The role of NAD+ in tissue regeneration and its application in orofacial harmonization
DOI:
https://doi.org/10.52076/eacad-v7i1.685Keywords:
Nicotinamide Adenine Dinucleotide, Tissue Regeneration, Regenerative Medicine.Abstract
Skin aging represents a significant challenge in dermatology, with decreased levels of nicotinamide adenine dinucleotide (NAD+) emerging as a key factor. This study aims to investigate the effects of NAD+ on facial tissue regeneration and its applicability in orofacial harmonization. Fifty-eight articles published between 2015 and 2024, selected from PubMed, Google Scholar, and Scopus databases, were analyzed. Inclusion criteria encompassed experimental and clinical studies in English that addressed: (1) molecular mechanisms of NAD+ in skin aging, (2) NAD+-based therapeutic strategies, and (3) applications in orofacial harmonization. The results demonstrated that the decline in NAD+ is directly correlated with mitochondrial dysfunction and reduced activity of sirtuins (SIRT1 and SIRT3), key factors in the skin aging process. Supplementation with nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR) has shown significant efficacy in improving skin elasticity, reducing wrinkles, and increasing collagen synthesis, demonstrating its regenerative potential. However, limitations such as low bioavailability and lack of standardized protocols were identified, impacting therapeutic efficacy. In practical application for orofacial harmonization, the results were encouraging, with significant improvement in skin texture and facial volumization, indicating that NAD+ can become an important pillar in facial rejuvenation protocols. However, the review revealed the need for longitudinal studies to establish optimized protocols and the safety of these interventions, especially the metabolic interactions of NAD+ in the body. The findings consolidate NAD+ as a therapeutic target with great potential in aesthetic dermatology.
References
Rajman, L., Chwalek, K., & Sinclair, D. A. (2018). Therapeutic potential of NAD-boosting molecules: The in vivo evidence. Cell Metabolism, 27(3), 529–547.
Yoshino, J., Baur, J. A., & Imai, S. I. (2018). NAD+ intermediates: The biology and therapeutic potential of NMN and NR. Cell Metabolism, 27(3), 513–528.
Verdin, E. (2015). NAD+ in aging, metabolism, and neurodegeneration. Science, 350(6265), 1208–1213.
Cantó, C., Menzies, K. J., & Auwerx, J. (2015). NAD+ metabolism and the control of energy homeostasis: A balancing act between mitochondria and the nucleus. Cell Metabolism, 22(1), 31–53.
Fang, E. F., Lautrup, S., Hou, Y., Demarest, T. G., Croteau, D. L., Mattson, M. P., et al. (2017). NAD+ in aging: Molecular mechanisms and translational implications. Trends in Molecular Medicine, 23(10), 899–916.
Camillo, L., Zavattaro, E., & Savoia, P. (2025). Nicotinamide: A multifaceted molecule in skin health and beyond. Medicina, 61(2), 254.
Martens, C. R., Denman, B. A., Mazzo, M. R., et al. (2018). Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD+ in healthy middle-aged and older adults. Nature Communications, 9(1), 1286.
Kang, S., Park, J., Cheng, Z., Ye, S., Jun, S. H., & Kang, N. G. (2024). Novel approach to skin anti-aging: Boosting pharmacological effects of exogenous NAD+ by synergistic inhibition of CD38 expression. Cells, 13(21), 1799.
Flagler, M. J., Tamura, M., Laughlin, T., Hartman, S., Ashe, J., Adams, R., et al. (2021). Combinations of peptides synergistically activate the regenerative capacity of skin cells in vitro. International Journal of Cosmetic Science, 43(5), 518–529.
Xie, N., Zhang, L., Gao, W., Huang, C., Huber, P. E., Zhou, X., et al. (2020). NAD+ metabolism: Pathophysiologic mechanisms and therapeutic potential. Signal Transduction and Targeted Therapy, 5(1), 227.
Sun, W., Liu, C., Chen, Q., Liu, N., Yan, Y., & Liu, B. (2018). SIRT3: A new regulator of cardiovascular diseases. Oxidative Medicine and Cellular Longevity, 2018, 7293861.
Sweeney, G., & Song, J. (2016). The association between PGC-1α and Alzheimer’s disease. Anatomy & Cell Biology, 49(1), 1–6.
