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Published on: September 17, 2020
Rapamycin: An InhibiTOR of Aging Emerges From the Soil of Easter Island
Sebastian I Arriola Apelo1, Dudley W Lamming2
1Department of Medicine, University of Wisconsin-Madison and William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin.
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.
Insights
Rapamycin extends lifespan by inhibiting mTORC1, but mTORC2 inhibition causes side effects. New strategies aim to target mTORC1 specifically, potentially enabling rapamycin as an antiaging therapy.
Area of Science:
- Biogerontology
- Pharmacology
- Molecular Biology
Background:
- Rapamycin (sirolimus) is an immunosuppressant targeting the mechanistic target of rapamycin (mTOR) kinase.
- mTORC1 inhibition extends lifespan in model organisms, but rapamycin's side effects limit its use as an antiaging therapy.
- mTORC1 is acutely sensitive to rapamycin, while mTORC2 is chronically sensitive, and mTORC2 inhibition contributes to rapamycin's adverse effects.
Purpose of the Study:
- Review recent advances in understanding rapamycin's molecular and physiological effects.
- Discuss strategies to mitigate rapamycin's side effects by targeting mTORC1.
- Explore the potential of rapamycin-based therapies for age-related diseases.
Main Methods:
- Literature review of studies on rapamycin, mTORC1, and mTORC2.
- Analysis of molecular mechanisms underlying rapamycin's effects.
- Evaluation of alternative treatment regimens and analogs.
Main Results:
- mTORC1 inhibition generally promotes longevity and delays aging.
- mTORC2 inhibition negatively impacts mammalian health and longevity, contributing to rapamycin's side effects.
- Targeting mTORC1 specifically offers a potential strategy to reduce adverse effects.
Conclusions:
- Rapamycin's antiaging potential is significant but hampered by side effects.
- Developing strategies to selectively inhibit mTORC1 is crucial for safe and effective antiaging therapies.
- Rapamycin-based treatments show promise for combating age-related diseases.
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