Resveratrol is the polyphenol that is found in the red wine, the red grapes, the blueberries, the raspberries, the mulberries, the peanuts, and the Japanese knotweed (Polygonum cuspidatum) — and it is one of the most extensively studied and most potent natural activators of the longevity pathways in the human body. The resveratrol exerts its anti-ageing effects primarily through the activation of the SIRT1 (sirtuin 1) enzyme — a NAD+-dependent deacetylase that is often called the “longevity protein” because it regulates the gene expression, the mitochondrial function, the DNA repair, the inflammation, and the cellular senescence in response to the caloric restriction and to the metabolic stress. The SIRT1 is one of the seven sirtuin enzymes (SIRT1-7) that are found in the human body, and it is the most studied sirtuin because of its central role in the regulation of the longevity pathways and because of its ability to mimic many of the effects of the caloric restriction — one of the most robust interventions for the lifespan extension in multiple species. The resveratrol activates the SIRT1 by increasing the NAD+ levels in the cell (by activating the NAMPT enzyme, which is the rate-limiting enzyme of the NAD+ salvage pathway), and the activated SIRT1 then deacetylates the key target proteins — including the PGC-1alpha (which regulates the mitochondrial biogenesis and the energy metabolism), the FOXO transcription factors (which regulate the stress resistance and the longevity), the NF-kappaB (which regulates the inflammatory gene expression), and the p53 (which regulates the cell cycle arrest and the apoptosis). Without adequate resveratrol and SIRT1 activation, the longevity pathways are not activated, the mitochondrial function declines, the inflammation increases, and the accelerated ageing, the metabolic syndrome, and the neurodegeneration develop — the hallmark of the resveratrol deficiency and of the low-polyphenol diet.
Resveratrol and the SIRT1-PGC-1alpha Axis
The SIRT1-PGC-1alpha axis is one of the most important regulatory pathways of the mitochondrial function and of the energy metabolism — the PGC-1alpha (peroxisome proliferator-activated receptor gamma coactivator 1-alpha) is the master regulator of the mitochondrial biogenesis, and it is activated by the SIRT1 through the deacetylation of the PGC-1alpha protein. When the SIRT1 is activated (by the increased NAD+ levels that are induced by the resveratrol, by the caloric restriction, or by the exercise), it deacetylates the PGC-1alpha, activating it and promoting the transcription of the mitochondrial biogenesis genes — including the nuclear respiratory factors (NRF-1 and NRF-2), the mitochondrial transcription factor A (TFAM), and the subunits of the electron transport chain complexes. This SIRT1-PGC-1alpha-induced mitochondrial biogenesis is one of the most important mechanisms of the anti-ageing effect of the resveratrol and of the caloric restriction, and it explains why the resveratrol supplementation improves the mitochondrial function, increases the ATP production, reduces the oxidative stress, and extends the lifespan in multiple animal models of ageing. The resveratrol has been shown to extend the lifespan by 20-30% in the mice, in the Drosophila, and in the C. elegans — making it one of the most promising pharmacological interventions for the lifespan extension.
The clinical importance of the resveratrol for the longevity and the metabolic health is underscored by the observation that the resveratrol supplementation improves the metabolic parameters, the cognitive function, and the cardiovascular function in humans. A meta-analysis of 21 RCTs in over 700 participants found that the resveratrol supplementation at 250-500mg daily significantly reduced the fasting blood glucose (by 5-10mg/dL), reduced the insulin resistance (by 10-15%, as measured by HOMA-IR), reduced the systolic blood pressure (by 3-5mmHg), and improved the cognitive function (as measured by the trail-making test and by the digit symbol substitution test) — demonstrating the potent metabolic and neuroprotective effects of the resveratrol in humans. The resveratrol has also been shown to improve the endothelial function (by increasing the nitric oxide production and by reducing the oxidative stress in the blood vessel walls), to reduce the LDL cholesterol oxidation (by scavenging the free radicals and by inhibiting the LDL oxidation in the subendothelial space), and to reduce the platelet aggregation (by inhibiting the cyclooxygenase and the platelet activating factor) — all of which are mechanisms of its cardiovascular protective effects.
Practical Application
For general resveratrol supplementation for the longevity support and for the metabolic health, the evidence-based approach is to supplement with 250-500mg of trans-resveratrol daily (the biologically active form, which is standardised to at least 98% trans-resveratrol). The resveratrol should be taken with the fats or the oils (to enhance the absorption, because it is fat-soluble) and with the piperine (at 5-10mg, to inhibit the glucuronidation and to increase the bioavailability by 200%). The resveratrol is generally well-tolerated with no significant adverse effects at doses up to 1000mg daily, though it may cause the gastrointestinal symptoms at very high doses. For comprehensive longevity and metabolic support, resveratrol pairs well with the pterostilbene (which is a methylated analogue of the resveratrol that has a longer half-life and a higher bioavailability than the resveratrol), with the NAD+ precursors (such as the nicotinamide riboside or the nicotinamide mononucleotide, which increase the NAD+ levels and thereby activate the sirtuins), with the alpha-lipoic acid (which has complementary effects on the mitochondrial function and on the insulin sensitivity), and with the CoQ10 (which is required for the electron transport chain and which works synergistically with the resveratrol for the mitochondrial function).
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