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Targeting adipose tissue thermogenesis for age-related vascular cognitive impairment

Award Number: K01AG073613
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 09/30/2021
PERIOD OF PERFORMANCE END DATE: 08/31/2026

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Targeting adipose tissue thermogenesis for age-related vascular cognitive impairment - Project Summary/ Abstract More than 50 million people aged 65 and above suffer in vascular cognitive impairment and dementia (VCID). The incidence of VCID is projected to nearly triple by 2050, which will cost more than 2 trillion US dollars in health and social care expenditures. Yet, there are no interventions to treat or prevent cognitive decline in the elderly. Microvascular endothelial dysfunction is a critical contributor to age-related VCID. Functional alterations in the microvascular endothelial cells lead to neurovascular uncoupling responses, the lack of a critical process of adjustment of cerebral blood flow required to support neuronal activity. Further, structural alterations in endothelial cells negatively affect the integrity of blood-brain barrier (BBB), which leads to increased capillary permeability and neuroinflammation. Endothelial dysfunction also contributes to decreased capillary density leading to a reduction in basal CBF. These pathological changes in the endothelial phenotype precedes the onset of cognitive decline in aged humans, suggesting that interventions that maintain or restore cerebrovascular health would be effective for the prevention and treatment of age-related VCID. Adipose tissue plays a pivotal role in the interplay between metabolism and aging. Emerging evidence links increased thermogenesis in the adipose tissue with extended longevity. Activation of the thermogenic program results in remodeling of both white and brown adipose tissue marked by increased fuel utilization and insulin sensitivity. It also results in an overall improvement in systemic inflammatory milieu and a favorable adipokine profile, which could have beneficial effects on the aging cerebral microvasculature. Our preliminary studies provide prima facie evidence that activation of adipose tissue thermogenesis improves cerebromicrovascular function and positively impacts cognition in aged mice. However, the circulating mediators or the cerebromicrovascular mechanisms behind thermogenesis-mediated positive cognitive outcome in aging are not known. Our central hypothesis is that activation of thermogenic program corrects metabolic dysfunction and ameliorates systemic inflammation, thereby improving microvascular endothelial function and preserving cognitive integrity in aging. To address this hypothesis the following aims are proposed: Aim 1: Characterize thermogenesis- induced alterations in metabolic and inflammatory milieu in aging. The thermogenesis mediated alterations in adipose tissue secretome will have beneficial effects on overall metabolism and systemic inflammation in aging. Aim 2: Determine the impact of thermogenesis on microvascular endothelial structure and function in aging. Prolonged activation of thermogenesis can improve cerebrovascular function and structure in aging and lead to improved cognitive health. The successful completion of the proposed studies will identify novel strategies to counteract age-related VCID.


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: 2025 ( Subtotal = $119,286 )
2025	2025	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Aging Research	000	5	7/31/2025	NON-COMPETING CONTINUATION	$119,286
														Subtotal = $119,286

Issue Date FY: 2024 ( Subtotal = $119,286 )
2024	2024	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Aging Research	000	4	8/27/2024	NON-COMPETING CONTINUATION	$119,286
														Subtotal = $119,286

Issue Date FY: 2023 ( Subtotal = $119,286 )
2023	2023	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Aging Research	000	3	8/3/2023	NON-COMPETING CONTINUATION	$119,286
														Subtotal = $119,286

Issue Date FY: 2022 ( Subtotal = $119,286 )
2022	2022	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY STE 530	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Aging Research	000	2	8/1/2022	NON-COMPETING CONTINUATION	$119,286
														Subtotal = $119,286

Issue Date FY: 2021 ( Subtotal = $119,286 )
2021	2021	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY STE 530	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Aging Research	000	1	9/17/2021	NEW	$119,286
														Subtotal = $119,286

Grand Total All Awards = $596,430

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Targeting adipose tissue thermogenesis for age-related vascular cognitive impairment

Award Number: K01AG073613

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 09/30/2021

PERIOD OF PERFORMANCE END DATE: 08/31/2026

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