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Thymic and Peripheral Aspects of T Cell Aging and Rejuvenation

Award Number: P01AG052359
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/15/2017
PERIOD OF PERFORMANCE END DATE: 02/29/2028

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Thymic and Peripheral Aspects of T Cell Aging and Rejuvenation - OVERALL- Abstract Infectious disease, cancer, and autoimmune disorders affect hundreds of millions of older adults. They reduce length and quality of life across the globe and inflict a massive economic burden on society, as vividly exemplified by the SARS-CoV-2 pandemic, that has claimed 93.1% of its victims amongst those 50 years and older, and 74.4% in those 64 and older. Yet, despite decades of research, restoring protective immunity in older adults has remained elusive. One critical factor contributing to age-related immune decline is a loss of naïve T (Tn) cell numbers and function, and their rejuvenation is highly desirable in order to enhance protective immunity and overall healthspan in older adults. The renewal of this T cell Rejuvenation Program Project is centered on two key questions: (1) why do Tn cell numbers and function deteriorate with age; and (2) what can be done about it? The premise of the program is that Tn cell aging is multifactorial and that it can only be resolved by targeting multiple defects. Thymic involution and the resulting decline in T cell production is the earliest event leading to immunosenescence. This reduction is compounded by a decline in bone marrow function, as well as by defects in Tn cell maintenance and function in the periphery. These deficiencies combine to erode the ability of the older immune system to detect and eliminate infectious agents and neoplastic cells, and to properly guard against autoimmunity. In the first program period, we strongly confirmed our initial hypotheses that lymphoid organ stromal elements deteriorate earlier than previously thought, and in a manner to decisively erode immunity, with aging. We will build on the synergy and success of the initial program period, where discoveries in one project are critically informing science in others, and continue to identify mechanistic reasons behind reduced central and peripheral lymphoid organ function with aging. We will then develop combined strategies to ameliorate these defects to improve immune defense in the elderly. Our hypothesis is that mechanistic dissection of defects in both thymic production AND peripheral Tn cell maintenance is required to devise and test effective interventions for T cell rejuvenation in the elderly. Three integrated projects led by experts in the field, supported by four cutting-edge cores, will test this hypothesis and achieve the following Program Goals: 1. Define mechanistic changes in primary and secondary lymphoid organ aging; 2. Determine the endogenous regenerative capacity of thymic and secondary lymphoid organ stroma over the lifespan; 3. Relate the progression of murine thymus, lymph node (LN) and T cell aging phenotypes to humans; and 4. Devise and test rejuvenation strategies to improve thymopoiesis, T cell survival and peripheral T cell maintenance and function, so as to enhance protective immunity. Over this support period, the above goals will provide a wealth of basic knowledge that will be translated to preclinical models and be poised for translation to older adults.


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 = $2,554,238 )
2025	2025	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Aging Research	000	8	3/25/2025	NON-COMPETING CONTINUATION	$2,345,731
2025	2025	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Aging Research	001	8	6/18/2025	NON-COMPETING CONTINUATION	$208,507
														Subtotal = $2,554,238

Issue Date FY: 2024 ( Subtotal = $2,615,632 )
2024	2024	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Aging Research	000	7	4/26/2024	NON-COMPETING CONTINUATION	$2,615,632
2024	2023	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Aging Research	002	6	7/24/2024	COMPETING CONTINUATION	$1,796
2024	2021	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Aging Research	001	5	7/24/2024	NON-COMPETING CONTINUATION	-$1,796
														Subtotal = $2,615,632

Issue Date FY: 2023 ( Subtotal = $2,712,996 )
2023	2023	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Aging Research	000	6	5/31/2023	COMPETING CONTINUATION	$2,712,996
														Subtotal = $2,712,996

Issue Date FY: 2021 ( Subtotal = $1,924,427 )
2021	2021	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Aging Research	000	5	7/1/2021	NON-COMPETING CONTINUATION	$1,924,427
														Subtotal = $1,924,427

Issue Date FY: 2020 ( Subtotal = $2,286,056 )
2020	2020	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Aging Research	000	4	7/31/2020	NON-COMPETING CONTINUATION	$1,963,309
2020	2020	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Aging Research	001	4	8/31/2020	SUPPLEMENT FOR EXPANSION	$322,747
														Subtotal = $2,286,056

Issue Date FY: 2019 ( Subtotal = $2,141,696 )
2019	2019	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Aging Research	000	3	6/28/2019	NON-COMPETING CONTINUATION	$1,989,909
2019	2019	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Aging Research	001	3	9/18/2019	SUPPLEMENT FOR EXPANSION	$151,787
														Subtotal = $2,141,696

Issue Date FY: 2018 ( Subtotal = $2,039,817 )
2018	2018	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Aging Research	001	2	8/31/2018	SUPPLEMENT FOR EXPANSION	$56,750
2018	2018	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Aging Research	002	2	9/8/2018	SUPPLEMENT FOR EXPANSION	$47,642
2018	2018	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Aging Research	000	2	8/3/2018	NON-COMPETING CONTINUATION	$1,935,425
														Subtotal = $2,039,817

Issue Date FY: 2017 ( Subtotal = $2,036,043 )
2017	2017	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Aging Research	000	1	9/6/2017	NEW	$2,036,043
														Subtotal = $2,036,043

Grand Total All Awards = $18,310,905

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Thymic and Peripheral Aspects of T Cell Aging and Rejuvenation

Award Number: P01AG052359

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/15/2017

PERIOD OF PERFORMANCE END DATE: 02/29/2028

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