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Effects of NAD restoration on neurovascular coupling in community dwelling older adults

Award Number: R01AG075834
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/15/2022
PERIOD OF PERFORMANCE END DATE: 04/30/2027

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Effects of NAD restoration on neurovascular coupling in community dwelling older adults - Age-related cognitive decline has emerged as one of the major public health challenges of our time. It is well known that normal cognitive function requires an adequate blood supply to support neuronal activity. In the healthy young brain, cerebral blood flow is rapidly adjusted to meet the increased oxygen and nutrient demands of active brain regions via a homeostatic mechanism known as neurovascular coupling (NVC, or functional hyperemia). Preclinical and clinical studies demonstrate that NVC is impaired in normal aging, and experimentally induced impairment of NVC responses in young animals results in cognitive impairment. Restoration of NVC in these animals by targeted pharmacological treatments improves cognitive function. Testing specific interventions in humans that have demonstrated efficacy in animal models is a reasonable and prudent approach that may improve impaired NVC and may be the key to developing effective therapies to reverse or prevent age-related cognitive decline and Alzheimer’s Disease/ Alzheimer’s Disease related dementias (AD/ADRD) in older adults. Endothelial dysfunction and impairment of NVC responses have been associated with increases in the production of reactive oxygen species (ROS) that are one of the well-defined ‘Hallmarks of Aging’. Nicotinamide Adenine Dinucleotide (NAD) is one of the major regulators of ROS and has been shown to attenuate ROS production. Our preliminary studies indicate that NAD levels are profoundly reduced in brain vascular endothelial cells of aged mice and that restoration of NAD levels in normal aged mice (equivalent of ≥60 years of age in humans) using an NAD precursor rescues age-related endothelial dysfunction, restores NVC responses and attenuates cognitive decline. Age-related NAD depletion, endothelial dysfunction, and impaired NVC responses are observed in older adults even in the absence of predisposing vascular pathology. Although supplementation with the NAD precursor, nicotinamide riboside (NR), has been reported to increase blood cell NAD levels in humans, effects on endothelial function and NVC responses have not been investigated. Addressing this scientific gap is essential to further develop our understanding of the etiology of NVC impairment and establish its role in the genesis of cognitive decline in aging and AD/ADRD. Our central hypothesis is that restoration of NAD levels with NR in older adults will improve NVC responses and micro- and macrovascular endothelial function. This hypothesis will be tested by assessing the effects of treatment with oral NR (1g/day per os for 8 weeks) or placebo (8 weeks) in community dwelling older adults (60-85 years of age) in a randomized, double-blinded, placebo-controlled, parallel study design. These studies will determine whether NR supplementation alleviates endothelial and neurovascular dysfunction and, potentially, cognitive decline. We anticipate that identifying NAD dysregulation during aging as a driver of vascular dysfunction will not only result in development of new and urgently needed tools to treat vascular dysfunction in aging, but also advance research related to the etiology of AD/ADRD.


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: 2024 ( Subtotal = $626,440 )
2024	2024	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Aging Research	000	3	7/1/2024	NON-COMPETING CONTINUATION	$626,440
														Subtotal = $626,440

Issue Date FY: 2023 ( Subtotal = $609,215 )
2023	2023	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Aging Research	001	2	6/13/2023	NON-COMPETING CONTINUATION	$609,215
2023	2022	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Aging Research	000	1	5/3/2023	NEW	$0
														Subtotal = $609,215

Issue Date FY: 2022 ( Subtotal = $653,661 )
2022	2022	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY STE 530	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Aging Research	000	1	8/10/2022	NEW	$653,661
														Subtotal = $653,661

Grand Total All Awards = $1,889,316

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Effects of NAD restoration on neurovascular coupling in community dwelling older adults

Award Number: R01AG075834

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/15/2022

PERIOD OF PERFORMANCE END DATE: 04/30/2027

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