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Nutritional Ketosis May Preserve Brain Health via Increasing NAD+/NADH Ratio

by Lewis Chang, PhD

Ketosis is the metabolic state in which ketone bodies—alternative energy substrates to glucose—are produced from fat and utilized as the main energy source for the body. An important study found that nutritional ketosis induced by consumption of medium-chain triglycerides (MCT) oil helped increase the redox NAD+/NADH ratio in the brain of healthy young adults.1

Disturbed glucose metabolism and the resulting inadequate energy supply to the brain contributes to the pathophysiology of neurodegenerative diseases such as Alzheimer’s disease (AD).2 Interestingly, in a previous study researchers from Research Center on Aging at Université de Sherbrooke (Sherbrooke, Canada) noticed that the brain uptake of ketone bodies remained the same as young healthy adults in subjects with mild-moderate AD.3 Subsequently, they showed that consumption of MCT oil increased the level of ketone bodies in the brain and compensated for the brain glucose deficit in patients with AD, demonstrating the potential therapeutic value of MCT oil in maintaining brain metabolism.4

Meanwhile, researchers from Center for Biomedical Imaging at Ecole Polytechnique Fédérale de Lausanne (Lausanne, Switzerland) were interested in whether external supply of ketone bodies via MCT oil would produce other metabolic changes in the brain, particularly on the energy-related compound nicotinamide adenine dinucleotide, both in its oxidized form (NAD+) and reduced form (NADH).1 Because a lower NAD+ level and NAD+/NADH ratio is directly linked to age-related neurodegenerative disorders and metabolic diseases,5 the investigators wanted to know whether MCT consumption could boost the NAD+ level and NAD+/NADH ratio.

In this study, 25 healthy adult volunteers first received a brain scan termed phosphorous magnetic resonance spectroscopy (31P-MRS), then consumed 250 mL of a complete liquid nutrition product containing 10 g MCT [a mixture of 60% octanoic acid (C8) and 40% dodecanoic acid (C10)], and then received another brain scan 45 minutes after consumption.1 Scanning schedule was based on the pharmacokinetic data indicating that maximum ketone levels in the brain occurred at approximately 45 minutes after intake of the MCT oil. The unique 31P-MPR allowed for the quantification of NAD+ and NADH in a non-invasive manner.6

The study investigators found that NAD+ was significantly increased by 3.4% and NADH was significantly reduced by 13% after consumption of MCT oil, resulting in a 18% increase in NAD+/NADH ratio.1 NAD+ is an important compound involved in many biological processes. The breakdown of glucose for energy requires 4 NAD+, whereas the breakdown of ketone body for energy requires only 1 NAD+.7 This study confirmed that ingesting MCT oil can have a NAD+ sparing effect, and this increase in the NAD+ level and NAD+/NADH ratio may help promote brain health by reducing oxidative stress and inflammation.

It is important to note that these are short-term results from healthy subjects. More studies are needed to determine whether long-term consumption of MCT oil can correct chronic NAD+/NADH deficits and leading to health improvement in subjects with neurodegenerative disorders.

Why is this Clinically Relevant?

  • Consumption of MCT oil helps promote nutritional ketosis, even in patients with AD4
  • Nutritional ketosis may help preserve brain health by increasing NAD+ level and NAD+/NADH ratio in the brain1

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  1. Xin L, Ipek O, Beaumont M, et al. Nutritional ketosis increases NAD(+)/NADH ratio in healthy human brain: an in vivo study by (31)P-MRS. Front Nutr. 2018;5:62.
  2. Mergenthaler P, Lindauer U, Dienel GA, Meisel A. Sugar for the brain: the role of glucose in physiological and pathological brain function. Trends Neurosci. 2013;36(10):587-597.
  3. Croteau E, Castellano CA, Fortier M, et al. A cross-sectional comparison of brain glucose and ketone metabolism in cognitively healthy older adults, mild cognitive impairment and early Alzheimer’s disease. Exp Gerontol. 2018;107:18-26.
  4. Croteau E, Castellano CA, Richard MA, et al. Ketogenic medium chain triglycerides increase brain energy metabolism in Alzheimer’s disease. J Alzheimers Dis. 2018;64(2):551-561.
  5. Verdin E. NAD(+) in aging, metabolism, and neurodegeneration. Science. 2015;350(6265):1208-1213.
  6. Zhu XH, Lu M, Lee BY, Ugurbil K, Chen W. In vivo NAD assay reveals the intracellular NAD contents and redox state in healthy human brain and their age dependences. Proc Natl Acad Sci U S A. 2015;112(9):2876-2881.
  7. Cotter DG, Schugar RC, Crawford PA. Ketone body metabolism and cardiovascular disease. Am J Physiol Heart Circ Physiol. 2013;304(8):H1060-1076.

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