NAD+ Miracle supplement or hype?

Heard of NAD or NAD+?

NAD+ is all the rage with celebrities – touted as a miracle supplement that promises to help you never get older. Between NAD+ pills and even IV drips, they’re going all in to fight antiaging. The science behind it, however, tells a far different story.

What is NAD?

Nicotinamide adenine dinucleotide (NAD) is a critical coenzyme found in every cell of the human body, playing a pivotal role in numerous metabolic processes. NAD exists in two forms: NAD+ (oxidized form) and NADH (reduced form), each essential for cellular respiration and energy production.

NAD+ is particularly vital as it participates in redox reactions, carrying electrons from one reaction to another, thus facilitating the production of adenosine triphosphate (ATP), the energy currency of cells. Moreover, NAD+ serves as a substrate for several enzymes involved in DNA repair, gene expression, and cellular signaling.

NAD+ Declines with Age

As we age, NAD+ levels naturally decline, which can be attributed to several factors:

1. Increased NAD+ Consumption: With age, the activity of NAD+-consuming enzymes, such as poly(ADP-ribose) polymerases (PARPs) and sirtuins, increases. These enzymes play crucial roles in DNA repair and metabolic regulation, consuming NAD+ in the process.
2. Decreased NAD+ Biosynthesis: The body’s ability to synthesize NAD+ diminishes over time. Key enzymes involved in NAD+ biosynthesis, such as nicotinamide phosphoribosyltransferase (NAMPT), exhibit reduced activity with aging.
3. Environmental and Lifestyle Factors: Poor diet, lack of physical exercise, excessive alcohol consumption, and chronic stress can further exacerbate the decline in NAD+ levels.

Consequences of Low NAD+ Levels

A decline in NAD+ levels can have widespread effects on health and longevity:

1. Impaired Cellular Energy Production: NAD+ is essential for ATP production in mitochondria. Lower NAD+ levels can lead to decreased energy availability, manifesting as fatigue and reduced physical endurance.
2. Accelerated Aging: NAD+ is critical for the function of sirtuins, a group of proteins which regulate aging and longevity. Reduced NAD+ impairs sirtuin activity, leading to accelerated aging processes, including the accumulation of DNA damage and cellular senescence.
3. Metabolic Disorders: Low NAD+ levels are associated with metabolic dysfunctions such as insulin resistance, obesity, and type 2 diabetes. NAD+ plays a role in glucose and lipid metabolism, and its decline disrupts these processes.
4. Neurodegenerative Diseases: NAD+ is vital for neuronal health and function. Reduced NAD+ levels are linked to neurodegenerative diseases like Alzheimer’s and Parkinson’s due to impaired mitochondrial function and increased oxidative stress.
5. Immune Dysfunction: Adequate NAD+ levels are necessary for maintaining a robust immune response. Declining NAD+ can lead to immune senescence, increasing susceptibility to infections and chronic inflammatory conditions.

Why NAD+ Supplements Don’t Work

Given the significant consequences of low NAD+ levels, it’s obvious why many people are looking into drugs and supplements.

Unfortunately, NAD+ supplements are mostly ineffective, as the molecules themselves are too big to readily be used by cells. Further, when taking NAD+ orally (the most popular method), gut bacteria will consume it, leaving you little to no benefit.

How to Increase NAD Levels

Fortunately, there are several natural strategies to boost NAD+ levels and mitigate the adverse effects of its decline:

1. Dietary Interventions

• Low-Carb Diet: Adopting a low-carbohydrate diet can positively impact NAD+ levels. Low-carb diets reduce the insulin spike and promote ketone production, enhancing mitochondrial function and NAD+ availability.
• NAD+ Precursors: Consuming foods rich in NAD+ precursors such as tryptophan, niacin (vitamin B3), and nicotinamide riboside (NR) can help replenish NAD+ levels. Foods like poultry, fish, and dairy products are excellent sources of these precursors.
• Intermittent Fasting: Intermittent fasting has been shown to increase NAD+ levels by enhancing NAMPT activity and promoting sirtuin activation.

