title: Testosterone deficiency accelerates neuronal and vascular aging of SAMP8 mice: protective role of eNOS and SIRT1.
abstract: Oxidative stress and atherosclerosis-related vascular disorders are risk factors for cognitive decline with aging. In a small clinical study in men, testosterone improved cognitive function; however, it is unknown how testosterone ameliorates the pathogenesis of cognitive decline with aging. Here, we investigated whether the cognitive decline in senescence-accelerated mouse prone 8 (SAMP8), which exhibits cognitive impairment and hypogonadism, could be reversed by testosterone, and the mechanism by which testosterone inhibits cognitive decline. We found that treatment with testosterone ameliorated cognitive function and inhibited senescence of hippocampal vascular endothelial cells of SAMP8. Notably, SAMP8 showed enhancement of oxidative stress in the hippocampus. We observed that an NAD(+)-dependent deacetylase, SIRT1, played an important role in the protective effect of testosterone against oxidative stress-induced endothelial senescence. Testosterone increased eNOS activity and subsequently induced SIRT1 expression. SIRT1 inhibited endothelial senescence via up-regulation of eNOS. Finally, we showed, using co-culture system, that senescent endothelial cells promoted neuronal senescence through humoral factors. Our results suggest a critical role of testosterone and SIRT1 in the prevention of vascular and neuronal aging.
authors.affiliation: Department of Geriatric Medicine, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo, Japan.
authors.forename: Hidetaka
authors.initials: H
authors.lastname: Ota
authors.forename: Masahiro
authors.initials: M
authors.lastname: Akishita
authors.forename: Takuyu
authors.initials: T
authors.lastname: Akiyoshi
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Kahyo
authors.forename: Mitsutoshi
authors.initials: M
authors.lastname: Setou
authors.forename: Sumito
authors.initials: S
authors.lastname: Ogawa
authors.forename: Katsuya
authors.initials: K
authors.lastname: Iijima
authors.forename: Masato
authors.initials: M
authors.lastname: Eto
authors.forename: Yasuyoshi
authors.initials: Y
authors.lastname: Ouchi
mesh_terms: D000818:Animals; D001808:Blood Vessels / Q000378:metabolism / Q000502:physiology*; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000187:drug effects / Q000235:genetics* / Q000502:physiology; D003071:Cognition / Q000187:drug effects / Q000502:physiology; D003072:Cognition Disorders / Q000188:drug therapy / Q000209:etiology / Q000235:genetics / Q000473:pathology; D004353:Drug Evaluation, Preclinical; D005786:Gene Expression Regulation / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D008954:Models, Biological; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D013739:Testosterone / Q000031:analogs & derivatives / Q000172:deficiency* / Q000627:therapeutic use
chemical_list: D013739:Testosterone; C013915:boldenone; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1