Tapias, V., McCoy, J. L., & Greenamyre, J. T. (2019). Phenothiazine normalizes the NADH/NAD+ ratio, maintains mitochondrial integrity and protects the nigrostriatal dopamine system in a chronic rotenone model of Parkinson’s disease. Redox Biology, 24, 101164.
Conlon, N. J. (2022). The role of NAD+ in regenerative medicine. Plastic and Reconstructive Surgery, 150(1S), 41S–48S.
Hogan, K. A., Chini, C. C., & Chini, E. N. (2019). The multi-faceted ecto-enzyme CD38: Roles in immunomodulation, cancer, aging, and metabolic diseases. Frontiers in Immunology, 10, 1187.
Abdellatif, M., Sedej, S., & Kroemer, G. (2021). NAD+ metabolism in cardiac health, aging, and disease. Circulation, 144(22), 1795–1817.
You, Y., & Liang, W. (2023). SIRT1 and SIRT6: The role in aging-related diseases. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 1869(7), 166815.
Korge, P., Calmettes, G., & Weiss, J. N. (2016). Reactive oxygen species production in cardiac mitochondria after complex I inhibition. Free Radical Biology and Medicine, 96, 22–33.
Sun, H., Li, D., Wei, C., Liu, L., Xin, Z., Gao, H., et al. (2024). The relationship between SIRT1 and inflammation: A systematic review and meta-analysis. Frontiers in Immunology, 15, 1465849.
Son, M. J., Kwon, Y., Son, T., & Cho, Y. S. (2016). Restoration of mitochondrial NAD+ levels delays stem cell senescence. Stem Cells, 34(12), 2840–2851.
Zareba, I., & Palka, J. (2016). Prolidase-proline dehydrogenase axis and collagen biosynthesis. BioFactors, 42(4), 341–348.
Wei, C. C., Kong, Y. Y., Hua, X., Li, G. Q., Zheng, S. L., Cheng, M. H., et al. (2017). NAD replenishment with NMN protects BBB integrity. British Journal of Pharmacology, 174(21), 3823–3836.
Zhang, J., Tang, Y., Zhang, S., Xie, Z., Ma, W., Liu, S., et al. (2025). Mitochondrial NAD+ deficiency and aneurysm. Nature Cardiovascular Research, 1–18.
Casey-Power, S., Vardar, C., Ryan, R., Behl, G., McLoughlin, P., & Byrne, M. E. (2023). NAD+-associated complexes for ocular delivery. European Journal of Pharmaceutics and Biopharmaceutics, 192, 62–78.
Airhart, S. E., Shireman, L. M., Risler, L. J., Anderson, G. D., Nagana Gowda, G. A., Raftery, D., et al. (2017). Pharmacokinetics of NR supplement. PLoS ONE, 12(12), e0186459.
Wong, W., Crane, E. D., Zhang, H., Li, J., Day, T. A., & Green, A. E. (2022). PGC-1α and epidermal stem cell fate. Molecular Metabolism, 65, 101575.
Oh, H., Kwak, J. S., Yang, S., Gong, M. K., Kim, J. H., & Rhee, J. (2015). HIF-2α and NAMPT-NAD+ axis in osteoarthritis. Osteoarthritis and Cartilage, 23(12), 2288–2296.
Yi, L., Maier, A. B., Tao, R., Lin, Z., Vaidya, A., Pendse, S., et al. (2023). NMN supplementation clinical trial. Geroscience, 45(1), 29–43.
Liu, K. K., Sun, W., Qin, Z. H., & Zhang, Z. L. (2025). The application of nicotinamide coenzymes. In Biology of Nicotinamide Coenzymes (pp. 757–776). Springer.
Radenkovic, D., Reason, & Verdin, E. (2020). Clinical evidence for targeting NAD therapeutically. Pharmaceuticals, 13(9), 247.
Gregorio, N. E., Levine, M. Z., & Oza, J. P. (2019). A user’s guide to cell-free protein synthesis. Methods and Protocols, 2(1), 24.
Lee, J., Lee, J. H., Chakraborty, K., Hwang, J., & Lee, Y. K. (2022). Exosome-based drug delivery systems. RSC Advances, 12(29), 18475–18492.
Deng, S., Cao, H., Cui, X., Fan, Y., Wang, Q., & Zhang, X. (2023). Exosome-based strategies in tissue regeneration. Acta Biomaterialia, 171, 68–84.
