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Targeting p21-Highly Expressing Cells to Increase Lifespan and Healthspan in Old Age

Award Number: R01AG076642
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/2022
PERIOD OF PERFORMANCE END DATE: 02/28/2027

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Targeting p21-Highly Expressing Cells to Increase Lifespan and Healthspan in Old Age - Project Summary Chronological age is the leading risk factor for most chronic diseases, frailty, and mortality worldwide. Thus, the elderly population usually has multiple chronic conditions at the same time, resulting in poor health and reduced quality of life (prolonged morbidity period) at the later stage of life. There is a big challenge to compress morbidity period and increase healthspan (lifespan with good health). In this project, we propose to examine the role of p21high senescent cells in lifespan and healthspan. We have generated and validated a new p21-Cre transgenic mouse model containing a p21 promoter driving a bicistronic message consisting of Cre fused to a tamoxifen- inducible estrogen receptor (ER) element. This model enables us to monitor, sort, kill or modulate p21high cells with aging in vivo. Our preliminary data shows that p21high and p16high cells are two distinct cell populations, and the p21-Cre mouse model targets 1.5-10% of cells in various tissues in 23-month-old mice. Monthly clearance of p21high cells in mice starting at 20 months reduces frailty index, extends lifespan, and more importantly, improves physical function at the end of life. In this proposal, we will further characterize the role and mechanisms of p21high cells in lifespan and healthspan. Our overarching hypothesis is that targeting p21high cells can extend lifespan and compress morbidity in old age. In aim 1.1, we will investigate whether clearance of p21high cells could extend lifespan and healthspan using a larger group size. We will examine potential sex difference and perform postmortem pathological analysis to examine the cause of death and disease burden. Moreover, we will follow physical function and frailty index of these mice every month from 20-month-old to the end of life to assess late life health status. In aim 1.2, we will leverage p21-Cre mouse models to sort and enrich p21high cells from 6 tissues of 23-month-old mice where we observed p21high cells (2-10%), and perform single cell RNA sequencing on these cells along with non-p21high cells. In addition, we will perform single nucleus sequencing and imaging mass cytometry. In aim 2, we will investigate the role of NF-κB pathway in p21high cells in lifespan and healthspan shortening. This project is likely to have a broad impact on aging research by gaining a comprehensive understanding of p21high cells at both functional and transcriptomic levels in vivo. Results from this project will also enable future testing of pharmacological interventions that eliminate these cells to improve lifespan and compress morbidity.


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 = $405,493 )
2026	2026	REGENTS OF THE UNIVERSITY OF MINNESOTA	2221 UNIVERSITY AVE SE STE 100	MINNEAPOLIS	MN	55414	HENNEPIN	USA	Aging Research	000	5	2/2/2026	NON-COMPETING CONTINUATION	$405,493
														Subtotal = $405,493

Issue Date FY: 2025 ( Subtotal = $450,817 )
2025	2025	REGENTS OF THE UNIVERSITY OF MINNESOTA	2221 UNIVERSITY AVE SE STE 100	MINNEAPOLIS	MN	55414	HENNEPIN	USA	Aging Research	001	4	7/30/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$450,817
2025	2024	UNIVERSITY OF CONNECTICUT HEALTH CENTER	263 FARMINGTON AVE	FARMINGTON	CT	06030	CAPITOL	USA	Aging Research	000	3	7/30/2025	NON-COMPETING CONTINUATION	$0
2025	2024	UNIVERSITY OF CONNECTICUT HEALTH CENTER	263 FARMINGTON AVE	FARMINGTON	CT	06030	CAPITOL	USA	Aging Research	002	3	8/8/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $450,817

Issue Date FY: 2024 ( Subtotal = $479,636 )
2024	2024	UNIVERSITY OF CONNECTICUT HEALTH CENTER	263 FARMINGTON AVE	FARMINGTON	CT	06030	CAPITOL	USA	Aging Research	001	3	6/28/2024	NON-COMPETING CONTINUATION	$47,963
2024	2024	UNIVERSITY OF CONNECTICUT HEALTH CENTER	263 FARMINGTON AVE	FARMINGTON	CT	06030	CAPITOL	USA	Aging Research	000	3	2/19/2024	NON-COMPETING CONTINUATION	$431,673
														Subtotal = $479,636

Issue Date FY: 2023 ( Subtotal = $486,637 )
2023	2023	UNIVERSITY OF CONNECTICUT	263 FARMINGTON AVE, ASB #3	FARMINGTON	CT	06032	CAPITOL	USA	Aging Research	000	2	1/24/2023	NON-COMPETING CONTINUATION	$486,637
														Subtotal = $486,637

Issue Date FY: 2022 ( Subtotal = $497,766 )
2022	2022	UNIVERSITY OF CONNECTICUT	263 FARMINGTON AVE, ASB #3	FARMINGTON	CT	06032	CAPITOL	USA	Aging Research	000	1	5/25/2022	NEW	$497,766
														Subtotal = $497,766

Grand Total All Awards = $2,320,349

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Targeting p21-Highly Expressing Cells to Increase Lifespan and Healthspan in Old Age

Award Number: R01AG076642

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/01/2022

PERIOD OF PERFORMANCE END DATE: 02/28/2027

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