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K63 polyubiquitination as a mechanism linking obesity and age-related memory decline

Award Number: R21AG094690
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/15/2026
PERIOD OF PERFORMANCE END DATE: 04/30/2027

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K63 polyubiquitination as a mechanism linking obesity and age-related memory decline - Project Summary/Abstract The broad goal of this proposal is to understand how obesity interacts with the aging process and accelerates memory decline across the lifespan. Age-related memory loss occurs in ~33% of adults over the age of 70, yet no treatment option exists that can prevent or reverse these impairments. One of the major risk factors for developing age-related memory impairments is obesity, which affects nearly 40% of U.S. adults. However, even though obesity and aging are both known to be associated with cognitive decline, very little is known about how they interact to affect memory across the lifespan. The ubiquitin-proteasome system (UPS) controls the majority of protein degradation in cells and is dysregulated with age and in Alzheimer’s disease. However, the ubiquitination process is complex, and few studies have examined the role of degradation-independent ubiquitin modifications in the brain. K63 polyubiquitination is the second most abundant form of ubiquitination and is independent of protein degradation. We recently found that reductions in K63 polyubiquitination the hippocampus is critical for normal memory formation in young adulthood. Interestingly, we also found that both aging and obesity in young adult rats leads to aberrant increases in K63 polyubiquitination in the hippocampus, the primary brain region involved in long-term memory formation, which correlates with obesity- and age-related memory impairments. Further, knockdown of K63 polyubiquitination in the aged hippocampus rescues age-related memory deficits. However, it is unknown whether the obesity-induced and age-induced K63 polyubiquitination dysregulation are directly connected or instead just share some common molecular mechanisms. The work in this proposal is designed to test 1) if obesity accelerates age-related memory decline via dysregulation K63 polyubiquitination in the hippocampus, and 2) whether reducing aberrant increases in K63 polyubiquitination in the hippocampus can prevent obesity- and aging-induced memory decline. Using a diet-controlled longitudinal design in combination with sophisticated protein purification methods and unbiased mass spectrometry whole proteome analyses, Aim 1 will test if obesity accelerates the aging process in the hippocampus or instead results in a unique process characterized by dysregulated K63 polyubiquitination of a distinct subset of proteins. Aim 2 will use a diet-controlled longitudinal design in combination with cutting-edge CRISPR-dCas13-mediated knockdown of hippocampal K63 polyubiquitination to test if preventing obesity-induced and aging-induced increases in K63 polyubiquitination can preserve memory across the lifespan. Collectively, this study will answer important questions about how obesity can accelerate age-related memory decline and increase the susceptibility to age-associated neurodegenerative disorders. Results from this project could provide critical insights that may lead to the development of novel treatment strategies designed to mediate the effects of obesity on the aging process


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 = $409,464 )
2026	2026	VIRGINIA POLYTECHNIC INSTITUTE & STATE UNIVERSITY	300 TURNER ST NW	BLACKSBURG	VA	24060	MONTGOMERY	USA	Aging Research	000	1	5/7/2026	NEW	$409,464
														Subtotal = $409,464

Grand Total All Awards = $409,464

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K63 polyubiquitination as a mechanism linking obesity and age-related memory decline

Award Number: R21AG094690

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/15/2026

PERIOD OF PERFORMANCE END DATE: 04/30/2027

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