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Roles of aging and cellular senescence in the development of intracranial aneurysm rupture

Award Number: R01AG077780
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/2023
PERIOD OF PERFORMANCE END DATE: 02/29/2028

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Roles of aging and cellular senescence in the development of intracranial aneurysm rupture - Project Summary Clinical studies have consistently shown a strong association between aging and increased risk for intracranial aneurysm rupture. Aging has traditionally been considered a non-modifiable risk factor. However, it is becoming evident that some of the biological changes associated with aging can be modifiable or partially reversible. Thus, pharmacological therapies targeting age-related biological events may be utilized to prevent aneurysmal rupture. Aging induces diverse changes in cellular homeostasis. One of the hallmarks of aging is cellular senescence, a state of permanent proliferative arrest. Senescent cells secrete pro-inflammatory and tissue remodeling cytokines collectively called the Senescence-Associated Secretory Phenotype (SASP). In addition to aging, cellular stresses induced by inflammation, reactive oxygen species, mitochondrial dysfunction, and hemodynamic stresses cause premature, pathological senescence in both young and aged individuals. Thus, we hypothesize that excessive senescent cell burden collectively caused by age-related and premature senescence may promote aneurysmal rupture through SASP-induced inflammation, tissue remodeling, and tissue damage. We will test whether the elimination of senescent cells prevents aneurysmal rupture. In addition, we will identify a rupture-promoting SASP profile using a proteomic approach. Aim 1 is to test whether aging promotes aneurysm rupture while increasing the total senescent cell burden. Using a mouse of aneurysm, we will establish the link between aging and the promotion of aneurysm rupture in both sexes. We will also assess potential sex differences in senescence and their contributions to aneurysm rupture. Aim 2 is to test whether cellular senescence promotes aneurysm rupture. We utilize pharmacological and transgene-mediated “senolytic” approaches to establish the causal link between cellular senescence and aneurysm rupture. We will employ (2a) a prototypical senolytic drug, ABT263 and (2b) transgene-mediated senolysis of p16-3MR mice. In addition, we will assess the relative contribution between age-related senescence and stress-induced premature senescence. Aim 3 is to identify rupture-promoting SASP profile and establish a screening platform for future studies. 3a. By applying proteomics to the cerebral arteries from Aims 1 and 2, we will identify a rupture-promoting SASP profile. 3b. We will identify the cell type that produces rupture-promoting SASPs. Using the data from 3a and 3b, we will establish an in vitro to in vivo screening platform for testing existing senolytics and senomorphs. 3c. We will validate the screening platform and key rupture-promoting SASPs. This proposal seeks to establish the causal links between aging, senescence, and aneurysmal rupture. The screening platform developed in this proposal will be used to test existing senolytics and senomorphs for preventing aneurysmal rupture in future studies.


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 = $608,992 )
2026	2026	DIGNITY HEALTH	185 BERRY ST STE 200	SAN FRANCISCO	CA	94107	SAN FRANCISCO	USA	Aging Research	000	4	2/23/2026	NON-COMPETING CONTINUATION	$608,992
														Subtotal = $608,992

Issue Date FY: 2025 ( Subtotal = $596,813 )
2025	2025	DIGNITY HEALTH	185 BERRY ST STE 200	SAN FRANCISCO	CA	94107	SAN FRANCISCO	USA	Aging Research	001	3	6/18/2025	NON-COMPETING CONTINUATION	$48,720
2025	2025	DIGNITY HEALTH	185 BERRY ST STE 200	SAN FRANCISCO	CA	94107	SAN FRANCISCO	USA	Aging Research	000	3	3/25/2025	NON-COMPETING CONTINUATION	$548,093
														Subtotal = $596,813

Issue Date FY: 2024 ( Subtotal = $608,992 )
2024	2024	DIGNITY HEALTH	185 BERRY ST STE 200	SAN FRANCISCO	CA	94107	SAN FRANCISCO	USA	Aging Research	001	2	6/28/2024	NON-COMPETING CONTINUATION	$60,899
2024	2024	DIGNITY HEALTH	185 BERRY ST STE 200	SAN FRANCISCO	CA	94107	SAN FRANCISCO	USA	Aging Research	000	2	3/7/2024	NON-COMPETING CONTINUATION	$548,093
														Subtotal = $608,992

Issue Date FY: 2023 ( Subtotal = $608,992 )
2023	2023	DIGNITY HEALTH	185 BERRY ST STE 300	SAN FRANCISCO	CA	94107	SAN FRANCISCO	USA	Aging Research	000	1	5/19/2023	NEW	$608,992
														Subtotal = $608,992

Grand Total All Awards = $2,423,789

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Roles of aging and cellular senescence in the development of intracranial aneurysm rupture

Award Number: R01AG077780

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/01/2023

PERIOD OF PERFORMANCE END DATE: 02/29/2028

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