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Mechanisms of cell non-autonomous signaling through the hypoxic response

Award Number: R01AG058717
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/15/2019
PERIOD OF PERFORMANCE END DATE: 11/30/2024

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Mechanisms of cell non-autonomous signaling through the hypoxic response - Project Summary/Abstract Led by groundbreaking studies in invertebrate models, our understanding of the mechanisms of aging has grown exponentially in the past 25 years. Despite this growth, there are many aspects of the genetic and molecular mechanisms of aging that are still not well understood. One of these mechanisms is the ability of small subsets of cells (frequently neurons) to modulate the aging process cell non-autonomously. Recently, multiple high-impact publications have identified individual genes and neurons that initiate signaling pathways and eventually modify the physiology of peripheral tissues to benefit health and longevity. These studies provide substantial evidence that cell non-autonomous control of aging is common to multiple longevity pathways, but they lack in detail as to the specific signals, receptors, and neural circuits involved. Our preliminary data identify a new cell non-autonomous longevity pathway, led by the transcription factor necessary to respond to low oxygen environments, the hypoxia-inducible factor (hif-1). We further find that stabilization of HIF-1 in neurons, through either genetic or environmental approaches, leads to induction of an intestinal protein, flavin-containing monooxygenase-2 (fmo-2), that is both necessary and sufficient to improve healthspan, stress resistance, and longevity. We observe that induction of fmo-2 and extension of lifespan by HIF-1 stabilization each depend on the presence of the serotonin producing enzyme tph-1 and the serotonin receptor ser-7. This project will map core neural components of the cell non-autonomous pathway initiated by stabilization of neuronal HIF-1 that eventually leads to intestinal fmo-2 induction and extension of lifespan. Aim 1 will focus on the initiation of the response, including the identity of the neurons and the timing and mechanism of HIF-1's promotion of physiological changes cell non-autonomously. The results will establish where and how a small subset of neurons initiates a broad response to low oxygen. The second aim focuses on the neuron expressing ser-7, a highly conserved serotonin receptor that propagates the HIF-1-mediated signal. The third aim will focus on the neural circuit downstream of HIF-1, identifying key propagating and integrating cells and core signals both unique to this pathway and shared by other cell non-autonomous networks. The results will define a neural circuit led by HIF-1 and utilizing serotonin that may partially overlap with other longevity pathways. The resulting data are crucial to our understanding of defined networks that control physiology and the rate of aging, and will likely lead to future studies designed to mimic signals in these networks. Together, these aims will act independently and synergistically to provide an understanding of a major signaling network that modifies aging. Our ultimate goal is to exploit this knowledge of control mechanisms of aging to develop approaches that promote human health.


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 = $0 )
2025	2023	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE STE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Aging Research	000	5	4/9/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $316,326 )
2023	2023	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON STREET	ANN ARBOR	MI	48109	WASHTENAW	USA	Aging Research	000	5	1/5/2023	NON-COMPETING CONTINUATION	$316,326
														Subtotal = $316,326

Issue Date FY: 2022 ( Subtotal = $315,792 )
2022	2022	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Aging Research	001	4	4/21/2022	NON-COMPETING CONTINUATION	$31,580
2022	2022	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Aging Research	000	4	11/30/2021	NON-COMPETING CONTINUATION	$284,212
														Subtotal = $315,792

Issue Date FY: 2021 ( Subtotal = $315,274 )
2021	2021	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Aging Research	000	3	2/4/2021	NON-COMPETING CONTINUATION	$315,274
														Subtotal = $315,274

Issue Date FY: 2020 ( Subtotal = $314,771 )
2020	2020	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Aging Research	001	2	1/30/2020	NON-COMPETING CONTINUATION	$31,478
2020	2020	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Aging Research	000	2	12/6/2019	NON-COMPETING CONTINUATION	$283,293
														Subtotal = $314,771

Issue Date FY: 2019 ( Subtotal = $337,279 )
2019	2019	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Aging Research	001	1	8/10/2019	NEW	$22,997
2019	2019	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Aging Research	000	1	1/15/2019	NEW	$314,282
														Subtotal = $337,279

Grand Total All Awards = $1,599,442

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Mechanisms of cell non-autonomous signaling through the hypoxic response

Award Number: R01AG058717

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/15/2019

PERIOD OF PERFORMANCE END DATE: 11/30/2024

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