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Systemic Mechanisms of Brain Rejuvenation

Award Number: R01AG077816
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/15/2022
PERIOD OF PERFORMANCE END DATE: 02/28/2027

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Systemic Mechanisms of Brain Rejuvenation - PROJECT SUMMARY/ABSTRACT The ability to enhance cognition by targeting circulating factors in the systemic milieu provides a unique and underexplored therapeutic approach to brain aging. We and others have shown that systemic manipulations, including exposure to young blood through heterochronic parabiosis (in which the circulatory system of a young and old animal are joined) and young blood plasma administration, revitalize the aged hippocampus and ameliorate cognitive decline in aged mice. The rejuvenating effects of young blood mirror those observed with exercise, positing common bloodborne mechanisms of action by which broad systemic interventions exert their beneficial effects. Preliminary data from our labs indicate that systemic administration of platelet factors derived from either naïve young mice or exercised mice reverses age-related impairments in adult neurogenesis, deceases neuroinflammation and restores cognitive function in aged mice. Moreover, using proteomics, our two groups have independently identified CXCL4/platelet factor 4 (PF4)—a chemokine released from platelets, involved in coagulation and a variety of immunomodulatory functions—as a potential young blood-derived and exercise-induced anti-geronic circulating factor. The proposed study will investigate the rejuvenating and therapeutic effects of platelet factors on the aged brain. Specifically, our hypothesis is that systemic exposure to platelet factors rejuvenates adult neurogenesis, attenuates neuroinflammation and improves cognition, while ameliorating neurodegenerative phenotypes. We will test this theory with three specific aims: 1: Determine mechanisms downstream of PF4 underlying cognitive and regenerative rejuvenation in the aged hippocampus. 2: Examine the rejuvenating effects of PF4 on neuroinflammation in the aged hippocampus. 3: Investigate the beneficial effects of PF4 in a mouse model of Alzheimer’s disease. Successful completion of these studies will have significant translational potential, identifying platelet-derived circulating factors as candidate therapeutic targets to restore age-related cognitive dysfunction and potentially treat dementia-related neurodegenerative disorders such as Alzheimer’s disease.


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 = $547,105 )
2026	2026	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Aging Research	000	5	3/24/2026	NON-COMPETING CONTINUATION	$547,105
														Subtotal = $547,105

Issue Date FY: 2025 ( Subtotal = $536,157 )
2025	2025	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Aging Research	000	4	3/7/2025	NON-COMPETING CONTINUATION	$492,389
2025	2025	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Aging Research	001	4	8/29/2025	NON-COMPETING CONTINUATION	$43,768
														Subtotal = $536,157

Issue Date FY: 2024 ( Subtotal = $547,071 )
2024	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Aging Research	001	3	6/28/2024	NON-COMPETING CONTINUATION	$54,707
2024	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Aging Research	000	3	3/22/2024	NON-COMPETING CONTINUATION	$492,364
														Subtotal = $547,071

Issue Date FY: 2023 ( Subtotal = $543,803 )
2023	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Aging Research	000	2	3/8/2023	NON-COMPETING CONTINUATION	$543,803
														Subtotal = $543,803

Issue Date FY: 2022 ( Subtotal = $559,152 )
2022	2022	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Aging Research	000	1	6/3/2022	NEW	$542,762
2022	2022	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Aging Research	001	1	6/9/2022	NEW	$16,390
														Subtotal = $559,152

Grand Total All Awards = $2,733,288

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Systemic Mechanisms of Brain Rejuvenation

Award Number: R01AG077816

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/15/2022

PERIOD OF PERFORMANCE END DATE: 02/28/2027

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