Rapamycin: An InhibiTOR of Aging Emerges From the Soil of Easter Island
Open Access
- 21 May 2016
- journal article
- review article
- Published by Oxford University Press (OUP) in The Journals of Gerontology: Series A
- Vol. 71 (7), 841-849
- https://doi.org/10.1093/gerona/glw090
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
Funding Information
- National Institute on Aging
- National Institutes of Health (R00 AG041765)
- University of Wisconsin–Madison School of Medicine and Public Health
- American Diabetes Association (1-16-PMF-001)
- American Federation for Aging Research
This publication has 121 references indexed in Scilit:
- Increased Mammalian Lifespan and a Segmental and Tissue-Specific Slowing of Aging after Genetic Reduction of mTOR ExpressionCell Reports, 2013
- Rapamycin Attenuates the Progression of Tau Pathology in P301S Tau Transgenic MicePLOS ONE, 2013
- mTORC1 in the Paneth cell niche couples intestinal stem-cell function to calorie intakeNature, 2012
- TOR Signaling and Rapamycin Influence Longevity by Regulating SKN-1/Nrf and DAF-16/FoxOCell Metabolism, 2012
- Rapamycin induces glucose intolerance in mice by reducing islet mass, insulin content, and insulin sensitivityJournal of Molecular Medicine, 2011
- Mechanisms of Life Span Extension by Rapamycin in the Fruit Fly Drosophila melanogasterCell Metabolism, 2010
- Rapamycin fed late in life extends lifespan in genetically heterogeneous miceNature, 2009
- mTOR complex 2 in adipose tissue negatively controls whole-body growthProceedings of the National Academy of Sciences of the United States of America, 2009
- Disruption of Tsc2 in pancreatic β cells induces β cell mass expansion and improved glucose tolerance in a TORC1-dependent mannerProceedings of the National Academy of Sciences of the United States of America, 2008
- Influence of TOR kinase on lifespan in C. elegansNature, 2003