The Ongoing Search for the Fountain of Youth

Authored By: Arjun Anugole

Art By: Caitlin Sweeney

For centuries, humans have searched for the elusive fountain of youth, longing for the coveted elixir of life that restores youthfulness. While such a remedy has yet to be discovered, scientists have come instrumentally close in their search to combat aging. While we have experienced the inevitable sensation of aging since the dawn of humanity, researchers are still extensively studying its etiologies in hopes of finding a therapeutic solution. 

Aging can be attributed to many factors, ranging from telomere attrition to metabolic mechanisms [1]. Recent discoveries have indicated that nicotinamide adenine dinucleotide (NAD+), a coenzyme found in every living cell of the body, can be a critical factor in aging. Discovered in 1906 as a fermentation cofactor, NAD+ is pivotal for energy metabolism. All organisms depend on energy to carry out basic processes and require specialized mechanisms to convert our intakes into energy. The molecule NAD+ is a crucial intermediate in these metabolic reactions, present in glycolysis, fatty acid β-oxidation, the tricarboxylic acid cycle, and numerous other pathways. In addition, NAD+ serves as a key regulator in several cell-signaling pathways, including genetic expression and DNA repair [2]. Depletion of NAD+ is associated with halted DNA repair, cellular senescence, and decreased cellular energy metabolism, contributing to aging and other neurodegenerative-associated aging disorders [3]. As aging progresses, DNA accumulates damage, increasing the demand for NAD+, which is likely a reason as to why NAD+ levels decrease with age [4]. 

In a 2024 study, researchers studied the effect of NAD+ environments on the metabolite’s concentration, discovering that different cell compartments share and stabilize their NAD+ levels through a series of interconnected “pools.” In addition, mitochondria act as a buffering “reservoir” for NAD+ that supply cells with the molecule when there is a demand for it [5,6]. Specifically, signaling enzymes such as poly-ADP-ribosyltransferase 1 (PARP 1) detect DNA damage and consume NAD+ to facilitate the repair process [6]. Researchers in the study developed cellular models that allow for the detection of NAD+ and its distribution across cells. Remarkably, NAD+ depletion was typically well-tolerated by cells [7]. Glaring issues arose when mitochondrial “reservoirs” were directly affected for extended periods of time, suggesting that extreme mitochondrial NAD+ consumption is a significant factor toward aging and its associated diseases [6]. 

These findings suggest promising possibilities for the future of therapeutics that combat aging. Methods of increasing NAD+ concentrations in animal models have demonstrated potential in treating age-related degenerative disorders [8]. While NAD+ supplementation is unlikely to halt the aging process in humans, these novel discoveries indicate that mitochondrial NAD+ restoration in affected “reservoirs” could slow aging. However, direct NAD+ supplementation is often not feasible due to its poor bioavailability and quick-metabolizing nature; instead, increasing NAD+ levels would require precursor molecules to NAD+, molecules that reduce NAD+ consumption (CD38 inhibitors), or molecules that restore NAD+ recycling (NAMPT activators) [9,10]. 

While further research is needed to validate the efficacy of such therapies, targeting the function of NAD+ in cells possesses groundbreaking potential to confront aging and aging-related illnesses. The entire human race is unavoidably affected by aging, but new advancements regarding NAD+ can serve as the first step in humanity’s persistent quest for the fountain of youth. 

References:

1. López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2023). Hallmarks of aging: An expanding universe. Cell, 186(2), 243–278. https://doi.org/10.1016/j.cell.2022.11.001

2. Fang, E. F., Lautrup, S., Hou, Y., Demarest, T. G., Croteau, D. L., Mattson, M. P., & Bohr, V. A. (2017). NAD + in Aging: Molecular Mechanisms and Translational Implications. Trends in Molecular Medicine, 23(10), 899–916. https://doi.org/10.1016/j.molmed.2017.08.001

3. Amjad, S., Nisar, S., Bhat, A. A., Shah, A. R., Frenneaux, M. P., Fakhro, K., Haris, M., Reddy, R., Patay, Z., Baur, J., & Bagga, P. (2021). Role of NAD+ in regulating cellular and metabolic signaling pathways. Molecular Metabolism, 49, 101195. https://doi.org/10.1016/j.molmet.2021.101195

4. Study unveils NAD's link to aging and disease development. (2024, December 23). News-Medical. https://www.news-medical.net/news/20241223/Study-unveils-NADs-link-to-aging-and-disease-development.aspx

5. Mitochondria as a Reservoir of NAD⁺: Regulating Cellular Energy and Metabolic Stability. World Mitochondria Society. https://wms-site.com/press-media/1321-mitochondria-as-a-reservoir-of-nad-regulating-cellular-energy-and-metabolic-stability

6. Høyland, L. E., VanLinden, M. R., Niere, M., Strømland, Ø., Sharma, S., Dietze, J., Tolås, I., Lucena, E., Bifulco, E., Sverkeli, L. J., Cimadamore-Werthein, C., Ashrafi, H., Haukanes, K. F., Van Der Hoeven, B., Dölle, C., Davidsen, C., Pettersen, I. K. N., Tronstad, K. J., Mjøs, S. A., … Ziegler, M. (2024). Subcellular NAD+ pools are interconnected and buffered by mitochondrial NAD+. Nature Metabolism, 6(12), 2319–2337. https://doi.org/10.1038/s42255-024-01174-w

7. Pelc, C. (2025, February 1). Slowing aging: Scientists discover how NAD energizes cells. MedicalNewsToday. Retrieved March 10, 2025, from https://www.medicalnewstoday.com/articles/stopping-nad-depletion-mitochondria-key-slowing-down-aging-supplements#Reduced-NAD-levels-and-the-aging-process

8. McReynolds, M. R., Chellappa, K., & Baur, J. A. (2020). Age-related NAD+ decline. Experimental Gerontology, 134, 110888. https://doi.org/10.1016/j.exger.2020.110888

9. Conlon, N. J. (2022). The Role of NAD+ in Regenerative Medicine. Plastic & Reconstructive Surgery, 150, 41S-48S. https://doi.org/10.1097/PRS.0000000000009673

10. Elevating NAD+ Levels in Brain May Improve Aging. (2024, January 5). UPMC Physician Resources. https://www.upmcphysicianresources.com/news/010524-nad-levels