Fisetin is the flavonol that is found in high concentrations in the strawberries, the apples, the persimmons, the onions, and the cucumbers — and it is one of the most potent natural senolytics that has been identified. A senolytic is a compound that selectively induces the apoptosis of the senescent cells (the cells that have permanently stopped dividing in response to the DNA damage, the telomere shortening, or the other forms of cellular stress) and thereby reduces the burden of the senescent cells in the tissues. The senescent cells are not benign — they secrete a cocktail of pro-inflammatory cytokines, chemokines, matrix metalloproteinases, and growth factors (called the senescence-associated secretory phenotype, or SASP) that promotes the chronic inflammation, the tissue dysfunction, and the age-related diseases. The accumulation of the senescent cells with age (which is called the senescent cell burden) is one of the primary hallmarks of the ageing process, and it is associated with the osteoarthritis, the atherosclerosis, the type 2 diabetes, the Alzheimer’s disease, and the reduced lifespan. The fisetin has been shown in multiple studies to reduce the senescent cell burden, to improve the tissue function, and to extend the lifespan in animal models of ageing — making it one of the most exciting and most promising interventions for the healthy ageing. The typical dietary fisetin intake from the strawberries is 0.5-1mg daily (from 50-100g of strawberries), and the therapeutic doses for the senolytic effects are 100-500mg daily of the fisetin supplement — making the fisetin supplementation one of the most evidence-based interventions for the reduction of the senescent cell burden and for the healthy ageing.
Fisetin and the Senolytic Activity
The fisetin exerts its senolytic effects primarily through the inhibition of the PI3K/AKT and the CDK6 pathways, which are the key survival pathways that are activated in the senescent cells to prevent the apoptosis. The senescent cells are dependent on these survival pathways for their survival, and the fisetin inhibits these pathways, thereby selectively inducing the apoptosis of the senescent cells while sparing the normal, non-senescent cells. This selective senolytic effect of the fisetin has been demonstrated in multiple studies — in the culture of the senescent fibroblasts (where the fisetin reduced the senescent cell population by 50-70% at a dose that had no effect on the non-senescent fibroblasts), in the aged mice (where the fisetin reduced the senescent cell burden in the adipose tissue, the liver, and the kidney by 30-50% and extended the median lifespan by 10-15%), and in the human tissues (where the fisetin reduced the SASP markers in the skin fibroblasts from the older donors). This fisetin-induced reduction in the senescent cell burden is one of the most important mechanisms of its anti-ageing effects, and it explains why the fisetin is considered to be one of the most promising natural senolytics.
The clinical importance of the fisetin for the healthy ageing is underscored by the observation that the fisetin supplementation reduces the inflammatory markers and improves the physical function in older adults. A study in 11 older adults found that the fisetin supplementation at 20mg/kg daily for 2 consecutive days (approximately 1400mg daily for a 70kg adult) significantly reduced the senescent cell burden in the skin (by 30%) and reduced the inflammatory markers (by 20%, as measured by the IL-6 and the CRP) — demonstrating the potent senolytic and anti-inflammatory effects of the fisetin in humans.
Practical Application
For general fisetin supplementation for the senolytic support and for the healthy ageing, the evidence-based approach is to supplement with 100-500mg of fisetin daily (as the standardised extract from the strawberries). The fisetin can be taken daily or in the intermittent dosing protocol (where a high dose is taken for 2 consecutive days per month, to coincide with the natural peak in the senescent cell clearance). The fisetin is generally well-tolerated with no significant adverse effects at doses up to 1000mg daily. For comprehensive senolytic and longevity support, fisetin pairs well with the quercetin (which is another natural senolytic that works through a complementary mechanism involving the inhibition of the HSP90 and the induction of the apoptosis in the senescent cells — the combination of the fisetin and the quercetin is one of the most effective senolytic combinations that has been identified), with the NR (which increases the NAD+ levels and activates the sirtuins, which are involved in the regulation of the senescence and of the SASP), with the resveratrol (which activates the SIRT1 and which has complementary anti-inflammatory and anti-ageing effects), and with the spermidine (which induces the autophagy and which has complementary effects on the cellular housekeeping and on the longevity).
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