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Time-Restricted Feeding as a Therapeutic Intervention Against Acute White Matter Ischemic Injury in Aging

Award Number: R01NS143112
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/21/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2031

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Time-Restricted Feeding as a Therapeutic Intervention Against Acute White Matter Ischemic Injury in Aging - PROJECT SUMMARY: Age-related declines in cerebromicrovascular health significantly contribute to the onset and progression of vascular cognitive impairment and dementia (VCID), which are major categories of Alzheimer's disease-related dementias (ADRD). White matter (WM) damage, characterized by demyelination, axonal loss, and disruptions in white matter tract integrity, is a critical factor in this process, primarily resulting from chronic hypoperfusion. This hypoperfusion impairs white matter connectivity, leading to cognitive decline and increased risk of neurodegenerative diseases in aging. Our research focuses on the hypothesis that time-restricted feeding (TRF) can prevent age-related WM damage by enhancing neurovascular function and preserving subcortical WM perfusion. TRF is proposed to improve endothelial health and cerebrovascular resilience by promoting the release of ketone bodies, which activate sirtuin 3 (SIRT3) and endothelial nitric oxide synthase (eNOS), protecting neurovascular cells from senescence. We aim to investigate the impact of TRF and ketone supplementation on WM perfusion and functional connectivity in aging. This includes assessing how TRF or ketone body administration can improve cerebrovascular resilience and the consequent effects on subcortical WM perfusion using novel functional ultrasound imaging techniques. Additionally, we will evaluate the mechanistic role of ketone bodies as mediators of TRF’s effects on cerebrovascular resilience. We hypothesize that the beneficial effects of TRF are mediated through the release of ketone bodies, which exert protective effects on endothelial cells. To test this hypothesis, we will use genetic mouse models to delineate the specific contributions of these pathways, evaluating the impact of TRF-induced ketogenesis on BBB integrity, neuroinflammation, cerebrovascular density, and cerebral blood flow (CBF) using advanced imaging techniques. Furthermore, we will characterize the ketone profile in the serum of TRF human participants and investigate its effects on endothelial cell function and molecular signaling pathway activation. By identifying elevated metabolites in human serum, we aim to understand TRF's effects on nitric oxide production, oxidative stress, and inflammation regulation using human endothelial cells. This study will build upon ongoing investigations funded by an awarded R03 and an R21. Overall, these studies aim to provide insight into the mechanisms underlying white matter damage due to aging and hypoperfusion, potentially unveiling new therapeutic targets to enhance vascular integrity and prevent cognitive decline in aging.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $566,715 )
2026	2026	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY STE 560	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	9/17/2026	NEW	$566,715
														Subtotal = $566,715

Grand Total All Awards = $566,715

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Time-Restricted Feeding as a Therapeutic Intervention Against Acute White Matter Ischemic Injury in Aging

Award Number: R01NS143112

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/21/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2031

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