Ketogenic Diet Reduces Midlife Mortality and Improves Memory in Aging Mice

Newman, John C.; Covarrubias, Anthony J.; Zhao, Minghao; Yu, Xinxing; Gut, Philipp; Ng, Che-Ping; Huang, Yu; Haldar, Saptarsi; Verdin, Eric

doi:10.1016/j.cmet.2017.08.004

Cited by 493Genetics, Aging, and Longevity in Model OrganismsDiet and metabolism studiesDietary Effects on Health

Ketogenic Diet Reduces Midlife Mortality and Improves Memory in Aging Mice

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Newman, John C., Covarrubias, Anthony J., Zhao, Minghao, Yu, Xinxing, Gut, Philipp, Ng, Che-Ping, Huang, Yu, Haldar, Saptarsi +1 more·2017·Cell Metabolism

DOI 10.1016/j.cmet.2017.08.004PMC PMC5605815

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Abstract

Ketogenic diets recapitulate certain metabolic aspects of dietary restriction such as reliance on fatty acid metabolism and production of ketone bodies. We investigated whether an isoprotein ketogenic diet (KD) might, like dietary restriction, affect longevity and healthspan in C57BL/6 male mice. We find that Cyclic KD, KD alternated weekly with the Control diet to prevent obesity, reduces midlife mortality but does not affect maximum lifespan. A non-ketogenic high-fat diet (HF) fed similarly may have an intermediate effect on mortality. Cyclic KD improves memory performance in old age, while modestly improving composite healthspan measures. Gene expression analysis identifies downregulation of insulin, protein synthesis, and fatty acid synthesis pathways as mechanisms common to KD and HF. However, upregulation of PPARα target genes is unique to KD, consistent across tissues, and preserved in old age. In all, we show that a non-obesogenic ketogenic diet improves survival, memory, and healthspan in aging mice.

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Several clinical studies have shown a positive effect of a ketogenic diet on patients with AD or mild cognitive impairment (MCI), consistent with preclinical results.
“Several clinical studies have shown a positive effect of a ketogenic diet on patients with AD or mild cognitive impairment (MCI), consistent with preclinical results [87–91] (Table 1).”
From Role of diet and its effects on the gut microbiome in the pathophysiology of mental disorders (2022) · cites this paper as [88]

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Authors: Newman, J. C., Covarrubias, A. J., Zhao, M., Yu, X., Gut, P., Ng, C.-P., Huang, Y., Haldar, S., & Verdin, E.
Affiliations: Gladstone Institutes (US)
Buck Institute for Research on Aging (US)
University of California, San Francisco (US)
Corresponding author: Verdin, Eric
ORCID: Covarrubias, Anthony J.
Yu, Xinxing
Gut, Philipp
Huang, Yu
Haldar, Saptarsi
Verdin, Eric
Venue: Cell Metabolism
Publisher: Elsevier BV
Published: 2017-09
Volume: 26
Issue: 3
Pages: 547-557.e8
ISSN: 1550-4131 (ISSN-L)
DOI: 10.1016/j.cmet.2017.08.004
PMC: PMC5605815
OpenAlex: W2750998547
Cited by: 493
References: 43
Citations by year: 2026: 39 · 2025: 50 · 2024: 68 · 2023: 63 · 2022: 68 · 2021: 57 · 2020: 66 · 2019: 42 · 2018: 32 · 2017: 7 · 2015: 1
FWCI: 17.12
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 370 d)
Locations: Cell Metabolism (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Funders: NIH (P30NS065780, K08AG048354, R24DK085610)
Gladstone Institutes
Buck Institute
Buck Impact Circle
Larry L. Hillblom Foundation (2012-A-016-FEL)
Glenn Foundation for Medical Research
American Federation for Aging Research
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
Health Sciences › Medicine › Physiology › Diet and metabolism studies
Health Sciences › Medicine › Physiology › Dietary Effects on Health
Keywords: ketogenic diet, midlife mortality, healthspan, aging, memory, high-fat diet, PPARα, insulin signaling, protein synthesis, fatty acid synthesis, ketone bodies, dietary restriction, longevity, obesity prevention, C57BL/6 mice
MeSH terms: Aging, Animals, Fasting, Gene Expression Regulation, Liver, Male, Memory, Mice, Inbred C57BL, Mortality, PPAR alpha, Diet, Ketogenic, Diet, High-Fat

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Ketogenic Diet Reduces Midlife Mortality and Improves Memory in Aging Mice

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