The DOI matches its Crossref record; 42 of the 43 references it cites were found in a registry or an index.
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.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“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]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Rapamycin fed late in life extends lifespan in genetically heterogeneous mice
Harrison, D. E., Strong, R., Sharp, Z. D., Nelson, J. F., Astle, C. M., Flurkey, K., Nadon, N. L., Wilkinson, J. E., Frenkel, K., Carter, C. S., et al. (2009) · Nature · doi:10.1038/nature08221 · Cited by 3,766
The ketone metabolite β-hydroxybutyrate blocks NLRP3 inflammasome-mediated inflammatory disease
Youm, Y.-H., Nguyen, K. Y., Grant, R. W., Goldberg, E. L., Bodogai, M., Kim, D., D'Agostino, D., Planavsky, N., Lupfer, C., Kanneganti, T. D., et al. (2015) · Nature Medicine · doi:10.1038/nm.3804 · Cited by 2,172
Suppression of Oxidative Stress by β-Hydroxybutyrate, an Endogenous Histone Deacetylase Inhibitor
Shimazu, T., Hirschey, M. D., Newman, J., He, W., Shirakawa, K., Le Moan, N., Grueter, C. A., Lim, H., Saunders, L. R., Stevens, R. D., et al. (2013) · Science · doi:10.1126/science.1227166 · Cited by 1,777
Self-citationBadman, M. K., Pissios, P., Kennedy, A. R., Koukos, G., Flier, J. S., & Maratos-Flier, E. (2007) · Cell Metabolism · doi:10.1016/j.cmet.2007.05.002 · Cited by 1,495
Metformin improves healthspan and lifespan in mice
Martin-Montalvo, A., Mercken, E. M., Mitchell, S. J., Palacios, H. H., Mote, P. L., Scheibye-Knudsen, M., Gomes, A. P., Ward, T. M., Minor, R. K., Blouin, M.-J., et al. (2013) · Nature Communications · doi:10.1038/ncomms3192 · Cited by 1,445
Impact of intermittent fasting on health and disease processes
Mattson, M. P., Longo, V. D., & Harvie, M. (2017) · Ageing Research Reviews · doi:10.1016/j.arr.2016.10.005 · Cited by 1,187
Metabolic regulation of gene expression through histone acylations
Sabari, B. R., Zhang, D., Allis, C. D., & Zhao, Y. (2016) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm.2016.140 · Cited by 1,162
Kimura, I., Inoue, D., Maeda, T., Hara, T., Ichimura, A., Miyauchi, S., Kobayashi, M., Hirasawa, A., & Tsujimoto, G. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1016088108 · Cited by 1,106
Metformin as a tool to target aging
Barzilai, N., Crandall, J. P., Kritchevsky, S. B., & Espeland, M. A. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2016.05.011 · Cited by 1,096 · cited 2×
“…responsive networks has led to the first drug found to extend lifespan in healthy mammals— rapamycin (Harrison et al., 2009)—and the first candidate intervention for testing healthspan extension in a human clinical trial—metformin (Barzilai et al., 2016; Martin-Montalvo et al., 2013).”
BackgroundPeroxisome Proliferator-Activated Receptor Alpha Target Genes
Rakhshandehroo, M., Knoch, B., Müller, M., & Kersten, S. (2010) · PPAR Research · doi:10.1155/2010/612089 · Cited by 1,020
Flagged first, then by citations
1 of the 43 references couldn’t be matched to a known paper.
Cited by
Sorted by citations
Items 201–300 of 492
Mani, K. M., Javaheri, A., & Diwan, A. (2018) · Comprehensive physiology · doi:10.1002/cphy.c180005 · Cited by 29
“Mice fed ketogenic diets also show decreases in mTOR activity with increases in Sirt1 and HIF-1 as well as AMPK activity (143,169).”
Tyshkovskiy, A., Kholdina, D., Ying, K., Davitadze, M., Molière, A., Tongu, Y., Kasahara, T., Kats, L., Vladimirova, A., Moldakozhayev, A., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.07.04.601982 · Cited by 32
Intermittent Fasting: Myths, Fakes and Truth on This Dietary Regimen Approach
Brogi, S., Tabanelli, R., Puca, S., & Calderone, V. (2024) · Foods · doi:10.3390/foods13131960 · Cited by 26
“Furthermore, serum levels of ketone bodies such as BHB, which is related to anti-aging and cardioprotective properties [185], were found to be still elevated after >6 months of ADF on fasting days; interestingly, after 4-weeks intervention BHB levels were high even on samplings collected on…”
Monsalves‐Álvarez, M., Morales, P. E., Castro‐Sepúlveda, M., Sepúlveda, C., Rodriguez, J. M., Chiong, M., Eisner, V., Lavandero, S., & Troncoso, R. (2020) · Nutrients · doi:10.3390/nu12071930 · Cited by 28
“Importantly, plasma β-HB values obtained in our study are similar to those reported with ketogenic diets in mouse models [63,64], indicating that this protocol is an effective way to induce mild hyperketonemia without a reduction in or restriction of carbohydrates.”
