Studies suggest that NAD+ (nicotinamide adenine dinucleotide) is a coenzyme that may play a possible role in several biological processes, notably cellular metabolism. It is generated from the B-vitamin niacin (vitamin B3) in redox processes, transferring electrons during metabolic reactions.
The oxidized (NAD+) and reduced (NADH) versions of NAD+ are both endogenous instances of the coenzyme. The oxidized form, NAD+, is thought to take electrons during processes, whereas the reduced form, NADH, is thought to contribute electrons, as suggested by the scientific hypothesis. Research suggests that energy and electrons may be transferred between molecules in metabolic pathways via this interconversion of NAD+ and NADH.
Investigations purport that several crucial metabolic activities, such as cellular respiration, DNA repair, redox reactions, and metabolic control, may include adenine dinucleotide. Findings imply that Glycolysis, the Krebs cycle (citric acid process), and oxidative phosphorylation are metabolic pathways that may need NAD+. Scientists speculate that NAD+ may get reduced to NADH during these activities, with the possibility that it may transport these electrons down the electron transport chain to fuel ATP synthesis. Lipid metabolism and macromolecule production are only two examples of the many metabolic processes that NAD+ seems to regulate.
In addition, sirtuins, a family of enzymes, may rely on NAD+ to repair DNA. Removal of acetyl groups from proteins by the enzymes sirtuins is thought to be regulated by the coenzyme NAD+, which also affects DNA repair, gene expression, and cellular lifespan.
NAD+ Peptide and Aging Cells
DNA repair and sirtuin-mediated control of gene expression are two areas where NAD+ has been proposed to have a role in extending cellular lifespan. Sirtuins are a group of proteins that could need NAD+ as a cofactor to perform their putative enzymatic functions. DNA repair, gene expression, and metabolic control are just a few of the many biological activities they may play a role in. They have been associated with increased cellular lifetime.
Sirtuins, like SIRT1, seem to be NAD+-dependent protein deacetylases and may be able to detect NAD+ levels, as purported by some research. There is some speculation in the scientific literature that sirtuins may detect NAD+ rather than NADH or the NAD+/NADH ratio. It is not yet clear, however, how enzymes like sirtuins react to redox changes in cells.
It has been hypothesized by researchers that age-related cellular dysfunction may be exacerbated by the reduction in NAD+ levels that may occur with aging and that restoring or maintaining NAD+ levels may alleviate this dysfunction. NAD(+) levels drop with age, as proposed by worm experiments, and lowering NAD(+) may further shorten longevity. NAD(+) restoration, whether genetic or other methods, seems to increase worm lifespan.
The scientists hypothesized that these events might rely on the functions of the SIRT1, otherwise known as Protein Deacetylase Sir-2.1 or Silent Information Regulator 2.1, and could include the induction of imbalances in mitochondrial proteins, as well as the stimulation of stress signaling systems like the mitochondrial unfolded protein response (UPR(mt)) and the nuclear translocation and activation of the FOXO transcription factor DAF-16. To further promote mitochondrial function, the scientists explored the possibility of increasing NAD(+) levels to improve mitochondrial stress signaling.
The importance of nicotinamide adenine dinucleotide in energy metabolism as a coenzyme for redox processes should not be lost on researchers. Studies suggest the process of cellular respiration, in which nutrients are converted into useful energy, may need NAD+. NAD+ has been hypothesized to have a role in two distinct phases of cellular respiration, namely Glycolysis and the citric acid process (also called the Krebs cycle or tricarboxylic acid/TCA process).
NAD+ Peptide and DNA
Research suggests that Poly(ADP-ribose) polymerase (PARP) seems to need NAD+, an essential cofactor for the enzyme. It is possible that when DNA is damaged, PARP is activated and binds to the damaged spot. Poly(ADP-ribosylation) is the process by which PARP is hypothesized to utilize NAD+ as a substrate to add ADP-ribose units to itself and other target proteins. This alteration may aid in the recruitment and activation of additional DNA repair proteins, speeding up the process of repairing DNA damage.
It seems that damaged DNA may trigger the production of poly(ADP-ribose) (PAR) chains via the poly(ADP-ribosylation) pathway. PARP may be involved in the detection and repair of DNA SSBs. PARP may aid in genomic stability by starting and directing DNA repair activities if NAD+ is a cofactor. However, findings imply this procedure may have the potential to decrease cellular NAD+ levels, which might affect energy metabolism and signaling, two cellular activities that rely on NAD+.
Scientists propose that “in response to DNA damage, the rate of PAR synthesis increases rapidly, up to 500-fold,” as the literature suggests, “which can consume a significant amount of NAD+.” Since PARP1 activation is hypothesized to cause intracellular NAD+ to be depleted, the researchers anticipate that this may disrupt the NAD+/SIRT1 axis, potentially resulting in abnormalities in mitochondrial homeostasis, ROS (reactive oxygen species) generation, DNA repair, and cell survival.
Scientists interested in further studying NAD+ may find the highest quality variant on the Core Peptides website.
References
[i] Imai, S., & Guarente, L. (2014). NAD+ and sirtuins in aging and disease. Trends in cell biology, 24(8), 464–471. https://doi.org/10.1016/j.tcb.2014.04.002
[ii] Wątroba, M., Dudek, I., Skoda, M., Stangret, A., Rzodkiewicz, P., & Szukiewicz, D. (2017). Sirtuins, epigenetics and longevity. Aging research reviews, 40, 11–19. https://doi.org/10.1016/j.arr.2017.08.001
[iii] Anderson, K. A., Madsen, A. S., Olsen, C. A., & Hirschey, M. D. (2017). Metabolic control by sirtuins and other enzymes that sense NAD+, NADH, or their ratio. Biochimica et biophysica acta. Bioenergetics, 1858(12), 991–998. https://doi.org/10.1016/j.bbabio.2017.09.005
[iv] Mouchiroud, L., Houtkooper, R. H., Moullan, N., Katsyuba, E., Ryu, D., Cantó, C., Mottis, A., Jo, Y. S., Viswanathan, M., Schoonjans, K., Guarente, L., & Auwerx, J. (2013). The NAD(+)/Sirtuin Pathway Modulates Longevity through Activation of Mitochondrial UPR and FOXO Signaling. Cell, 154(2), 430–441. https://doi.org/10.1016/j.cell.2013.06.016
[v] Covarrubias, A. J., Perrone, R., Grozio, A., & Verdin, E. (2021). NAD+ metabolism and its roles in cellular processes during ageing. Nature reviews. Molecular cell biology, 22(2), 119–141. https://doi.org/10.1038/s41580-020-00313-x
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