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

Autor:	Arriola Apelo SI; Department of Medicine, University of Wisconsin-Madison, Madison, WI, USA.; William S. Middleton Memorial Veterans Hospital, Madison, WI, USA., Neuman JC; William S. Middleton Memorial Veterans Hospital, Madison, WI, USA.; Interdisciplinary Graduate Program in Nutritional Sciences, University of Wisconsin-Madison, Madison, WI, USA., Baar EL; Department of Medicine, University of Wisconsin-Madison, Madison, WI, USA.; William S. Middleton Memorial Veterans Hospital, Madison, WI, USA., Syed FA; Department of Medicine, University of Wisconsin-Madison, Madison, WI, USA.; William S. Middleton Memorial Veterans Hospital, Madison, WI, USA., Cummings NE; 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., Brar HK; Department of Medicine, University of Wisconsin-Madison, Madison, WI, USA.; William S. Middleton Memorial Veterans Hospital, Madison, WI, USA., Pumper CP; Department of Medicine, University of Wisconsin-Madison, Madison, WI, USA.; William S. Middleton Memorial Veterans Hospital, Madison, WI, USA., Kimple ME; 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., Lamming DW; 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.
Jazyk:	angličtina
Zdroj:	Aging cell [Aging Cell] 2016 Feb; Vol. 15 (1), pp. 28-38. Date of Electronic Publication: 2015 Oct 13.
DOI:	10.1111/acel.12405
Abstrakt:	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. (© 2015 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.)
Databáze:	MEDLINE
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