Result3‐hydroxybutyrate in the brain: Biosynthesis, function, and disease therapy
Wang, B., Wu, J., Xiao, D., Wu, B., & Wei, D. (2023) · Brain‐X · doi:10.1002/brx2.6 · Cited by 26
The effect of ketogenic diet on behaviors and synaptic functions of naive mice
Huang, J., Li, Y., Wu, C., Zhang, Y., Zhao, S., Chen, Y., Deng, Y., Xuan, A., & Sun, X. (2019) · Brain and Behavior · doi:10.1002/brb3.1246 · Cited by 31
“Interestingly, KD has been demonstrated to have beneficial effect on motor activity in aged animals (Newman et al., 2017; Roberts et al., 2017).”
BackgroundIntermittent Fasting: Myths, Fakes and Truth on this Dietary Regimen Approach
Brogi, S., Tabanelli, R., Puca, S., & Calderone, V. (2024) · doi:10.20944/preprints202405.1820.v1 · Cited by 26
Acevedo, A., Torres, F., Kiwi, M., Baeza‐Lehnert, F., Barros, L. F., Lee‐Liu, D., & González-Billault, C. E. (2023) · Aging · doi:10.18632/aging.204663 · Cited by 27
Upregulation of hepatic autophagy under nutritional ketosis
Liśkiewicz, D., Liśkiewicz, A., Grabowski, M., Nowacka-Chmielewska, M. M., Grabowska, K., Wojakowska, A., Marczak, Ł., Barski, J. J., & Małecki, A. (2021) · The Journal of Nutritional Biochemistry · doi:10.1016/j.jnutbio.2021.108620 · Cited by 25
Recent Neurotherapeutic Strategies to Promote Healthy Brain Aging: Are we there yet?
Kim, C.-K., Sachdev, P. S., & Braidy, N. (2022) · Aging and Disease · doi:10.14336/ad.2021.0705 · Cited by 27
“In rodents, KD not only improved memory in mice and cognition in rats but also reduced amyloid beta levels and cell death [142-144].”
BackgroundFunction and treatment strategies of β-hydroxybutyrate in aging
Xiang, Y., Wang, Q., Lan, X., Zhang, H., & Wei, D. (2022) · Smart Materials in Medicine · doi:10.1016/j.smaim.2022.09.003 · Cited by 26
Acuña-Catalán, D., Shah, S., Wehrfritz, C., Nomura, M., Acevedo, A., Olmos, C., Quiroz, G., Huerta, H., Bons, J., Ampuero, E., et al. (2024) · Cell Reports Medicine · doi:10.1016/j.xcrm.2024.101593 · Cited by 29
“11,17 Such studies typically initiated diet changes starting at the middle stage of the animal’s life, and evaluated the consequences later in life, after more than a year of diet administration.”
InfluentialSelf-citationXie, S., Jiang, C., Wu, M. Y., Ye, Y., Wu, B., Sun, X., Lv, X., Chen, R., Yu, W., Sun, Q., et al. (2022) · Science Translational Medicine · doi:10.1126/scitranslmed.abn9061 · Cited by 26
Duan, H., Yu, Q., Ni, Y., Li, J., Yu, L., & Fan, L. (2023) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2023.127559 · Cited by 22
Mandelblatt, J. S., Antoni, M. H., Bethea, T. N., Cole, S. W., Hudson, B. I., Penedo, F. J., Ramírez, A. G., Rebeck, G. W., Sarkar, S., Schwartz, A. G., et al. (2024) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/djae211 · Cited by 25
Long-Term Feeding of a High-Fat Diet Ameliorated Age-Related Phenotypes in SAMP8 Mice
Oike, H., Ogawa, Y., & Azami, K. (2020) · Nutrients · doi:10.3390/nu12051416 · Cited by 25
“A recent study showed that long-term feeding of a ketogenic diet, which is composed of high fat (mainly vegetable oil) and low carbohydrate, to C57BL/6 mice alternated weekly reduced midlife mortality and improved memory in old age [41].”
