Tuesday, July 1, 2025 7/1/2025

Investigating the interface of epigenetics and metabolism underlying memory formation in the adult, aging, and AD brain

Award Number: R01AG076835
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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Investigating the interface of epigenetics and metabolism underlying memory formation in the adult, aging, and AD brain - Project Summary/Abstract The ability to learn, consolidate and retrieve information begins to decline with normal aging, a major risk factor for Alzheimer’s Disease (AD) and dementia. In addition to aging, sedentary behavior ranks first in the US and third in the world as a risk factor for causing cognitive decline and exacerbating AD. Greater and accelerated rates of cognitive impairment in women with AD underscore the need for identifying the mechanisms by which exercise prevents cognitive decline in normal aging and AD in both sexes. As observed by our labs and others, hippocampus-dependent learning is facilitated by exercise in situations that are usually subthreshold for encoding and memory consolidation and requires the induction of brain-derived neurotrophic factor (BDNF). Our data suggest that specific exercise patterns can engage a ‘molecular memory’ for that experience that persists through periods of sedentary behavior and enables a short exercise session, to again, induce hippocampal BDNF and facilitate memory. We have proposed that epigenetic mechanisms mediate this “molecular memory” of exercise, as the epigenome represents a signal transduction platform that is capable of encoding past experience, current metabolic states (because nearly every epigenetic modification is a metabolite) and establishing stable changes in cell function that lead to long-term changes in behavior. Preliminary data in this proposal lead us to propose the novel hypothesis that specific patterns of exercise establish a molecular feedback loop that integrates rate-limiting aspects of acetyl-CoA metabolism and histone acetylation/methylation mechanisms to modulate gene expression required for long-term memory formation and synaptic plasticity. Our goal in this proposal is to define, in aging wild type and 5xFAD female and male mice, the exercise parameters that establish a molecular memory, to investigate the effect of exercise on acetyl-CoA metabolic pathways and histone modifications and to determine whether manipulations to this molecular feedback loop overcome deficiencies in synaptic plasticity and memory formation in aging and 5xFAD female and male mice. We propose three Aims. Aim 1 - Determine how specific exercise patterns affect synaptic plasticity and memory formation in aging wild type mice and 5xFAD mice. Aim 2 - determine the effect of exercise on acetyl-CoA metabolic pathways, histone modification, and gene expression in aging wild type mice and 5xFAD mice. Aim 3 - determine the effect of ameliorating hippocampal acetyl-CoA deficiencies in aging and 5xFAD mice on gene expression, synaptic plasticity and memory formation. Overall, successful completion of the research in this proposal will improve our understanding of how the epigenome integrates information from metabolism (acetyl-CoA dynamics) and experience (exercise), how this interplay becomes impaired with aging and in the context of AD, and how pharmacological modulation of acetyl-CoA dynamics may improve age- and AD-related cognitive dysfunction.


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 = $706,614 )
2025	2025	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Aging Research	001	4	6/9/2025	NON-COMPETING CONTINUATION	$57,682
2025	2025	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Aging Research	000	4	3/7/2025	NON-COMPETING CONTINUATION	$648,932
														Subtotal = $706,614

Issue Date FY: 2024 ( Subtotal = $728,885 )
2024	2024	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Aging Research	000	3	3/5/2024	NON-COMPETING CONTINUATION	$655,997
2024	2024	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Aging Research	001	3	7/3/2024	NON-COMPETING CONTINUATION	$72,888
														Subtotal = $728,885

Issue Date FY: 2023 ( Subtotal = $736,735 )
2023	2023	UNIVERSITY OF CALIFORNIA, IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Aging Research	000	2	3/8/2023	NON-COMPETING CONTINUATION	$736,735
														Subtotal = $736,735

Issue Date FY: 2022 ( Subtotal = $666,023 )
2022	2022	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Aging Research	000	1	6/6/2022	NEW	$666,023
														Subtotal = $666,023

Grand Total All Awards = $2,838,257

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Investigating the interface of epigenetics and metabolism underlying memory formation in the adult, aging, and AD brain

Award Number: R01AG076835

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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