context: ad-hoc seed batch — question on what a DNA-methylation organ-system clock’s Musculoskeletal sub-score actually measures, which loci/genes drive it, and what interventions could move them toward a youthful state. Key framing surfaced: the organ-system MSK sub-clock (symphony-age) is blood-DNAm trained on grip-strength/gait/physical-function biomarkers — NOT muscle gene expression; its CpGs are predictive correlates, not mechanism. The mechanistic gene/protein program lives on the sarcopenia/skeletal-muscle pages.
added (all 3 seeded verified:false + ⚠️ banner; seeders ran full-text cross-checks but an independent verifier pass is still pending):
biomarkers/mskage-2025.md (type: biomarker, modality dna-methylation) — MskAge, Green DC et al., Aging Cell 2025; 24(9):e70149, doi:10.1111/acel.70149, PMID 40538142, PMC12419849 (preprint bioRxiv 2023.05.04.539347). First clock trained jointly across musculoskeletal tissues (muscle/cartilage/bone/tendon/MSC; 1,048 samples) via a genetic-algorithm islands model; 3,365 CpGs → SVD/PC → ridge. Disambiguated from MEAT v2 (Voisin/Eynon 2021, muscle-only) and the blood SYMPHONY MSK sub-clock. Authorship correction: dispatch brief guessed Voisin/Eynon — actually Green et al. (Liverpool); fixed in-page. Filename uses publication year 2025 (renamed from -2023 to match dunedinpace-2022 convention). Intervention-responsiveness: the paper’s own exercise dataset showed no significant MskAge change (null); intervention-responsive: partial reflects adjacent-clock literature only (Murach 2022 mouse, Chambers 2025 senolytic), framed honestly.
biomarkers/dnam-muscle-function-markers.md (type: biomarker, modality dna-methylation, training-target morbidity) — blood FGF2/CXCL12/FGF21 methylation loci correlated with grip strength + gait speed; Li JW et al., J Cachexia Sarcopenia Muscle 2024; 15(3):1209–1217, doi:10.1002/jcsm.13472, PMID 38641928, PMC11154778 (full text read by seeder). FGF2_30 promoter hypomethylation ↔ worse function (array: ASMI r=0.372 / grip r=0.334 / gait r=0.411, all p<0.001; pyrosequencing n=91 slightly higher); <0.15 predicts sarcopenia 84.6% sens / 70.1% spec, AUC 0.807. CXCL12_22 + FGF21_59 hypomethylated (secondary); CTSB/FGF19/SESN1 weaker. No direct reversibility evidence for FGF2_30 (indirect only: Voisin 2024 muscle methylome, Ammous 2025). Single East-Asian cohort lineage — #gap no independent replication.
cell-types/myofibers.md (type: cell-type) — multinucleated post-mitotic contractile cells; the “(planned)” page skeletal-muscle long referenced. Cell Ontology CL:0008002 (live OLS lookup). Human MYH-isoform→fiber-type map verified (Oldfors 2004): Type I=MYH7, IIa=MYH2, IIx=MYH1, IIb=MYH4 (minimal in adult human limb). Aging core: preferential Type II atrophy; FOXO1/3 → atrogin-1/MAFbx (FBXO32) + MuRF1 (TRIM63) UPS axis (Bodine/Sandri); anabolic resistance; mito/COX decline; NMJ denervation + 15-PGDH; inflammaging atrogene drive. Left gap-tagged for verifier: atrogin/MuRF1 fold-induction magnitude (human), MYH4 quantitative threshold, Atg7-cKO myopathy (mouse), senolytic/15-PGDH NMJ claims.
propagated (main agent): tissues/skeletal-muscle.md (myofibers “(planned)”→“(drafted)” ×2; +mskage-2025 + dnam-muscle-function-markers cross-refs), biomarkers/symphony-age.md (+both muscle pages as tissue-level counterparts to its blood MSK sub-clock), frameworks/biological-age-measurement.md (2 new rows in Other-modalities table + See-Also), phenotypes/sarcopenia.md (new “Related measurement & cell-biology pages” section linking all 4).