BackgroundSaito, E. R., Warren, C. E., Hanegan, C. M., Larsen, J. G., du Randt, J. D., Cannon, M. E., Saito, J. Y., Campbell, R. J., Kemberling, C. M., Miller, G., et al. (2022) · Metabolites · doi:10.3390/metabo12111019 · Cited by 24
Circulating α-Klotho Counteracts Transforming Growth Factor-β–Induced Sarcopenia
Ohsawa, Y., Ohtsubo, H., Munekane, A., Ohkubo, K., Murakami, T., Fujino, M., Nishimatsu, S., Hagiwara, H., Nishimura, H., Kaneko, R., et al. (2023) · American Journal Of Pathology · doi:10.1016/j.ajpath.2023.01.009 · Cited by 24
Ketogenic diets initiated in late mid-life improved measures of spatial memory in male mice
Zhou, Z., Kim, K., Ramsey, J. J., & Rutkowsky, J. M. (2023) · GeroScience · doi:10.1007/s11357-023-00769-7 · Cited by 25
“The beneficial effects of KDs on longevity and health span have been studied in early-middle-aged (12-month-old) mice [10, 18].”
BackgroundMethodResultInfluentialRole of liver FGF21-KLB signaling in ketogenic diet-induced amelioration of hepatic steatosis
Guo, W., Cao, H., Shen, Y., Li, W., Wang, W. J., Cheng, L., Cai, M., & Xu, F. L. (2024) · Nutrition and Diabetes · doi:10.1038/s41387-024-00277-3 · Cited by 24
Metabolic regulation of immunological aging
Kim, H., & Dixit, V. D. (2025) · Nature Aging · doi:10.1038/s43587-025-00921-2 · Cited by 30
“In concert with these findings, the ketogenic diet decreases mortality in middle age and extends healthspan and lifespan 124,159 .”
Stephan, J. S., & Sleiman, S. F. (2021) · Frontiers in Neurology · doi:10.3389/fneur.2021.600365 · Cited by 25
“They also extend longevity, improve memory and enhance brain health in aging mice (43, 44).”
BackgroundHepatic Suppression of Mitochondrial Complex II Assembly Drives Systemic Metabolic Benefits
Wang, X., Lv, W., Xu, J., Zheng, A., Zeng, M., Cao, K. J., Wang, X., Cui, Y., Li, H., Yang, M., et al. (2022) · Advanced Science · doi:10.1002/advs.202105587 · Cited by 23
The Impact of Ketone Body Metabolism on Mitochondrial Function and Cardiovascular Diseases
Arima, Y. (2023) · Journal of Atherosclerosis and Thrombosis · doi:10.5551/jat.rv22011 · Cited by 24
“Furthermore, a ketogenic diet has been shown to improve cognitive function in aging mice 57) .”
BackgroundObesity-associated deterioration of the hippocampus is partially restored after weight loss
Liśkiewicz, A., Liśkiewicz, D., Marczak, Ł., Przybyła, M., Grabowska, K., Student, S., Dębiec, M., Sługocka, A., & Lewin‐Kowalik, J. (2021) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2021.05.030 · Cited by 22
Chelette, B. M., Loeven, A. M., Gatlin, D. N., Conde, D. R. L., Huffstetler, C. M., Qi, M., & Fadool, D. A. (2021) · The Journal of Physiology · doi:10.1113/jp282112 · Cited by 22
“For example, ketogenic diets have been reported to benefit individuals suffering from epilepsy, cancer, neuronal loss and cognitive deficits (Newman et al. 2017; Roberts et al. 2017; Li et al. 2020), but their high-fat nature may be disruptive to sensory neurons and hence satiety signals.”
BackgroundWu, X., Shu, Q., Wang, B., Dong, L., & Hao, B. (2022) · American Journal of Alzheimer s Disease & Other Dementias® · doi:10.1177/15333175221124949 · Cited by 24
Gallop, M. R., Vieira, R. F. L., Matsuzaki, E. T., Mower, P. D., Liou, W., Smart, F. E., Roberts, S., Evason, K. J., Holland, W. L., & Chaix, A. (2025) · Science Advances · doi:10.1126/sciadv.adx2752 · Cited by 21
“In addition, for similar insu- lin-and glucose-lowering reasons and potential benefits of ketone bodies themselves, a KD has been proposed to treat cancer and Alzheimer’s disease, increase longevity, and improve metabolic health ( 8 , 9 ).”
InfluentialDietary Interventions in Autosomal Dominant Polycystic Kidney Disease
Pickel, L., Iliuta, I.-A., Scholey, J. W., Pei, Y., & Sung, H. (2021) · Advances in Nutrition · doi:10.1093/advances/nmab131 · Cited by 21
Kalafut, K. C., Mitchell, S. J., MacArthur, M. R., & Mitchell, J. R. (2022) · Frontiers in Nutrition · doi:10.3389/fnut.2022.839341 · Cited by 22
“In addition, a 96 recent report showed that one-week cycles of KD alternated with a control diet reduces midlife 97 mortality and improves measures of healthspan and memory in mice (39).”
