Fisetin vs Rapamycin (Sirolimus)

Mechanism

Fisetin is a naturally occurring flavonol (3,7,3',4'-tetrahydroxyflavone) found in strawberries, apples, and persimmons that acts as a senolytic by inhibiting the PI3K/Akt/mTOR survival pathway and BCL-2 family anti-apoptotic proteins in senescent cells. It also activates sirtuin-mediated pathways (SIRT1), reduces NF-kB-driven inflammation, and scavenges free radicals as a direct antioxidant. Fisetin demonstrated the most potent senolytic activity among 10 flavonoids screened in a 2018 study, reducing senescent cell burden in aged mice and extending both healthspan and lifespan markers.

Standard Dosing

Research indicates 20 mg/kg/day for 2 consecutive days as an intermittent senolytic protocol (approximately 1400-2000 mg for a 70-100 kg individual).

Timing

Take with fat-containing meal for improved bioavailability (fisetin is lipophilic with poor water solubility). Liposomal or lipophilic formulations preferred.

Cycle Duration

Intermittent senolytic courses ongoing. Daily low-dose use for antioxidant/anti-inflammatory effects can be continuous.

Side Effects

• GI discomfort at high senolytic doses
• Diarrhea
• Headache
• Generally well-tolerated — no serious adverse events reported in clinical trials to date

Contraindications

• Known hypersensitivity to fisetin or flavonoids
• Pregnancy and breastfeeding (insufficient safety data)
• Active chemotherapy without oncologist coordination

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Mechanism

Rapamycin binds the intracellular protein FKBP12, and the rapamycin-FKBP12 complex inhibits mechanistic target of rapamycin complex 1 (mTORC1), a serine/threonine kinase that integrates nutrient sensing, growth factor signaling, and cellular energy status. mTORC1 inhibition suppresses S6K1-mediated ribosomal protein synthesis, activates ULK1-mediated autophagy and mitophagy, enhances lysosomal biogenesis via TFEB nuclear translocation, reduces senescent cell accumulation, and suppresses the SASP (senescence-associated secretory phenotype). At higher chronic doses, rapamycin also inhibits mTORC2, which regulates Akt-mediated insulin signaling — this is believed to drive the metabolic side effects.

Standard Dosing

Research indicates 5-6 mg once weekly (intermittent/pulsed dosing) for longevity protocols. This weekly pulsed approach preferentially inhibits mTORC1 while allowing mTORC2 to remain functional.

Timing

Once weekly, consistent day each week. Take with or without food (food increases bioavailability by ~35% — be consistent either way). Grapefruit juice significantly increases rapamycin bioavailability via CYP3A4 inhibition — some practitioners use this intentionally to reduce pill burden.

Cycle Duration

Long-term (years) for longevity applications. The PEARL trial assessed up to 12 months of treatment in healthy older adults.

Side Effects

• Mouth ulcers/canker sores (most common, dose-dependent)
• Elevated lipids (triglycerides and LDL — typically manageable with weekly dosing)
• Impaired wound healing
• Mild immunosuppression (increased susceptibility to infections)
• Insulin resistance (primarily from mTORC2 inhibition at higher/daily doses)
• Acne-like skin eruptions
• Thrombocytopenia and leukopenia (rare at longevity doses)

Contraindications

• Active infections (immunosuppression risk)
• Poorly healing wounds or planned surgery (delays wound healing)
• Severe hepatic impairment
• Uncontrolled hyperlipidemia
• Pregnancy and breastfeeding
• Organ transplant patients on calcineurin inhibitors (specialized dosing required)
• Active infection
• Immunocompromised states
• Poorly controlled diabetes
• Wound healing (pause 2 weeks pre-surgery)

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