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Mechanisms Specific to the Beneficial Effects of Dietary Restriction

Award Number: R01AG044346
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/30/2013
PERIOD OF PERFORMANCE END DATE: 01/31/2031

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Mechanisms Specific to the Beneficial Effects of Dietary Restriction - ABSTRACT: Dietary restriction (DR), via reduced food intake or periods of increased fasting, is the most potent method for promoting healthy aging and age-onset disease resistance in animal models. However, DR’s therapeutic potential to humans is limited by associated negative physiological effects, including impaired growth, immunity and reproductive capacity. Although nutrient sensing mediators of DR have been identified, such as mTOR, FOXO/As and the sirtuins, these central nodes recapitulate the entirety of the response, making them sub- optimal therapeutic targets. Our long-term objective is to uncover molecular mechanisms that specifically mediate only the pro-longevity effects of DR to develop optimal therapeutics. Two key mediators of DR are AMP-activated protein kinase (AMPK), a cellular fuel gauge activated when energy levels are low and mTORC1, a nutrient and growth factor sensing kinase that acts antagonistically to AMPK. However, like DR, both AMPK and mTORC1 modulation increases lifespan at the cost of impaired growth and reproduction. The objective in this project is to use the genetically tractable model system C. elegans and human cell lines to identify mechanisms by which AMPK, mTORC1 and DR specifically mediate longevity, in order to elucidate the first molecular targets that recapitulate only the pro-health effects of DR. The central hypothesis is that beneficial and detrimental effects of DR can be uncoupled. In support of this hypothesis, specific amino acid combinations in the diet increase lifespan while maintaining normal reproduction, establishing that the positive effects of DR on lifespan do not require obligate detrimental side effects. In addition, highlighted research from the previous two funding periods demonstrates that the transcriptional coactivator and AMPK direct target CRTC-1 could uncouple the longevity effects of AMPK from other negative side effects such as developmental delay, reproduction suppression and reduced body size. Further, using targeted protein degradation of neuronal mTORC1 activators, we showed that mTORC1 mediated longevity can be achieved in C. elegans without associated tradeoffs from suppressed anabolism. Together, the prior work was proof of principle that the benefits of mTORC1 and AMPK mediated longevity need not be obligatorily linked to negative side-effects. However, to date, the field has focused on leveraging AMPK and mTORC1 via chronic suppression of the kinase. We now seek to better define how these kinases become deregulated with age, if they become refractory to specific nutrient and metabolic inputs, and how we might increase the dynamics of their activity in old age to increase organismal resilience. Lastly, using cutting edge in vivo multi-organelle mapping tools, we will define how mTORC1 and AMPK alter metabolic state via systemic remodeling of the cytosolic organellar landscape.


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 = $479,583 )
2026	2026	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	1033 MASSACHUSETTS AVE STE 3	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Aging Research	001	11	1/16/2026	COMPETING CONTINUATION	$479,583
2026	2024	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	1033 MASSACHUSETTS AVE STE 3	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Aging Research	000	10	1/5/2026	OTHER REVISION	$0
														Subtotal = $479,583

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2024	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	1033 MASSACHUSETTS AVE STE 3	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Aging Research	002	10	9/23/2025	OTHER REVISION	$0
2025	2024	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	1033 MASSACHUSETTS AVE STE 3	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Aging Research	001	10	9/9/2025	OTHER REVISION	$0
2025	2024	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	1033 MASSACHUSETTS AVE STE 3	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Aging Research	000	10	5/14/2025	TERMINATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $326,975 )
2024	2024	HARVARD COLLEGE PRESIDENT & FELLOWS OF	677 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Aging Research	000	10	6/26/2024	NON-COMPETING CONTINUATION	$326,975
														Subtotal = $326,975

Issue Date FY: 2023 ( Subtotal = $326,975 )
2023	2023	HARVARD COLLEGE PRESIDENT & FELLOWS OF	677 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Aging Research	000	9	6/22/2023	NON-COMPETING CONTINUATION	$326,975
														Subtotal = $326,975

Issue Date FY: 2022 ( Subtotal = $326,975 )
2022	2022	HARVARD COLLEGE PRESIDENT & FELLOWS OF	677 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Aging Research	000	8	7/7/2022	NON-COMPETING CONTINUATION	$326,975
														Subtotal = $326,975

Issue Date FY: 2021 ( Subtotal = $326,975 )
2021	2021	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	677 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Aging Research	000	7	7/8/2021	NON-COMPETING CONTINUATION	$326,975
														Subtotal = $326,975

Issue Date FY: 2020 ( Subtotal = $321,296 )
2020	2020	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	677 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Aging Research	001	6	9/21/2020	COMPETING CONTINUATION	$326,975
2020	2017	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	677 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Aging Research	000	5	1/22/2020	NON-COMPETING CONTINUATION	-$5,679
														Subtotal = $321,296

Issue Date FY: 2017 ( Subtotal = $331,075 )
2017	2017	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	677 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Aging Research	001	5	6/23/2017	NON-COMPETING CONTINUATION	$331,075
2017	2015	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	677 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Aging Research	000	3	12/7/2016	NON-COMPETING CONTINUATION	$0
														Subtotal = $331,075

Issue Date FY: 2016 ( Subtotal = $331,075 )
2016	2016	HARVARD UNIVERSITY, SCHOOL OF PUBLIC HEALTH	55 SHATTUCK STREET	BOSTON	MA	02115	SUFFOLK	USA	Aging Research	000	4	6/1/2016	EXTENSION WITH OR WITHOUT FUNDS	$331,075
														Subtotal = $331,075

Issue Date FY: 2015 ( Subtotal = $321,142 )
2015	2015	HARVARD UNIVERSITY, SCHOOL OF PUBLIC HEALTH	55 SHATTUCK STREET	BOSTON	MA	02115	SUFFOLK	USA	Aging Research	000	3	5/15/2015	NON-COMPETING CONTINUATION	$321,142
														Subtotal = $321,142

Issue Date FY: 2014 ( Subtotal = $331,075 )
2014	2014	HARVARD UNIVERSITY, SCHOOL OF PUBLIC HEALTH	55 SHATTUCK STREET	BOSTON	MA	02115	SUFFOLK	USA	Aging Research	000	2	6/30/2014	NON-COMPETING CONTINUATION	$331,075
														Subtotal = $331,075

Issue Date FY: 2013 ( Subtotal = $331,075 )
2013	2013	HARVARD UNIVERSITY, SCHOOL OF PUBLIC HEALTH	55 SHATTUCK STREET	BOSTON	MA	02115	SUFFOLK	USA	Aging Research	000	1	9/25/2013	NEW	$331,075
														Subtotal = $331,075

Grand Total All Awards = $3,754,221

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Mechanisms Specific to the Beneficial Effects of Dietary Restriction

Award Number: R01AG044346

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/30/2013

PERIOD OF PERFORMANCE END DATE: 01/31/2031

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