preclude the long‐term prophylactic use of rapamycin as a therapy for age‐related diseases (Lamming et al ., 2013b). While investigating the mechanistic basis for the effect of rapamycin on glucose tolerance, we discovered that long‐term treatment with rapamycin also inhibits a second mTOR complex, mTORC2, in vivo , resulting in hepatic insulin resistance (Lamming et al ., 2012, 2013a).…”

Longer lifespan in male mice treated with a weakly estrogenic agonist, an antioxidant, an α‐glucosidase inhibitor or a Nrf2‐inducer

“…The decision to test the combination of Met and Rapa was based on the idea that the disturbances in glucose homeostasis induced by Rapa might limit its benefits on lifespan (Lamming et al ., 2013) and that Met, by increasing insulin sensitivity, might therefore compensate for potentially harmful side effects. Our new data are consistent with this idea, in that male and female mice treated with Met (at 1000 ppm) and Rapa (at 14 ppm) showed a greater percentage increase in median lifespan than in either of two previous cohorts of mice treated with Rapa (at 14 ppm) alone.…”