Fisetin — Polyphenol flavonoid — dietary compound with senolytic and senomorphic properties, CD38 inhibitor
Fisetin is a natural flavonoid found in strawberries, apples, persimmons, and onions. Senolytic mechanism: inhibits pro-survival SCAPs in senescent cells via multiple targets — BCL-2/Bcl-xL inhibition (anti-apoptotic proteins upregulated in senescent cells), PI3K/AKT pathway suppression, and p53/p21 pathway modulation. Additional mechanisms: (1) Potent CD38 inhibition — elevates NAD+ levels by reducing CD38-mediated NAD+ consumption; (2) Anti-inflammatory — inhibits NF-κB and AP-1 pathways, reduces SASP (Senescence-Associated Secretory Phenotype) cytokines; (3) Neuroprotective — reduces oxidative stress and promotes neurotrophic factor expression; (4) Anti-diabetic — improves insulin sensitivity via AMPK activation. Fisetin's senolytic potency exceeds quercetin by ~2-fold in some preclinical models but is lower than dasatinib for adipocyte senescence.
Overview
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Compound Class
Polyphenol flavonoid — dietary compound with senolytic and senomorphic properties, CD38 inhibitor
Mechanism of Action
Fisetin is a natural flavonoid found in strawberries, apples, persimmons, and onions. Senolytic mechanism: inhibits pro-survival SCAPs in senescent cells via multiple targets — BCL-2/Bcl-xL inhibition (anti-apoptotic proteins upregulated in senescent cells), PI3K/AKT pathway suppression, and p53/p21 pathway modulation. Additional mechanisms: (1) Potent CD38 inhibition — elevates NAD+ levels by reducing CD38-mediated NAD+ consumption; (2) Anti-inflammatory — inhibits NF-κB and AP-1 pathways, reduces SASP (Senescence-Associated Secretory Phenotype) cytokines; (3) Neuroprotective — reduces oxidative stress and promotes neurotrophic factor expression; (4) Anti-diabetic — improves insulin sensitivity via AMPK activation. Fisetin's senolytic potency exceeds quercetin by ~2-fold in some preclinical models but is lower than dasatinib for adipocyte senescence.
Regulatory Status
NOT FDA approved for any indication. Generally Recognized As Safe (GRAS) as a food component. Sold as dietary supplement. No IND for longevity approved.
Evidence Level
C — AFFIRM-LITE Phase 1 pilot (Hanson et al. 2020, n=40 older adults with frailty, fisetin 20 mg/kg × 2 days): significant reduction in plasma p21 (senescence marker) and adipose tissue senescent cell counts (p<0.05). Alzheimer's Phase 2 trial (NCT03675724) ongoing. No large Phase 3 RCT as of 2024. Preclinical data very robust.