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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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The Ketogenic Diet and Cardiovascular Diseases
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Hwang, C. Y., Choe, W., Yoon, K., Ha, J., Kim, S. S., Yeo, E., & Kang, I. (2022) · Nutrients · doi:10.3390/nu14224932 · Cited by 115
Ketone-Based Metabolic Therapy: Is Increased NAD+ a Primary Mechanism?
Elamin, M., Ruskin, D. N., Masino, S. A., & Sacchetti, P. (2017) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2017.00377 · Cited by 105
“At the cognitive level, beneficial effects on learning and memory were reported (Brownlow et al., 2017; Newman et al., 2017).”
BackgroundVery‐low‐carbohydrate diet enhances human T‐cell immunity through immunometabolic reprogramming
Hirschberger, S., Strauß, G., Effinger, D., Marstaller, X., Ferstl, A., Müller, M. B., Wu, T., Hübner, M., Rahmel, T., Mascolo, H., et al. (2021) · EMBO Molecular Medicine · doi:10.15252/emmm.202114323 · Cited by 99
“In animal models, BHB has been shown to dampen inappropriate innate immune responses via suppression of the NLRP3 inflammasome, thus ameliorating chronic low-grade inflammation and associated diseases (Youm et al, 2015; Goldberg et al, 2017; Newman et al, 2017).”
BackgroundDorling, J. L., van Vliet, S., Huffman, K. M., Kraus, W. E., Bhapkar, M. V., Pieper, C. F., Stewart, T. M., Das, S. K., Racette, S. B., Roberts, S. B., et al. (2020) · Nutrition Reviews · doi:10.1093/nutrit/nuaa085 · Cited by 108
“dogenous ketogenesis by severely restricting carbohydrate intake, can improve mortality rates in rodents.(129) Likewise, a collection of researchers posit that protein restriction is pivotal in mediating the aging-related benefits of CR,(130)”
BackgroundGrandl, G., Straub, L., Rudigier, C., Arnold, M., Wueest, S., Konrad, D., & Wolfrum, C. (2018) · The Journal of Physiology · doi:10.1113/jp275173 · Cited by 97
The intersection of frailty and metabolism
Mishra, M., Wu, J., Kane, A. E., & Howlett, S. E. (2024) · Cell Metabolism · doi:10.1016/j.cmet.2024.03.012 · Cited by 103
The ketogenic diet preserves skeletal muscle with aging in mice
Wallace, M. A., Aguirre, N. W., Marcotte, G. R., Marshall, A. G., Baehr, L. M., Hughes, D. C., Hamilton, K. L., Roberts, M. N., Lopez‐Dominguez, J. A., Miller, B. F., et al. (2021) · Aging Cell · doi:10.1111/acel.13322 · Cited by 93
“Consequently, we (Roberts et al., 2018) and others (Newman et al., 2017) have shown that a KD increases life and health span in mice, while the ketone, β- hydroxybutyrate (BHB), increases life span in C. elegans (Edwards et al., 2014).”
BackgroundCircadian blueprint of metabolic pathways in the brain
Greco, C. M., & Sassone‐Corsi, P. (2018) · Nature reviews. Neuroscience · doi:10.1038/s41583-018-0096-y · Cited by 94
Current nutritional and pharmacological anti-aging interventions
Ros, M., & Carrascosa, J. M. (2020) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2019.165612 · Cited by 86
Vinciguerra, F., Graziano, M., Hagnäs, M. P., Frittitta, L., & Tumminia, A. (2020) · Nutrients · doi:10.3390/nu12041019 · Cited by 92
Park, S., Zhang, T., Wu, X., & Qiu, J. Y. (2020) · Journal of Clinical Biochemistry and Nutrition · doi:10.3164/jcbn.19-87 · Cited by 93
Mihaylova, M. M., Chaix, A., Delibegović, M., Ramsey, J. J., Bass, J. T., Melkani, G. C., Singh, R., Chen, Z., Ja, W. W., Shirasu-Hiza, M., et al. (2023) · Cell Metabolism · doi:10.1016/j.cmet.2023.06.008 · Cited by 97
Hu, E., Du, H., Zhu, X., Wang, L., Shang, S., Wu, X., Lü, H., & Lu, X. (2018) · Neuroscience · doi:10.1016/j.neuroscience.2018.06.036 · Cited by 92
Targeting metabolic pathways for extension of lifespan and healthspan across multiple species
Parkhitko, A. A., Filine, E., Mohr, S. E., Moskalev, A., & Perrimon, N. (2020) · Ageing Research Reviews · doi:10.1016/j.arr.2020.101188 · Cited by 91
“In mice, a cyclic isoprotein ketogenic diet started in middle age and alternated weekly with a control diet generated plasma beta-hydroxybutyrate levels similar to fasting (1− 2 mM), reduced midlife mortality, and improved healthspan, but did not affect maximum lifespan (Newman et al., 2017).”
BackgroundKetogenic diet induces p53-dependent cellular senescence in multiple organs
Wei, S., Schell, J. R., Chocrón, E. S., Varmazyad, M., Xu, G., Chen, W. H., Martinez, G. M., Dong, F. F., Sreenivas, P., Trevino, R., et al. (2024) · Science Advances · doi:10.1126/sciadv.ado1463 · Cited by 90
“Multiple publications provide evidence that the primary ketone produced in ketogenesis, β - hydroxybutyrate ( β - HB), may be anti-inflammatory ( 14 , 66 ), suggesting that this could play a mechanistic role in the beneficial effects of KDs ( 8 , 10 ).”
