Aging-induced pro-inflammatory phenotypic alterations of the cerebral vasculature critically contribute to the pathogenesis of vascular cognitive impairment. Cellular senescence is a fundamental aging process that promotes inflammation; however, its role in cerebrovascular aging remains unexplored. The present study was undertaken to test the hypothesis that advanced aging promotes cellular senescence in the cerebral vasculature. We found that in cerebral arteries of 24-month-old mice, expression of molecular markers of senescence (p16 INK4a , p21) is upregulated as compared to that in young controls. Induction of senescence programs in cerebral arteries is associated by an upregulation of a wide range of inflammatory cytokines and chemokines, which are known to contribute to the senescence-associated secretory phenotype (SASP) in vascular cells. Age-related cerebrovascular senescence and inflammation are associated with neuroinflammation, as shown by the molecular footprint of microglia activation in the hippocampus. Genetic depletion of the pro-survival/anti-aging transcriptional regulator Nrf2 exacerbated age-related induction of senescence markers and inflammatory SASP factors and resulted in a heightened inflammatory status of the hippocampus. In conclusion, our studies provide evidence that aging and Nrf2 dysfunction promote cellular senescence in cerebral vessels, which may potentially cause or exacerbate age-related pathology.

Aging-induced structural and functional alterations of the neurovascular unit lead to impairment of neurovascular coupling responses, dysregulation of cerebral blood flow, and increased neuroinflammation, all of which contribute importantly to the pathogenesis of age-related vascular cognitive impairment (VCI). There is increasing evidence showing that a decrease in NAD + availability with age plays a critical role in age-related neurovascular and cerebromicrovascular dysfunction. Our recent studies demonstrate that restoring cellular NAD + levels in aged mice rescues neurovascular function, increases cerebral blood flow,

BACKGROUND Incidence of ovulatory disorders is common in obese animal models. The mechanism behind this effect is not clear. We hypothesized that high fat (HF) diet induces alterations in neuroendocrine mechanisms resulting in anovulation in diet-induced obese (DIO) animals. METHODS Adult female DIO and diet-resistant (DR) rats were fed either chow or HF diet (45% calories from fat) for 6 weeks. Oestrous cyclicity and body weight were monitored regularly. At the end of treatment, rats were implanted with a jugular catheter to monitor luteinising hormone (LH) levels on the day of prooestrous. Rats were sacrificed on the following prooestrous, their brains and ovaries were collected. Plasma from trunk blood was analyzed for oestradiol and leptin concentrations. Ovaries were fixed and sectioned for histological analysis. Brains were removed, frozen and sectioned and norepinephrine (NE) concentrations in discrete hypothalamic areas were measured using HPLC-EC. RESULTS HF diet affected oestrous cyclicity in both DIO and DR rats with the effect being more pronounced in DIO animals. HF diet increased leptin levels in both DIO and DR rats. Oestradiol levels were low in the DIO-HF group. NE levels in the hypothalamus were unaffected by HF diet or genotype. A normal LH surge was observed in DR-Chow rats and LH levels were low in the rest of the groups. CONCLUSION DIO rats have an inherently reduced reproductive capacity and exposure to a HF diet decreases it further. A reduction in oestradiol and LH surge levels could contribute to this effect, however the underlying mechanisms need to be studied further.

Chronic sympathetic nervous system overactivity is a hallmark of aging and obesity and contributes to the development of cardiovascular diseases including hypertension and heart failure. The cause of this chronic sympathoexcitation in aging and obesity is multifactorial and centrally mediated. In this mini-review, we have provided an overview of the key and emerging central mechanisms contributing to the pathogenesis of sympathoexcitation in obesity and healthy aging, specifically focusing on hypertension. A clear understanding of these mechanisms will pave way for targeting the sympathetic nervous system for the treatment of cardiovascular diseases in obesity and aging.

Obesity is one of the major risk factors for cardiovascular diseases and its prevalence is increasing in all age groups, with the biggest impact observed in middle-aged and older adults. A critical mechanism by which obesity promotes vascular pathologies in these patients involves impairment of endothelial function. While endothelial dysfunction in large vessels promotes atherogenesis, obesity-induced microvascular endothelial dysfunction impairs organ perfusion and thereby is causally related to the pathogenesis of ischemic heart disease, chronic kidney disease, intermittent claudication, exercise intolerance, and exacerbates cognitive decline in aging. Reduction of weight via calorie-based diet and exercise in animal models of obesity results in significant improvement of endothelial function both in large vessels and in the microcirculation, primarily due to attenuation of oxidative stress and inflammation. Clinical data on the protective effects of weight loss on endothelial function is limited to studies of flow-mediated dilation assessed in brachial arteries. Currently, there is no guideline on testing the effects of different weight management strategies on microvascular endothelial function in obese patients. Here, we provide proof-of-concept that weight loss-induced improvement of microvascular endothelial function can be reliably assessed in the setting of a geriatric outpatient clinic using a fast, reproducible, non-invasive method: laser speckle contrast imaging-based measurement of endothelium-dependent microvascular responses during post-occlusive reactive hyperemia tests. Our study also provides initial evidence that short-term weight loss induced by consumption of a low-carbohydrate low-calorie diet can reverse microvascular endothelial dysfunction associated with obesity.