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Energy production in cells

The foods we eat and the liquids we drink are turned into energy in the body. Carbohydrates, protein, and lipids are the three basic nutrients required for the delivery of energy in the body. These nutrients from foods and beverages are digested and used by cells to produce Adenosine Triphosphate (ATP), the primary molecule for storing and transmitting energy to power cellular processes.1

The process of energy production is located in the mitochondria (Figure 1). The overall energy production process can be divided into three main metabolic stages: glycolysis, the Krebs cycle (tricarboxylic acid cycle, TCA), and the electron transfer cycle (respiratory-chain phosphorylation).2

Figure 1. Energy production process in cells.

Nicotinamide adenine dinucleotide (NAD+) is an essential component in biological metabolism and ATP generation. NAD is available in two forms: oxidised (NAD+) and reduced (NADH), with the redox ratio (NAD+/NADH) being a key driver of cytosolic and mitochondrial metabolic balance. Because of its ability to take hydride equivalents and generate NADH during ATP generation, NAD+ is vital in glycolysis and the TCA cycle. Numerous in-vitro and pre-clinical studies have linked NAD and energy homeostasis. 3-7

Recent scientific researches of NAD+ on energy production

Brain NAD is associated with ATP energy production

A very recent study conducted in Switzerland, the United Kingdom, and Canada looked at the relationships between brain NAD, energy generation, and membrane phospholipid metabolism in 50 healthy people of various ages.8

The first finding is that the middle-aged and young groups had considerable disparities in NAD-related parameters. As demonstrated in Figure 2, there was a considerable decline in energy-related ATP (3.1%) and PE (3.1%) levels as people got older. The average value of NAD-related parameters decreased by 2–5% as age increasing.

Figure 2. Percent change in phospho-metabolites and in metabolic rate constants between the middle-aged group vs. the young group.8

In addition, the study revealed that brain NAD+ and tNAD levels were positively associated with brain ATP level, as was the NAD+/NADH redox ratio with the two ATP energy generation rate constants, kATP and kCK. NAD was also discovered to be a component of a metabolic network that connects membrane phospholipid metabolism, energy levels, and ageing (Figure 3). 

Figure 3. Scheme summarizing the network between ATP and PCr production and utilization.8

The final discovery is that NAD is linked to phospholipid membrane metabolism. One of the hallmarks of brain ageing is a reduction in brain volume,9 which is caused by a decrease in neurogenesis and synaptogenesis. Phospholipids, which provide considerable structural integrity to the neuropil and myelin, are intimately implicated in these processes. Many biological processes, including Sirtuins and enzymes involved in NAD production, are also thought to be implicated in the relationship between NAD and phospholipid metabolism.5, 7, 10, 11

In conclusion, because NAD level and redox state have been discovered to be important roles in the efficiency of brain energy metabolism, efforts to improve brain NAD and redox ratio should help to improve energy metabolism, which is a major factor in brain ageing.12 Additionally, the results in this research show that the age effect on NAD is more heterogenous between 19 and 59-year-old, implying that some middle-aged persons could benefit from a NAD-boosting intervention. As numerous pre-clinical reports demonstrated positive effect of NAD precursor in model of neurological disease,4-6 and a nutritional ketogenic intervention could raise the NAD+/NADH redox ratio in the brain of healthy young participants indirectly,13 the modulation of NAD in human brain in the future is possible.

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For more about NAD+ and the NAD+ supplements, please refer to: White Paper – NAD+ Boosting: A Way to Fight Ageing.

Reference:

  1. Alberts, B., Johnson, A., Lewis, J., et al. Molecular Biology of the Cell. 4th edition. New York: Garland Science; 2002. How Cells Obtain Energy from Food.
  2. https://www.biologyonline.com/dictionary/cellular-respiration 
  3. Shen, Y., Kapfhamer, D., Minnella, A. M., Kim, J. E., Won, S. J., Chen, Y., et al. (2017). Bioenergetic state regulates innate inflammatory responses through the transcriptional co-repressor CtBP. Nat. Commun. 8:624.
  4. Dienel, G. A. (2019). Brain glucose metabolism: integration of energetics with function. Physiol. Rev. 99, 949-1045.
  5. Lautrup, S., Sinclair, D. A., Mattson, M. P., and Fang, E. F. (2019). NAD+ in brain aging and neurodegenerative disorders. Cell Metab. 30, 630–655.
  6. Gilmour, B. C., Gudmundsrud, R., Frank, J., Hov, A., Lautrup, S., Aman, Y., et al. (2020). Targeting NAD+ in translational research to relieve diseases and conditions of metabolic stress and ageing. Mech. Ageing Dev. Dev. 186:111208. 
  7. Katsyuba, E., Romani, M., Hofer, D., and Auwerx, J. (2020). NAD+ homeostasis in health and disease. Nat. Metab. 2, 9–31.
  8. Cuenoud, B., Ipek, Ö., Shevlyakova, M., Beaumont, M., Cunnane, S. C., Gruetter, R., Xin, L. (2020). Brain NAD is associated with ATP energy production and membrane phospholipid turnover in humans.  Front. Aging Neurosci.,12, 458. 
  9. Resnick, S. M., Pham, D. L., Kraut, M. A., Zonderman, A. B., and Davatzikos, C. (2003). Longitudinal magnetic resonance imaging studies of older adults: a shrinking brain. J. Neurosci. 23, 3295–3301.
  10. Verdin, E. (2015). NAD? in aging, metabolism, and neurodegeneration. Science 350, 1208–1213. 
  11. Satoh, A., Imai, S. I., and Guarente, L. (2017). The brain, sirtuins, and ageing. Nat. Rev. Neurosci. 18, 362–374.
  12. Cunnane, S. C., Trushina, E., Morland, C., Prigione, A., Casadesus, G., Andrews, Z. B., et al. (2020). Brain energy rescue: an emerging therapeutic concept for neurodegenerative disorders of ageing. Nat. Rev. Drug Discov. 19, 609–633.
  13. Xin, L., Ipek, Ö., Beaumont, M., Shevlyakova, M., Christinat, N., Masoodi, M., et al. (2018). Nutritional ketosis increases NAD+/NADH ratio in healthy human brain: an in vivo study by 31P-MRS. Front. Nutr. 5:62.

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