InfluentialChu, C., Yu, L., Qi, G., Mi, Y., Wu, W., Lee, Y. K., Zhai, Q., Tian, F., & Chen, W. (2022) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2022.104556 · Cited by 87
Evans, A. K., Saw, N. L., Woods, C. E., Vidano, L. M., Blumenfeld, S. E., Lam, R. K., Chu, E. K., Reading, C., & Shamloo, M. (2024) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2024.02.025 · Cited by 86
Ketogenic Diets and Exercise Performance
Harvey, K. L., Holcomb, L. E., & Kolwicz, S. C. (2019) · Nutrients · doi:10.3390/nu11102296 · Cited by 92
“However, KDs may decrease mortality [81,82], improve memory [81], and increase muscle citrate synthase [82] in aged mice.”
BackgroundChd2 Is Necessary for Neural Circuit Development and Long-Term Memory
Kim, Y. J., Khoshkhoo, S., Frankowski, J. C., Zhu, B., Abbasi, S., Lee, S., Wu, Y. E., & Hunt, R. F. (2018) · Neuron · doi:10.1016/j.neuron.2018.09.049 · Cited by 81
“com/ groups/1462485137354985/), and there is evidence of improved memory performance with this treatment in agingmice (Newman et al., 2017).”
Targeting Cell Senescence and Senolytics: Novel Interventions for Age-Related Endocrine Dysfunction
Suda, M., Paul, K. H., Tripathi, U., Minamino, T., Tchkonia, T., & Kirkland, J. L. (2024) · Endocrine Reviews · doi:10.1210/endrev/bnae010 · Cited by 83
Multi-dimensional Transcriptional Remodeling by Physiological Insulin In Vivo
Batista, T. M., García-Martín, R., Cai, W., Konishi, M., O'Neill, B. T., Sakaguchi, M., Kim, J. H., Jung, D. Y., Kim, J. K., & Kahn, C. R. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.02.081 · Cited by 76
“This is in line with an upregulation of this lncRNA in livers of mice on a ketogenic diet, which lowers insulin levels (Newman et al., 2017).”
BackgroundFasting-mimicking diet prevents high-fat diet effect on cardiometabolic risk and lifespan
Mishra, A. K., Mirzaei, H., Guidi, N., Vinciguerra, M., Mouton, A., Linardić, M., Rappa, F., Barone, R., Navarrete, G., Wei, M., et al. (2021) · Nature Metabolism · doi:10.1038/s42255-021-00469-6 · Cited by 77
The Aging Metabolome—Biomarkers to Hub Metabolites
Sharma, R. B., & Ramanathan, A. (2020) · PROTEOMICS · doi:10.1002/pmic.201800407 · Cited by 81
From Obesity to Hippocampal Neurodegeneration: Pathogenesis and Non-Pharmacological Interventions
Lee, T. H.-Y., & Yau, S. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms22010201 · Cited by 78
Ketogenic diet reshapes cancer metabolism through lysine β-hydroxybutyrylation
Qin, J., Huang, X., Gou, S., Zhang, S., Gou, Y., Zhang, Q., Chen, H., Sun, L., Chen, M., Liu, D., et al. (2024) · Nature Metabolism · doi:10.1038/s42255-024-01093-w · Cited by 85
Investigating Ketone Bodies as Immunometabolic Countermeasures against Respiratory Viral Infections
Stubbs, B. J., Koutnik, A. P., Goldberg, E. L., Upadhyay, V., Turnbaugh, P. J., Verdin, E., & Newman, J. C. (2020) · Med · doi:10.1016/j.medj.2020.06.008 · Cited by 71
Self-citationGuo, Y., Zhang, C., Shang, F., Luo, M., You, Y., Zhai, Q., Xia, Y., & Suxin, L. (2020) · Aging and Disease · doi:10.14336/ad.2019.0510 · Cited by 76
“Another study found that the KD reduces midlife mortality and improves memory in aging mice [19].”
BackgroundMethodNutrition, metabolism, and epigenetics: pathways of circadian reprogramming
Sato, T., & Sassone‐Corsi, P. (2022) · EMBO Reports · doi:10.15252/embr.202152412 · Cited by 77
“Following the administration of KD and HFD, a transcriptional analysis identified the downregulation of multiple metabolic pathways such as insulin signaling and protein synthesis, common to KD and HFD (Newman et al , 2017).”
InfluentialPromising Effect of a New Ketogenic Diet Regimen in Patients with Advanced Cancer
Hagihara, K., Kajimoto, K., Osaga, S., Nagai, N., Shimosegawa, E., Nakata, H., Saito, H., Nakano, M., Takeuchi, M., Kanki, H., et al. (2020) · Nutrients · doi:10.3390/nu12051473 · Cited by 75
Are ketogenic diets promising for Alzheimer’s disease? A translational review
Lilamand, M., Porte, B., Cognat, E., Hugon, J., Mouton‐Liger, F., & Paquet, C. (2020) · Alzheimer s Research & Therapy · doi:10.1186/s13195-020-00615-4 · Cited by 71
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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