Fisetin

Fisetin is a naturally occurring flavonoid polyphenol found in various fruits and vegetables, most notably strawberries. It was first isolated in 1833 from the smoke tree (Cotinus coggygria) and has been studied for decades for its antioxidant and anti-inflammatory properties.

Recent breakthrough research identified fisetin as the most potent senolytic compound among 10 tested flavonoids. Senolytics are a new class of compounds that selectively clear senescent cells - aged "zombie" cells that have stopped dividing but resist death and secrete harmful inflammatory factors. These senescent cells accumulate with age and drive many age-related diseases.

The landmark 2018 study by the Mayo Clinic demonstrated that fisetin extends both healthspan and lifespan in mice, even when treatment begins in old age. Treated mice showed improved tissue function, reduced age-related pathology, and lived approximately 10% longer than controls.

Beyond its senolytic effects, fisetin crosses the blood-brain barrier and shows neuroprotective properties in animal models of Alzheimer's, stroke, and traumatic brain injury. It also modulates multiple signaling pathways involved in inflammation, cancer prevention, and metabolism.

As a natural compound found in common foods, fisetin has an excellent safety profile. However, bioavailability is limited, requiring higher supplemental doses to achieve therapeutic effects observed in studies. Current human trials are investigating its effects on aging biomarkers and age-related diseases.

Fisetin operates through multiple complementary mechanisms that contribute to its anti-aging effects:

1. Senolytic Activity: Fisetin's most notable mechanism is selectively inducing apoptosis (programmed cell death) in senescent cells while sparing healthy cells. Senescent cells accumulate with age and secrete pro-inflammatory cytokines (SASP - Senescence-Associated Secretory Phenotype), driving inflammation and tissue dysfunction. By clearing these cells, fisetin reduces inflammation and restores tissue function.

2. Autophagy Induction: Fisetin activates autophagy, the cellular recycling process that removes damaged components. This overlaps with pathways activated by calorie restriction and exercise.

3. SIRT1 Activation: Fisetin activates sirtuins, particularly SIRT1, which are NAD+-dependent deacetylases associated with longevity. This pathway enhances mitochondrial function, DNA repair, and cellular stress resistance.

4. mTOR Inhibition: Fisetin inhibits the mTOR pathway, which regulates cell growth and metabolism. mTOR inhibition is associated with lifespan extension in multiple organisms.

5. Anti-inflammatory Effects: Fisetin inhibits NF-κB signaling and reduces production of pro-inflammatory cytokines including TNF-α, IL-6, and IL-1β.

6. Antioxidant Properties: As a flavonoid, fisetin directly scavenges free radicals and upregulates endogenous antioxidant defenses through Nrf2 pathway activation.

7. Neuroprotection: Fisetin crosses the blood-brain barrier and reduces neuroinflammation, protects against excitotoxicity, and promotes neuronal survival through multiple mechanisms.

The "hit-and-run" senolytic mechanism is particularly important - fisetin appears to clear senescent cells acutely without requiring continuous administration, potentially allowing for intermittent dosing protocols.

Fisetin is found in various fruits and vegetables, with strawberries containing the highest concentrations among common foods.

No established RDA. Animal studies suggest doses equivalent to 100-500 mg/day in humans for senolytic effects. Common supplemental doses range from 100-500 mg daily, often taken intermittently (e.g., monthly pulses).

Fisetin is the most potent senolytic flavonoid identified, extending lifespan in mice by ~10% even when started in old age. Reduces senescent cell burden and improves tissue function across multiple organs.

Fisetin has poor bioavailability due to rapid metabolism and elimination. Liposomal and formulated versions aim to improve absorption.