Nicotinamide riboside (NR) is the vitamin B3 precursor that is the most efficient and most specific booster of the cellular NAD levels — it is converted to NAD+ through the Nramp (nicotinamide riboside kinase) pathway, which is a dedicated NAD+ salvage pathway that is independent of the niacin (nicotinic acid) and the nicotinamide pathways and that does not produce the flushing or the other adverse effects that are associated with the high-dose niacin. The NAD+ is the essential electron carrier and the co-substrate for the sirtuin enzymes (SIRT1-7), for the PARP enzymes (poly-ADP-ribose polymerases), and for the CD38/CD157 ectoenzymes — and it is the declining NAD+ levels with age that are one of the primary drivers of the ageing process, of the mitochondrial dysfunction, of the metabolic syndrome, and of the age-related diseases. The supplementation with the NAD+ precursors (NR, NMN, nicotinamide) has been shown to restore the youthful NAD+ levels, to activate the sirtuins, to improve the mitochondrial function, and to extend the lifespan in multiple animal models of ageing — making it one of the most promising and most exciting areas of the longevity research. The typical dietary NR intake from the milk, the yeast, and the meat is very low (less than 1mg daily), and the therapeutic doses for the NAD+ boosting effects are 250-500mg of NR daily — making the supplementation essential for anyone who wants to maintain the youthful NAD+ levels and to support the sirtuin activity.
NAD+ and the Sirtuin Function
The sirtuins (SIRT1-7) are the NAD+-dependent deacetylases that regulate the gene expression, the mitochondrial function, the DNA repair, the inflammation, and the cellular senescence — and they are often called the “longevity proteins” because they mediate many of the beneficial effects of the caloric restriction, of the exercise, and of the NAD+ supplementation. The SIRT1 is the most studied sirtuin — it is located in the nucleus and the cytoplasm, and it deacetylates the PGC-1alpha (the master regulator of the mitochondrial biogenesis), the FOXO transcription factors (the regulators of the stress resistance and the longevity), the NF-kappaB (the master regulator of the inflammatory gene expression), and the p53 (the regulator of the cell cycle and the apoptosis). The SIRT3 is located in the mitochondria, and it deacetylates the mitochondrial proteins (including the superoxide dismutase, the IDH2, and the LCAD) to regulate the mitochondrial antioxidant defence, the TCA cycle, and the fatty acid oxidation. The SIRT6 is located in the nucleus and regulates the DNA repair, the inflammation, and the metabolic homeostasis — and it is one of the most important sirtuins for the longevity, because the SIRT6 overexpression extends the lifespan in mice by 15-20%, while the SIRT6 deletion causes the premature ageing and the shortened lifespan. Without adequate NAD+ and sirtuin activity, the mitochondrial function declines, the inflammation increases, the DNA damage accumulates, and the cellular senescence accelerates — the hallmark of the ageing process and of the NAD+ deficiency.
The clinical importance of the NR for the NAD+ boosting is underscored by the observation that the NR supplementation increases the NAD+ levels and improves the metabolic parameters in humans. A study in 12 healthy adults found that the NR supplementation at 500mg twice daily (total 1000mg daily) for 2 weeks significantly increased the NAD+ levels in the blood mononuclear cells (by 40-60%), increased the SIRT1 activity, and improved the systolic blood pressure (by 5-10mmHg) — demonstrating the potent NAD+-boosting and metabolic effects of the NR in humans. The NR has also been shown to improve the cognitive function in older adults with the mild cognitive impairment, to reduce the fatigue in people with the chronic fatigue syndrome, and to improve the muscle endurance in older adults with the sarcopenia — all of which are conditions that are associated with the declining NAD+ levels and the mitochondrial dysfunction.
Practical Application
For general NR supplementation for the NAD+ support and for the longevity, the evidence-based approach is to supplement with 250-500mg of NR daily (as the chloride or the tartrate form, which are the most stable and the most bioavailable forms). The NR should be taken in the morning or at the midday (because the NAD+ levels peak during the day and the sirtuin activity is highest in the morning), and it should be taken with the resveratrol (which activates the NAMPT enzyme and thereby enhances the conversion of the NR to the NAD+). The NMN (nicotinamide mononucleotide) is an alternative NAD+ precursor that is also highly effective and that can be taken at 100-250mg daily in the place of the NR. The NR is generally well-tolerated with no significant adverse effects at doses up to 2000mg daily, and it does not cause the flushing that is associated with the niacin. For comprehensive NAD+ and longevity support, NR pairs well with the resveratrol (which activates the NAMPT and enhances the NAD+ synthesis), with the alpha-lipoic acid (which has complementary effects on the mitochondrial function and on the insulin sensitivity), with the CoQ10 (which is required for the electron transport chain and which works synergistically with the sirtuins for the mitochondrial function), and with the pterostilbene (which activates the SIRT1 and which has complementary anti-ageing effects through the upregulation of the longevity genes).
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