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Network-Driven Dynamics of Replicative Aging

Award Number: R01AG056440
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2017
PERIOD OF PERFORMANCE END DATE: 02/29/2028

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Network-Driven Dynamics of Replicative Aging - Project Summary This project aims at integrating computational modeling and innovative measurement technologies to understand the complexity of single-cell aging and the emergent dynamics from the underlying regulatory networks. Aging is closely associated with many diseases, such cancer, diabetes, and neurodegenerative diseases. Advances in understanding the basic biology of aging will facilitate the development of new interventional strategies to mitigate age-related diseases and prolong human healthspan. Although studies in model organisms have identified many genes and factors that influence lifespan in eukaryotes, emerging challenges are to understand how these genes and factors interact and operate dynamically to drive the aging process and to determine the lifespan. During the previous funding period, our multidisciplinary team, using microfluidic and imaging technologies combined with computational modeling, discovered that isogenic yeast cells age with two distinct forms: one with decreased ribosomal DNA (rDNA) silencing and nucleolar decline (Mode 1) whereas the other with heme depletion and mitochondrial decline (Mode 2). We further identified a core molecular circuit, consisting of the lysine deacetylase Sir2 and the heme-activated protein (HAP) transcriptional complex, that governs the fate decision toward one of the aging paths in single cells. Building upon these results, for the next funding period, we will investigate the age-dependent dynamics of the energy homeostasis and protein homeostasis systems, two conserved aging hallmark pathways in eukaryotes, and their interactions with the Sir2-HAP fate-decision circuit. In Aim 1, we will quantitatively characterize the interactions between aging and the energy homeostasis system and develop a model that simulates the aging dynamics of the system. In Aim 2, we will quantitatively characterize the interactions between aging and the protein homeostasis system and develop a dynamic model of proteostasis in aging based on the data collected. In Aim 3, we will combine experiments with modeling to characterize, simulate, and predict single-cell aging trajectories and lifespan under complex environmental conditions, with a combination of different nutrients and stresses. The proposed research will advance a quantitative and predictive understanding of regulatory networks underlying single-cell aging under complex environmental conditions, laying the foundation for interventional strategies for ameliorating age-related diseases and promoting longevity.


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 = $533,021 )
2025	2025	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Aging Research	000	8	3/6/2025	NON-COMPETING CONTINUATION	$489,509
2025	2025	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Aging Research	001	8	6/17/2025	NON-COMPETING CONTINUATION	$43,512
														Subtotal = $533,021

Issue Date FY: 2024 ( Subtotal = $560,533 )
2024	2024	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Aging Research	003	7	3/5/2024	NON-COMPETING CONTINUATION	$504,480
2024	2024	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Aging Research	004	7	7/5/2024	NON-COMPETING CONTINUATION	$56,053
2024	2023	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Aging Research	002	6	2/13/2024	COMPETING CONTINUATION	$3
2024	2021	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Aging Research	000	5	2/13/2024	NON-COMPETING CONTINUATION	-$3
2024	2021	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Aging Research	001	5	2/13/2024	SUPPLEMENT FOR EXPANSION	-$1
														Subtotal = $560,533

Issue Date FY: 2023 ( Subtotal = $576,551 )
2023	2023	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Aging Research	000	6	5/5/2023	COMPETING CONTINUATION	$576,551
														Subtotal = $576,551

Issue Date FY: 2021 ( Subtotal = $675,615 )
2021	2021	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Aging Research	001	5	6/17/2021	SUPPLEMENT FOR EXPANSION	$118,469
2021	2021	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Aging Research	000	5	6/16/2021	NON-COMPETING CONTINUATION	$557,146
														Subtotal = $675,615

Issue Date FY: 2020 ( Subtotal = $686,770 )
2020	2020	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Aging Research	001	4	9/8/2020	SUPPLEMENT FOR EXPANSION	$118,125
2020	2020	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Aging Research	000	4	6/1/2020	NON-COMPETING CONTINUATION	$568,645
														Subtotal = $686,770

Issue Date FY: 2019 ( Subtotal = $744,785 )
2019	2019	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR DEPT 621	LA JOLLA	CA	92093	SAN DIEGO	USA	Aging Research	000	3	6/28/2019	NON-COMPETING CONTINUATION	$744,785
														Subtotal = $744,785

Issue Date FY: 2018 ( Subtotal = $753,768 )
2018	2018	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR DEPT 621	LA JOLLA	CA	92093	SAN DIEGO	USA	Aging Research	001	2	8/31/2018	SUPPLEMENT FOR EXPANSION	$163,280
2018	2018	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR DEPT 621	LA JOLLA	CA	92093	SAN DIEGO	USA	Aging Research	000	2	5/8/2018	NON-COMPETING CONTINUATION	$590,488
														Subtotal = $753,768

Issue Date FY: 2017 ( Subtotal = $543,106 )
2017	2017	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR DEPT 621	LA JOLLA	CA	92093	SAN DIEGO	USA	Aging Research	000	1	7/31/2017	NEW	$543,106
														Subtotal = $543,106

Grand Total All Awards = $5,074,149

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Network-Driven Dynamics of Replicative Aging

Award Number: R01AG056440

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2017

PERIOD OF PERFORMANCE END DATE: 02/29/2028

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