Bounded Rapamycin signal: rapamycin at 42 ppm extended female median lifespan by 26%

Selected angle: source

One-sentence thesis

The cited A/B receipts support a specific working claim: rapamycin at 42 ppm extended female median lifespan by 26%; rapamycin reduced 90th-percentile mortality by 14% in females (Harrison 2009 NIA-ITP, 14 ppm). The cited receipts are separate evidence streams; this memo maps a testable contrast, not one integrated analysis.

Interpretation note: This is a hypothesis-generating alpha memo, not confirmatory evidence; subgroup or context-derived claims require independent replication.

Why this is surprising

Real tension: the surprise is bounded to the cited receipt bundle; separate direct sources report measurable effects in female heterogeneous-stock mice (UM-HET3); ITP; female heterogeneous-stock mice (UM-HET3); 4-site NIA Interventions Testing Program cohort; genetically heterogeneous mice (ITP). Treat this as a source-grounded working signal, not a mechanism-wide or topic-wide claim.

Evidence Landscape

Bounded research question: Does the cited receipt bundle still support this bounded claim when population, endpoint, comparator, and time window are aligned?

Evidence receipts

• fact_id=rapamycin/itp/miller_2014/dose_response_high_female (A_core) — rapamycin at 42 ppm extended female median lifespan by 26% doi=10.1111/acel.12194
• fact_id=rapamycin/itp/harrison_2009/lifespan_female (A_core) — rapamycin reduced 90th-percentile mortality by 14% in females (Harrison 2009 NIA-ITP, 14 ppm) doi=10.1038/nature08221
• fact_id=166319 (A_core) — Metformin (0.1%) combined with rapamycin (14 ppm) robustly extended lifespan, suggestive of an added benefit. doi=10.1111/acel.12496
• fact_id=rapamycin/transient/bitto_2016/lifespan_male (A_core) — 3 months of rapamycin extended median lifespan by 52% in male middle-aged mice doi=10.7554/eLife.16351
• fact_id=135475 (A_core) — rapamycin led to a 217% and 106% increase of M1 (CD45+CD64+CD206−) ATMs in females doi=10.1093/gerona/glz177

What this changes

Treat this as a focused working signal, not a broad topic claim. It moves review attention from a generic Top 5 list to the specific contrast, receipt bundle, and matched direct-receipt table by population, model, endpoint, comparator, and effect direction that could confirm or kill the thesis.

Limitations

• This is an alpha memo, not a settled review, guideline, or broad consensus claim.
• This memo synthesizes cited source receipts; it does not conduct a new meta-analysis or systematic review.
• Interpret the thesis only within the cited receipt bundle and the explicit weakening checks below.
• Independent receipts fail to reproduce the claimed contrast.
• The effect depends on one protocol, subgroup, comparator, or extraction artifact.

What would weaken this

• Independent receipts fail to reproduce the claimed contrast.
• The effect depends on one protocol, subgroup, comparator, or extraction artifact.

Strongest counter-evidence

• Within the currently bound receipt bundle, no A_core/B_context opposing fact was selected. Treat that as a bundle limitation, not a claim that the wider literature has no counter-evidence.

Next extraction

• Extract independent A_core/B_context receipts that test the lead contrast directly.
• Audit whether each direct receipt remains comparable on population, endpoint, comparator, and measurement method.