By Stephen Phipps, ND, PhD

There is an increasing understanding of the intricacies between metabolism and aging. At the center of this web of enzymes and biochemical markers lies nicotinamide adenine dinucleotide (NAD), a coenzyme found in all living cells. As we age, our NAD pools naturally decline, and in doing so restrict the activity of numerous enzymes. One important subset of enzymes that rely heavily on NAD is the sirtuin family of proteins that have been studied for many years for their role in metabolism and aging. To date there are seven subtypes of sirtuin (SIRT) proteins, each of which have slightly different activities, locations and overall functions. In general, SIRT activity is dependent on NAD, which is how these two are linked to cellular lifespan, metabolism and even regulation of inflammation.

It is thought that NAD pools naturally decline during the aging process. Because of this decline, SIRT function declines as well. Decline in SIRT1 activity impacts mitochondrial function in two ways. First, declines in SIRT1 have been linked to decreases in mitochondrial biogenesis via transcriptional activator PCG1α.

Second, decreased SIRT1 activity leads to decreased mitochondrial function due to a reduction in mitochondrial DNA replication and transcription. Because the mitochondria are the energy powerhouses in every cell of the body, a decline in mitochondrial function has been linked to many age-associated pathologies, including metabolic syndrome, obesity, neurodegenerative diseases, and cognitive decline.

Since one in three adults has metabolic syndrome, the importance of the SIRT family to metabolism can’t be over-emphasized. A study found that in individuals with fatty liver who had a specific single nucleotide polymorphism (SNP) for SIRT3 were more likely to progress to metabolic syndrome.

But how can we increase NAD? It turns out that recent human research has concluded that nicotinamide riboside (NR) , a newly-researched vitamin B3 analog, increases NAD levels in healthy humans – proof that NR is able to cross into the mitochondria and supplement NAD levels.

The use of NR to increase NAD has been studied in animal models of metabolic syndrome. The findings of these studies linked NR use to: increased SIRT1 and SIRT3 activity that then ameliorates fatty liver incidence after a high-fat, high-sucrose diet; regulation of hepatic inflammation in models of type 2 diabetes; decreased cholesterol through SIRT1 activation; and prevention of weight gain in animals fed a high-fat diet.

To summarize, NR increases NAD, which upregulates SIRT1 and SIRT3.

Increased SIRT1:

  • inhibits hepatic glucose formation in obesity
  • prevents hepatic lipid accumulation in the presence of elevated blood sugar
  • increases production of good (HDL) cholesterol
  • regulates insulin release, improving overall glucose tolerance
  • increases leptin sensitivity

Increased SIRT3:

  • inhibits lipid accumulation in the liver
  • increases mitochondrial biogenesis in skeletal muscle
  • increases thermogenesis in brown fat stores

The bottom line – in a NAD world, NR rules!

 References

  1. Imai S, Guarente L. NAD+ and sirtuins in aging and disease. Trends Cell Biol 2014;24(8):464-471.
  2. Cantó C, Houtkooper RH, Pirinen E, et al. The NAD(+) precursor nicotinamide riboside enhances oxidative metabolism and protects against high-fat diet-induced obesity. Cell Metab 2012;15(6):838-847.
  3. Hirschey MD, Shimazu T, Jing E, et al. SIRT3 deficiency and mitochondrial protein hyperacetylation accelerate the development of the metabolic syndrome. Mol Cell 2011;44(2):177-190.
  4. Imai S. “Clocks” in the NAD World: NAD as a metabolic oscillator for the regulation of metabolism and aging. Biochim Biophys Acta 2010;1804(8):1584-1590.
  5. Sasaki T. Age-associated weight gain, leptin, and SIRT1: A possible role for hypothalamic SIRT1 in the prevention of weight gain and aging through modulation of leptin sensitivity. Front Endocrinol (Lausanne) 2015;6:109.
  6. First human clinical study of ChromaDex’s NIAGEN nicotinamide riboside meets primary endpoint. http://www.news-medical.net/news/20150211/First-human-clinical-study-of-ChromaDexs-NIAGEN-nicotinamide-riboside-meets-primary-endpoint.aspx [Accessed March 9, 2016]

*These statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure or prevent any disease.