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Kynurenine accumulation drives loss of muscle and bone function with aging

Award Number: P01AG036675
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/2011
PERIOD OF PERFORMANCE END DATE: 05/31/2027

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Kynurenine accumulation drives loss of muscle and bone function with aging - This is a competitive renewal application of our currently funded Program Project (P01) award now titled “Kynurenine Accumulation Drives Loss of Muscle and Bone Function with Aging”. Loss of muscle and bone mass with age are underlying factors contributing to falls and fractures in the elderly, and these fractures are very costly both in terms of financial burden and quality of life. A critical barrier to progress in correcting the problem of muscle and bone loss with aging is a poor understanding of the molecular and cellular mechanisms driving age-related musculoskeletal dysfunction. Major findings from the previous four years of funding include: (1) aging results in increased serum levels of the tryptophan (Trp) metabolite kynurenine (Kyn), a by-product of Trp degradation by the enzyme indoleamine 2,3-dioxygenase 1 (IDO1); (2) elevated Kyn levels in older patients are significantly associated with fragility hip fractures and markers of frailty; and (3) the aryl hydrocarbon receptor (AhR), which is activated by Kyn and its downstream metabolites, likely mediates the effects of Kyn on muscle and bone. Our central hypothesis is that AhR activation by Kyn and its metabolites with aging induces muscle and bone loss. Four individual projects, focused on Kyn-AhR interactions with the aging musculoskeletal system, comprise this application. The proposal also includes three Core facilities that will provide essential support to the Projects: an Administrative Core (Core A) that will serve to coordinate the activities of the different projects, supervise recruitment and mentoring of junior aging researchers including medical students from Puerto Rico, and provide biostatistics and bioinformatics support; a Functional Outcomes Core (Core B), which will provide resources for body composition (DXA), bone and muscle histomorphometry, bone imaging and RNAscope, bone mechanical testing, muscle functional testing, and mouse gait assessments; and a Cellular Aging Core (Core C) which will measure inflammatory cytokines associated with the senescence-associated secretory phenotype (SASP) and provide bone- and muscle-derived stem cells to all investigators, as well as perform assays of mitochondrial function, mitophagy, and autophagy in muscle and bone cells. The project has three specific aims: Aim 1 will test the hypothesis that age-related increases in AhR signaling by Kyn and its metabolites alter musculoskeletal stem cell function and muscle-bone crosstalk; Aim 2 tests the hypothesis that specific interventions that either reduce Kyn accumulation with aging or inhibit AhR signaling with aging can prevent age- related changes in muscle and bone stem cell function; and Aim 3 will determine the mechanism(s) by which increased activation of the Kyn-AhR pathway leads to musculoskeletal dysfunction in a sex-specific manner. The long-term impact of this Program Project will be the identification and development of new targets and countermeasures for preventing or reversing musculoskeletal aging.


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 = $2,262,480 )
2026	2026	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC	AUGUSTA UNIVERSITY 1120 15TH STREET	AUGUSTA	GA	30912	RICHMOND	USA	Aging Research	000	15	6/19/2026	NON-COMPETING CONTINUATION	$2,262,480
														Subtotal = $2,262,480

Issue Date FY: 2025 ( Subtotal = $2,218,187 )
2025	2025	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC	AUGUSTA UNIVERSITY 1120 15TH STREET	AUGUSTA	GA	30912	RICHMOND	USA	Aging Research	000	14	7/7/2025	NON-COMPETING CONTINUATION	$2,218,187
														Subtotal = $2,218,187

Issue Date FY: 2024 ( Subtotal = $2,648,602 )
2024	2024	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC	AUGUSTA UNIVERSITY 1120 15TH STREET	AUGUSTA	GA	30912	RICHMOND	USA	Aging Research	001	13	6/7/2024	SUPPLEMENT FOR EXPANSION	$384,199
2024	2024	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC	AUGUSTA UNIVERSITY 1120 15TH STREET	AUGUSTA	GA	30912	RICHMOND	USA	Aging Research	000	13	6/4/2024	NON-COMPETING CONTINUATION	$2,264,403
														Subtotal = $2,648,602

