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claude 5665d74e32 Deep dive: Rapamycin (Section 4.4, Tier 4 — Avoid) — replaces 5-line stub with full ~420-line analysis. Discovery from Streptomyces hygroscopicus on Rapa Nui (1972), CYP3A4 metabolism with CYP3A4*22 pharmacogenomic concern. FKBP12-FRB binding mechanism with full mTORC1 vs mTORC2 architecture diagram. Mouse evidence: Harrison 2009 ITP (9-14% lifespan extension), Miller 2011/2014 dose-dependent, Wilkinson 2012 female bias, Bitto 2016 brief treatment sufficient. Mouse-to-human translation problems: cancer-dominated mouse mortality, species-specific mTOR signaling differences, lab mouse environmental artifacts. Human evidence: PEARL trial (2023) NEGATIVE on primary endpoints, Mannick 2014/2018 RAD001 vaccine response (specific not generalizable), transplant cohort no anti-aging signal. Side effect profile (table): hyperlipidemia 50-80%, glucose intolerance, mouth ulcers 30-50%, edema, wound healing impairment, immunosuppression, pneumonitis, proteinuria. Framework's six mechanistic objections: anti-anabolic (Drummond 2009, Dickinson 2011), anti-glucose-oxidation (Lamming 2012, TCF7L2 TT amplification), anti-thyroid CR-mimetic profile (DIO2 het), anti-mitochondrial-biogenesis (Cunningham 2007, UA/cordyceps preferred), immunosuppression, wound healing/fertility. Blagosklonny hyperfunction theory critique. Genotype interaction table covering CYP3A4*22, TCF7L2, APOE ε4, DIO2, TNF-α, methylation hets, UCP2/J1c, FOXO3, COL1A1, 9p21, TERT. Low-dose intermittent defense and its limits. Stack interactions: metformin double-negative, statins additive, urolithin A preferred alternative, exercise adaptation abolished. Specific clinical scenarios where rapamycin IS appropriate (TSC, LAM, transplant, RCC, drug-eluting stents, HGPS). Evidence summary table 14 claims. 16 references. Harm reduction protocol if used against recommendation.

2026-05-10 09:18:52 +08:00

ALUMINUM_DETOXIFICATION.md

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2026-05-02 15:30:26 +08:00

COMPUTATIONAL_BIOLOGY.md

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2026-05-02 15:30:21 +08:00

DIET.md

Correct framework framing of mannoheptulose in avocado section. Original framing pitched mannoheptulose as a longevity-positive bonus via 'CR mimetic' effect — this is mechanistically inconsistent with the framework's actual stance. Hexokinase inhibition suppresses glucose oxidation (the framework's preferred fuel pathway), forces fat oxidation via Randle cycle, mimics caloric restriction (which the framework views as anti-thyroid, pro-cortisol, metabolic-rate-suppressing). Mannoheptulose mechanistically belongs in the same category as metformin, rapamycin, acarbose, berberine — drugs the framework is skeptical of. The CR longevity benefit (where it exists) more plausibly attributes to PUFA depletion than to glucose restriction. Re-framed as 'framework-cautionary, not framework-positive', noted that dietary dose from ripe avocado (~600mg) is 25-50x below pharmacological threshold (15-30g human equivalent) so practically inert. Flagged as framework-contraindicated: eating unripe avocados for mannoheptulose, mannoheptulose supplements, stacking with other glucose-suppressing strategies. Updated framework alignment summary line accordingly.

2026-05-06 11:45:22 +08:00

EXPOSURES.md

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FAT_LOSS_GUIDE.md

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FAT_LOSS_QUICK_START.md

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LONGEVITY_GUIDELINES.md

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MERCURY_DETOXIFICATION.md

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METABOLISM_AND_AGING.md

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METABOLISM_AND_ALZHEIMERS.md

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METABOLISM_AND_CANCER.md

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MULTI_LAYER_BIOLOGICAL_FOUNDATION_MODEL.md

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PLAN.md

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SUPPLEMENTS.md

Deep dive: Rapamycin (Section 4.4, Tier 4 — Avoid) — replaces 5-line stub with full ~420-line analysis. Discovery from Streptomyces hygroscopicus on Rapa Nui (1972), CYP3A4 metabolism with CYP3A4*22 pharmacogenomic concern. FKBP12-FRB binding mechanism with full mTORC1 vs mTORC2 architecture diagram. Mouse evidence: Harrison 2009 ITP (9-14% lifespan extension), Miller 2011/2014 dose-dependent, Wilkinson 2012 female bias, Bitto 2016 brief treatment sufficient. Mouse-to-human translation problems: cancer-dominated mouse mortality, species-specific mTOR signaling differences, lab mouse environmental artifacts. Human evidence: PEARL trial (2023) NEGATIVE on primary endpoints, Mannick 2014/2018 RAD001 vaccine response (specific not generalizable), transplant cohort no anti-aging signal. Side effect profile (table): hyperlipidemia 50-80%, glucose intolerance, mouth ulcers 30-50%, edema, wound healing impairment, immunosuppression, pneumonitis, proteinuria. Framework's six mechanistic objections: anti-anabolic (Drummond 2009, Dickinson 2011), anti-glucose-oxidation (Lamming 2012, TCF7L2 TT amplification), anti-thyroid CR-mimetic profile (DIO2 het), anti-mitochondrial-biogenesis (Cunningham 2007, UA/cordyceps preferred), immunosuppression, wound healing/fertility. Blagosklonny hyperfunction theory critique. Genotype interaction table covering CYP3A4*22, TCF7L2, APOE ε4, DIO2, TNF-α, methylation hets, UCP2/J1c, FOXO3, COL1A1, 9p21, TERT. Low-dose intermittent defense and its limits. Stack interactions: metformin double-negative, statins additive, urolithin A preferred alternative, exercise adaptation abolished. Specific clinical scenarios where rapamycin IS appropriate (TSC, LAM, transplant, RCC, drug-eluting stents, HGPS). Evidence summary table 14 claims. 16 references. Harm reduction protocol if used against recommendation.

2026-05-10 09:18:52 +08:00

THERAPIES.md

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2026-05-02 15:30:41 +08:00