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Cytoplasmic chromatin fragments in cell senescence - novel mechanisms and interventions

Award Number: R01AG071861
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/2021
PERIOD OF PERFORMANCE END DATE: 02/28/2027

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Cytoplasmic chromatin fragments in cell senescence - novel mechanisms and interventions - PROJECT SUMMARY Cellular senescence is a cause of cell and tissue aging. Senescence is caused by a range of cellular stresses and characterized by an irreversible proliferation arrest and a potent pro-inflammatory phenotype, the senescence-associated secretory phenotype (SASP). Senescence-associated proliferation arrest and SASP cooperate in tumor suppression, by arresting proliferation of damaged pre-malignant cells and promoting immune clearance of the damaged cells. However, over the longer term, as a source of chronic inflammation, SASP also promotes tissue aging and disease. Consequently, there is currently much effort devoted to development of pharmacologic approaches to eliminate senescent cells to promote healthy aging. However, these so-called senolytic drugs tend to show unwanted toxicities. An alternative, perhaps less toxic approach, is to use senomorphic drugs to specifically inhibit the pro-aging SASP. Importantly, inhibition of SASP does not necessarily impair the tumor suppressive role of senescence. On the contrary, elimination of SASP can prevent cancer. Hence, it is important to define the mechanism of SASP activation, because its inhibition may be an approach to combat the pro-aging effects of senescent cells. Recently, we showed that senescent cells shed fragments of nuclear chromatin into the cytoplasm, cytoplasmic chromatin fragments (CCF), via a nucleus-to-cytoplasmic blebbing process. CCF are very strongly positive for a DNA damage marker, phosphorylated histone γH2AX. Formation of CCF depends upon a novel manifestation of the cellular recycling process autophagy, specifically nuclear autophagy. CCF signal through cytoplasmic DNA sensors to activate NFκB, the major transcriptional activator of SASP. Most recently, we have defined an unanticipated upstream trigger of CCF and SASP, namely dysfunctional mitochondria in senescent cells. Dysfunctional mitochondria are themselves already linked to chronic inflammation and aging. We hypothesize that nuclear expulsion of CCF harboring DNA double strand breaks is a mechanism for senescent cells with impaired DNA repair pathways to decrease the intranuclear load of toxic DNA double strand breaks. We also hypothesize that dysfunctional mitochondria trigger autophagy-dependent formation of CCF in senescent cells by retrograde mitochondria-to-nucleus signaling, involving JNK kinase and the transcription factors Hypoxia Inducible Factor 1a (HIF1a), the “JNK-CCF” and “HIF-CCF” pathways, respectively. Delineation of the JNK-CCF and HIF-CCF pathways and their interactions will provide new opportunities to intervene to suppress chronic inflammation driven by SASP in vivo, thereby potentiating healthy aging and longevity.


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	2025	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Aging Research	000	5	2/20/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $419,931 )
2025	2025	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Aging Research	001	5	6/9/2025	NON-COMPETING CONTINUATION	$34,279
2025	2025	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Aging Research	000	5	3/7/2025	NON-COMPETING CONTINUATION	$385,652
														Subtotal = $419,931

Issue Date FY: 2024 ( Subtotal = $428,501 )
2024	2024	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Aging Research	001	4	7/5/2024	NON-COMPETING CONTINUATION	$42,849
2024	2024	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Aging Research	000	4	2/2/2024	NON-COMPETING CONTINUATION	$385,652
														Subtotal = $428,501

Issue Date FY: 2023 ( Subtotal = $393,372 )
2023	2023	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Aging Research	000	3	3/6/2023	NON-COMPETING CONTINUATION	$393,372
														Subtotal = $393,372

Issue Date FY: 2022 ( Subtotal = $393,372 )
2022	2022	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Aging Research	000	2	4/6/2022	NON-COMPETING CONTINUATION	$393,372
														Subtotal = $393,372

Issue Date FY: 2021 ( Subtotal = $628,610 )
2021	2021	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Aging Research	000	1	4/30/2021	NEW	$628,610
														Subtotal = $628,610

Grand Total All Awards = $2,263,786

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Cytoplasmic chromatin fragments in cell senescence - novel mechanisms and interventions

Award Number: R01AG071861

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/01/2021

PERIOD OF PERFORMANCE END DATE: 02/28/2027

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