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Reversing age-related epigenetic changes and characterizing microglia heterogeneity in obesity and aging

Award Number: F99AG079813
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 12/01/2022
PERIOD OF PERFORMANCE END DATE: 01/31/2024

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Reversing age-related epigenetic changes and characterizing microglia heterogeneity in obesity and aging - Project Summary Neuroinflammation is a hallmark of brain aging that may contribute to declines in function and neurodegenerative diseases. As the resident macrophage of the brain, microglial are crucial to brain maintenance but have been demonstrated to take on pro-inflammatory phenotypes with aging. The proposed research will examine the role of microglia-specific epigenetic mechanisms in aging and determine the effects of obesity and aging interactions on microglia phenotypic heterogeneity. We will determine whether aberrant age-related microglia-specific epigenetic patterns can be reversed by heterochronic plasma approaches. Additionally, we will determine how microglia subpopulations differ with age and obesity at a single-cell level with special interests in lipid-droplet- accumulating microglia (LDAM). The goals of the training are to: 1) obtain a strong knowledge and foundation in animal and nutritional models of anti-aging and obesity 2) gain hands-on experience in technologies and bioinformatic skills needed for various omics approaches in specific hippocampal cells and at a single-cell level 3) apply these skills to achieve the research aims outlined in this proposal and 5) gain experience and improve oral and presentation skills, manuscript and grant writing to enable a transition to independence. In Aim 1, we hypothesize that exposure of old mice to young plasma will reverse age-related microglia-specific DNA modifications to restore ‘youthful’ epigenomic patterns. This is based on the premise that DNA modifications are key regulators of the diverse phenotypes required for the fulfillment of microglia functions which are disrupted in aging. We will determine whether the administration of plasma from young into old mice can reverse age-related microglial-specific hippocampal epigenetic and transcriptomic changes in Cx3cr1:NuTRAP mice using whole genome oxidative bisulfite sequencing (WGoxBS) and RNA sequencing, respectively. These studies will identify specific genomic sites amenable to the rejuvenating interventions and serve as targets for future epigenome editing studies. In Aim 2, we will determine how the interaction of obesity and aging affect microglia heterogeneity. We hypothesize that high-fat diet leads to expansion of pathological LDAM resulting in impaired microglial function, which can be reversed by late-life calorie restriction. We will use single-cell transcriptomic analysis, bulk transcriptomics and microglia functional assays (phagocytic uptake and cytokine/chemokine analysis) to determine changes in microglia subpopulations in dietary-induced obese mice with age. In addition, we will determine whether starting calorie restriction at 12 months in dietary-induced obese mice can mitigate the effects of obesity on microglia heterogeneity. This will help identify mechanistic insights into microglia heterogeneity, LDAM and obesity-associated neuroinflammation. In total, the training goals and objectives will provide the needed skills and expertise to pursue a research career focused on developing anti-aging interventions.


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 = -$8,843 )
2025	2024	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Aging Research	000	2	11/27/2024	NON-COMPETING CONTINUATION	-$8,843
														Subtotal = -$8,843

Issue Date FY: 2024 ( Subtotal = $13,893 )
2024	2024	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Aging Research	000	2	10/25/2023	NON-COMPETING CONTINUATION	$36,513
2024	2024	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Aging Research	001	2	2/2/2024	NON-COMPETING CONTINUATION	-$22,620
														Subtotal = $13,893

Issue Date FY: 2022 ( Subtotal = $37,071 )
2022	2022	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY STE 530	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Aging Research	001	1	9/22/2022	NEW	$0
2022	2022	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY STE 530	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Aging Research	000	1	9/22/2022	NEW	$37,071
														Subtotal = $37,071

Grand Total All Awards = $42,121

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Reversing age-related epigenetic changes and characterizing microglia heterogeneity in obesity and aging

Award Number: F99AG079813

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 12/01/2022

PERIOD OF PERFORMANCE END DATE: 01/31/2024

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