• Triple Helix

NAD+: From Contributor to Champion of a Novel Pharmaceutical Avenue

Updated: 2 days ago

Written by Shrey Mehta '26

Edited by Yuliya Velhan '25

Introduction

Discovering the “Fountain of Youth” is a venture deeply rooted in historical and philosophical conversation. Intriguingly, this search extends closely within the biomedical field for many, many years. Prolonging youthfulness continues to be a significant field of research despite the various obstacles faced in understanding the biological mechanisms of the aging human body.


Arguably the most critical process that is impacted by natural aging is cellular respiration, the process that the body uses to generate energy. One of the primary reasons for weakening in a process like cellular respiration is a decline in nicotinamide adenine dinucleotide (NAD+) levels, an integral metabolic enzyme. Consequently, diminished levels of this molecule can lead to severe disease. Unexpectedly and recently, focus has shifted onto this molecule through a pharmacological perspective, an innovative venture to combat the bodily issues induced by aging. By harnessing the function of the body’s own elements, scientists now have the potential to re-strengthen pathways that weaken with age and increase longevity.

Figure 1: Diagram Illustrating Age-Related Bodily Issues (Xu 2020)

Figure 2: Chemical Representation of NAD+ Molecule (BD Editors 2018)


Cellular Respiration: The Role of NAD+

Energy levels are often correlated with human age. Biologically and metabolically, cellular respiration is the series of pathways that generates the chemical energy the body needs to consistently execute important functions as humans grow. Primarily in the mitochondria, one of the most critical organelles of living cells, cellular respiration converts glucose molecules to adenosine triphosphate (ATP). To do so efficiently, cells utilize the capabilities of various enzymes and molecules which facilitate the conversion of molecules and the coordination of the different steps in cellular respiration.


Of the several facilitators which work to maintain energy levels for the body, lots of studies have been completed to discern the function of NAD+. NAD+ is classified as a coenzyme, a non-protein compound which supports the optimal functioning of a primary enzyme. During the latter stages of the cellular respiration processes, NAD+ essentially functions as a “temporary energy carrier”, accepting and donating electrons to create an electrochemical gradient that ultimately leads to the formation of ATP (Byjus 2022).

Figure 3: Role of NAD+ in the Electron Transport Chain for ATP Generation (Miranda n.d.)


The efficiency of this integral process, however, declines over time, as shown by various studies on aging. Further research has also confirmed that this decline in functional processes is directly related to the decline in NAD+ levels over time, which can lead to a wide range of bodily issues: metabolic issues like diabetes to neurodegenerative conditions like Alzheimer’s disease. Knowing this relationship, researchers are now determined to robustly explore NAD+.


NAD+: A New Champion

Decades after the role of NAD+ was confirmed in cellular respiration, the scientific community realized that the coenzyme had a life much more secretive than previously believed. Beyond facilitating the redox reactions of cellular respiration, NAD+ is also a major player in the processes of mitochondrial growth, DNA transcription and translation, and extracellular matrix organization. Clearly, NAD+ is a vital functional component of many intertwined systems of the body, indicating that decline in its quantity significantly affects the body’s ability to execute actions optimally.


As a result, a new therapeutic approach was designed: one that focuses on reaching the aging cell’s ability to enhance NAD+ levels in the body. However, the path to doing so is not as straightforward as “carefully adding more NAD+.” NAD+ is too large of a molecule to cross cell membranes, meaning that there must be a more clever method to “program” aging cells to produce more NAD+. To accomplish this innovative task currently, pharmaceutical companies such as MetroBiotech are using small precursor molecules of NAD+ which are small enough to enter cells and signal elevated production of NAD+. Thus far, the tested therapies (all in Phase 2) yield positive results in improving bodily components like muscle strength and mitochondrial function (Harlan 2020).

Figure 4: The Natural NAD+ Production Cycle in Cells (MetroBiotech n.d.)

Figure 5: NAD+ is a Critical Molecule in the Role of Various Signaling (MetroBiotech n.d.)