new implicit stubs surfaced (multiply-referenced, not yet seeded): [[molecules/proteins/fgf2]], [[molecules/proteins/cxcl12]], [[tgf-beta]], [[frameworks/cancer-aging-tradeoffs]].
follow-ups: independent wiki-verifier pass on all 3 pages (MskAge published-PDF spot-check vs PMC; dnam-markers 9 correlation coefficients + AUC/OR; myofibers closed-access Nilwik 2013 Type II CSA claim). Consider biomarkers/skin-methylation-clocks-style tissue-clock MOC note already covers the cross-clock framing.
added (main agent): biomarkers/symphony-age.md § “Deep-dive: the Musculoskeletal sub-clock” — answers “what blood markers does the SYMPHONY/TruAge muscle score use.” Crux: (1) the assay reads only blood CpG methylation (per-system CpGs undisclosed, predictive-not-causal); (2) the training target is a composite of musculoskeletal clinical/functional biomarkers measured in HRS, NOT in the customer draw — reconstructed as grip strength / gait / balance / mobility-self-report / BMI + serum IGF-1, DHEA-S, 25-OH vitamin D (endocrine-anabolic trio). New footnote [^agingbiomarker2024] (Aging Biomarker Consortium 2024 skeletal-muscle-aging consensus, doi:10.1093/lifemedi/lnaf001, abstract-level gap/no-fulltext-access). Reconstruction is best-guess, gap/needs-replication (exact per-system assignment not peer-reviewed-published).
dnam-muscle-function-markers.md → verified:true — corrections: Pearson r → Spearman rho (magnitudes 0.33–0.43 confirmed, mislabeled); FGF21_59 FAILED overall sarcopenic-vs-control validation (p=0.367; significant only in moderate-vs-severe subgroup) — only FGF2_30 carried to validation set 2; secondary-loci count 4→5 (CTSB_15/CTSB_17/CXCL12_22/FGF19_28/FGF2_30 all p<0.001 set 1); OR 9.223 confirmed adjusted (age/sex/BMI); population Jiangsu, China (no non-East-Asian replication). FGF2 numbers exact (gait rho 0.411, grip 0.334, AUC 0.807, sens 84.6/spec 70.1).
mskage-2025.md → verified:true — corrections: seeder fabrication caught — “grip strength/gait null associations reported” was false; Green 2025 does not test functional outcomes at all → changed to “not tested,” gap/contradictory-evidence dropped. The exercise null IS real (Fig S12, but no dataset ID / no power analysis in main text). Adjacent-clock citation fixes: Murach 2022 = aged male mice, PoWeR weighted-wheel protocol, n=5/grp, DNAge™ (not cited by Green); Jankowski 2024 = n=30 total (12 PWH + 18 controls) not ≈50/grp, MEAT v2 clock, exercise null p=0.79. CpG count 3,365 + 1,048-sample multi-tissue confirmed (per-tissue breakdown in suppl. Table S3, not main text).
myofibers.md → verified:true (partial-scope; 5 primary PDFs read, Nilwik/Oldfors abstract-only) — corrections: Masiero 2009 Cre driver MCK-Cre → MLC1f-Cre (+~40% CSA reduction, atrogin/MuRF1 upregulation added); Bodine 2001 transcript profiling was rat (Sprague-Dawley gastrocnemius), not mouse (mouse only for KO validation; +MAFbx-KO 56% / MuRF1-KO 36% sparing at 14d denervation); Nilwik 2013 n=25 young + 26 elderly (not ~12/grp), Type I trend P=0.052 (not flat null); Oldfors 2004 DOI invalid (404) → PMID-only + flagged as congenital-myopathy paper, not a fiber-type atlas (Schiaffino/Reggiani preferred); MYH map + CL:0008002 confirmed.
propagation audit (verifier-flagged): checked skeletal-muscle / disabled-macroautophagy / sarcopenia for inherited Bodine-organism / Masiero-MCK-Cre errors → clean (those pages flag the UPS/Atg7 biology #gap/unsourced and carry no Cre/organism specifics); no fix needed.
no downstream propagation broke from the biomarker corrections either: propagated cross-refs (skeletal-muscle/sarcopenia/biological-age-measurement) cite FGF2-specifically or gene-list-generically, not the corrected FGF21/stat-type numerics; MOC MskAge-row exercise-null claim still accurate.
hygiene: cleaned grandfathered private-tooling annotations from 5 footnotes on skeletal-muscle.md in passing (page was touched for cross-ref propagation); open/closed-access flags retained.