BackgroundExploring the effect of different diet types on ageing and age-related diseases
Mensah, E. O., Danyo, E. K., & Asase, R. V. (2024) · Nutrition · doi:10.1016/j.nut.2024.112596 · Cited by 23
Transient vitamin B5 starving improves mammalian cell homeostasis and protein production
Pourcel, L., Buron, F., Garcia, F., Delaloix, M.-S., Fourn, V. L., Girod, P., & Mermod, N. (2020) · Metabolic Engineering · doi:10.1016/j.ymben.2020.03.008 · Cited by 21
Aged mice exhibit widespread metabolic changes but preserved major fluxes
Jankowski, C. S. R., Samarah, L. Z., MacArthur, M. R., Mitchell, S. J., Weilandt, D. R., Hunter, C. J., Zeng, X., McReynolds, M. R., & Rabinowitz, J. D. (2025) · Cell Metabolism · doi:10.1016/j.cmet.2025.09.009 · Cited by 19
Oliveira, T. P. D., Morais, A. L. B., dos Reis, P. L. B., Palotás, A., & Vieira, L. B. (2023) · Metabolites · doi:10.3390/metabo14010025 · Cited by 24
“Studies with preclinical models demonstrate that the KD can provide benefits regarding inflammation [130,132,133], pain [134,135], cancer [136], metabolic disorders [137–139], epilepsy [140,141], aging [142], memory [143,144], mood [145,146] and neurodegenerative diseases [147–149].”
BackgroundXu, Y., Song, J., Huang, Q., Wei, X., Deng, Z., Song, Z., Huang, H., Luo, C., Zhang, D., & Li, H. (2025) · Journal of Functional Foods · doi:10.1016/j.jff.2025.106786 · Cited by 23
Early-life exercise extends healthspan but not lifespan in mice
Feng, M., Li, M., Lou, J., Wu, G., Gao, T., Wu, F., Tan, Y., Zhang, N., Zhao, Y., Lin, Z., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-61443-4 · Cited by 21
Ghosh, I., Liu, C. S., Swardfager, W., Lanctôt, K. L., & Anderson, N. D. (2021) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2021.103683 · Cited by 20
The road ahead of dietary restriction on anti-aging: focusing on personalized nutrition
Duan, H., Li, J., Yu, L., & Fan, L. (2022) · Critical Reviews in Food Science and Nutrition · doi:10.1080/10408398.2022.2110034 · Cited by 20
“The ketogenic diet (KD), an extremely low-carbohydrate (about 5% of energy) diet, has various beneficial functions, such as epilepsy treatment and lifespan extension (Roberts et al. 2018; Newman et al. 2017).”
BackgroundLindberg, D. M., Ho, A. M., Peyton, L., & Choi, D. (2019) · Alcoholism Clinical and Experimental Research · doi:10.1111/acer.14137 · Cited by 20
“Ketogenic diets and ketone supplementation have been demonstrated to improve memory, enhance hippocampal long-term potentiation, and reduce the severity of ethanol withdrawal syndrome (Dencker et al., 2018; Hernandez et al., 2018; Newman et al., 2017).”
BackgroundFanjul, V., Jorge, I., Camafeita, E., Macías, Á., González‐Gómez, C., Barettino, A., Dorado, B., Andrés‐Manzano, M. J., Rivera, J., Vázquez, J., et al. (2020) · Aging Cell · doi:10.1111/acel.13203 · Cited by 21
“Ketone body supplementation pro-longs health span in old WT mice (Newman et al., 2017), suggesting that the increased ketone body metabolism in prematurely aged mouse and pig hearts reported here may constitute a pro-survival mechanism.”
Stubbs, B. J., Koutnik, A. P., Volek, J. S., & Newman, J. C. (2020) · GeroScience · doi:10.1007/s11357-020-00277-y · Cited by 22
Self-citationKetone bodies to the rescue for an aging heart?
Sedej, S. (2017) · Cardiovascular Research · doi:10.1093/cvr/cvx218 · Cited by 20
“Studies built on carefully chosen macronutrient compositions and prudent experiments as exemplified by the study from Newman et al.(4) are warranted to advance our understanding whether boosting ketone utilization supports healthy cardiac aging.”
BackgroundMethodInfluentialA ketogenic diet impacts markers of mitochondrial mass in a tissue specific manner in aged mice
Zhou, Z., Hagopian, K., López-Domínguez, J. A., Kim, K., Jasoliya, M., Roberts, M. N., Cortopassi, G. A., Showalter, M. R., Roberts, B. S., González-Reyes, J. A., et al. (2021) · Aging · doi:10.18632/aging.202834 · Cited by 19
“Although there is evidence that KDs increase transcription of proteins involved in mitochondrial energy metabolism [9], increase markers of mitochondrial biogenesis [16], and induce posttranslational modification of mitochondrial proteins [8, 17], there is currently no convincing evidence showing an increase in mitoch…”
BackgroundWang, D., Li, P., Odle, J., Lin, X., Zhao, J., Xiao, K., & Liu, Y. (2021) · Nutrition Research Reviews · doi:10.1017/s0954422421000172 · Cited by 20
“Ketogenic diet is characterised by high fat, moderate protein and low carbohydrate, which dramatically elevates circulating ketone body levels(60).”
