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.
Highlights
Advancing age is the most significant risk factor for the development of cognitive impairment [1,2]; what agerelated changes underlie this effect remains uncertain
In order to assess the effects of testosterone on cognitive function, we used an in vivo model of aging, senescenceaccelerated mouse prone 8 (SAMP8), and a control counterpart strain, SAMR1
SAMP8 was originally derived from AKR/J strain, litters of which show the characteristic of cognitive decline with aging
Summary
Advancing age is the most significant risk factor for the development of cognitive impairment [1,2]; what agerelated changes underlie this effect remains uncertain. In a small clinical study of men recently diagnosed with cognitive impairment, testosterone treatment improved performance on cognitive tests [4]. With a relationship between age-related testosterone decline in men and increased risk for cognitive impairment reasonably well established, a critical issue is how testosterone contributes to the pathogenesis of cognitive decline with aging. It is becoming increasingly clear that not all aspects of cognitive decline can be explained by Aß [6,7] Findings from such diverse lines of investigations as neuroimaging and clinical trials suggest that nonAß factors contribute to memory deficit in aged men
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