Issue Date FY: 2023 ( Subtotal = $2,265,327 )
2023	2023	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC.	1120 15TH ST STE CJ3301	AUGUSTA	GA	30912	RICHMOND	USA	Aging Research	002	12	8/11/2023	NON-COMPETING CONTINUATION	$2,265,327
2023	2022	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC.	1120 15TH ST STE CJ3301	AUGUSTA	GA	30912	RICHMOND	USA	Aging Research	001	11	5/16/2023	COMPETING CONTINUATION	$836,434
2023	2021	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC.	1120 15TH ST STE CJ3301	AUGUSTA	GA	30912	RICHMOND	USA	Aging Research	000	10	5/16/2023	NON-COMPETING CONTINUATION	-$836,434
														Subtotal = $2,265,327

Issue Date FY: 2022 ( Subtotal = $2,249,838 )
2022	2022	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC.	1120 15TH ST STE CJ3301	AUGUSTA	GA	30912	RICHMOND	USA	Aging Research	001	11	8/26/2022	COMPETING CONTINUATION	$2,249,838
2022	2021	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC.	1120 15TH ST STE CJ3301	AUGUSTA	GA	30912	RICHMOND	USA	Aging Research	000	10	8/18/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $2,249,838

Issue Date FY: 2021 ( Subtotal = $2,181,655 )
2021	2021	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC.	1120 15TH ST STE CJ3301	AUGUSTA	GA	30912	RICHMOND	USA	Aging Research	000	10	5/19/2021	NON-COMPETING CONTINUATION	$2,181,655
														Subtotal = $2,181,655

Issue Date FY: 2020 ( Subtotal = $2,362,881 )
2020	2020	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC.	1120 15TH ST STE CJ3301	AUGUSTA	GA	30912	RICHMOND	USA	Aging Research	001	9	7/17/2020	SUPPLEMENT FOR EXPANSION	$154,000
2020	2020	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC.	1120 15TH ST STE CJ3301	AUGUSTA	GA	30912	RICHMOND	USA	Aging Research	002	9	7/20/2020	SUPPLEMENT FOR EXPANSION	$0
2020	2020	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC.	1120 15TH ST STE CJ3301	AUGUSTA	GA	30912	RICHMOND	USA	Aging Research	000	9	3/23/2020	NON-COMPETING CONTINUATION	$2,208,881
														Subtotal = $2,362,881

Issue Date FY: 2019 ( Subtotal = $2,236,306 )
2019	2019	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC.	1120 15TH ST STE CJ3301	AUGUSTA	GA	30912	RICHMOND	USA	Aging Research	000	8	3/28/2019	NON-COMPETING CONTINUATION	$2,236,306
														Subtotal = $2,236,306

Issue Date FY: 2018 ( Subtotal = $2,373,762 )
2018	2018	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC.	1120 15TH ST # CJ3301	AUGUSTA	GA	30912	RICHMOND	USA	Aging Research	002	7	5/11/2018	NON-COMPETING CONTINUATION	$0
2018	2018	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC.	1120 15TH ST # CJ3301	AUGUSTA	GA	30912	RICHMOND	USA	Aging Research	003	7	5/23/2018	SUPPLEMENT FOR EXPANSION	$115,667
2018	2018	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC.	1120 15TH ST # CJ3301	AUGUSTA	GA	30912	RICHMOND	USA	Aging Research	001	7	5/2/2018	NON-COMPETING CONTINUATION	$0
2018	2018	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC.	1120 15TH ST # CJ3301	AUGUSTA	GA	30912	RICHMOND	USA	Aging Research	000	7	4/13/2018	NON-COMPETING CONTINUATION	$2,258,095
														Subtotal = $2,373,762

