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Investigating the role of cytosolic mitochondrial double-stranded RNA in cellular senescence and aging

Award Number: R01AG082708
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/15/2023
PERIOD OF PERFORMANCE END DATE: 05/31/2028

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Investigating the role of cytosolic mitochondrial double-stranded RNA in cellular senescence and aging - PROJECT SUMMARY/ABSTRACT This application investigates the relationship between mitochondrial RNA, inflammation, senescence, and aging. Cellular senescence is a well-established driver of tissue and organismal aging, a process thought to be partly mediated via the induction of a chronic Senescence-associated secretory phenotype (SASP). Consequently, there is great interest in selectively targeting senescent cells as a strategy to promote healthy aging. Our work has demonstrated that mitochondrial dysfunction is a hallmark of cellular senescence and a driver of the SASP and that by targeting them we may be able to suppress the detrimental SASP known to contribute to aging. Mitochondrial double-stranded RNA (mtdsRNA) when present in the cytosol is known to be especially immunogenic and trigger an inflammatory response. We observed that senescent cells contain increased levels of cytosolic mtdsRNA together with increased expression of RNA sensors. Furthermore, we found that transfection of cells with mtdsRNA triggers an inflammatory response and inhibition of mitochondrial DNA transcription in senescent cells, decreases the SASP. Finally, we observed that mtdsRNA requires the cytosolic DNA sensor cGAS to induce inflammation suggesting an interplay between RNA and DNA sensing pathways in the process. This led us to hypothesize that cytosolic mdsRNA plays a role in the regulation of the SASP and may be a novel target for interventions to improve healthspan during aging. In this project, we will dissect the mechanisms by which mtdsRNA increases in the cytosol of senescent cells as well as investigate if activation of RNA sensing pathways contributes to the SASP. Additionally, we will explore the mechanisms mediating the interplay between mitochondrial DNA and RNA in the development of the SASP. Our ultimate goal is to identify new interventions that target senescent cells to alleviate age-related dysfunction.


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: 2025 ( Subtotal = $571,621 )
2025	2025	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Aging Research	001	3	6/20/2025	NON-COMPETING CONTINUATION	$46,662
2025	2025	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Aging Research	000	3	4/18/2025	NON-COMPETING CONTINUATION	$524,959
														Subtotal = $571,621

Issue Date FY: 2024 ( Subtotal = $507,781 )
2024	2024	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Aging Research	000	2	4/18/2024	NON-COMPETING CONTINUATION	$507,781
														Subtotal = $507,781

Issue Date FY: 2023 ( Subtotal = $455,881 )
2023	2023	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Aging Research	000	1	9/14/2023	NEW	$455,881
														Subtotal = $455,881

Grand Total All Awards = $1,535,283

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Investigating the role of cytosolic mitochondrial double-stranded RNA in cellular senescence and aging

Award Number: R01AG082708

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/15/2023

PERIOD OF PERFORMANCE END DATE: 05/31/2028

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