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Circadian epigenetic regulation of aging skeletal muscle & the impact of exercise

Award Number: K99AG092932
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 07/03/2026
PERIOD OF PERFORMANCE END DATE: 06/30/2028

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Circadian epigenetic regulation of aging skeletal muscle & the impact of exercise - Skeletal muscle mass, quality and function decline with age, leading to a reduction in quality of life, an increased risk of falls, and higher mortality rates. By 2030, 1 in 6 people worldwide are predicted to be over 60 years of age. Recent estimates suggest that extending health span and increasing life expectancy by just 1 year is worth $38 trillion per year to the global economy, around 6 times the federal budget. Developing a comprehensive understanding of the molecular underpinnings of biological aging to enhance and maintain health span into old age is an imminent global challenge and is therefore the focus of this proposal. Age related loss of homeostatic control is well characterized. However, little is known about the potential role of the age-related decline in the circadian clock mechanism as a driving force of reduced homeostatic control, leading to dysfunction and disease. Preliminary data suggest that there is a progressive loss in the number of genes that present circadian oscillations in skeletal muscle, leading to a progressive decline between 6 and 27 months of age (~50% ). This proposal puts forward the concept that circadian oscillations within the skeletal muscle epigenome and transcriptome are an essential homeostatic feature that is lost with aging but is modifiable by exercise training. Male and female mice from the NIA colony will be assessed at 6, 18 and 28 months of age. Gastrocnemius muscle tissue from these mice will be collected every 4-hours for 24-hours. Muscle will be used in different molecular assays including RNA-sequencing, assays for transposase accessible chromatin, and chromatin immunoprecipitation with sequencing targeting RNA Polymerase II. Integrative bioinformatic analyses will provide the first genome-wide, circadian epigenetic/ transcriptomic map of skeletal muscle and how it is altered with age, in addition to identifying sexually dimorphisms. To test the plasticity of these declining CCG programs, we will employ an 8-week exercise intervention to identify responsive/nonresponsive elements, identifying relationships with physiological outcomes. We will also elucidate the role of the pioneer circadian transcription factor BMAL 1 in the age-related decline and exercise induced remodeling of the circadian epigenome/ transcriptome. We will compare 6- and 28-month-old muscle-specific BMAL 1 KO mice to naturally aged mice, with and without an exercise intervention. My global hypotheses are that aging will dysregulate chromatin accessibility at promoters which converge, leading to more aberrant transcriptional profiles and a reduction in the number of genes that show circadian oscillations. I hypothesize that many features will be restored to more 'youthful' levels by exercise training. I also hypothesize that loss of muscle BMAL 1 will recapitulate many features of natural aging and that its loss will suppress exercise related remodeling of the epigenome and thus, circadian transcriptome. The experiments and training opportunities afforded by this proposal will facilitate my transition into independent research, focused on interventions and therapeutics that improve muscle molecular clock function and health span in humans


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 = $103,969 )
2026	2026	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Aging Research	000	1	7/7/2026	NEW	$103,969
														Subtotal = $103,969

Grand Total All Awards = $103,969

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Circadian epigenetic regulation of aging skeletal muscle & the impact of exercise

Award Number: K99AG092932

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 07/03/2026

PERIOD OF PERFORMANCE END DATE: 06/30/2028

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