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Exercise-Associated Signaling Against CNS Aging and Alzheimer's Disease

Award Number: R01AG077536
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/30/2022
PERIOD OF PERFORMANCE END DATE: 05/31/2027

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Exercise-Associated Signaling Against CNS Aging and Alzheimer's Disease - ABSTRACT Skeletal muscle has recently arisen as a novel regulators of Central Nervous System (CNS) function and aging, secreting bioactive molecules known as myokines with proteostasis and metabolism-modifying functions in targeted tissues, including the CNS. Myokine secretion is heavily modified by exercise, suggesting that myokine signaling in the periphery may underlie the well documented geroprotective benefits of exercise on the brain. The following studies address muscle proteostasis, a pathway highly activated during exercise, as a potential new regulator of the neurocognitive benefits of exercise. We have recently generated a novel transgenic mouse with enhanced muscle proteostasis via moderate overexpression of Transcription Factor E-B (TFEB), a powerful master regulator of cellular clearance and proteostasis. We have discovered that the resulting enhanced skeletal muscle proteostasis function can significantly ameliorate proteotoxicity in the aging CNS and also improve cognition and memory in aging mice. Enhancing muscle proteostasis also reduced neuroinflammation and accumulation of AD-associated pathological hallmarks in plaque based and a tau- based models of AD. We have also identified previously unreported alterations in the transcriptome of skeletal muscle from patients with AD, as well as potential unique populations of skeletal muscle factors that may be driving these CNS benefits. In this project, we will determine if enhanced skeletal muscle proteostasis promotes neuroprotection against AD-associated phenotypes, and using powerful transfer learning and computational modeling approaches, identify exercise-associated circulating factors as new therapeutic interventions for the preservation of CNS function during AD.


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 = $539,185 )
2025	2025	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90033	LOS ANGELES	USA	Aging Research	000	4	1/16/2025	SUPPLEMENT FOR EXPANSION	$25,581
2025	2025	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90033	LOS ANGELES	USA	Aging Research	001	5	7/11/2025	NON-COMPETING CONTINUATION	$436,862
2025	2025	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90033	LOS ANGELES	USA	Aging Research	002	5	7/30/2025	SUPPLEMENT FOR EXPANSION	$76,742
														Subtotal = $539,185

Issue Date FY: 2024 ( Subtotal = $445,778 )
2024	2024	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90089	LOS ANGELES	USA	Aging Research	000	4	5/22/2024	NON-COMPETING CONTINUATION	$445,778
														Subtotal = $445,778

Issue Date FY: 2023 ( Subtotal = $447,376 )
2023	2023	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST	LOS ANGELES	CA	90089	LOS ANGELES	USA	Aging Research	004	3	6/9/2023	NON-COMPETING CONTINUATION	$445,778
2023	2022	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Aging Research	002	1	6/5/2023	NEW	-$1
2023	2022	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST	LOS ANGELES	CA	90089	LOS ANGELES	USA	Aging Research	003	2	6/5/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$1
2023	2022	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Aging Research	000	1	2/2/2023	NEW	-$475,861
2023	2022	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST	LOS ANGELES	CA	90089	LOS ANGELES	USA	Aging Research	001	2	2/2/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$477,459
														Subtotal = $447,376

Issue Date FY: 2022 ( Subtotal = $475,862 )
2022	2022	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Aging Research	000	1	9/22/2022	NEW	$475,862
														Subtotal = $475,862

Grand Total All Awards = $1,908,201

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Exercise-Associated Signaling Against CNS Aging and Alzheimer's Disease

Award Number: R01AG077536

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/30/2022

PERIOD OF PERFORMANCE END DATE: 05/31/2027

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