Issue Date FY: 2017 ( Subtotal = $2,277,404 )
2017	2017	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC.	1120 15TH ST # CJ3301	AUGUSTA	GA	30912	RICHMOND	USA	Aging Research	004	6	9/24/2017	COMPETING CONTINUATION	$409,937
2017	2017	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC.	1120 15TH ST # CJ3301	AUGUSTA	GA	30912	RICHMOND	USA	Aging Research	001	6	4/12/2017	COMPETING CONTINUATION	$1,867,467
2017	2017	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC.	1120 15TH ST # CJ3301	AUGUSTA	GA	30912	RICHMOND	USA	Aging Research	003	6	8/24/2017	COMPETING CONTINUATION	$18,746
2017	2015	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC.	1120 15TH ST # CJ3301	AUGUSTA	GA	30912	RICHMOND	USA	Aging Research	002	5	8/24/2017	NON-COMPETING CONTINUATION	-$18,746
2017	2015	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC.	1120 15TH ST # CJ3301	AUGUSTA	GA	30912	RICHMOND	USA	Aging Research	000	5	4/11/2017	NON-COMPETING CONTINUATION	$0
														Subtotal = $2,277,404

Issue Date FY: 2015 ( Subtotal = $1,169,820 )
2015	2015	GEORGIA REGENTS RESEARCH INSTITUTE INC	1120 15TH STREET	AUGUSTA	GA	30912	RICHMOND	USA	Aging Research	000	5	4/21/2015	NON-COMPETING CONTINUATION	$1,169,820
														Subtotal = $1,169,820

Issue Date FY: 2014 ( Subtotal = $1,240,396 )
2014	2014	GEORGIA REGENTS RESEARCH INSTITUTE INC	1120 15TH STREET	AUGUSTA	GA	30912	RICHMOND	USA	Aging Research	000	4	5/14/2014	NON-COMPETING CONTINUATION	$1,198,174
2014	2014	GEORGIA REGENTS RESEARCH INSTITUTE INC	1120 15TH STREET	AUGUSTA	GA	30912	RICHMOND	USA	Aging Research	001	4	6/30/2014	SUPPLEMENT FOR EXPANSION	$42,222
														Subtotal = $1,240,396

Issue Date FY: 2013 ( Subtotal = $1,225,553 )
2013	2013	GA HEALTH SCIENCE UNIVERSITY RESEARCH INSTITUTE, INC	1120 15TH STREET	AUGUSTA	GA	30912	RICHMOND	USA	Aging Research	000	3	5/20/2013	NON-COMPETING CONTINUATION	$1,225,553
														Subtotal = $1,225,553

Issue Date FY: 2012 ( Subtotal = $1,283,597 )
2012	2012	MEDICAL COLLEGE OF GEORGIA, RESEARCH INSTITUTE	1120 15TH STREET	AUGUSTA	GA	30912	RICHMOND	USA	Aging Research	001	2	7/19/2012	SUPPLEMENT FOR EXPANSION	$83,490
2012	2012	MEDICAL COLLEGE OF GEORGIA, RESEARCH INSTITUTE	1120 15TH STREET	AUGUSTA	GA	30912	RICHMOND	USA	Aging Research	000	2	4/26/2012	NON-COMPETING CONTINUATION	$1,200,107
														Subtotal = $1,283,597

Issue Date FY: 2011 ( Subtotal = $1,256,197 )
2011	2011	MEDICAL COLLEGE OF GEORGIA, RESEARCH INSTITUTE	1120 15TH STREET	AUGUSTA	GA	30912	RICHMOND	USA	Aging Research	000	1	4/26/2011	NEW	$1,256,197
														Subtotal = $1,256,197

Grand Total All Awards = $29,252,005

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Kynurenine accumulation drives loss of muscle and bone function with aging

Award Number: P01AG036675

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/01/2011

PERIOD OF PERFORMANCE END DATE: 05/31/2027

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