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Investigations of targets, mechanisms, and optimal delivery of therapeutic ketosis for functional longevity and treatment of Alzheimer's disease

Award Number: P01AG062817
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Summary – Overall 'Investigation of targets, mechanisms, and optimal delivery of therapeutic ketosis for functional longevity and treatment of Alzheimer's disease' We recently demonstrated, for the first time anywhere, that the isocaloric continuous Ketogenic diet extends cognitive and memory and muscle functions in mice, and significantly increases median longevity by 13%1. In the same issue of Cell Metabolism, others showed that the intermittent Ketogenic diet (iKD) preserves many late life functions in mice. These simultaneously-published findings have profound mechanistic (for understanding the biology of aging) and translational (for US public health) implications. Mechanistically, they suggest the hypothesis that 'ketosis delays aging'. The PPG application is designed to identify mechanistic targets and biomarkers by which therapeutic ketosis delays aging in mice, and are consistent with the geroscience concept, i.e. that interventions that delay aging should delay age related disease, in this case AD, Alzheimer's. By identifying the KD mechanisms and biomarkers in mice, this study will lay the ground work for future human studies. In order to serve these mechanistic and translational goals, we propose these four projects. 1, Cortopassi, involves the mechanistic dissection of the ketolongevity mechanism, using transcriptomics, protein arrays and knockout mice, and Shc antagonists for Alzheimer's disease. 2, Pelicci, maps the epigenetic consequences of aging, and how the KD reverses them, and to what extent these overlap with aging and Alzheimer's. 3, Baar, addresses KAT and acetylation mechanisms by which improved muscle function delays brain aging in wild-type and Alzheimer's mouse model. 4, Ramsey, identifies the 'ketotherapeutic envelope' necessary for preservation of late-life functions and longevity, and with respect to an Alzheimer's mouse model. These Projects are all interactive as shown in the text. They are also supported by an outstanding Animal Core C, led by Kent Lloyd DVM PHD and Lee-Way Jin MD PHD with stellar experience in mouse biology and Alzheimer's disease, brilliant support by Biostatistics Core B, Kyoungmi Kim, and a well- organized Administrative Core A. The completion of this project will lead to new mechanistic inside into the therapeutic ketosis longevity mechanism, and identify biomarkers of ketotherapeutic effect that could be relevant to preservation of functions and longevity in aging Americans, and those with Alzheimer's disease.


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: 2023 ( Subtotal = $2,214,911 )
2023	2023	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Aging Research	001	5	7/7/2023	NON-COMPETING CONTINUATION	$2,234,244
2023	2021	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Aging Research	000	3	12/15/2022	NON-COMPETING CONTINUATION	-$19,333
														Subtotal = $2,214,911

Issue Date FY: 2022 ( Subtotal = $2,235,177 )
2022	2022	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Aging Research	001	4	8/17/2022	NON-COMPETING CONTINUATION	$2,235,177
2022	2021	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Aging Research	000	3	8/16/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $2,235,177

Issue Date FY: 2021 ( Subtotal = $2,342,299 )
2021	2021	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Aging Research	000	3	4/28/2021	NON-COMPETING CONTINUATION	$2,342,299
														Subtotal = $2,342,299

Issue Date FY: 2020 ( Subtotal = $2,358,242 )
2020	2020	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Aging Research	001	2	6/9/2020	SUPPLEMENT FOR EXPANSION	$63,215
2020	2020	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Aging Research	002	2	8/25/2020	SUPPLEMENT FOR EXPANSION	$58,304
2020	2020	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Aging Research	000	2	4/30/2020	NON-COMPETING CONTINUATION	$2,236,723
														Subtotal = $2,358,242

Issue Date FY: 2019 ( Subtotal = $2,242,722 )
2019	2019	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Aging Research	000	1	6/14/2019	NEW	$2,242,722
														Subtotal = $2,242,722

Grand Total All Awards = $11,393,351

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Investigations of targets, mechanisms, and optimal delivery of therapeutic ketosis for functional longevity and treatment of Alzheimer's disease

Award Number: P01AG062817

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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