Chang, M., Li, L., Hu, H., Hu, Q., Wang, A., Cao, X., et al. (2017). Quantifying NADH/NAD+ via biosensors. Scientific Reports, 7(1), 4209.
Iha, K., et al. (2022). Ultrasensitive ELISA detection in exosomes. Analytical Biochemistry, 654, 114831.
Kalluri, R., & LeBleu, V. S. (2020). The biology of exosomes. Science, 367(6478), eaau6977.
Skibska, A., & Perlikowska, R. (2021). Signal peptides in cosmetics. Current Protein and Peptide Science, 22(10), 716–728.
Aman, Y., et al. (2018). NAD+ boosting in aging. Translational Medicine of Aging, 2, 30–37.
Sharma, A., et al. (2023). Synergistic NAD+ supplementation strategies. Nutrients, 15(2), 445.
Pan, S. Y., & Luo, L. (2025). Coenzyme I and intestinal diseases. In Biology of Nicotinamide Coenzymes (pp. 489–497). Springer.
Chini, C. C., Zeidler, J. D., Kashyap, S., Warner, G., & Chini, E. N. (2021). Evolving concepts in NAD+ metabolism. Cell Metabolism, 33(6), 1076–1087.
Gindri, I. D. M., et al. (2024). NAD safety and effectiveness: A systematic review. American Journal of Physiology-Endocrinology and Metabolism, 326(4), E417–E427.
Song, Q., et al. (2023). NMN safety and anti-aging effects. Advances in Nutrition, 14(6), 1416–1435.
Boo, Y. C. (2021). Nicotinamide in skin aging. Antioxidants, 10(8), 1315.
Katayoshi, T., et al. (2021). NAMPT and keratinocyte survival. Journal of Photochemistry and Photobiology B, 221, 112238.
Whitson, J. A., et al. (2020). SS-31 and NMN in aged hearts. Aging Cell, 19(10), e13213.
Mehmel, M., Jovanović, N., & Spitz, U. (2020). Nicotinamide riboside: Current research. Nutrients, 12(6), 1616.
Sreeraj, H., et al. (2024). Exosomes in skin treatment. Nano TransMed, 100048.
Lautrup, S., Sinclair, D. A., Mattson, M. P., & Fang, E. F. (2019). NAD+ in brain aging. Cell Metabolism, 30(4), 630–655.
Yoshino, M., et al. (2021). NMN improves insulin sensitivity. Science, 372(6547), 1224–1229.
Poddar, S. K., et al. (2019). NMN therapeutic applications. Biomolecules, 9(1), 34.
Covarrubias, A. J., Perrone, R., Grozio, A., & Verdin, E. (2021). NAD+ metabolism in ageing. Nature Reviews Molecular Cell Biology, 22(2), 119–141.
Srivastava, S. (2016). NAD+ in mitochondrial disorders. Clinical and Translational Medicine, 5, 1–11.
Gurunathan, S., et al. (2019). Exosomes: Therapeutic approaches. Cells, 8(4), 307.
Ashfaq, U. A., et al. (2017). Nanoparticle drug delivery systems. Critical Reviews in Therapeutic Drug Carrier Systems, 34(4).
Sysak, S., et al. (2023). Metal nanoparticle-flavonoid connections. Nanomaterials, 13(9), 1531.
Poljšak, B., et al. (2022). Challenges in NAD+ boosting. Antioxidants, 11(9), 1637.
Katsyuba, E., & Auwerx, J. (2017). Modulating NAD+ metabolism. EMBO Journal, 36(18), 2670–2683.
Snyder, H. (2019). Literature review as a research methodology. Journal of Business Research, 104, 333–339. https://doi.org/10.1016/j.jbusres.2019.07.039
Risemberg, R. I. C., et al. (2026). A importância da metodologia científica. E-Acadêmica, 7(1), e0171675.
Pereira, A. S., et al. (2018). Metodologia da pesquisa científica. Editora da UFSM.
Fernandes, J. M. B., Vieira, L. T., & Castelhano, M. V. C. (2023). Revisão narrativa enquanto metodologia científica. REDES – Revista Educacional da Sucesso, 3(1), 1–7.
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Copyright (c) 2026 Maiana Werneck Guiotti Galvão, Pierangelo Angeletti, Diogo Belas Lustosa
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