Time restricted eating for prevention of age-related vascular cognitive decline in older adults

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PROJECT SUMMARY/ABSTRACT Cognitive impairment associated with Alzheimer’s disease and Related Dementias (ADRD) and aging has emerged as one of the major public health challenges of our time. Recent clinical studies, as well as those in animal models, support that preservation of cognitive health depends on an adequate cerebral blood flow (CBF) supply to the active brain regions. Importantly, in the healthy, young brain cerebral blood supply is readily adjusted to meet the increased oxygen and nutrient demand of activated neurons. This homeostatic mechanism, termed "neurovascular coupling" (NVC) or "functional hyperemia", is required for normal brain function. Preclinical and clinical evidence shows that aging per se significantly impairs endothelium mediated NVC responses, which play a causal role in age- related vascular cognitive impairment (VCI) and the development of ADRD. Lifestyle factors, including nutrition and dietary habits, significantly affect cerebrovascular health and, thereby, influence the pathogenesis of age-related cognitive impairment and ADRD. Caloric restriction (CR), which exerts multifaceted anti-aging and lifespan-extending effects, has been demonstrated to be an effective nutritional intervention that can improve vascular health and cognitive function. CR activates SIRT1-dependent pathways in the vasculature, which attenuates cellular oxidative stress and rescues endothelial vasodilation. However, adherence to CR remains a challenge and a translational barrier as most humans may not be able, or willing, to reduce their caloric intake by 30% over extended periods of time. Intermittent fasting can recapitulate the benefits of CR without limiting calorie intake in older adults. Time restricted eating (TRE) is considered the best approach to intermittent fasting for elderly individuals as it allows consumption of required calories within a condensed daily eating window (4-10 hours), resulting in the greatest fasting stimulus without a net reduction in calorie intake. Yet, the impact of TRE on cerebrovascular function and, potentially the delay of ADRD and age-related VCI, to preserve cognition is currently unknown. Our central hypothesis is that closer adherence to TRE will improve NVC responses and micro- and macrovascular endothelial function, potentially through activation of SIRT1-dependent vasoprotective pathways, resulting in the improvement of cognitive performance. This hypothesis will be tested by assessing the effects of TRE (10 hours eating window) in community dwelling older adults (55-80 years of age) in a 6-month study. Aim 1 will determine the impact of TRE on NVC responses using innovative technologies such as functional near-infrared spectroscopy (fNIRS) and dynamic retinal vessel analysis (DVA), and on microvascular endothelial function using laser speckle contrast imaging and flow-mediated dilation approaches in community dwelling older adults. Aim 2 will determine the impact of TRE on circulating biomarkers and cerebromicrovascular endothelial cell SIRT1 activity.