[2026-06-15] seed+verify | FGF2 + CXCL12 protein pages (ad-hoc, from dnam-muscle-function-markers)
context: user-requested seed/verify of the two protein loci linked from biomarkers/dnam-muscle-function-markers.md. Both seeded→verified same-day (verified:true).
molecules/proteins/fgf2.md — FGF2 / basic FGF. UniProt P09038, NCBI 2247, HGNC 3676, ENSG00000138685, mouse Fgf2. Aging core: aged-myofiber FGF2 disrupts satellite-cell quiescence (Chakkalakal 2012 Nature 490:355–360, doi:10.1038/nature11438, PMC3605795). Verifier fixed an INVERTED Spry1 framing — Spry1 (Sprouty1) is high in quiescent label-retaining cells and suppressed by FGF2 signaling (a quiescence mediator), NOT “upregulated by aged cells to resist FGF2”; Spry1 deletion → ~50% Pax7+ loss; FGFR1 inhibition / Spry1 overexpression prevents depletion. druggability tier null (#gap/no-opentargets-entry; FGFR inhibitors oncology-only). Also SASP/angiogenesis/fibrosis roles.
molecules/proteins/cxcl12.md — CXCL12 / SDF-1. UniProt P48061, NCBI 6387, HGNC 10672, ENSG00000107562, mouse Cxcl12 (P40224). Aging core: dominant HSC-niche retention signal via CXCR4 (CAR cells); satellite-cell migration in muscle regen; SASP factor; druggability tier 2 (plerixafor/AMD3100 CXCR4 antagonist, not aging-validated). Verifier corrections (7): protein length 119→93 aa (SDF-1β canonical 93 / mature 72; SDF-1α 89/68); canonical isoform = SDF-1β (P48061-1); Sugiyama 2006 = inducible Cxcr4 deletion in HSCs, not Cxcl12 deletion in CAR cells; Mahoney upgraded preprint→published (Aging Cell 2026;25(5):e70500, doi:10.1111/acel.70500); Jiang/Ni/Hardy citation fixes.
propagated (main agent): cell-types/satellite-cells.md (+fgf2 wikilink + aged-niche FGF2–Spry1 cross-ref), cell-types/hematopoietic-stem-cells.md (+cxcl12 wikilink); dnam-muscle-function-markers.md already links both. Audited: fisetin.md already cites the published Mahoney DOI (no stale-preprint fix needed); mesenchymal-stem-cells.md Sugiyama framing correct (CAR-cell identification, not the deletion experiment) — no fix.
context: user-requested seed/verify of the 3 stubs surfaced by the SPRY1/FGFR1/CXCR4/ACKR3 batch. All seeded→verified same-day (verified:true). Verifiers again caught real seeder errors (fabricated author lists, wrong DOI, overclaims).
pathways/fgf-signaling.md (type: pathway; expanded a pre-existing stub from the initial public release) — Reactome R-HSA-190236 (“Signaling by FGFR”); KEGG hsa04010 documented as a proxy (no dedicated FGF KEGG entry). Two arms: paracrine FGF2–FGFR1–SPRY1 satellite-cell quiescence axis (Chakkalakal 2012; Bigot 2015 human epigenetic; SU5402-quiescence vs Spry1OX-depletion endpoints preserved; Yeh 2025 / Chang 2026-preprint dose complexity) + endocrine FGF21 (Zhang 2012 lifespan; mitokine/ISR; thymus Youm 2025) and FGF23–α-Klotho aging/phosphate axis (Kuro-o 1997). Verifier: adult mouse age 2mo→4–8mo, biopsy-site fix; propagated a DOI fix to fgfr1.md ([^ornitz2015] 10.1002/wrna.1232 [unrelated RNA paper] → 10.1002/wdev.176). druggability tier 2.
