Diet‐induced obesity in the elderly promotes the development of vascular cognitive impairment, which develops in the absence of Alzheimer‐type senile plaques as a result of decreased cerebral blood flow due to vascular alterations. To test the hypothesis that obesity in aging impairs local vasoregulatory mechanisms in cerebral arteries, young (3 mo) and aged (24 mo) C57BL/6 mice were fed a high fat diet (HFD) or a standard diet (SD) for 6 months. In middle cerebral arteries (MCA) isolated from obese aged mice stepwise increases in transmural pressure (from 10 to 160 mmHg) elicited impaired steady‐state myogenic constriction as compared to responses obtained in vessels of young SD‐ and HFD‐fed and aged SD‐fed mice. MCAs from aged obese mice also exhibited impaired dynamic myogenic responses and flow‐induced constriction. Furthermore, obesity impaired metabolic vasodilation in response to adenosine in young mice, whereas its effect was exacerbated in aged mice. Collectively, aging exacerbates obesity‐induced cerebrovascular autoregulatory dysfunction, which likely promotes microvascular damage contributing to the development of vascular cognitive impairment in aged obese individuals. (Funding: AHA, AFAR, NIH).

Previous studies suggest that age‐related decline in circulating growth hormone (GH) and IGF‐1 levels significantly contribute to vascular dysfunction in aging by impairing cellular oxidative stress resistance pathways. Obesity in the elderly is increasing at alarming rates and elderly individuals are more vulnerable to deleterious cardiovascular effects of obesity than younger individuals. However, the specific mechanisms through which aging, GH/IGF‐1 deficiency and obesity interact to promote the development of cardiovascular disease remain unclear. To test the hypothesis that low circulating GH/IGF‐1 levels exacerbate pro‐oxidant and pro‐inflammatory vascular effects of obesity, GH/IGF‐ 1 deficient Lewis dwarf rats and control rats were fed a standard diet (SD) or a high fat diet (HFD) for 7 months. HFD‐fed Lewis dwarf rats exhibited an increase in blood glucose levels, lower insulin and impaired glucose tolerance compared to HFD‐fed control rats. Analysis of serum cytokine expression indicated that GH/IGF‐1 deficiency exacerbates HFD‐induced inflammation. GH/IGF‐1 deficiency also exacerbated HFD‐induced endothelial dysfunction, oxidative stress and expression of inflammatory cytokines in aortas of Lewis dwarf rats. Our results suggest that GH/IGF‐1 deficiency renders the cardiovascular system more vulnerable to the deleterious effects of obesity.