title: Nicotinamide mononucleotide supplementation reverses vascular dysfunction and oxidative stress with aging in mice.
abstract: We tested the hypothesis that supplementation of nicotinamide mononucleotide (NMN), a key NAD(+) intermediate, increases arterial SIRT1 activity and reverses age-associated arterial dysfunction and oxidative stress. Old control mice (OC) had impaired carotid artery endothelium-dependent dilation (EDD) (60 ± 5% vs. 84 ± 2%), a measure of endothelial function, and nitric oxide (NO)-mediated EDD (37 ± 4% vs. 66 ± 6%), compared with young mice (YC). This age-associated impairment in EDD was restored in OC by the superoxide (O2-) scavenger TEMPOL (82 ± 7%). OC also had increased aortic pulse wave velocity (aPWV, 464 ± 31 cm s(-1) vs. 337 ± 3 cm s(-1) ) and elastic modulus (EM, 6407 ± 876 kPa vs. 3119 ± 471 kPa), measures of large elastic artery stiffness, compared with YC. OC had greater aortic O2- production (2.0 ± 0.1 vs. 1.0 ± 0.1 AU), nitrotyrosine abundance (a marker of oxidative stress), and collagen-I, and reduced elastin and vascular SIRT1 activity, measured by the acetylation status of the p65 subunit of NFκB, compared with YC. Supplementation with NMN in old mice restored EDD (86 ± 2%) and NO-mediated EDD (61 ± 5%), reduced aPWV (359 ± 14 cm s(-1) ) and EM (3694 ± 315 kPa), normalized O2- production (0.9 ± 0.1 AU), decreased nitrotyrosine, reversed collagen-I, increased elastin, and restored vascular SIRT1 activity. Acute NMN incubation in isolated aortas increased NAD(+) threefold and manganese superoxide dismutase (MnSOD) by 50%. NMN supplementation may represent a novel therapy to restore SIRT1 activity and reverse age-related arterial dysfunction by decreasing oxidative stress.
authors.affiliation: Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO.
authors.forename: Natalie E
authors.initials: NE
authors.lastname: de Picciotto
authors.affiliation: Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO.
authors.forename: Lindsey B
authors.initials: LB
authors.lastname: Gano
authors.affiliation: Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO.
authors.forename: Lawrence C
authors.initials: LC
authors.lastname: Johnson
authors.affiliation: Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Martens
authors.affiliation: Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO.
authors.forename: Amy L
authors.initials: AL
authors.lastname: Sindler
authors.affiliation: Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Kathryn F
authors.initials: KF
authors.lastname: Mills
authors.affiliation: Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Shin-Ichiro
authors.initials: S
authors.lastname: Imai
authors.affiliation: Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO.
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Seals
mesh_terms: D000375:Aging / Q000473:pathology*; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D019587:Dietary Supplements; D004548:Elasticity; D004730:Endothelium, Vascular / Q000187:drug effects / Q000473:pathology* / Q000503:physiopathology*; D008297:Male; D008810:Mice, Inbred C57BL; D009537:Nicotinamide Mononucleotide / Q000494:pharmacology*; D009569:Nitric Oxide / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects*; D056564:Sirtuin 1 / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism; D059289:Vascular Stiffness / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects
chemical_list: D009537:Nicotinamide Mononucleotide; D009569:Nitric Oxide; D013482:Superoxide Dismutase; D056564:Sirtuin 1
keywords: NAD+; SIRT1; arterial stiffness; endothelial dysfunction; oxidative stress