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Ketogenic Diet Reduces Midlife Mortality and Improves Memory in Aging Mice
Open accessAbstract
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 [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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“Therapies that increase levels of the ketone body D-beta-hydroxybutyrate (D-BHB) have also been shown to increase the lifespan of mice (Newman et al., 2017; Roberts et al., 2017), fruit flies (Fan et al.”
Background[Ketone Body Metabolism and Renal Diseases].
Liu, Y., Ma, L., & Fu, P. (2023) · 四川大学学报：医学版 · doi:10.12182/20231160202 · Cited by 5
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Gut microbiota dysbiosis: the hidden roles in human aging and age-related diseases
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Improvement in age-related cognitive functions and life expectancy by ketogenic diets
Astrup, A. V., & Hjorth, M. F. (2017) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2017.142 · Cited by 4
Anti-inflammatory and Anti-infectious Dietary Paradigms May Be Crucial for Visceral Weight Reduction
Chen, D., Zhang, M.-L., Shi, Z., Li, C., Wang, Q., Song, J., Xu, Q., Li, H., & Zeng, Q.-P. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.00422 · Cited by 4
“Crosstalk between KD-mediated histone deacetylase (HDAC) inhibition and mechanistic target of rapamycin catalysis subunit 1 (mTORC1) signaling has been shown to contribute to lifespan extension in mice (44, 45).”
BackgroundIntegration of immune-metabolic signals to preserve healthy aging
Goldberg, E. L. (2020) · Translational Medicine of Aging · doi:10.1016/j.tma.2020.07.005 · Cited by 4
“Switching mice to a longevity-associated ketogenic diet [18,19], which is a very high-fat (90% of calories) low-carbohydrate (<1% of calories) diet that forces a metabolic switch favoring fatty acid oxidation by limiting glucose availability, activates a protective subset of γδ T cells in the lung and adipose tissue.”
BackgroundBridging the Gap: A Geroscience Primer for Neuroscientists With Potential Collaborative Applications
Hoffman, J. M., Hernandez, C. M., Hernandez, A. R., Bizon, J. L., Burke, S. N., Carter, C. S., & Buford, T. W. (2021) · The Journals of Gerontology Series A · doi:10.1093/gerona/glab314 · Cited by 4
da Rocha, L. S., Mendes, C. B., Silva, J. S., Alcides, R. L. G. F., Mendonça, I. P., Andrade-da-Costa, B. L. S., Machado, S. S., & Ximenes-da-Silva, A. (2023) · Nutritional Neuroscience · doi:10.1080/1028415x.2023.2178096 · Cited by 4
“KD improved a visuospatial learning and memory in aged mice [9]; but accelerated apoptosis and inhibited neurogenesis was reported in the rat hippocampus [10].”
BackgroundKetones to the rescue of the starving fly
Wilson, K. A., Bar, S., & Kapahi, P. (2022) · Nature Metabolism · doi:10.1038/s42255-022-00527-7 · Cited by 4
AlHilli, M. M., Sangwan, N., Myers, A., Tewari, S., Lindner, D. J., Cresci, G., & Reizes, O. (2025) · Journal of Ovarian Research · doi:10.1186/s13048-025-01731-1 · Cited by 3
“All murine diets were irradiated and provided by Tekland Envigo [19, 25].”
Hay, B., Brun, A., Fougerat, A., Mazurak, V. C., Bacquer, O. L., Talvas, J., & Capel, F. (2025) · Translational Oncology · doi:10.1016/j.tranon.2025.102596 · Cited by 3
“For example, KD has been shown to extend longevity and health span in mice [147,148].”
Leveraging cancer metabolism to translate into effective therapeutics
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“meal timing via intermittent fasting [5,6], the composition of macronutrients [7,8], or specific dietary components, such as branched-chain amino acids (BCAA) [9] or methionine [10–12], thereby revealing marked improvements in health and/or lifespan.”