BackgroundLifespan-extending interventions induce consistent patterns of fatty acid oxidation in mouse livers
Watanabe, K., Wilmanski, T. M., Baloni, P., Robinson, M., Garcia, G. G., Hoopmann, M. R., Midha, M. K., Baxter, D. H., Maes, M., Morrone, S. R., et al. (2023) · Communications Biology · doi:10.1038/s42003-023-05128-y · Cited by 20
Along the microbiota–gut–brain axis: Use of plant polysaccharides to improve mental disorders
Gao, J., Liang, Y., & Liu, P. (2024) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2024.130903 · Cited by 21
Principles of brain aging: Status and challenges of modeling human molecular changes in mice
Kluever, V., & Fornasiero, E. F. (2021) · Ageing Research Reviews · doi:10.1016/j.arr.2021.101465 · Cited by 18
Handheld device quantifies breath acetone for real-life metabolic health monitoring
Bastide, G. M. G. B. H., Remund, A. L., Oosthuizen, D. N., Derron, N., Gerber, P. A., & Weber, I. C. (2023) · Sensors & Diagnostics · doi:10.1039/d3sd00079f · Cited by 19
Dietary therapy to halt the progression of diabetes to diabetic kidney disease
Hu, H., Ding, G., & Liang, W. (2025) · Food & Function · doi:10.1039/d4fo06011c · Cited by 17
Compression of morbidity by interventions that steepen the survival curve
Yang, Y., Mayo, A., Levy, T., Raz, N., Shenhar, B., Jarosz, D. F., & Alon, U. (2025) · Nature Communications · doi:10.1038/s41467-025-57807-5 · Cited by 18
“An intriguing class of steepening interventions includes cyclic ketogenic diet 60,61 , the ketogenic agent 1,3-butanediol (BD) and the diabetes drugs acarbose 54 and canagli fl ozin 55 .”
Fan, S., Sung, C., Tsai, Y.-H., Yeh, S., Lin, W., & Wang, P. (2020) · The Journals of Gerontology Series A · doi:10.1093/gerona/glaa203 · Cited by 16
Castro, R., Whalen, C. A., Gullette, S., Mattie, F. J., Florindo, C., Heil, S. G., Huang, N. K., Neuberger, T., & Ross, A. C. (2021) · Nutrients · doi:10.3390/nu13103576 · Cited by 17
Xu, Y., Zheng, F., Zhong, Q., & Zhu, Y. (2023) · Journal of Alzheimer s Disease · doi:10.3233/jad-230002 · Cited by 20
“Newman et al. reveal that a cyclic KD (feeding every other week) prevents memory decline and reduces midlife mortality as mice age, but does not improve maximum lifespan [108].”
Are fat and sugar just as detrimental in old age?
Valencia, A. P., Nagaraj, N., Osman, D. H., Rabinovitch, P. S., & Marcinek, D. J. (2021) · GeroScience · doi:10.1007/s11357-021-00390-6 · Cited by 18
Impact of intermittent fasting on human health: an extended review of metabolic cascades
Ahmed, A., Saeed, F., Arshad, M. U., Afzaal, M., Imran, A., Ali, S. W., Niaz, B., Ahmad, A., & Imran, M. (2018) · International Journal of Food Properties · doi:10.1080/10942912.2018.1560312 · Cited by 16
“The autophagy is believed to be a tumour oppressive due to abnormalities in autophagy drive oxidation stress, defective mitochondria, damaged DNA, genomic instability and tumour growth.([38]) Alternatively, it is thought to be involved in tumour proliferation as tumours can exploit autophagy to decrease oxidative stre…”
BackgroundKoppel, S. J., Wilkins, H., Weidling, I. W., Wang, X., Menta, B. W., & Swerdlow, R. H. (2022) · Mitochondrion · doi:10.1016/j.mito.2022.12.004 · Cited by 15
β-Hydroxybutyrate alleviates cartilage senescence through hnRNP A1-mediated up-regulation of PTEN
Xia, G., Wen, Z., Zhang, L., Huang, J., Wang, X., Liang, C., Cui, X., Cao, X., & Wu, S. J. (2023) · Experimental Gerontology · doi:10.1016/j.exger.2023.112140 · Cited by 16
“Moreover, BHB has also been shown to alleviate senescence by activating a unique transcription program of the peroxisome proliferator activated receptor alpha (PPARa) target gene, reducing midlife mortality, and improving brain function in aging mice (Newman et al., 2017).”
