testosterone deficiency accelerates neuronal and vascular aging of samp8 mice protective role of enos and sirt1睾酮缺乏加速神经和血管老化以挪士和sirt1 samp8小鼠的保护作用.pdf

Testosterone Deficiency Accelerates Neuronal and Vascular Aging of SAMP8 Mice: Protective Role of eNOS and SIRT1 1 1 1 2 2 Hidetaka Ota , Masahiro Akishita *, Takuyu Akiyoshi , Tomoaki Kahyo , Mitsutoshi Setou , Sumito 1 1 1 1 Ogawa , Katsuya Iijima , Masato Eto , Yasuyoshi Ouchi 1 Department of Geriatric Medicine, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo, Japan, 2 Hamamatsu University School of Medicine, Department of Molecular Anatomy, Hamamatsu, Shizuoka, Japan 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-regulat