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Principal Investigator: Stefano Tarantini
Organization: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
Fiscal Year: 2024
Award: $181,250
Funding agency: National Institute on Aging
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.
Terms: <AD dementia><AD related dementia><ADRD><Address><Adherence><Affect><Age><Age Years><Age-associated cognitive decline><Age-associated memory impairment><Age-related cognitive decline><Aging><Alzheimer Type Dementia><Alzheimer disease dementia><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Disease><Alzheimer's and related dementias><Alzheimer's disease and related dementia><Alzheimer's disease and related disorders><Alzheimer's disease or a related dementia><Alzheimer's disease or a related disorder><Alzheimer's disease or related dementia><Alzheimer's disease related dementia><Alzheimers Dementia><Amentia><Animal Model><Animal Models and Related Studies><Approaches to prevention><Attenuated><Benign senescent forgetfulness><Bioavailability><Biological Availability><Blood><Blood Reticuloendothelial System><Blood Serum><Blood Vessels><Brain><Brain Nervous System><Brain Vascular><Brain region><Caloric Intake><Caloric Restriction><Calories><Cerebrovascular 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