BackgroundStubbs, B. J., Azañedo, G. A., Peralta, S., Diaz, S. R., Gray, W., Alexander, L. E. C., Silverman-Martin, W., Garcia, T. Y., Blonquist, T. M., Upadhyay, V., et al. (2024) · PLoS ONE · doi:10.1371/journal.pone.0307951 · Cited by 5
Self-citationStubbs, B. J., Nikiforov, A. I., Rihner, M. O., Weston, S. L., Higley, N. A., Stump, D. G., Krane, G. A., Gadupudi, G. S., Verdin, E. M., & Newman, J. C. (2021) · Food and Chemical Toxicology · doi:10.1016/j.fct.2021.112084 · Cited by 3
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“Corroborating our results, a study by Newman et al. (2017) found that the LC and KD diets applied continuously and in the long term, caused excess weight and obesity in mice.”
Nucleoside Diphosphate Kinases Are ATP-Regulated Carriers of Short-Chain Acyl-CoAs
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“HFD triggers a transcriptional response in mouse liver cells, involving the repression or activation of a specific set of genes [20].”
BackgroundA ketogenic diet regulates microglial activation to treat drug addiction
Ji, J., & Tang, Y. (2025) · Frontiers in Pharmacology · doi:10.3389/fphar.2025.1462699 · Cited by 3
“…and the nucleotide-binding, leucine-rich repeat, pyrin-domain-containing 3 (NLRP3) in fl ammasome (Guo et al., 2018; Trotta et al., 2019) in addition to an increase in the synthesis of substances such as peroxisome proliferator-activated receptor (PPAR) and interleukin (IL)-10 (Newman et al., 2017).”
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Sirtuins, healthspan, and longevity in mammals
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Unveiling the Anti-Aging Potential of 3HB: Lifespan Extension and Cellular Senescence Delay
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“Intriguingly, the ketogenic diet, known to elevate 3HB levels, also exhibits lifespan-extending effects in mice, suggesting a potential link between 3HB and the diet’s longevity benefits [20,21].”
Jiang, N., Xu, Z., Zhao, S., Gelfond, J., Strong, R., & Nelson, J. F. (2025) · The Journals of Gerontology Series A · doi:10.1093/gerona/glaf138 · Cited by 4
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“…the optimal macronutrient composition for longevity and reproductive health remains debated [76–79]. diets such as the Okinawan, Mediterranean, and dASH diets show consistent anti-ageing potential, whereas the long-term safety and efficacy of ketogenic diets require further evaluation [80,81].”
Tagliafico, L., Canevelli, M., Barreto, P. D. S., Cesari, M., Ferrucci, L., Vellas, B. J., & Rolland, Y. (2026) · The Journal of Frailty & Aging · doi:10.1016/j.tjfa.2026.100147 · Cited by 3
“…that a ketogenic diet in mice can reduce midlife mortality and enhance memory in older age, thereby extending overall longevity and healthspan [45,46]. β -hydroxybutyrate, a well-known ketone ester, has been shown to regulate protein solubility and selectively target mis-folded proteins,…”
Mózes, N., Fehér, Á., Csípő, T., Fazekas‐Pongor, V., Lipécz, Á., Major, D., Lehoczki, A., Dósa, N., Pártos, K., Csík, B., et al. (2026) · Nutrients · doi:10.3390/nu18071091 · Cited by 2
“Achieving nutritional ketosis, the metabolic state typically targeted by KDTs, involves substantial restriction of carbohydrate intake, moderate protein consumption, and an increased proportion of energy derived from dietary fats [73,74,77–79].”
InfluentialRole of the gut microbiome in the pathophysiology of brain disorders
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You are what you eat: How to best fuel your immune system
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“3-Hydroxybutyrate, alternatively known as β-hydroxybutyrate, is a naturally occurring metabolite in humans, synthesized from adipose tissue within the liver [16].”
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Metadata
- 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
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2017-09
- Volume
- 26
- Issue
- 3
- Pages
- 547-557.e8
- ISSN
- 1550-4131 (ISSN-L)
- 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
- FWCI
- 17.12
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- 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 (medical) › Diet and metabolism studies
- Health Sciences › Medicine › Physiology (medical) › 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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