Abstract
The ketogenic diet’s (KD) anti-seizure effects have long been documented. Recently, its therapeutic potential in multiple neurodegenerative and neurodevelopmental disorders has emerged. Yet experimental evidence for a fundamental mechanism underlying beneficial effects across numerous diseases remains lacking. We previously showed that feeding rats a KD produced an early (within 2 days) and persistent elevation of hippocampal nicotinamide adenine dinucleotide+ (NAD+), an essential metabolic coenzyme and signaling molecule. NAD+ is a marker of cellular health and a substrate for enzymes implicated in longevity and DNA damage repair such as sirtuins and poly-ADP ribose polymerase-1 (PARP-1). As a result, activation of NAD+-dependent enzymes’ downstream pathways could be the origin of KD’s broad beneficial effects. Here rats were fed ad libitum regular chow or KD for 2 days or 3 weeks and the levels of hippocampal sirtuins, PARP-1, and the oxidative DNA damage marker 8-hydroxy-2’-deoxyguanosine were quantified. We found a significant immediate and persistent increase in the collective activity of nuclear sirtuin enzymes, and a significant augmentation of Sirt1 mRNA at 2 days. Levels of PARP-1 and 8-hydroxy-2’-deoxyguanosine decreased after 2 days of treatment and further declined at 3 weeks. Our data show that a KD can rapidly modulate energy metabolism by acting on NAD+-dependent enzymes and their downstream pathways. Thus, therapy with a KD can potentially enhance brain health and increase overall healthspan via NAD+-related mechanisms that render cells more resilient against DNA damage and a host of metabolic, epileptic, neurodegenerative, or neurodevelopmental insults.
Highlights
The ketogenic diet (KD) is a high-fat, low-carbohydrate, moderate protein therapy that shifts energy production away from glucose-based and toward ketone-based ATP production
Consistent with this prediction, we demonstrated that KD can induce rapid and sustained changes in the nicotinamide adenine dinucleotide (NAD)+/NADH ratio in rat hippocampus - an energetically demanding brain region considered a seizure gate (Heinemann et al, 1992) - but not in the cerebral cortex (Elamin et al, 2017)
To re-establish previous observations on rapid and sustained KDinduced increases in NAD+ availability (Elamin et al, 2017), we treated a new cohort of rats with control diet or KD
Summary
The ketogenic diet (KD) is a high-fat, low-carbohydrate, moderate protein therapy that shifts energy production away from glucose-based and toward ketone-based ATP production. Because fewer NAD molecules are reduced during ketone-based vs glucose-based metabolism in brain, elevated levels of the oxidized form (NAD+) can be expected Consistent with this prediction, we demonstrated that KD can induce rapid and sustained changes in the NAD+/NADH ratio in rat hippocampus - an energetically demanding brain region considered a seizure gate (Heinemann et al, 1992) - but not in the cerebral cortex (Elamin et al, 2017). Similar results have been found in aged mice with a ketone ester supplemented diet (Pawlosky et al, 2017)
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