Current Advancements in NAD+ Pharmaceuticals & Closing Remarks

Over the last 10 years, NAD+ precursor therapies have shown highly promising potential in suppressing age-related issues in the body. First, one study in 2014 by Khan et al., sought to treat mitochondrial myopathy (death) using a vitamin B3 molecule, a known precursor to NAD+. Mitochondrial myopathy is one of the most common disorders in adult-onset mitochondrial disorders and can only be managed with palliative care as of now. This group of researchers used a vitamin called nicotinamide riboside (NR) and developed oral supplements for this study. The team learned that NR effectively prevented development and progression of mitochondrial myopathy in mice by delaying undesired structural changes and mitochondrial DNA mutations, and increasing mitochondrial biogenesis and lipid oxidation in skeletal muscle. The data collected in this research emphasized the usability and applicability of nutrient signaling using NAD+ precursors to slow disease progression with age.


Expressing how the fine-tuning of cellular signaling with NAD+ can resolve age-induced bodily issues commenced many more studies focused on the practicality of this therapy on specific organ systems. For example, in regard to the muscular and nervous system, two research projects by Dongreyeol et. al. (2016) and Vincenzo et. al. (2017, respectively, report data enhancing NAD+ levels to restore mitochondrial function and cellular signaling improves muscle function and decreases pathological hallmarks of Alzheimer’s disease (Sorrentino 2017 & Harlan 2020)!


As the scientific community’s understanding of the human aging processes increases over time, researchers will have more clarity on which underlying mechanisms to truly hone in on. This increase in knowledge will further embed the feasibility of cell-signaling therapies, such as NAD+ precursor molecules, as a means to increase the longevity and quality of life of ill patients.

 

References

1. Sorrentino V, Romani M, Mouchiroud L, Beck JS, Zhang H, D'Amico D, Moullan N, Potenza F, Schmid AW, Rietsch S, Counts SE, Auwerx J. Enhancing mitochondrial proteostasis reduces amyloid-β proteotoxicity. Nature. 2017 Dec 14;552(7684):187-193. doi: 10.1038/nature25143. Epub 2017 Dec 6. PMID: 29211722; PMCID: PMC5730497.


2. Hyperelastic “bone”: A highly versatile, growth factor ... - science [Internet]. [cited 2022Oct23]. Available from: https://www.science.org/doi/10.1126/scitranslmed.aaf7704

3. Harlan BA, Killoy KM, Pehar M, Liu L, Auwerx J, Vargas MR. Evaluation of the NAD+ biosynthetic pathway in ALS patients and effect of modulating NAD+ levels in HSOD1-linked ALS mouse models [Internet]. Experimental Neurology. Academic Press; 2020 [cited 2022Oct23]. Available from: https://www.sciencedirect.com/science/article/pii/S0014488620300509


4. Lin JB, Kubota S, Ban N, Yoshida M, Santeford A, Sene A, Nakamura R, Zapata N, Kubota M, Tsubota K, Yoshino J, Imai SI, Apte RS. NAMPT-Mediated NAD(+) Biosynthesis Is Essential for Vision In Mice. Cell Rep. 2016 Sep 27;17(1):69-85. doi: 10.1016/j.celrep.2016.08.073. PMID: 27681422; PMCID: PMC5104206.


5. Brown KD, Maqsood S, Huang J-Y, Pan Y, Harkcom W, Li W, et al. Activation of Sirt3 by the NAD+ precursor nicotinamide riboside protects from noise-induced hearing loss [Internet]. Cell Metabolism. Elsevier; 2014 [cited 2022Oct23]. Available from: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(14)00500-2?code=cell-site


6. What is the role of NAD+ in cellular respiration? - byjus.com. (n.d.). Retrieved November 11, 2022, from https://byjus.com/question-answer/what-is-the-role-of-nad-plus-in-cellular-respiration/


7. Xu, W. (n.d.). The untwining of immunosenescence and aging - researchgate. Retrieved November 13, 2022, from https://www.researchgate.net/journal/Seminars-in-Immunopathology-1863-2300/publication/346528029_The_untwining_of_immunosenescence_and_aging/links/5fc63a0b92851c301299f3ff/The-untwining-of-immunosenescence-and-aging.pdf


8. BD Editors. (2018, August 22). Electron Transport Chain and Oxidative Phosphorylation. Biology Dictionary. https://biologydictionary.net/electron-transport-chain-and-oxidative-phosphorylation/

9. Miranda, D. (n.d.). NAD+ vs. NADH. NAD vs. NADH. Retrieved November 13, 2022, from https://www.nad.com/nad-vs-nadh


10. Our science. MetroBiotech, LLC. (n.d.). Retrieved November 13, 2022, from https://www.metrobiotech.com/our-science


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