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.

Keywords: Alzheimer’s disease; epilepsy; hippocampus; ketone bodies; longevity; metabolism; neurodegeneration; nicotinamide adenine dinucleotide.

Figure 1

Schematic of NAD⁺ consumption during metabolism of glucose vs. ketone bodies. Both glucose and ketone bodies lead to the formation of two molecules of acetyl-CoA which subsequently enter the citric acid cycle and participate in energy production. Although glucose provides a higher final yield of ATP, the consumption of NAD⁺ is significantly higher in this pathway (4:1). Glucose will reduce 111 molecules of NAD⁺ per 1000 molecules of ATP made, while ketone bodies reduce only 41 to produce a comparable amount of ATP. Decreased use of NAD⁺ by ketone bodies in energy production pathways could increase the amount of free NAD⁺ available as substrate for enzymes and cellular signaling processes.

Figure 2

Changes in blood ketones and brain nicotinamide adenine dinucleotide (NAD) after ketogenic diet (KD) treatment. (A) Blood levels of β-hydroxybutyrate (β-OHB; mmol/L) after 2 days (2d KD; n = 3) and 3 weeks (3w KD; n = 4) of KD treatment vs. control chow diet (CD; n = 8; P < 0.0001). (B) Hippocampal changes in NAD⁺/NADH ratio after 3 weeks KD treatment. A significant increase in the NAD⁺/NADH ratio was quantified in the hippocampi of animals fed KD for 3 weeks (n = 4) vs. animals maintained on control diet (n = 8; P < 0.005). (C) Cortical NAD⁺/NADH ratio after 3 weeks KD treatment. No differences were detected in NAD⁺/NADH ratio in frontal cortex between the dietary groups. Control CD (n = 8); KD 3 weeks (3w KD; n = 4; P = ns). (D) NAD⁺/NADH ratios in the hippocampus after 2 days KD treatment. A significant increase in the NAD⁺/NADH ratio was quantified in hippocampi obtained from animals fed KD for 2 days (2d KD; n = 3) compared to animals maintained on control diet (CD; n = 5; P < 0.0001). All comparisons were unpaired t-tests. Data are expressed as mean ± SEM. **P < 0.005; ****P < 0.0001.