BackgroundKetogenic diet and behavior: insights from experimental studies
Grabowska, K., Grabowski, M., Przybyła, M., Pondel, N., Barski, J. J., Nowacka-Chmielewska, M. M., & Liśkiewicz, D. (2024) · Frontiers in Nutrition · doi:10.3389/fnut.2024.1322509 · Cited by 16
Dasgupta, A., Kim, J., Manakkadan, A., Arumugam, T. V., & Sajikumar, S. (2017) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2017.12.004 · Cited by 16
“Indeed, it has been reported recently that ketogenic diet can significantly improve memory in aging mice and lower the risk of mortality (Newman et al., 2017).”
BackgroundKetogenic diet for mood disorders from animal models to clinical application
Smolensky, I. V., Zajac-Bakri, K., Gass, P., & Inta, D. (2023) · Journal of Neural Transmission · doi:10.1007/s00702-023-02620-x · Cited by 17
Pharmacological interventions in human aging
Petr, M. A., Matiyevskaya, F., Osborne, B., Berglind, M., Reves, S., Zhang, B., Ezra, M. B., Carmona-Marin, L. M., Syadzha, M. F., Mediavilla, M. C., et al. (2024) · Ageing Research Reviews · doi:10.1016/j.arr.2024.102213 · Cited by 20
The Cardioprotective Effects of Nutritional Ketosis: Mechanisms and Clinical Implications
Venturini, C., Mancinelli, L., Matacchione, G., Olivieri, F., & Antonicelli, R. (2024) · Nutrients · doi:10.3390/nu16234204 · Cited by 15
“Notably, BHB was found to decrease the secretory phenotype associated with vascular cell senescence in aging mice [52].”
Molecular harvesting with electroporation for tissue profiling
Golberg, A., Sheviryov, J., Solomon, O., Anavy, L., & Yakhini, Z. (2019) · Scientific Reports · doi:10.1038/s41598-019-51634-7 · Cited by 15
The impact of ageing on lipid-mediated regulation of adult stem cell behavior and tissue homeostasis
Demarco, R. S., Clémot, M., & Jones, D. L. (2020) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2020.111278 · Cited by 16
“KD has been associated with extended longevity in mice (Newman et al., 2017; Roberts et al., 2017) and has neuroprotective effects that are potentially beneficial against age-related neurodegenerative disorders, such as Alzheimer’s and Parkinson’s diseases (Balietti et al.”
BackgroundHernandez, A. R., Kemp, K. M., Burke, S. N., Buford, T. W., & Carter, C. S. (2022) · Nutrients · doi:10.3390/nu14091758 · Cited by 15
“Moreover, chronic dietary interventions such as this one may have lower translational potential and the utility of other paradigms, such as cycling on and off the ketogenic diet, may be better targets for future studies [78,79].”
BackgroundKetogenic Diet Increases Serum and White Adipose Tissue SIRT1 Expression in Mice
Tozzi, R., Campolo, F., Baldini, E., Venneri, M. A., Lubrano, C., Ulisse, S., Gnessi, L., & Mariani, S. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232415860 · Cited by 16
“Alterations evoked by endogenous or exogenous ketosis [6] improve anti-inflammatory and mitochondrial activities, mnemonic and muscle performance, and reduce the incidence of tumors in middle-aged mice—ultimately improving the general health of the animals, with a net effect on the increase in life expectancy [7,8].”
BackgroundKetone body metabolism declines with age in mice in a sex-dependent mannerPreprint
Eap, B., Nomura, M., Panda, O., Garcia, T. Y., King, C. D., Rose, J., Leone, T. C., Kelly, D. P., Schilling, B., & Newman, J. C. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.10.05.511032 · Cited by 18
Self-citationNucleoside diphosphate kinases 1 and 2 regulate a protective liver response to a high-fat diet
Iuso, D., Garcia-Saez, I., Couté, Y., Yamaryo-Botté, Y., Boeri Erba, E., Adrait, A., Zeaiter, N., Tokarska-Schlattner, M., Jilkova, Z. M., Boussouar, F., et al. (2023) · Science Advances · doi:10.1126/sciadv.adh0140 · Cited by 14
Cai, Y.-W., Gao, J., Wu, M., Xie, Y.-X., You, S., Liao, G.-H., Chen, Z.-T., Liu, P., Wang, J., Chen, Y.-X., et al. (2025) · American Journal of Clinical Nutrition · doi:10.1016/j.ajcnut.2025.04.030 · Cited by 14
Nagahisa, T., Kosugi, S., & Yamaguchi, S. (2023) · Nutrients · doi:10.3390/nu15061494 · Cited by 14
Mechchate, H., Abdualkader, A. M., Bernacchi, J. K. B., Gopal, K., Dakhili, S. A. T., Yang, K., Greenwell, A. A., Kong, X., Crawford, P. A., & Batran, R. A. (2023) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00206.2022 · Cited by 14
Association of the dietary inflammatory index with phenotypic age in the United States adults
Sun, M., Fang, J., Gao, W., He, Y., Ma, Y., & Jin, L. (2023) · Epidemiology and Health · doi:10.4178/epih.e2023051 · Cited by 15
“and aging, including caloric restriction diets [33, 34], different dietary patterns such as 193 the plant-based Mediterranean diet [17, 35], and specific nutrients such as long-chain 194 omega-3 fatty acids (docosahexaenoic acid and eicosapentaenoic acid) [36].”