2. Exercise

Regular physical exercise is a powerful stimulator of NAD+ biosynthesis. Exercise induces mild oxidative stress, which activates pathways that increase NAD+ production. Both aerobic and resistance training have been shown to boost NAD+ levels, improve mitochondrial function, and enhance overall metabolic health.

3. Sleep and Circadian Rhythm

Maintaining a healthy sleep pattern and aligning with the natural circadian rhythm can positively influence NAD+ metabolism. The circadian clock regulates the activity of enzymes involved in NAD+ biosynthesis. Disruptions in sleep patterns can impair NAD+ production and sirtuin activity.

4. Smart Supplementation

• Skip NAD+ supplements, and instead take Nicotinamide Riboside (NR) and Nicotinamide Mononucleotide (NMN): These supplements are direct precursors to NAD+ and have been shown to effectively increase NAD+ levels in humans. Studies indicate that NR and NMN supplementation can improve metabolic health, enhance cognitive function, and extend lifespan.
• Other Nutraceuticals: Compounds such as resveratrol, quercetin, and pterostilbene have been found to activate sirtuins and support NAD+ levels.

5. Stress Management

Chronic stress can deplete NAD+ levels through increased consumption by PARPs and other stress-response enzymes. Practicing stress-reducing activities such as religious practices, meditation, yoga, and mindfulness can help preserve NAD+ levels and promote overall well-being.

References

1. Zhang, H., Ryu, D., Wu, Y., Gariani, K., Wang, X., Luan, P., … & Auwerx, J. (2016). NAD+ repletion improves mitochondrial and stem cell function and enhances life span in mice. Science, 352(6292), 1436-1443.
2. Verdin, E. (2015). NAD+ in aging, metabolism, and neurodegeneration. Science, 350(6265), 1208-1213.
3. 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.
4. Mills, K. F., Yoshida, S., Stein, L. R., Grozio, A., Kubota, S., Sasaki, Y., … & Imai, S. I. (2016). Long-term administration of nicotinamide mononucleotide mitigates age-associated physiological decline in mice. Cell Metabolism, 24(6), 795-806.
5. Gariani, K., Menzies, K. J., Ryu, D., Wegner, C. J., Wang, X., Ropelle, E. R., … & Auwerx, J. (2016). Eliciting the mitochondrial unfolded protein response via NAD+ repletion reverses fatty liver disease. Hepatology, 63(4), 1190-1204.
6. Canto, C., & Auwerx, J. (2011). NAD+ as a signaling molecule modulating metabolism. Cold Spring Harbor Symposia on Quantitative Biology, 76, 291-298.
7. Satoh, A., Brace, C. S., Rensing, N., Cliften, P., Wozniak, D. F., Herzog, E. D., … & Imai, S. I. (2013). Sirt1 extends life span and delays aging in mice through the regulation of Nk2 homeobox 1 in the DMH and LH. Cell Metabolism, 18(3), 416-430.
8. Gomes, A. P., Price, N. L., Ling, A. J., Moslehi, J. J., Montgomery, M. K., Rajman, L., … & Sinclair, D. A. (2013). Declining NAD+ induces a pseudohypoxic state disrupting nuclear-mitochondrial communication during aging. Cell, 155(7), 1624-1638.
9. 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.
10. 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.
11. Gano, L. B., Donato, A. J., Pasha, H. M., Hearon, C. M., Jr., Sindler, A. L., & Seals, D. R. (2014). The effects of lifelong exercise on vascular endothelial function with aging: Insights from a novel athlete cohort. Journal of Applied Physiology, 117(5), 371-379.
12. Reang, N., & Agarwal, S. (2019). Low carbohydrate diet and its impact on body fat composition. Journal of Clinical and Diagnostic Research, 13(2), CC05-CC08.