Testosterone Deficiency Accelerates Neuronal and Vascular Aging of SAMP8 Mice: Protective Role of eNOS and SIRT1

PLoS One

Katsuya Iijima¹  Hidetaka Ota¹  Masahiro Akishita¹  Takuyu Akiyoshi¹  Sumito Ogawa¹  Masato Eto¹  Yasuyoshi Ouchi¹  Mitsutoshi Setou²  Tomoaki Kahyo² 

[1] Department of Geriatric Medicine, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo, Japan;Hamamatsu University School of Medicine, Department of Molecular Anatomy, Hamamatsu, Shizuoka, Japan

关键词: Testosterone;    Cognitive impairment;    Endothelial cells;    Hippocampus;    Senescence;    Oxidative stress;    Small interfering RNAs;    Alzheimer's disease;   

DOI  :  10.1371/journal.pone.0029598

学科分类：医学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY