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Targeting Senescence to Improve Wound Healing in Aging

Award Number: K76AG083300
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2023
PERIOD OF PERFORMANCE END DATE: 05/31/2028

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Targeting Senescence to Improve Wound Healing in Aging - Impaired or delayed wound healing is a major problem affecting primarily older adults, millions of older adults in the United States are affected per year. Delayed wound healing increases aged patients’ risk of chronic wounds, wound infections, and tissue necrosis, resulting in significant morbidity and mortality. Wound care is also a rising economic problem with an estimated $10 billion annually spent on wound care for older adults. The various causes for delayed healing of aging ultimately result in perturbations of normal wound healing processes. This includes a recently discovered wound healing response incorporating cellular senescence, a biologically active state of permanent growth arrest caused by various stressors like tissue injury. Senescent cells (SnC) that arise acutely in cutaneous wounds have beneficial effects in wound healing when they are transiently present, however, specific SnC identities and their associated functions during wound healing have still not been thoroughly characterized. My preliminary data generated during my GEMSSTAR award confirm a robust and transient increase in beneficial senescence during excisional wound healing in young (2 month) mice, required for timely wound resolution. However, my data also demonstrates that in aged (24 month) mice with delayed wound healing, this acute wound senescence response is significantly attenuated. A similar diminished acute senescence-like response occurs during aged human wound healing suggesting that attenuation is conserved between species. To gain better understanding of wound SnCs that benefit wound healing and which are diminished in aging, my lab has isolated high-expressing p16Ink4a (a common senescence marker) cells from the wounds of young p16tdTom mice. Preliminary single-cell RNAseq analysis reveals multiple wound cell types with high p16+ expression during wound healing. A majority are within distinct clusters of fibroblasts (Fb) and macrophages (Mϕ) with p16+ expression associated with positive regulation of wound healing: p16+ wound Fbs upregulate genes for protein synthesis and certain collagens while p16+ wound Mϕs are more anti-inflammatory and promote extracellular matrix deposition with both cell types being more apoptosis-resistant compared to their respective p16-negative counterparts. As transient senescence is important for optimal wound healing in younger organisms this project’s goals are to uncover the cellular mechanisms by which specific wound SnCs positively influence wound healing and determine their roles in delayed healing of aging. I will test the overall hypothesis that age-related attenuation of beneficial wound SnCs contributes to delayed wound healing in aged mammals and that restoration of these key wound SnCs can promote more timely wound resolution. The following Aims are designed to elucidate changes in wound SnCs throughout aging, define their beneficial impact on wound healing, and provide the therapeutic framework for treatment of delayed healing of aging with senescence modification.


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 = $243,000 )
2025	2025	TRUSTEES OF BOSTON UNIVERSITY	85 EAST NEWTON ST # M-921	BOSTON	MA	02118	SUFFOLK	USA	Aging Research	000	3	5/9/2025	NON-COMPETING CONTINUATION	$243,000
														Subtotal = $243,000

Issue Date FY: 2024 ( Subtotal = $243,000 )
2024	2024	TRUSTEES OF BOSTON UNIVERSITY	85 EAST NEWTON ST # M-921	BOSTON	MA	02118	SUFFOLK	USA	Aging Research	000	2	6/28/2024	NON-COMPETING CONTINUATION	$243,000
														Subtotal = $243,000

Issue Date FY: 2023 ( Subtotal = $243,000 )
2023	2023	TRUSTEES OF BOSTON UNIVERSITY	85 EAST NEWTON ST # M-921	BOSTON	MA	02118	SUFFOLK	USA	Aging Research	001	1	9/11/2023	NEW	$78,283
2023	2023	TRUSTEES OF BOSTON UNIVERSITY	85 EAST NEWTON ST # M-921	BOSTON	MA	02118	SUFFOLK	USA	Aging Research	000	1	8/17/2023	NEW	$164,717
														Subtotal = $243,000

Grand Total All Awards = $729,000

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Targeting Senescence to Improve Wound Healing in Aging

Award Number: K76AG083300

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2023

PERIOD OF PERFORMANCE END DATE: 05/31/2028

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