Ketogenic Diet Reduces Midlife Mortality and Improves Memory in Aging Mice

Abstract

Summary A ketogenic diet (KD) recapitulates certain metabolic aspects of dietary restriction such as reliance on fatty acid metabolism and production of ketone bodies. We investigated whether KD might, like dietary restriction, affect longevity and healthspan in C57BL/6 male mice. We find that an isoprotein KD, fed on alternate weeks to prevent obesity (Cyclic KD), reduces mid-life 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 down-regulation of insulin, TOR, and fatty acid synthesis pathways as mechanisms common to KD and HF. However, up-regulation 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.

Daily Fasting Improves Health and Survival in Male Mice Independent of Diet Composition and Calories

“…A recent paper in which mice were fed a ketogenic diet did not show this daily rhythm despite having several health benefits (Roberts et al, 2017), implying that mechanisms underlying ketogenic and MF paradigms are different. Two recent studies indicated that mice on ketogenic diets exhibited either a weight gain and slight reduction in midlife mortality or a slight decrease in weight and increase in healthspan and lifespan (Newman et al, 2017; Roberts et al, 2017). Although ketogenic diets, when given in a paired feeding paradigm, extended lifespan, it is unclear whether periods of fasting may have been a contributing factor.…”

The Aging Metabolome—Biomarkers to Hub Metabolites

“…A recent study has shown that ketogenic diet can improve the midlife mortality of mice and provide neurological benefits such as improved memory in aging mice. [ 82 ] The caloric restriction/anti‐aging mechanism of βHB has been ascribed to two overlapping mechanisms. i) in an energetic role, βHB provides an alternative (anaplerotic) source of carbon to the mitochondrial TCA cycle in the context of an aging‐associated mitochondrial dysfunction, ii) direct inhibition of HDAC I and IIa histone deacetylases (IC 50 ≈1 × 10 −3 m ) causing the deacetylation of FOXO3a promoter leading to transcriptional activation.…”

Lysosomes Mediate Benefits of Intermittent Fasting in Cardiometabolic Disease: The Janitor Is the Undercover Boss

“…By themselves, ketone bodies also appear to target the metabolism and cardiac function via changes in nuclear transcription by acting as inhibitors of HDAC1, resulting in protection from oxidative stress (192). Mice fed ketogenic diets also show decreases in mTOR activity with increases in Sirt1 and HIF-1 as well as AMPK activity (145, 171). Besides states of nutritional deprivation, ketone bodies appear to play a significant role in cardiac metabolism in the post natal remodeling (43) as well as in models of heart failure (16, 22).…”

“…Besides states of nutritional deprivation, ketone bodies appear to play a significant role in cardiac metabolism in the post natal remodeling (43) as well as in models of heart failure (16, 22). Ketone bodies also drive acetylation reactions, which may explain its benefits on extending lifespan and improving healthspan seen when mice are maintained on a ketogenic diet chronically (171) or intermittently (145). In addition, among TCA cycle intermediates, oxaloacetate, and a-ketoglutarate appear to play roles outside their role in mitochondrial acetyl CoA/TCA metabolism.…”

“…By inhibition of the F1F0 ATP synthase, lifespan in C. elegans is increased with decreased O2 consumption, which resulted in mTOR inhibition and increased autophagy (41). Intriguingly, long term persistent administration of ketogenic diet resulted in impaired glucose tolerance (171) and reduced beta cell mass in mice (59), an area of concern that will need to be examined with intermittent ketogenic diet feeding protocols (145) to evaluate its safety for clinical application in humans, long term.…”