title: Dietary rapamycin supplementation reverses age-related vascular dysfunction and oxidative stress, while modulating nutrient-sensing, cell cycle, and senescence pathways.
abstract: 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.
authors.affiliation: 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.
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Lesniewski
authors.affiliation: Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO, USA.
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Seals
authors.affiliation: Division of Geriatrics, Department of Internal Medicine, Salt Lake City, UT, USA.
authors.forename: Ashley E
authors.initials: AE
authors.lastname: Walker
authors.affiliation: Department of Exercise and Sports Science, University of Utah, Salt Lake City, UT, USA.
authors.forename: Grant D
authors.initials: GD
authors.lastname: Henson
authors.affiliation: Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO, USA.
authors.forename: Mark W
authors.initials: MW
authors.lastname: Blimline
authors.affiliation: Division of Geriatrics, Department of Internal Medicine, Salt Lake City, UT, USA.
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Trott
authors.affiliation: Division of Geriatrics, Department of Internal Medicine, Salt Lake City, UT, USA.
authors.forename: Gary C
authors.initials: GC
authors.lastname: Bosshardt
authors.affiliation: Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO, USA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: LaRocca
authors.affiliation: Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO, USA.
authors.forename: Brooke R
authors.initials: BR
authors.lastname: Lawson
authors.affiliation: Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO, USA.
authors.forename: Melanie C
authors.initials: MC
authors.lastname: Zigler
authors.affiliation: 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.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Donato
mesh_terms: D000263:Adenylate Kinase / Q000378:metabolism; D000375:Aging / Q000473:pathology*; D000818:Animals; D001158:Arteries / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D015415:Biomarkers / Q000378:metabolism; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects*; D018797:Cell Cycle Proteins / Q000378:metabolism; D016922:Cellular Senescence / Q000187:drug effects*; D019587:Dietary Supplements; D004730:Endothelium, Vascular / Q000187:drug effects / Q000473:pathology* / Q000503:physiopathology*; D006706:Homeostasis / Q000187:drug effects; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D008297:Male; D008810:Mice, Inbred C57BL; D009929:Organ Size / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects*; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D059289:Vascular Stiffness / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects
chemical_list: D015415:Biomarkers; D001786:Blood Glucose; D018797:Cell Cycle Proteins; D007328:Insulin; D058570:TOR Serine-Threonine Kinases; D000263:Adenylate Kinase; D020123:Sirolimus
keywords: 
  mTOR
  ; AMPK; aging; arterial stiffness; endothelial function; oxidative stress; rapamycin