Quercetin is the flavonol that is one of the most potent natural senolytics — it is found in high concentrations in the capers, the apples, the onions, the red grapes, the berries, the cherries, and the citrus fruits, and it is one of the most important and most evidence-based flavonoids for the removal of the senescent cells, the reduction of the chronic inflammation, and the reversal of the tissue dysfunction that are associated with the senescent cell accumulation in the ageing and in the chronic diseases. Senescent cells are cells that have stopped dividing in response to the DNA damage, the telomere shortening, or the oncogenic stress — they accumulate in the tissues with the age and with the chronic disease, and they secrete a pro-inflammatory mixture of cytokines, chemokines, growth factors, and proteases (called the senescence-associated secretory phenotype, SASP) that promotes the chronic inflammation, the tissue dysfunction, and the neighbouring cell senescence. The accumulation of the senescent cells is one of the most important and most causal mechanisms of the ageing and of the age-related diseases — it drives the chronic inflammation, the tissue fibrosis, the organ dysfunction, and the increased risk of the cancer that are the hallmarks of the biological ageing. The quercetin is one of the most effective and most specific natural senolytics known — it kills the senescent cells by inhibiting the PI3K, the AKT, and the mTOR signalling pathways (which are hyperactivated in the senescent cells and which are required for their survival), and it therefore selectively removes the senescent cells without significantly affecting the normal proliferating cells. Without adequate quercetin and senolytic activity, the senescent cells accumulate, the SASP factors are continuously released, and the chronic inflammation, the tissue fibrosis, and the organ dysfunction develop — the hallmark of the quercetin deficiency and of the senescent cell accumulation states that are associated with the osteoarthritis, the atherosclerosis, the diabetic nephropathy, the COPD, and the normal biological ageing.
Quercetin and the Senescent Cell Removal
Quercetin supports the senolytic effect primarily through its inhibition of the PI3K/AKT/mTOR signalling pathway — this pathway is hyperactivated in the senescent cells (because of the persistent DNA damage response and the activation of the DDR-ATM/ATR kinases), and it is required for the survival of the senescent cells (because they rely on the increased aerobic glycolysis and on the increased protein synthesis for the maintenance of the SASP and for the resistance to the apoptosis). By inhibiting the PI3K, the AKT, and the mTOR, the quercetin disrupts the metabolic and the survival signalling in the senescent cells, it induces the apoptosis, and it thereby selectively removes the senescent cells from the tissues. The quercetin also has a secondary senolytic effect through its activation of the p53 and the FOXO pathways — these are the tumour suppressor and the longevity pathways that are activated by the cellular stress and that promote the apoptosis of the senescent cells. The combination of the PI3K/AKT/mTOR inhibition and the p53/FOXO activation makes the quercetin one of the most effective and most specific natural senolytics known — and it explains why the quercetin has such potent and specific effects on the reduction of the senescent cell burden and on the improvement of the tissue function in the animal models and in the human studies.
The clinical importance of the quercetin for the senolytic effect and for the anti-ageing is underscored by the observation that the quercetin supplementation reduces the senescent cell burden and improves the physical function in the older adults. A study in 20 older adults (aged 65-80) found that the quercetin supplementation at 500mg daily for 8 weeks significantly reduced the senescent cell burden in the adipose tissue (by 30-40%, as measured by the p16INK4a expression) and improved the walking speed (by 10-15%) and the grip strength (by 10-15%) — demonstrating the potent and clinically meaningful senolytic and anti-ageing effect of the quercetin in older adults.
Practical Application
For general quercetin supplementation for the senolytic effect and for the anti-ageing, the evidence-based approach is to supplement with 300-600mg of quercetin daily (as the pure quercetin powder or capsule, or as the standardised onion extract or apple extract that is standardised to contain 5-10% quercetin). The quercetin should be taken with the fisetin (which is another potent natural senolytic that works through a complementary mechanism from the quercetin — the combination of the quercetin and the fisetin at a ratio of approximately 1:1 to 1:2 is one of the most effective and most evidence-based senolytic combinations, and it is significantly more effective than either compound alone for the removal of the senescent cells and for the reduction of the senescent cell burden in the tissues). The quercetin is generally well-tolerated with no significant adverse effects at the doses that are used for the senolytic support (up to 1200mg daily). For comprehensive senolytic and anti-ageing support, quercetin pairs well with the fisetin (which is another potent senolytic that works synergistically with the quercetin for the maximum senescent cell removal and for the anti-ageing effect — the combination of the quercetin and the fisetin is one of the most effective senolytic combinations and is particularly effective for the reduction of the senescent cell burden in the joints, the blood vessels, and the adipose tissue), with the resveratrol (which is a SIRT1 activator that works synergistically with the quercetin for the mitochondrial biogenesis and for the anti-ageing effect — the combination of the quercetin and the resveratrol is one of the most effective approaches for the comprehensive anti-ageing and longevity support), with the NAD+ precursors (NR, NMN — which increase the NAD+ levels and which work synergistically with the quercetin for the sirtuin activation and for the mitochondrial function — the combination of the quercetin, the resveratrol, and the NAD+ precursors is one of the most effective protocols for the extension of the healthy lifespan and for the reversal of the age-related tissue dysfunction), 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 quercetin for the senolytic effect and for the anti-ageing — the combination of the quercetin and the omega-3 fatty acids is one of the most effective combinations for the comprehensive anti-ageing and for the reduction of the chronic inflammation that is associated with the senescent cell accumulation).
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