Rapamycin: An InhibiTOR of Aging Emerges From the Soil of Easter Island

Abstract

Rapamycin (sirolimus) is a macrolide immunosuppressant that inhibits the mechanistic target of rapamycin (mTOR) protein kinase and extends lifespan in model organisms including mice. Although rapamycin is an FDA-approved drug for select indications, a diverse set of negative side effects may preclude its wide-scale deployment as an antiaging therapy. mTOR forms two different protein complexes, mTORC1 and mTORC2; the former is acutely sensitive to rapamycin whereas the latter is only chronically sensitive to rapamycin in vivo. Over the past decade, it has become clear that although genetic and pharmacological inhibition of mTORC1 extends lifespan and delays aging, inhibition of mTORC2 has negative effects on mammalian health and longevity and is responsible for many of the negative side effects of rapamycin. In this review, we discuss recent advances in understanding the molecular and physiological effects of rapamycin treatment, and we discuss how the use of alternative rapamycin treatment regimens or rapamycin analogs has the potential to mitigate the deleterious side effects of rapamycin treatment by more specifically targeting mTORC1. Although the side effects of rapamycin are still of significant concern, rapid progress is being made in realizing the revolutionary potential of rapamycin-based therapies for the treatment of diseases of aging.

Keywords: Intermittent rapamycin; Lifespan; Mouse; Rapamycin analogs.

Figure 1.

Theoretical model of rapamycin regulation of lifespan by mTOR signaling. Rapamycin acutely inhibits mTORC1, while chronic administration also inhibits mTORC2 in the majority of tissues. Intermittent administration of rapamycin in the form of single acute doses (eg, 2mg/kg of rapamycin every 5 days) more precisely targets mTORC1 (45). Repression of mTORC1 promotes longevity through pathways that likely include the inhibition of S6K1, protein translation, and increased autophagy. Conversely, mTORC2 inhibition results in metabolic dysfunction and decreases the lifespan of male mice through an as yet undetermined mechanism.