biostudies-literature00510Newman JCGladstone InstitutesNIA NIH HHSNIDDK NIH HHSBuck Impact CircleGlenn Foundation for Medical ResearchLarry L. Hillblom FoundationBuck InstituteNINDS NIH HHSAmerican Federation for Aging ResearchNIH547-557.e8https://www.ebi.ac.uk/biostudies/studies/S-EPMC5605815biostudies-literatureUnknown26(3)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.Cell metabolismKetogenic Diet Reduces Midlife Mortality and Improves Memory in Aging Mice.PMC5605815K08 AG048354K08AG0483542012-A-016-FELP30 NS065780R24DK085610P30NS065780P30 DK098722T32 AG000266R24 DK085610Newman JCZhao MHuang YGut PCovarrubias AJYu XNg CPHaldar SVerdin E51falseKetogenic Diet Reduces Midlife Mortality and Improves Memory in Aging Mice.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.2017-01-01T00:00:00Z2017 Sep2024-11-12T02:03:20.903Z2019-03-26T23:54:15ZS-EPMC56058152887745810.1016/j.cmet.2017.08.004