Dietary rapamycin supplementation reverses age-related vascular dysfunction and oxidative stress, while modulating nutrient-sensing, cell cycle, and senescence pathways.

Autor: Lesniewski LA; Division of Geriatrics, Department of Internal Medicine, Salt Lake City, UT, USA.; Veteran's Affairs Medical Center-Salt Lake City, Geriatrics Research Education and Clinical Center, Salt Lake City, UT, USA.; Department of Exercise and Sports Science, University of Utah, Salt Lake City, UT, USA., Seals DR; Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO, USA., Walker AE; Division of Geriatrics, Department of Internal Medicine, Salt Lake City, UT, USA., Henson GD; Department of Exercise and Sports Science, University of Utah, Salt Lake City, UT, USA., Blimline MW; Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO, USA., Trott DW; Division of Geriatrics, Department of Internal Medicine, Salt Lake City, UT, USA., Bosshardt GC; Division of Geriatrics, Department of Internal Medicine, Salt Lake City, UT, USA., LaRocca TJ; Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO, USA., Lawson BR; Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO, USA., Zigler MC; Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO, USA., Donato AJ; Division of Geriatrics, Department of Internal Medicine, Salt Lake City, UT, USA.; Veteran's Affairs Medical Center-Salt Lake City, Geriatrics Research Education and Clinical Center, Salt Lake City, UT, USA.; Department of Exercise and Sports Science, University of Utah, Salt Lake City, UT, USA.; Department of Biochemistry, University of Utah, Salt Lake City, UT, USA.
Jazyk: angličtina
Zdroj: Aging cell [Aging Cell] 2017 Feb; Vol. 16 (1), pp. 17-26. Date of Electronic Publication: 2016 Sep 22.
DOI: 10.1111/acel.12524
Abstrakt: Inhibition of mammalian target of rapamycin, mTOR, extends lifespan and reduces age-related disease. It is not known what role mTOR plays in the arterial aging phenotype or if mTOR inhibition by dietary rapamycin ameliorates age-related arterial dysfunction. To explore this, young (3.8 ± 0.6 months) and old (30.3 ± 0.2 months) male B6D2F1 mice were fed a rapamycin supplemented or control diet for 6-8 weeks. Although there were few other notable changes in animal characteristics after rapamycin treatment, we found that glucose tolerance improved in old mice, but was impaired in young mice, after rapamycin supplementation (both P < 0.05). Aging increased mTOR activation in arteries evidenced by elevated S6K phosphorylation (P < 0.01), and this was reversed after rapamycin treatment in old mice (P < 0.05). Aging was also associated with impaired endothelium-dependent dilation (EDD) in the carotid artery (P < 0.05). Rapamycin improved EDD in old mice (P < 0.05). Superoxide production and NADPH oxidase expression were higher in arteries from old compared to young mice (P < 0.05), and rapamycin normalized these (P < 0.05) to levels not different from young mice. Scavenging superoxide improved carotid artery EDD in untreated (P < 0.05), but not rapamycin-treated, old mice. While aging increased large artery stiffness evidenced by increased aortic pulse-wave velocity (PWV) (P < 0.01), rapamycin treatment reduced aortic PWV (P < 0.05) and collagen content (P < 0.05) in old mice. Aortic adenosine monophosphate-activated protein kinase (AMPK) phosphorylation and expression of the cell cycle-related proteins PTEN and p27kip were increased with rapamycin treatment in old mice (all P < 0.05). Lastly, aging resulted in augmentation of the arterial senescence marker, p19 (P < 0.05), and this was ameliorated by rapamycin treatment (P < 0.05). These results demonstrate beneficial effects of rapamycin treatment on arterial function in old mice and suggest these improvements are associated with reduced oxidative stress, AMPK activation and increased expression of proteins involved in the control of the cell cycle.
(© 2016 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.)
Databáze: MEDLINE
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