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Non-Autonomous control of aging in Drosophila

Award Number: R01AG059586
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2018
PERIOD OF PERFORMANCE END DATE: 05/31/2025

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Non-Autonomous control of aging in Drosophila - Project Summary: Aging is associated with functional decline in metabolic, physiological, proliferative, and tissue homeostasis leading to deterioration on the organismal level. The identification of therapeutic strategies that prevent or postpone age-related decline has become an urgent goal of biomedical science research. A key issue is the identification of tissue(s) that can drive organismal ageing. We will test a model of tissue-specific metabolic, physiological and molecular changes that drive organismal aging non-autonomously. Indy (I'm not dead yet) encodes a plasma membrane citrate transporter predominantly expressed in fly metabolic tissues: the midgut, fat body and oenocytes (fly liver). We have shown that organism-wide reduction in Indy activity extends fly health and longevity by altering energy metabolism. Indy flies have decreased lipid and glucose levels, increased insulin sensitivity, increased mitochondrial biogenesis and reduced oxidative damage, among other effects. Additionally, we have shown that down-regulation of Indy expression preserves intestinal stem cell homeostasis, suggesting an important link between metabolic changes in the midgut, physiological homeostasis and organismal aging. Moreover, we have obtained preliminary data that specific Indy reduction in fly midgut mimics many beneficial effects of Indy reduction found in whole body Indy hypomorphs including longer lifespan. Therefore, our working hypothesis is that INDY reduction in the midgut regulates citrate levels leading to metabolic changes that preserve tissue homeostasis and slows aging non- autonomously. We propose the following specific aims. Confirm that the midgut has a key role in longevity regulation by comparing the effects on fly health and lifespan when INDY is reduced solely in the midgut, the fat body, or the oenocytes (Aim 1). Determine effects and mechanism of Indy reduction by using an integrated approach involving study of metabolism, and determination of the transcriptomic and targeted metabolomics profile in Indy flies (Aim 2). Determine the physiological mechanism by which Indy reduction in the midgut slows aging on organismal level (Aim 3). Our proposed study will advance our basic knowledge on the molecular and physiological mechanisms underlying non-autonomous effects on organismal aging. Reducing INDY homologs in worms, mice, rats and non-human primates leads to similar metabolic outcome, suggesting that our findings could be translated to mammalian organisms.


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 = $0 )
2026	2022	UNIVERSITY OF CONNECTICUT HEALTH CENTER	263 FARMINGTON AVE	FARMINGTON	CT	06030	CAPITOL	USA	Aging Research	000	5	12/1/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2022	UNIVERSITY OF CONNECTICUT HEALTH CENTER	263 FARMINGTON AVE	FARMINGTON	CT	06030	CAPITOL	USA	Aging Research	000	5	6/3/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $410,000 )
2022	2022	UNIVERSITY OF CONNECTICUT	263 FARMINGTON AVE, ASB #3	FARMINGTON	CT	06032	CAPITOL	USA	Aging Research	000	5	6/22/2022	NON-COMPETING CONTINUATION	$410,000
														Subtotal = $410,000

Issue Date FY: 2021 ( Subtotal = $410,000 )
2021	2021	UNIVERSITY OF CONNECTICUT	263 FARMINGTON AVE, ASB #3	FARMINGTON	CT	06032	CAPITOL	USA	Aging Research	000	4	6/9/2021	NON-COMPETING CONTINUATION	$410,000
														Subtotal = $410,000

Issue Date FY: 2020 ( Subtotal = $820,000 )
2020	2020	UNIVERSITY OF CONNECTICUT	263 FARMINGTON AVE, ASB #3	FARMINGTON	CT	06032	CAPITOL	USA	Aging Research	001	3	7/24/2020	SUPPLEMENT FOR EXPANSION	$410,000
2020	2020	UNIVERSITY OF CONNECTICUT	263 FARMINGTON AVE, ASB #3	FARMINGTON	CT	06032	CAPITOL	USA	Aging Research	000	3	6/2/2020	NON-COMPETING CONTINUATION	$410,000
														Subtotal = $820,000

Issue Date FY: 2019 ( Subtotal = $409,688 )
2019	2019	UNIVERSITY OF CONNECTICUT	263 FARMINGTON AVE, ASB #3	FARMINGTON	CT	06032	CAPITOL	USA	Aging Research	000	2	5/29/2019	NON-COMPETING CONTINUATION	$409,688
														Subtotal = $409,688

Issue Date FY: 2018 ( Subtotal = $406,250 )
2018	2018	UNIVERSITY OF CONNECTICUT	263 FARMINGTON AVE, ASB #3	FARMINGTON	CT	06032	CAPITOL	USA	Aging Research	000	1	8/24/2018	NEW	$406,250
														Subtotal = $406,250

Grand Total All Awards = $2,455,938

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Non-Autonomous control of aging in Drosophila

Award Number: R01AG059586

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2018

PERIOD OF PERFORMANCE END DATE: 05/31/2025

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