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

/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 Project Number: 1R21AG094690-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute on Aging (NIA) | Principal Investigator: TIMOTHY JAROME | Institution: VIRGINIA POLYTECHNIC INST AND ST UNIV, BLACKSBURG, VA | Award Amount: $409,464 | Activity Code: R21 | Study Section: Learning, Memory and Decision Neuroscience Study Section[LMDN] View on NIH RePORTER: https://reporter.nih.gov/project-details/11343102