Aging Exacerbates Obesity-induced Cerebromicrovascular Rarefaction, Neurovascular Uncoupling, and Cognitive Decline in Mice

Epidemiological studies show that obesity has deleterious effects on the brain and cognitive function in the elderly population. However, the specific mechanisms through which aging and obesity interact to promote cognitive decline remain unclear. To test the hypothesis that aging exacerbates obesity-induced cerebromicrovascular impairment, we compared young (7 months) and aged (24 months) high-fat diet-fed obese C57BL/6 mice. We found that aging exacerbates the obesity-induced decline in microvascular density both in the hippocampus and in the cortex. The extent of hippocampal microvascular rarefaction and the extent of impairment of hippocampal-dependent cognitive function positively correlate. Aging exacerbates obesity-induced loss of pericyte coverage on cerebral microvessels and alters hippocampal angiogenic gene expression signature, which likely contributes to microvascular rarefaction. Aging also exacerbates obesity-induced oxidative stress and induction of NADPH oxidase and impairs cerebral blood flow responses to whisker stimulation. Collectively, obesity exerts deleterious cerebrovascular effects in aged mice, promoting cerebromicrovascular rarefaction and neurovascular uncoupling. The morphological and functional impairment of the cerebral microvasculature in association with increased blood-brain barrier disruption and neuroinflammation (Tucsek Z, Toth P, Sosnowsk D, et al. Obesity in aging exacerbates blood-brain barrier disruption, neuroinflammation and oxidative stress in the mouse hippocampus: effects on expression of genes involved in beta-amyloid generation and Alzheimer's disease. J Gerontol Biol Med Sci. 2013. In press, PMID: 24269929) likely contribute to obesity-induced cognitive decline in aging.