BackgroundKetogenic diet inhibits neointimal hyperplasia by suppressing oxidative stress and inflammation
Xu, X., Xie, L., Chai, L., Wang, X., Dong, J., Wang, J., & Yang, P.-W. (2023) · Clinical and Experimental Hypertension · doi:10.1080/10641963.2023.2229538 · Cited by 14
“Growing evidence has demonstrated that KD has multiple beneficial effects in many diseases, including colitis (14), Alzheimer’s disease (15), hypertension (16), as well as improves survival and memory in aging rat (17).”
BackgroundChen, H., Tang, H., Zhang, X., Huang, J., Luo, N., Guo, Q., & Wang, X. (2024) · Revista Española de Cardiología (English Edition) · doi:10.1016/j.rec.2024.04.004 · Cited by 14
Sex- and Age-Specific Differences in Mice Fed a Ketogenic Diet
Sprankle, K. W., Knappenberger, M. A., Locke, E. J., Thompson, J. H., Vinovrski, M. F., Knapsack, K., & Kolwicz, S. C. (2024) · Nutrients · doi:10.3390/nu16162731 · Cited by 14
“Given some of the controversy regarding whether the KD improves longevity [25,26] or promotes cellular senescence [27], we included two commonly used age groups (i.e., 3 months and 6 months) in mouse studies to gain insight into the effects of KD in aging.”
MethodTargeting ketone body metabolism to treat fatty liver disease
Kwon, S., Jeyaratnam, R., & Kim, K.-H. (2024) · Journal of Pharmacy & Pharmaceutical Sciences · doi:10.3389/jpps.2024.13375 · Cited by 17
State-Dependent Changes in Brain Glycogen Metabolism
DiNuzzo, M., Walls, A. B., Öz, G., Seaquist, E. R., Waagepetersen, H. S., Bak, L. K., Nedergaard, M., & Schousboe, A. (2019) · Advances in neurobiology · doi:10.1007/978-3-030-27480-1_9 · Cited by 13
The mystery of the ketogenic diet: benevolent pseudo-diabetes
Blagosklonny, M. V. (2019) · Cell Cycle · doi:10.1080/15384101.2019.1644765 · Cited by 16
“Even a cyclic (alternated weekly) KD improves survival, health and memory in aged mice [33].”
BackgroundWei, S., Schell, J. R., Qian, W., Silguero, M., Baseviciene, A., Chen, W. H., Trevino, R., Chocrón, E. S., Ogle, M. M., Varmazyad, M., et al. (2025) · Cell Reports · doi:10.1016/j.celrep.2025.116026 · Cited by 15
New prebiotics by ketone donation
Satoh, T. (2023) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2023.05.001 · Cited by 14
Schimidt, H. L., Garcia, A., Martins, A., Garcia, M., Soares, M. B., Cibin, F. W. S., Mello‐Carpes, P. B., & Carpes, F. P. (2018) · Journal of Functional Foods · doi:10.1016/j.jff.2018.08.026 · Cited by 13
Modulation of frailty syndrome by diet: A review of evidence from mouse studies
Mitchell, S. J., Mitchell, G. J., & Mitchell, J. R. (2019) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2019.04.003 · Cited by 11
Ketogenic diet and adipose tissue inflammation—a simple story? Fat chance!
Stubbs, B. J., & Newman, J. C. (2020) · Nature Metabolism · doi:10.1038/s42255-019-0164-2 · Cited by 13
Self-citationUdumula, M. P., Singh, H., Rashid, F., Poisson, L., Tiwari, N., Dimitrova, I. K., Hijaz, M., Gogoi, R. P., Swenor, M., Munkarah, A. R., et al. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.03.08.531740 · Cited by 13
Qi, D., Huang, D., Ba, M., Xuan, S., Si, H., Lu, D., Pei, X., Zhang, W., Huang, S., & Li, Z. (2024) · Experimental Eye Research · doi:10.1016/j.exer.2024.110008 · Cited by 13
Ketogenic diet and cancer: multidimensional exploration and research
Wan, S., Zhou, X., Xie, F., Zhou, F., & Zhang, L. (2025) · Science China Life Sciences · doi:10.1007/s11427-023-2637-2 · Cited by 13
“Interestingly, research has shown that KD may contribute to lifespan extension (Roberts et al., 2018), reducing midlife mortality rates and improving memory in aged mice (Newman et al., 2017).”
