Sunday, May 18, 2025 5/18/2025

Unconventional regulation of mTORC1 signaling by inositol phosphate: implications for nutrient-induced premature aging

Award Number: R21AG071975
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

Group Awards By:

View Award Description

Unconventional regulation of mTORC1 signaling by inositol phosphate: implications for nutrient-induced premature aging - Nutrient accelerates cellular aging processes through metabolic stress. The detrimental effects of nutrient overload to health span are partially mediated by mTORC1 (mechanistic Target of Rapamycin Complex 1), an evolutionarily conserved nutrient-sensing kinase that signals for increase in anabolic processes. mTORC1 activity has been directly linked to aging and age-associated diseases in a diverse range of organisms including humans, mice, flies and worms. Remarkably, genetic or pharmacological inhibition of mTORC1 improved the health and increased the lifespan of several animal models of premature aging. Although the molecular mechanisms for mTORC1 activation by amino acids and growth factors are well established, recent findings indicate that excess glucose stimulates mTORC1 signaling through unconventional mechanisms that are not completely understood. Glucose metabolism directly and indirectly stimulates the production of the small metabolite inositol hexakisphosphate (IP6). Recent structural studies revealed that IP6 is tightly associated with mTOR, the catalytic subunit of mTORC1. Preliminary data suggest that IP6 binding to mTOR stabilizes the in vitro association between mTOR and RAPTOR, the regulatory subunit of mTORC1. The goal of this proposal is to establish a role for IP6 in the regulation of mTORC1 signaling in vivo and to assess whether targeting the metabolic pathways for IP6 synthesis will prevent cellular aging and promote longevity. In specific aim 1, the impact of IP6 metabolism on mTOR signaling and cellular ageing will be investigated. IP6 synthesis will be manipulated by suppression of the two critical kinases that catalyze the synthesis of IP6 – IPMK and IPK1. In addition we will suppress ISYNA1, the enzyme that catalyzes de novo synthesis of inositol from glucose. The direct effects of cellular IP6 on mTORC1/2 complex assembly and stability will be examined using recombinant mTOR mutants that are unable to bind to IP6. In specific aim 2, the crosstalk between IP6 metabolism and mTORC1 signaling will be genetically tested using C. elegans as a model for assessing longevity. Epistasis studies will be performed to determine how IPMK and IPK1 interact with of mTORC1. Suppression of enzymes involved in IP6 synthesis are predicted to protect worms from mTORC1- induced premature aging. Understanding the impact of IP6 on mTORC1 signaling and in aging will open up new opportunities for targeting these pathways to improve 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	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Aging Research	001	2	4/16/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$242,751
2025	2023	UNIVERSITY OF SOUTH ALABAMA	307 N UNIVERSITY BLVD	MOBILE	AL	36608	MOBILE	USA	Aging Research	003	3	4/22/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$45,634
2025	2023	UNIVERSITY OF SOUTH ALABAMA	307 N UNIVERSITY BLVD	MOBILE	AL	36608	MOBILE	USA	Aging Research	005	3	4/25/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$197,117
2025	2023	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Aging Research	004	2	4/25/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$197,117
2025	2023	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Aging Research	000	2	4/9/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$242,751
2025	2023	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Aging Research	002	2	4/22/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$45,634
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2023	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Aging Research	001	2	12/20/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$197,116
2024	2022	VANDERBILT UNIVERSITY	110 21ST AVE S	NASHVILLE	TN	37203	DAVIDSON	USA	Aging Research	000	1	12/20/2023	NEW	-$197,116
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $188,352 )
2023	2023	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Aging Research	001	2	7/28/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$188,352
2023	2022	VANDERBILT UNIVERSITY	110 21ST AVE S	NASHVILLE	TN	37203	DAVIDSON	USA	Aging Research	000	1	7/27/2023	NEW	$0
														Subtotal = $188,352

Issue Date FY: 2022 ( Subtotal = $294,163 )
2022	2022	VANDERBILT UNIVERSITY, THE	110 21ST AVENUE S STE 800	NASHVILLE	TN	37203	DAVIDSON	USA	Aging Research	000	1	2/15/2022	NEW	$294,163
														Subtotal = $294,163

Grand Total All Awards = $482,515

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Unconventional regulation of mTORC1 signaling by inositol phosphate: implications for nutrient-induced premature aging

Award Number: R21AG071975

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer