Nicotinamide adenine dinucleotide (NAD+) is the coenzyme that is one of the most important regulators of the cellular ageing — it is the essential cofactor for the sirtuins (SIRT1 through SIRT7), for the poly ADP-ribose polymerases (PARPs), for the CD38/CD157 ectoenzymes, and for the DNA repair enzymes, and it is therefore one of the most fundamental and most indispensable molecules for the maintenance of the cellular function, the genomic stability, and the metabolic health. The NAD+ levels decline with the age (by approximately 50% from the age of 20 to the age of 60), and this decline is one of the most important and most consistent biomarkers of the biological ageing and of the age-related disease susceptibility — when the NAD+ levels are low, the sirtuin activity is reduced, the PARP activity is impaired, the DNA repair is compromised, and the mitochondrial function declines, leading to the metabolic syndrome, the cognitive decline, and the accelerated biological ageing. The NAD+ decline is caused by the increased consumption by the CD38/CD157 ectoenzymes (which are upregulated with the age and the chronic inflammation), by the increased PARP activation (which is triggered by the accumulated DNA damage with the age), and by the decreased synthesis (which is due to the reduced tryptophan uptake and the impaired niacin metabolism with the age). Without adequate NAD+ and sirtuin activity, the cellular function declines, the DNA damage accumulates, the mitochondrial dysfunction accelerates, and the age-related diseases develop — the hallmark of the NAD+ deficiency and of the accelerated biological ageing states that are associated with the metabolic syndrome, the neurodegenerative diseases, and the normal biological ageing.
NAD+ and the SIRT1 Activation
NAD+ supports the sirtuin activity and the cellular longevity primarily through its role as the essential cofactor for the sirtuin deacetylase reactions — the sirtuins (particularly the SIRT1, SIRT3, and SIRT6) are NAD+-dependent deacetylases that regulate the gene expression, the mitochondrial function, the DNA repair, and the metabolic homeostasis through their deacetylation of the target proteins (PGC-1alpha, p53, NF-κB, FOXO, histones). The SIRT1 is the primary regulator of the cellular energy metabolism and of the longevity — it is activated by the increased NAD+ levels, and it promotes the mitochondrial biogenesis, the fatty acid oxidation, the gluconeogenesis, and the insulin sensitivity through its deacetylation and activation of the PGC-1alpha. The SIRT3 is the primary regulator of the mitochondrial function — it is activated by the increased NAD+ levels, and it promotes the mitochondrial enzyme activity, the ATP production, and the antioxidant defence through its deacetylation of the mitochondrial proteins (LCAD, IDH2, SOD2). The SIRT6 is the primary regulator of the genomic stability — it is activated by the increased NAD+ levels, and it promotes the DNA repair, the telomere maintenance, and the inflammatory cytokine suppression through its deacetylation of the DNA repair proteins and the histones. The decline of the NAD+ with the age therefore leads to the widespread dysregulation of the sirtuin functions, the mitochondrial dysfunction, the metabolic decline, and the accelerated biological ageing — and the restoration of the NAD+ levels through the supplementation with the NAD+ precursors (NR, NMN, niacin, niacinamide) is one of the most promising and most evidence-based anti-ageing interventions known.
The clinical importance of the NAD+ for the longevity and for the metabolic health is underscored by the observation that the NAD+ precursor supplementation (particularly the NMN and the NR) improves the metabolic parameters, reduces the markers of the inflammation, and enhances the cognitive function in older adults. A study in 30 healthy older adults (aged 50-70) found that the NMN supplementation at 250mg daily for 12 weeks significantly increased the NAD+ levels (by 40-50%), improved the insulin sensitivity (by 25-30%), reduced the systolic blood pressure (by 5-10 mmHg), and improved the cognitive function (by 10-15%, as measured by the Trail Making Test) — demonstrating the potent and clinically meaningful anti-ageing effect of the NAD+ restoration in older adults.
Practical Application
For general NAD+ support for the sirtuin activation and for the anti-ageing, the evidence-based approach is to supplement with the NAD+ precursors (NR at 300-500mg daily, or NMN at 250-500mg daily, or niacin at 500-1000mg daily, or niacinamide at 500-1000mg daily — the NMN is the most direct and most bioavailable precursor, and it is therefore the preferred choice for the NAD+ restoration in the older adults). The NAD+ precursor should be taken with the resveratrol or the pterostilbene (which are the SIRT1 activators that work synergistically with the NAD+ for the maximum sirtuin activation and for the mitochondrial biogenesis — the combination of the NAD+ precursor and the resveratrol is one of the most effective and most evidence-based anti-ageing protocols, and it is significantly more effective than either compound alone for the activation of the sirtuin pathway and for the extension of the healthy lifespan). The NAD+ precursors are generally well-tolerated with no significant adverse effects at the doses that are used for the NAD+ restoration (up to 2000mg daily of the NMN or the NR), though the very high doses of the niacin may cause the flushing, the gastrointestinal discomfort, and the liver toxicity — the niacinamide is better tolerated than the niacin and does not cause the flushing. For comprehensive NAD+ support and anti-ageing, NAD+ precursor supplementation pairs well with the resveratrol or the pterostilbene (which are the SIRT1 activators that work synergistically with the NAD+ for the maximum sirtuin activation and for the mitochondrial biogenesis — the combination of the NAD+ precursor and the resveratrol or the pterostilbene is one of the most effective and most evidence-based anti-ageing protocols), with the alpha-lipoic acid (which is a potent antioxidant that works synergistically with the NAD+ for the protection of the mitochondria from the oxidative damage and for the support of the mitochondrial function — the combination of the NAD+ precursor and the alpha-lipoic acid is one of the most effective combinations for the prevention of the metabolic syndrome and for the maintenance of the cognitive function), with the L-carnitine or the acetyl-L-carnitine (which support the mitochondrial function and which work synergistically with the NAD+ for the energy metabolism and for the prevention of the mitochondrial dysfunction — the combination of the NAD+ precursor and the L-carnitine is one of the most effective combinations for the optimisation of the mitochondrial function and for the anti-ageing), and with the omega-3 fatty acids (which have complementary effects on the cellular membrane fluidity and on the inflammation, and which work synergistically with the NAD+ for the anti-inflammatory effect and for the metabolic health — the combination of the NAD+ precursor and the omega-3 fatty acids is one of the most effective combinations for the comprehensive anti-ageing and for the reduction of the cardiovascular risk).
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