pathways/cxcl12-cxcr4-pathway.md (type: pathway) — KEGG hsa04062, Reactome R-HSA-380108. CXCL12→CXCR4 (Gαi/PLCβ/PI3K/MAPK) + GRK→β-arrestin-2 desensitization; ACKR3 biased scavenger. Aging: HSC-niche retention (Sugiyama 2006 Cxcr4-deletion), DPP4/CD26-truncated CXCL12→skeletal-stem-cell senescence (Elmansi 2020/2023), SASP-CXCL12 + vascular (Mahoney 2026 Aging Cell). Verifier: removed non-standard reactome-specific-reaction: frontmatter field (R-HSA-374214 moved to body as a Reaction sub-event); Jiang 2019 cell-type + SASP-conditioned-media attribution tightened. druggability tier 2.
[2026-06-15] sim | M7 — timeline becomes the sole editing surface (retire Lifestyle tab + graph freeze panel)
context: user-corrected the M6/M7 framing (the timeline already had full node parity with the graph freeze controls — same 23 non-stub provenance!=="stub" nodes), so M7 (UI consolidation) no longer depends on M6 (engine work) and was reordered before it. Design note §13 + milestone list corrected; “M7 build decisions” section added to model/timeline-history-import-design.md.
decisions (user): (1) Lifestyle/extrinsic-risk scalar → moved onto the timeline as a time-varyinglifestyle:extrinsic exposure; (2) global coupling scalar → dropped from the UI (pinned at engine default 1.0); (3) causal-graph diagram → kept read-only + a “Add a node-freeze on the timeline →” jump button replaces the inline freeze sliders.
engine (model/engine.mjs): simulate()lifestyle opt now accepts a scalar (back-compat, byte-identical) OR an age-profile {byAge,mode:"step"} via resolveProfile(lifestyle,AGES,1.0,"step"); compileTimeline() emits a lifestyle profile (id-validated to extrinsic, values clamped ≥0, non-finite dropped); canonicalizeHistoryEvents() treats lifestyle as a step channel. Rebuilt into the viz via build-app.mjs.
app (viz/aging-simulator.html): removed the modtab-blayer tab+panel (lifestyle slider, inputsGrid, treatToggles, labGrid, currentage) and the graph freeze/coupling sub-panel; added the timeline lifestyle channel (add-bar option + editor × extrinsic risk field + meta/default/clamp); switchModTab(), addSelectedNodeFreezeToTimeline(), effectiveIntervention() (reads freeze from the timeline, mirrors currentOpts merge order: timeline wins, last-wins); removed the now-dead B-layer builders + ownership/disable-cue subsystem (buildBlayerControls/fmtNum/applyIntervFromControls/updateInputDisabledStates/updateTimelineOwnershipCues/anchoredMediators/INPUT_DISABLE_INFO/coupleInfo). Stale “slider/Labs panel” copy repointed at the timeline.
tests: model/test.mjs +9 M7 cases (scalar↔profile byte-identity; extrinsic-only invariance; pre-first-knot fallback; unknown-id ignored; ≥0 clamp + non-finite drop; compiled end-to-end) → 289/289. model/e2e-playwright.mjs rewritten to drive every scenario through the timeline + M7 structural checks + lifestyle channel + add-bar/editor UI path + jump button → 33/33 real-browser (Chromium), zero console/page errors. (e2e baseline asserts now read the cohort #leCond figure, not the conditioned #leVal headline.)
