The essential redox coenzyme nicotinamide adenine dinucleotide (NAD+) is present in every living cell that carries out redox reactions and manages energy metabolism. NAD+ functions as an essential coenzyme, which plays a critical role in mitochondrial support, especially during electron transport chain operations. This compound enables the transformation of nutrients into adenosine triphosphate (ATP), which cells use as their main energy source.
Fig. 1 NAD+ metabolism. (Poljšak B, et al., 2023)
Existence Forms of NAD+
NAD+ has two forms: oxidized (NAD+) and reduced (NADH). Cells must sustain a consistent balance between oxidized NAD+ and reduced NADH for metabolic stability.
- NAD+ serves as an essential oxidized coenzyme for electron transfer in redox reactions throughout metabolic processes. Glycolysis, the citric acid cycle, and oxidative phosphorylation hinge on this process, which produces ATP together.
- The mitochondrion turns high-energy electrons derived from NADH into ATP by utilizing an electron transport chain.
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- Anti-Aging Healthcare R&D Services: CD BioSciences offers a diverse range of anti-aging healthcare R&D services to address the complex challenges of aging, including NAD+ supplements.
The Effects of NAD+ on Aging and Longevity
NAD+ concentration tends to decline in each of the major tissues. Furthermore, there is an age dependence of the NAD+ decline in Caenorhabditis elegans (C. elegans) and mice, as well as in deceased human tissues, which corroborates the universal age-associated decrement of NAD+.
Fig. 2 NAD+ decline at the core of hallmarks of aging. (Aman Y, et al., 2018)
- NAD+ serves as a substrate of sirtuins, a family of proteins involved in DNA repair, inflammation, and cellular stress response. Increased sirtuin activity leads to better cellular health and longevity.
- NAD+ affects glucose metabolism and insulin signaling. Elevated NAD+ levels could increase insulin sensitivity, potentially lowering the likelihood of age-related metabolic diseases.
- There is evidence from some studies in the literature that NAD+ can support neuronal health and that reconstitution of NAD+ levels might protect from neurodegenerative diseases due to its ability to ameliorate oxidative stress and inflammation.
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How to Regulate NAD+ Levels?
PARP Inhibition
Poly(ADP-ribose) polymerases (PARPs) utilize NAD+ as a key substrate to promote DNA repair processes. Excessive activation of PARPs during DNA damage responses results in NAD+ depletion, which accelerates cellular aging and dysfunction. By suppressing PARP activity, cells maintain their NAD+ levels because DNA repair processes use less NAD+. Conserving NAD+ allows for greater availability to sustain vital cellular functions, including energy production and activating sirtuins.
CD38 Inhibition
The CD38 enzyme converts NAD+ into nicotinamide and ADP-ribose and causes a reduction in cellular NAD+ levels. Organisms experience reduced NAD+ availability because CD38 activity increases with age. CD38 inhibition prevents NAD+ degradation and preserves its cellular levels. The approach focuses on lowering NAD+ concentrations within aging cells while promoting better cellular health.
NNMT Knockdown
Nicotinamide N-methyltransferase (NNMT) enzyme attaches a methyl group to nicotinamide, which acts as a precursor to NAD+, ultimately reducing its availability for NAD+ synthesis. The NNMT enzyme displays elevated activity during aging and metabolic disease progression. When NNMT activity is inhibited, nicotinamide becomes more available for NAD+ production, which leads to higher NAD+ concentrations. Scientific efforts aim to increase NAD+ levels by targeting metabolic pathways that limit precursor availability.
How to Detect Subcellular NAD+?
By measuring NAD+ concentrations across different subcellular compartments, researchers gain insights into its impact on cellular metabolism and aging processes. Several methods exist for measuring NAD+ concentrations:
| Methods |
Description |
Advantages |
Limitations |
| Fluorometric assays |
The fundamental mechanism of fluorometric assays involves utilizing the fluorescence characteristics inherent in NAD+ and its derivatives. The enzymatic transformation of NAD+ into a fluorescent product enables these assays to measure NAD+ levels through fluorescence intensity analysis. |
The method offers straightforward application and sensitivity while being suitable for high-throughput screening. |
Specific conditions, including optimal pH and temperature, are needed for fluorometric assays, while the presence of other fluorescent compounds can impact their results. |
| Mass spectrometry |
Mass spectrometry (MS) functions as a robust analytical method to determine the mass-to-charge ratio of ions. Samples are ionized for NAD+ detection, and their resultant ions are analyzed to measure the levels of NAD+ and its metabolites. |
MS delivers strong sensitivity and specificity, which enables researchers to analyze NAD+ concentrations in complex biological samples. The technology can distinguish between NAD+ and NADH while detecting different NAD+ precursor molecules. |
MS requires advanced equipment and expert knowledge, while the preparation of samples involves intricate steps. |
| NAD+ biosensors |
Modern advancements in biosensor technology enable scientists to develop probes capable of measuring NAD+ levels within living cells. Researchers use electrochemical and fluorescent sensors to measure NAD+ dynamics in real time to understand its effects on cellular aging. |
Biosensors facilitate non-invasive detection of NAD+ levels in live cells, which helps to analyze cellular metabolism and responses to different stimuli. |
The detection capabilities of biosensors show variability in specificity and sensitivity with potential influences from cellular conditions and metabolite presence. |
NAD+ leads current scientific studies that target both increasing life span and reversing signs of aging. CD BioSciences helps clients develop novel health solutions targeting aging populations through its studies of NAD+ regulatory mechanisms and detection techniques. If you are interested in our services, please feel free to contact us or make an online inquiry.
References
- Poljšak B, et al. The Central Role of the NAD+ Molecule in the Development of Aging and the Prevention of Chronic Age-Related Diseases: Strategies for NAD+ Modulation. Int J Mol Sci, 2023, 4 (3): 2959.
- Aman Y, et al. Therapeutic potential of boosting NAD+ in aging and age-related diseases. Translational Medicine of Aging, 2018.
