The Scientific Research Behind NAD Supplements
As with any health intervention, scientific credibility is essential when making decisions about supplementation. Fortunately, there is a wealth of research that supports the concept of NAD supplementation and how it is possible to fundamentally restore the body's ability to make and recycle it's own NAD+.
NAD+ declines with age because it is destroyed
Since the initial discovery of NAD+ in 1906 understanding of NAD, its functions and its role in ageing have greatly developed. Currently, focus is on the implications of declining NAD+ in ageing.
It is now well established that NAD+ levels decline as we age with ~50% of our NAD being lost every 20 years. Initially researchers were unsure as to why this occurred. Now we appreciate this decline is due to several changes in older cells.
The first reason is that older cells simply synthesize less NAD+. The largest NAD production pathway the Salvage Pathway declines in activity as we get older.
The second reason is an increase in NAD+ consumption via PARPS (DNA repair proteins) and CD38 (inflammatory proteins).
The increase in CD38 was confirmed with mouse studies. When the gene for CD38 was removed these mice showed no decrease in NAD+ levels as they aged. Interestingly, they also consumed more oxygen and had better functioning mitochondria.
Although, we cannot simply just knock out the gene for CD38 in people, the good news is we can inhibit CD38 with apigenin. In mice this inhibitor provided the same NAD+ elevation and equally protected the mitochondria.
The Lone Precursors Approach
There is substantial evidence suggesting that increasing levels of precursors: NR, NMN and NAM increases levels of cellular NAD+.
NMN and NR are converted to NAD+ via the Preiss-Handler pathway, with the reaction being stimulated by the NRK enzymes. However, studies have shown that this pathway isn’t actually responsible for the majority of NAD+ synthesis. Cells predominantly utilize the salvage pathway (which converts waste nicotinamide back into fresh NAD+) which is dependent on the NAMPT enzyme.
In older cells the efficiency of the salvage pathway is reduced due to declining levels of the NAMPT enzyme. This reasoning is used to justify the preference towards NR and NMN supplements, despite their minimal role in NAD+ synthesis.
The preferred precursor of the cell is nicotinamide (NAM), alongside the salvage pathway they are the greatest NAD+ manufacturer in the cell. Therefore, it seems logical to fix the largest NAD+ source, the salvage pathway to restore NAD+ levels. By increasing levels of NAMPT and feeding the cells NAM, the levels of cellular NAD+ will display even greater increases.
The need for a multitarget approach
Enhancing cellular NAD+ has beneficial effects on metabolic health and physiological decline. In diseased mice models NAD+ supplementation normalized glucose tolerance, restored mitochondrial function and protects neurons from damage. High NAD+ levels also increase sirtuin activation to increase longevity.
However, looking at the data the precursor approach to boosting NAD+ does not address the reasons why NAD+ declines with age. A recent paper published by the Buck Institute highlighted the need for a multi-target approach. It describes how using NAD+ precursors such as NR or NMN alone is like refilling a sink which has lots of leaks. This may temporarily increase the water in the sink but until you fix the leaks the problem will continue. To plug the leak, we must inhibit the greatest consumer of NAD+, CD38. Using a combination CD38 inhibitors, to fix the sink and adding precursors will provide a greater long-term solution.
Further utilizing our knowledge of the salvage pathway, NAD+ levels can be increased even more. Supplying the cell with NAMPT we can restore the function of the largest NAD+ manufacturer, whilst inhibiting its largest consumer to provide a whole-system approach to boosting NAD+.
To get the best results we must utilize the knowledge gained from the years of research into NAD+. The existing precursor approach to boosting NAD+ does not fit with our understanding of why NAD+ declines. Therefore, to reap the benefits of maintaining your NAD+ levels as you age a science-based approach is required, to fix the leaks and refill the sink.
To learn more about the promising research of NAD Supplementation in mice.
References
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.
Fletcher, R. S., Ratajczak, J., Doig, C. L., Oakey, L. A., Callingham, R., Xavier, G. D. S., ... & Philp, A. (2017). Nicotinamide riboside kinases display redundancy in mediating nicotinamide mononucleotide and nicotinamide riboside metabolism in skeletal muscle cells. Molecular metabolism, 6(8), 819-832.
Ratajczak, J., Joffraud, M., Trammell, S. A., Ras, R., Canela, N., Boutant, M., ... & Auwerx, J. (2016). NRK1 controls nicotinamide mononucleotide and nicotinamide riboside metabolism in mammalian cells. Nature communications, 7(1), 1-12.
Zhang, H., Ryu, D., Wu, Y., Gariani, K., Wang, X., Luan, P., ... & Schoonjans, K. (2016). NAD+ repletion improves mitochondrial and stem cell function and enhances life span in mice. Science, 352(6292), 1436-1443.
Anderson, R. M., Bitterman, K. J., Wood, J. G., Medvedik, O., Cohen, H., Lin, S. S., ... & Sinclair, D. A. (2002). Manipulation of a nuclear NAD+ salvage pathway delays aging without altering steady-state NAD+ levels. Journal of Biological Chemistry, 277(21), 18881-18890.
Escande, C., Nin, V., Price, N. L., Capellini, V., Gomes, A. P., Barbosa, M. T., ... & Chini, E. N. (2013). Flavonoid apigenin is an inhibitor of the NAD+ ase CD38: implications for cellular NAD+ metabolism, protein acetylation, and treatment of metabolic syndrome. Diabetes, 62(4), 1084-1093.
Camacho-Pereira, J., Tarragó, M. G., Chini, C. C., Nin, V., Escande, C., Warner, G. M., ... & Chini, E. N. (2016). CD38 dictates age-related NAD decline and mitochondrial dysfunction through an SIRT3-dependent mechanism. Cell metabolism, 23(6), 1127-1139.