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Mitonuclear signaling pathways in senescence-associated inflammation

Award Number: K99AG073450
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 09/15/2022
PERIOD OF PERFORMANCE END DATE: 08/31/2025

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Mitonuclear signaling pathways in senescence-associated inflammation - PROJECT SUMMARY Cellular senescence is a hallmark of the aging process and contributes to chronic disease vulnerability. Although senescence acts acutely as a tumor suppressor mechanism, chronically it also contributes to inflammation in aged tissue through the senescence-associated secretory phenotype (SASP). Hence, removal of senescent cells in vivo improves healthspan and lifespan, and rescues pathology associated with a plethora of phenotypes and diseases of aging. However, pharmacological “senolytic” approaches tend to have toxic side effects, likely limiting the utility of senolytics as tools to promote healthy aging. As proof-of-concept for an alternative approach, suppression of SASP in vivo reduces chronic liver inflammation and delays onset of hepatocellular carcinoma. Recently, we have shown that SASP is dependent on expulsion of cytosolic chromatin fragments (CCF) from the nucleus into the cytoplasm of senescent cells. Senescent cells harbor dysfunctional mitochondria, as reflected by decreased membrane potential, elevated ROS production, decreased mitophagic turnover, and altered intermediary metabolism. We have recently linked dysfunctional mitochondria in senescent cells to CCF production, and hence SASP, through a retrograde mitonuclear signaling pathway. This pathway involves mitochondrial ROS-mediated activation of the kinase JNK1/2, which is required for CCF formation, and the DNA repair protein 53BP1, which suppresses CCF formation. However, the mechanism linking JNK1/2 to 53BP1 is unknown. Extending these findings, studies in non-vertebrate organisms also suggest that mitochondria-nucleus retrograde signaling pathways can modify aging and longevity, altogether suggesting that identification and targeting of these pathways has therapeutic potential in the treatment of age-associated diseases. However, these pathways are poorly understood in mammalian systems. I hypothesize that mitonuclear signaling in senescent cells modulates the senescent cell phenotype and hence senescence-associated human disease. This proposal has two Aims in the mentored K99 phase, to: 1) Determine the mechanism by which JNK1/2 regulates 53BP1 to induce CCF formation; 2) Investigate the 53BP1-independent role of JNK1/2 senescent cells; and an additional Aim in the independent R00 phase, to 3) Investigate the role of mitochondria-mediated suppression of ATF4 and crosstalk between other stress responses in senescent cells. Elucidation of these mitonuclear signaling pathways in mammalian cells is of broad general interest to all biologists but can also identify therapeutic targets for reduction of SASP. This approach can uncover alternatives to senolytic drugs for treatment of age-associated disease and promote healthy 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 = $0 )
2026	2023	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Aging Research	000	2	1/13/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2023	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Aging Research	000	2	9/25/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $117,979 )
2023	2023	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Aging Research	000	2	8/15/2023	NON-COMPETING CONTINUATION	$117,979
														Subtotal = $117,979

Issue Date FY: 2022 ( Subtotal = $117,979 )
2022	2022	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Aging Research	000	1	8/12/2022	NEW	$117,979
														Subtotal = $117,979

Grand Total All Awards = $235,958

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Mitonuclear signaling pathways in senescence-associated inflammation

Award Number: K99AG073450

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 09/15/2022

PERIOD OF PERFORMANCE END DATE: 08/31/2025

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