Identity the archetypal senolytics — agents that selectively kill senescent ("zombie") cells. Dasatinib (D) is an FDA-approved tyrosine-kinase inhibitor (a leukemia drug since 2006); Quercetin (Q) is a natural flavonoid (the bitterness in apple peels); the two are used together (D+Q) for synergy. Fisetin is a separate natural flavonoid (most concentrated in strawberries) — the most potent senolytic flavonoid found and the safest-profiled of the three. None is a peptide; they're grouped as the register's real-world senolytic entry. ## Mechanism (as proposed) (Zhu et al., Aging Cell 2015, Kirkland/Tchkonia). The insight: senescent cells, like cancer cells, depend on anti-apoptotic "survival" pathways (SCAPs) to avoid dying from their own toxic inflammatory secretions. Block those survival pathways and the senescent cells self-destruct — while normal cells, which don't depend on them, survive. Bioinformatics mapped the survival networks; D+Q were the prototype drugs that came out. This made them the first senolytics ever identified.
- The players and their mechanisms: Dasatinib kills senescent cells by inhibiting Src/tyrosine kinases (dependence-receptor apoptosis); Quercetin hits Bcl-xL, PI3K, and mTOR — and because each covers different senescent cell types (D favors senescent preadipocytes, Q favors senescent endothelial cells), the combination clears more than either alone. Fisetin, screened as the top of 10 flavonoids (Yousefzadeh/Kirkland, EBioMedicine 2018), reduced senescence markers across tissues and extended lifespan in old mice.
- ⚠ The "hit-and-run" insight (why a cancer drug becomes tolerable): senolytics need only brief pulses — famously ~2 days of dosing every couple of weeks, not continuous use. Because the senescent cells are killed and stay gone for a while, this intermittent schedule achieves the effect while avoiding the sustained toxicity dasatinib causes as a daily chemotherapy. "The dose makes the poison" — short-burst senolytic use has looked safe and well-tolerated in trials so far.
- ⚠ The human translation (the decisive contrast): unlike most longevity compounds here, senolytics have genuinely entered the clinic. The first human evidence of senescent-cell clearance came in 2019 (Hickson et al., EBioMedicine, diabetic kidney disease) — D+Q measurably reduced senescent cells in people. Numerous trials followed (Alzheimer's, osteoporosis, frailty, IPF, sepsis, PAD, osteoarthritis). But the clinical outcomes so far are mixed and modest (see evidence): a Phase 1 Alzheimer's trial (SToMP-AD) found "very few significant results and no suggestion of effectiveness"; a Mayo osteoporosis Phase 2 missed on the whole group (with a burden-dependent subgroup signal); frailty (fisetin, AFFIRM-LITE) has been "mixed." The senescent-cell-clearing is real; the clinical payoff is still unproven.