In recent years, there has been a noticeable rise in health consciousness, especially among younger generations. This demographic is increasingly interested in aging and how to slow or even reverse it. Social media platforms like YouTube are showing a trend in anti-aging channels and biohackers sharing their strategies to maintain youthfulness. This surge in interest raises an important question: are NAD+ precursors truly necessary since our bodies can produce NAD+ from various dietary sources naturally? Before delving into the necessity and benefits of these supplements, it is crucial to understand the fundamental role of NAD+ in our health and the historical context that brought attention to its importance.
NAD+ (Nicotinamide Adenine Dinucleotide) is indispensable for life, functioning as a critical coenzyme in cellular metabolism. It plays a vital role in the conversion of nutrients into cellular energy, supports DNA repair mechanisms, and regulates circadian rhythms and gene expression. This multifaceted molecule is central to numerous biological processes, and its levels within our cells significantly impact overall health and vitality.
Pellagra, a disease caused by NAD+ deficiency, manifested through symptoms such as sun-sensitive dermatitis, diarrhea and dementia. The term “pellagra” comes from the Italian phrase “pelle agra,” meaning rough skin, which describes the skin condition of the patients.
The disease was first identified in the 18th century in Spain and Italy, where epidemics of sun-induced skin lesions affected outdoor workers who usually had a very corn-rich diet (Polenta). By the late 19th century, similar outbreaks occurred in the southern United States, predominantly affecting low-income populations. Pellagra remained a significant public health issue until the mid-20th century when researchers Joseph Goldberger and Conrad Elvehjem discovered that the lack of bioavailable niacin (vitamin B3) in corn-based diets was the cause1,2. Supplementing diets with nicotinic acid (niacin) or nicotinamide, both precursors to NAD+, effectively treated and prevented pellagra3. Today, flour products in the USA and Canada are routinely enriched with niacin to prevent this deficiency.
NAD+ precursors like nicotinamide riboside (NR) are together with Niacin and nicotinamide the three forms of Vitamin B3. Nicotinamide mononucleotide (NMN) is NR with a phosphate group added to it. These are the most popular precursors in the biohacking community. Given the body’s ability to produce NAD+ from various precursors, one might question the necessity of supplementation. However, factors such as age, lifestyle, diet, and genetic predispositions can affect NAD+ synthesis. For some individuals, particularly those experiencing age-related NAD+ decline or specific health conditions for example Ataxia telangiectasia (A-T), Cockayne syndrome (CS), supplementing with NAD+ precursors could provide significant benefits by supporting optimal cellular function and health4,5.
As we age, our body’s ability to maintain NAD+ levels diminishes, leading to increased vulnerability to metabolic and age-related diseases6,7. The decline in NAD+ has been linked to all hallmarks of aging, underscoring the central role of NAD+ metabolism in maintaining cellular functionality8. These hallmarks include genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, disabled macroautophagy, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, altered intercellular communication, chronic inflammation, and dysbiosis9. Together, these represent a set of cellular processes that have been associated with aging. Supplementation aims to counteract this age-dependent decline, helping our cells to maintain energy homeostasis and improve metabolic health.
Most fascinatingly, supplementation with NAD+ precursors might offer therapeutic benefits for age-related neurodegenerative diseases. Notably, two human trials on Parkinson’s disease demonstrated that NR supplementation improved motor scores on Parkinson’s disease assessments, increased brain NAD+ levels, and enhanced mitochondrial, lysosomal, and proteasomal function in blood and muscle. Additionally, it decreased levels of inflammatory cytokines in serum and cerebrospinal fluid, suggesting a broad spectrum of benefits for neurodegenerative conditions10,11. These are all important processes to improve cellular energy status, remove waste products from the brain and maintain functionality of our neurons. More studies are currently recruiting or being conducted, including those on Alzheimer’s disease (AD), the major cause of dementia worldwide.
Despite the promising research, NAD+ supplementation should be approached with care. Although initial studies have shown that NR appears to be safe, there is no clear indication of benefits for healthy individuals nor are long-term effects characterised. Additionally, NAD+ precursors are notoriously unstable, and there are limited sources that are FDA-approved. This instability poses challenges for effective delivery within the body.
Currently, NR is produced with FDA approval by ChromaDex, while NMN is not approved to my knowledge. Many sources available online are not trustworthy, with regular reports revealing that some products contain toxic substances or have degraded due to improper storage. Additionally, there is currently a preprint of a study available online showing adverse effects on kidney inflammation12. This lack of reliability and potential for harm underscores the importance of cautious consideration and consultation with healthcare professionals before starting any NAD+ supplementation regimen.
Figure 1: This image has been generated using Microsoft Image Creator.
While not everyone may need to supplement with NAD+ precursors, understanding their role and potential benefits is crucial for making informed health decisions. As research continues to unfold, the use of NAD+ precursors may become a valuable tool to improve vitality, longevity, and prevent age-related diseases.
Until more studies provide better knowledge on NAD+ precursors, I personally prefer boosting my NAD+ levels through regular exercise and fasting regimes. These natural methods have been shown to support healthy NAD+ levels and overall cellular health, providing a safer and well-understood approach to maintaining vitality as we age.
Author: Johannes Frank
1. Morabia, A. Joseph Goldberger’s research on the prevention of pellagra. J. R. Soc. Med. 101, 566–568 (2008).
2. Elvehjem, C. A., Madden, R. J., Strong, F. M. & Wolley, D. W. The isolation and identification of the anti-black tongue factor. 1937. J. Biol. Chem. 277, e22 (2002).
3. SPIES, T. D., COOPER, C. & BLANKENHORN, M. A. THE USE OF NICOTINIC ACID IN THE TREATMENT OF PELLAGRA. J. Am. Med. Assoc. 110, 622–627 (1938).
4. Fang, E. F. et al. Defective mitophagy in XPA via PARP-1 hyperactivation and NAD(+)/SIRT1 reduction. Cell 157, 882–896 (2014).
5. Scheibye-Knudsen, M. et al. A high-fat diet and NAD(+) activate Sirt1 to rescue premature aging in cockayne syndrome. Cell Metab. 20, 840–855 (2014).
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7. Lautrup, S., Hou, Y., Fang, E. F. & Bohr, V. A. Roles of NAD + in Health and Aging. Cold Spring Harb. Perspect. Med. 14, a041193 (2024).
8. Fang, E. F. et al. NAD+ in Aging: Molecular Mechanisms and Translational Implications. Trends Mol. Med. 23, 899–916 (2017).
9. López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M. & Kroemer, G. Hallmarks of aging: An expanding universe. Cell 186, 243–278 (2023).
10. Brakedal, B. et al. The NADPARK study: A randomized phase I trial of nicotinamide riboside supplementation in Parkinson’s disease. Cell Metab. 34, 396-407.e6 (2022).
11. Berven, H. et al. NR-SAFE: a randomized, double-blind safety trial of high dose nicotinamide riboside in Parkinson’s disease. Nat. Commun. 14, 7793 (2023).
12. Saleh, T. A. et al. Metabolite accumulation from oral NMN supplementation drives aging-specific kidney inflammation. BioRxiv Prepr. Serv. Biol. 2024.04.09.588624 (2024) doi:10.1101/2024.04.09.588624.
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