Much of the attention on the benefits of restoring NAD+ levels focus on its role in activating sirtuins. However, scientific research shows that NAD supplementation has a clear beneficial effect not only on ageing itself but also on a vast range of age-related disorders through improving the levels of ATP.
Declining ATP as we age
Adenosine triphosphate (ATP) is the main biological fuel used by our body. It provides every cell with energy for the essential processes such as muscle contraction or chemical synthesis.
Just as with NAD+, if we stopped producing ATP, we would die almost instantly.
Also as with NAD+, the levels of ATP decline as we age and is accompanied by a gradual decline in physiological function and an increased risk of death.
The chart above shows the ATP content is significantly higher in young healthy individuals (ages 16-40) when compared to the levels in old healthy individuals (ages 41-91). (r)
How do ATP levels influence aging?
Exposing human fibroblasts (the most common cells of connective tissue) to hydrogen peroxide leads to cell death – however the mode of cell death is dependent upon the levels of free ATP. (r)
Younger cells (<60 years) which have higher levels of free ATP are significantly more resistant to necrosis induced by exposure to hydrogen peroxide than older cells (>60 years).
When the cells – young or old – are treated with inhibitors of ATP synthesis such as oligomycin they become not only more susceptible to death but also switch their death mode from apoptosis (programmed cell suicide) to necrosis (uncontrolled cell death).
Role of ATP in cell death
Apoptosis is an evolutionarily conserved mechanism of cell death that involves chromatin condensation, nuclear fragmentation and formation of apoptotic bodies – it is crucial for an effective removal of unnecessary cells.
Necrosis, however, is a very rapid process which involves dysregulation of ion homeostasis which then leads to cell swelling and mitochondrial dilation. The integrity of plasma membrane is lost and the leakage of the cytoplasm that follows the disruption of the membrane induces necrotic inflammation.
The switch from apoptosis to necrosis that has been observed in cells with lower levels of ATP may be responsible for the onset of age-dependent disorders.
ATP supplements do not restore ATP levels
Could we not simply take ATP supplements to ward off necrotic inflammation as we get older?
Unfortunately, acute oral supplementation of ATP has been shown to be ineffective. (r)
In this randomized placebo-controlled study, participants were given single doses of either 5,000 mg of ATP or placebo. To ensure that that ATP does not degrade in the acidic environment of the stomach the supplement was given via two types of pH-sensitive, enteric-coated pellets (release in the proximal or distal small intestine), or via a naso-duodenal tube. After administration blood ATP and metabolite concentrations were monitored.
A single dose of oral ATP supplement is not bioavailable, whether administered as proximal-release or distal-release enteric coated pellets, or directly instilled in the small-intestine.
None of these methods of ATP supplementation led to an increase in ATP or adenosine concentrations in blood. The administered ATP was degraded to uric acid by xanthine oxidase – an enzyme expressed primarily in the liver and in endothelial cells of blood vessels.
NAD+ restores ATP levels
Fortunately, NAD+ is known to be able to restore healthy levels of ATP.
This has been of particular interest in the study of Mitochondrial DNA Depletion Syndromes which are characterised by a reduction in mitochondrial DNA and ATP production. These rare disorders usually lead to death in infancy due to liver failure.
In humans, NAD+ administered by IV was shown to raise levels of ADPR (ATP precursor) by 400%.
A recent study utilized a library of 2,400 drugs to screen for drugs that could restore ATP levels. They successfully identified 15 drugs, influencing a variety of metabolic processes, which significantly increased ATP levels. (r)
Of these, the strongest impact on the production of ATP was NAD+.
The researchers demonstrated that NAD+ activates a transcription cascade that results in increased expression of mitochondrial proteins involved in ATP production.
This finding was further validated on DGUOK-deficient rats (their livers have an impaired ATP production).
Administering nicotinamide riboside (a NAD precursor) significantly improved their ATP levels – a finding that is promising not only for prevention but also for treatment of the affected patients.
NAD+ in the bloodstream elevates ATP inside cells
NAD+ is involved in many important biological functions including energy metabolism, DNA repair as well as mitochondrial activity and cell death.
How does it exactly improve the ATP levels? According to a recent study of BV2 microglia the effects of NAD+ are produced by its degradation product adenosine as follows:
- NAD+ is degraded into adenosine outside of the cells
- Adenosine enters BV2 microglia through equilibrative nucleoside transporters under basal conditions
- Adenosine inside the cell is converted to AMP by adenosine kinase which increases the ATP.
The numerous associations between mitochondrial dysfunction and a wide range of disorders show the importance of healthy mitochondria for health and longevity.
Restoring youthful ATP levels through NAD+ supplementation may alleviate symptoms not only in mtDNA depletion syndromes but also in many other age-related conditions.
Supplementing NAD+ is an effective method of increasing ATP levels.
- Arts, I. C., Coolen, E. J., Bours, M. J., Huyghebaert, N., Stuart, M. A. C., Bast, A., & Dagnelie, P. C. (2012). Adenosine 5′-triphosphate (ATP) supplements are not orally bioavailable: a randomized, placebo-controlled cross-over trial in healthy humans. Journal of the International Society of Sports Nutrition, 9(1). https://doi.org/10.1186/1550-2783-9-16
- Jing R., Corbett J. L., Cai J., Beeson G.C., Beeson C. C., Chan S.S., Dimmock D.P., Lazcares L., Geurts A.M., Lemasters J.J., Duncan S.A. A Screen Using iPSC-Derived Hepatocytes Reveals NAD+ as a Potential Treatment for mtDNA Depletion Syndrome. Cell Reports, 2018; 25 (6): 1469 DOI: 10.1016/j.celrep.2018.10.036
- Miyoshi, N., Oubrahim, H., Chock, P. B., & Stadtman, E. R. (2006). Age-dependent cell death and the role of ATP in hydrogen peroxide-induced apoptosis and necrosis. Proceedings of the National Academy of Sciences, 103(6), 1727–1731. https://doi.org/10.1073/pnas.0510346103
- G.L. Nicolson Mitochondrial dysfunction and chronic disease: treatment with natural supplements Alt. Ther. Health Med., 19 (2013)
- Rabini, R. A., Petruzzi, E., Staffolani, R., Tesei, M., Fumelli, P., Pazzagli, M., & Mazzanti, L. (1997). Diabetes mellitus and subjects’ ageing: a study on the ATP content and ATP‐related enzyme activities in human erythrocytes. European Journal of Clinical Investigation, 27(4), 327–332. https://doi.org/10.1046/j.1365-2362.1997.1130652.x
- Tsujimoto, Y. (1997). Apoptosis and necrosis: Intracellular ATP level as a determinant for cell death modes. Cell Death & Differentiation, 4(6), 429–434. https://doi.org/10.1038/sj.cdd.4400262
- Zhang, J., Wang, C., Shi, H., Wu, D., & Ying, W. (2018). Extracellular Degradation Into Adenosine and the Activities of Adenosine Kinase and AMPK Mediate Extracellular NAD+-Produced Increases in the Adenylate Pool of BV2 Microglia Under Basal Conditions. Frontiers in Cellular Neuroscience, 12. https://doi.org/10.3389/fncel.2018.00343