Ketone-Based Metabolic Therapy: Is Increased NAD+ a Primary Mechanism?

Abstract

The ketogenic diet’s (KD) anticonvulsant effects have been well-documented for nearly a century, including in randomized controlled trials. Some patients become seizure-free and some remain so after diet cessation. Many recent studies have explored its expanded therapeutic potential in diverse neurological disorders, yet no mechanism(s) of action have been established. The diet’s high fat, low carbohydrate composition reduces glucose utilization and promotes the production of ketone bodies. Ketone bodies are a more efficient energy source than glucose and improve mitochondrial function and biogenesis. Cellular energy production depends on the metabolic coenzyme nicotinamide adenine dinucleotide (NAD), a marker for mitochondrial and cellular health. Furthermore, NAD activates downstream signaling pathways (such as the sirtuin enzymes) associated with major benefits such as longevity and reduced inflammation; thus, increasing NAD is a coveted therapeutic endpoint. Based on differential NAD+ utilization during glucose- vs. ketone body-based acetyl-CoA generation for entry into the tricarboxylic cycle, we propose that a KD will increase the NAD+/NADH ratio. When rats were fed ad libitum KD, significant increases in hippocampal NAD+/NADH ratio and blood ketone bodies were detected already at 2 days and remained elevated at 3 weeks, indicating an early and persistent metabolic shift. Based on diverse published literature and these initial data we suggest that increased NAD during ketolytic metabolism may be a primary mechanism behind the beneficial effects of this metabolic therapy in a variety of brain disorders and in promoting health and longevity.

Metabolism of Exogenous D-Beta-Hydroxybutyrate, an Energy Substrate Avidly Consumed by the Heart and Kidney

“…Moreover, as this conversion requires the co-factor, nicotinamide adenine dinucleotide (NAD + ), to be reduced to NADH, a higher AcAc/D-BHB might better preserve the mitochondrial NAD + /NADH ratio. Interestingly, a higher NAD + /NADH ratio has been associated to better health (30,31), and can be increased in the brain by nutritional ketosis (32,33), suggesting that D-BHB might be superior to MCT or KE in this respect, a point meriting further investigation.…”

How Can a Ketogenic Diet Improve Motor Function?

“…Some studies evoked that KBs provide more efficient energy source than glucose, even for the brain. They are metabolized faster than glucose and bypass the glycolytic pathway by directly entering the TCA cycle, whereas glucose has to first undergo glycolysis ( Veech et al, 2001 ; LaManna et al, 2009 ; Elamin et al, 2017 ). Consequently, KBs lead to a decrease in glycolytic ATP generation and an increase in ATP generation by mitochondrial oxidation ( Kim et al, 2010 ; Steriade et al, 2014 ; Hyatt et al, 2016 ).…”

“…Consequently, KBs lead to a decrease in glycolytic ATP generation and an increase in ATP generation by mitochondrial oxidation ( Kim et al, 2010 ; Steriade et al, 2014 ; Hyatt et al, 2016 ). Moreover, Elamin et al (2017) showed that whereas both glucose and KBs produce two molecules of acetyl-CoA, glucose reduces four molecules of NAD + and KBs reduce either one (for conversion of BOHB in acetoacetate), or none (for conversion of acetoacetate in acetyl-CoA) during acetyl-CoA synthesis. KD is associated with a coordinated upregulation of hippocampal genes encoding metabolic and mitochondrial enzymes ( Bough et al, 2006 ).…”

Nutritional ketosis as an intervention to relieve astrogliosis: Possible therapeutic applications in the treatment of neurodegenerative and neuroprogressive disorders

“…Under physiological conditions, acetyl CoA produced by FA oxidation enters the tricarboxylic acid (TCA) cycle and subsequently engages in a chemical reaction with oxaloacetate to produce citrate. However, under metabolic conditions induced by the KD, oxaloacetate is exported out of the mitochondria, being utilized for the process of gluconeogenesis [72]. In this scenario, levels of acetyl CoA synthesis greatly exceed the amount of oxaloacetate in the mitochondrial environment and the former engages in a series of condensation reactions, which are the hallmark of ketogenesis [73].…”