Muscedere, J., Kim, P. M., Afilalo, J., Balion, C. M., Baracos, V. E., Bowdish, D. M. E., Cesari, M., Erusalimsky, J. D., Fülöp, T., Heckman, G. A., et al. (2019) · The Journal of Frailty & Aging · doi:10.14283/jfa.2019.12 · Cited by 12
“Metabolomics has already produced results that are leading to frailty interventions, such as ketogenic compounds, for which clinical trials are about to start (85, 86).”
BackgroundGreenwell, A. A., Saed, C. T., Dakhili, S. A. T., Ho, K. L., Gopal, K., Chan, J. S. F., Kaczmar, O. O., DYER, S. A., Eaton, F., Lopaschuk, G. D., et al. (2022) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00435.2021 · Cited by 13
The effects of macronutrients metabolism on cellular and organismal aging
Nehme, J., Altulea, A., Gheorghe, T., & Demaria, M. (2023) · Biomedical Journal · doi:10.1016/j.bj.2023.02.005 · Cited by 13
“Notably, some studies have demonstrated the beneficial properties of ketogenic diets on longevity [114,115] which might be, at least in part, driven by high BHB levels (Fig.”
BackgroundOn standardization of controls in lifespan studies
Spiridonova, O., Kriukov, D. V., Nemirovich-Danchenko, N., & Peshkin, L. (2024) · Aging · doi:10.18632/aging.205604 · Cited by 12
Frailty in rodents: Models, underlying mechanisms, and management
Liu, P., Li, Y., & Ma, L. (2022) · Ageing Research Reviews · doi:10.1016/j.arr.2022.101659 · Cited by 13
Sirtuins, Healthspan, and Longevity in Mammals
Giblin, W., & Lombard, D. B. (2015) · Elsevier eBooks · doi:10.1016/b978-0-12-411596-5.00003-4 · Cited by 12
The Ketogenic Diet in the Prevention of Migraines in the Elderly
Fila, M., Chojnacki, J., Pawłowska, E., Sobczuk, P., Chojnacki, C. J., & Błasiak, J. (2023) · Nutrients · doi:10.3390/nu15234998 · Cited by 11
“Caloric restriction and resulting ketogenesis are the most consistently reported factors that may prolong life span [78].”
BackgroundAging-induced MCPH1 translocation activates necroptosis and impairs hematopoietic stem cell function
He, H., Wang, Y., Tang, B., Dong, Q., Wu, C., Sun, W., & Wang, J. (2024) · Nature Aging · doi:10.1038/s43587-024-00609-z · Cited by 11
“Additionally, two studies indicate that a ketogenic diet, which mimics certain metabolic aspects of calorie restriction, elevates protein acetylation levels in the liver 52,53 , suggesting that acetylation alterations may play a role in aging and related processes.”
Myths and Facts Regarding Low-Carbohydrate Diets
Teicholz, N., Croft, S. M., Cuaranta, I., Cucuzzella, M. T., Glandt, M., Hafez, D., Jerome-Zapadka, K., Kalayjian, T., Murphy, K. C., Nelson, M., et al. (2025) · Nutrients · doi:10.3390/nu17061047 · Cited by 15
“These studies are also a weak form of evidence that can only rarely establish cause-and-effect relationships, and they are contradicted by mouse experiments using a ketogenic diet, which found reduced mid-life mortality [57] and increased total lifespan compared to controls [58].”
Ravaut, G., Carneiro, A., & Mounier, C. (2024) · Frontiers in Nutrition · doi:10.3389/fnut.2024.1290540 · Cited by 12
“In previous studies, several sources of fat were used, such as cocoa butter (26), vegetable oils (27) or lard (28, 29).”
BackgroundYuan, H., Zhang, T., Huang, S., Zhou, J., & Park, S. (2020) · European Journal of Integrative Medicine · doi:10.1016/j.eujim.2020.101119 · Cited by 11
Jiang, N., Gelfond, J., Liu, Q., Strong, R., & Nelson, J. F. (2024) · GeroScience · doi:10.1007/s11357-024-01161-9 · Cited by 12
“Ketogenic diet prolonged lifespan and improved health conditions in C57BL/6 mice [32, 33].”
BackgroundBeta-Hydroxybutyrate: A Supplemental Molecule for Various Diseases
Shahtaghi, N. R., Soni, B., Bakrey, H., Bigdelitabar, S., & Jain, S. K. (2024) · Current Drug Targets · doi:10.2174/0113894501312168240821082224 · Cited by 10
The Interplay between the Gut and Ketogenic Diets in Health and Disease
Mu, C., Rho, J. M., & Shearer, J. (2025) · Advanced Science · doi:10.1002/advs.202504249 · Cited by 11
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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
