title: Alternative rapamycin treatment regimens mitigate the impact of rapamycin on glucose homeostasis and the immune system.
abstract: Inhibition of the mechanistic target of rapamycin (mTOR) signaling pathway by the FDA-approved drug rapamycin has been shown to promote lifespan and delay age-related diseases in model organisms including mice. Unfortunately, rapamycin has potentially serious side effects in humans, including glucose intolerance and immunosuppression, which may preclude the long-term prophylactic use of rapamycin as a therapy for age-related diseases. While the beneficial effects of rapamycin are largely mediated by the inhibition of mTOR complex 1 (mTORC1), which is acutely sensitive to rapamycin, many of the negative side effects are mediated by the inhibition of a second mTOR-containing complex, mTORC2, which is much less sensitive to rapamycin. We hypothesized that different rapamycin dosing schedules or the use of FDA-approved rapamycin analogs with different pharmacokinetics might expand the therapeutic window of rapamycin by more specifically targeting mTORC1. Here, we identified an intermittent rapamycin dosing schedule with minimal effects on glucose tolerance, and we find that this schedule has a reduced impact on pyruvate tolerance, fasting glucose and insulin levels, beta cell function, and the immune system compared to daily rapamycin treatment. Further, we find that the FDA-approved rapamycin analogs everolimus and temsirolimus efficiently inhibit mTORC1 while having a reduced impact on glucose and pyruvate tolerance. Our results suggest that many of the negative side effects of rapamycin treatment can be mitigated through intermittent dosing or the use of rapamycin analogs.
authors.affiliation: Department of Medicine, University of Wisconsin-Madison, Madison, WI, USA.|William S. Middleton Memorial Veterans Hospital, Madison, WI, USA.
authors.forename: Sebastian I
authors.initials: SI
authors.lastname: Arriola Apelo
authors.affiliation: William S. Middleton Memorial Veterans Hospital, Madison, WI, USA.|Interdisciplinary Graduate Program in Nutritional Sciences, University of Wisconsin-Madison, Madison, WI, USA.
authors.forename: Joshua C
authors.initials: JC
authors.lastname: Neuman
authors.affiliation: Department of Medicine, University of Wisconsin-Madison, Madison, WI, USA.|William S. Middleton Memorial Veterans Hospital, Madison, WI, USA.
authors.forename: Emma L
authors.initials: EL
authors.lastname: Baar
authors.affiliation: Department of Medicine, University of Wisconsin-Madison, Madison, WI, USA.|William S. Middleton Memorial Veterans Hospital, Madison, WI, USA.
authors.forename: Faizan A
authors.initials: FA
authors.lastname: Syed
authors.affiliation: Department of Medicine, University of Wisconsin-Madison, Madison, WI, USA.|William S. Middleton Memorial Veterans Hospital, Madison, WI, USA.|Endocrinology and Reproductive Physiology Graduate Training Program, University of Wisconsin-Madison, Madison, WI, USA.
authors.forename: Nicole E
authors.initials: NE
authors.lastname: Cummings
authors.affiliation: Department of Medicine, University of Wisconsin-Madison, Madison, WI, USA.|William S. Middleton Memorial Veterans Hospital, Madison, WI, USA.
authors.forename: Harpreet K
authors.initials: HK
authors.lastname: Brar
authors.affiliation: Department of Medicine, University of Wisconsin-Madison, Madison, WI, USA.|William S. Middleton Memorial Veterans Hospital, Madison, WI, USA.
authors.forename: Cassidy P
authors.initials: CP
authors.lastname: Pumper
authors.affiliation: Department of Medicine, University of Wisconsin-Madison, Madison, WI, USA.|William S. Middleton Memorial Veterans Hospital, Madison, WI, USA.|Interdisciplinary Graduate Program in Nutritional Sciences, University of Wisconsin-Madison, Madison, WI, USA.|Endocrinology and Reproductive Physiology Graduate Training Program, University of Wisconsin-Madison, Madison, WI, USA.
authors.forename: Michelle E
authors.initials: ME
authors.lastname: Kimple
authors.affiliation: Department of Medicine, University of Wisconsin-Madison, Madison, WI, USA.|William S. Middleton Memorial Veterans Hospital, Madison, WI, USA.|Interdisciplinary Graduate Program in Nutritional Sciences, University of Wisconsin-Madison, Madison, WI, USA.|Endocrinology and Reproductive Physiology Graduate Training Program, University of Wisconsin-Madison, Madison, WI, USA.|University of Wisconsin Carbone Cancer Center, Madison, WI, USA.
authors.forename: Dudley W
authors.identifier: http://orcid.org/0000-0002-0079-4467
authors.initials: DW
authors.lastname: Lamming
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D018149:Glucose Intolerance / Q000188:drug therapy; D006706:Homeostasis / Q000187:drug effects*; D007107:Immune System / Q000187:drug effects*; D050417:Insulin-Secreting Cells / Q000187:drug effects; D008810:Mice, Inbred C57BL; D015398:Signal Transduction / Q000187:drug effects*; D020123:Sirolimus / Q000008:administration & dosage / Q000009:adverse effects* / Q000031:analogs & derivatives / Q000494:pharmacology*
chemical_list: D001786:Blood Glucose; C401859:temsirolimus; D020123:Sirolimus
keywords: aging; mechanistic target of rapamycin; mice; rapamycin