Codex review (gpt-5.5/high, two checkpoints): ckpt-1 (engine+compile) folded id-validation + clamp + canonicalizer channel + stronger extrinsic-only test; ckpt-2 (full diff) folded effectiveIntervention merge-order fix + an add-bar/editor e2e check + stale-copy fixes. No live dangling refs; boot-safe; resetAll complete; couple safe at 1.0.
units (follow-up, user-requested): the timeline options now carry units like the old sliders did — histChannelMeta gained a unit field (exposure EXO_BY_ID.unit, biomarker LAB_UNIT_BY_MED, treatment dose 0–1, lifestyle ×, categorical/operator none); surfaced in the add-bar dropdown (“Physical activity (min/week MVPA)”, “LDL (mg/dL)”, “Statin (dose 0–1)”) and the editor value-field label (“value (min/week MVPA)”, ”× extrinsic risk (1 = pop. avg)”, “age (yr)”). Treatment labels also fixed to use t.label (“Statin” not “statin”). Browser-confirmed; 289/289 + 33/33 still green.
still M6 (not this change): direct clamp of mediators + ∫rate state nodes, edge editing, #gap/freeze-nonmonotonic-liver engine clamp.
context: user reported that after loading a history bundle, editing an exposure (saturated fat at the current age) had NO future effect. Root cause (confirmed empirically): dietSatFat’s only LIVE downstream is dietSatFat→LDL (the →chronic-inflammation edge is still a stub); a loaded LDL lab anchors LDL, and the offset solver re-derived the personal residual from the changed input, EXACTLY absorbing a constant upstream change (LDL pinned). With an LDL anchor, satfat 10→3 moved LE 0.000; without, +0.255. (Mediator-only exposures all go inert after import; direct-cause exposures like activity/smoking still work.)
forward-planning anchor fix (part of the deferred §10 b2 rework): currentOpts() now solves the lab-anchor offset against the HISTORICAL regime (input/treatment step-knots with age<now stripped via stripFutureProfiles; interventions startAge<now via stripFutureInterventions; operator pulse-ages<now via stripFutureOperators) and runs the forward sim with the FULL planned profile. A change at/after now now MOVES the mediator’s future trajectory instead of being re-absorbed. <now strict so an edit at the current age counts as a plan. Engine solveOffsets UNTOUCHED (split is app-layer only); draws at age<now still reproduce their measured value exactly. e2e: with LDL@40 anchored, satfat 10→3 now Δ LE=0.300; LDL@35 historical draw still reproduces 150.
terminology (user-requested): renamed the user-facing “node-freeze” control → “node override (slow aging)” / “Slow / override this node” across the graph button, selMeta, hint, add-bar type, tooltip, readout, legend, import-report summary, the parser “multiple node-override windows” warning, and the editor efficacy→strength 0–1 (slow fraction). Element id #addFreezeToTimeline + fn name kept (internal; e2e depends on the id). params.json node descriptions still say “freeze” (descriptive prose; out of scope). Bundle field stays efficacy (schema field name).
privacy banner (user-requested): added a teal .privacy-note in <header> — app is 100% client-side, no PII/PHI leaves the device. Verified the viz has NO fetch/XHR/sendBeacon/WebSocket/localStorage/sessionStorage/external-resource calls; the only external URL is WIKI_BASE (optional <a target=_blank rel=noopener> wiki reference links the user clicks). Claim scoped to “no personal data … transmitted” + a parenthetical about the optional wiki links.
renamed the timeline tab/panel label “History & plan timeline” → “Biomarker & Intervention timeline” (label only; data-tab="timeline" + logic unchanged; 9 occurrences in viz).
“Load example” button next to “Load file” in the importer: loads the built-in parser-validated, person-agnostic fictional demo bundle (model/history-bundle.example.json — 12 events: LDL trend, statin, smoking→former, alcohol taper, senolytic). Inlined by build-app.mjs as HISTORY_BUNDLE_EXAMPLE (NOT fetched — preserves the 100% client-side guarantee); wired in buildHistoryImporter via importHistoryBundle(JSON.stringify(...)) with _historyImportGen++ + typeof guard. model/test.mjs now validates the example parses clean (12|male|1980-04-12, LDL biomarker present) so the demo can’t drift out of parser-spec.
made the timeline ”+ Add at now” button green (#1e8449) as the primary add action.
tests: 292/292 headless (+3 example-validation cases); 39/39 real-browser e2e (+Load-example checks; added a dialog auto-accept for the replace-confirm). Codex (gpt-5.5/high, checkpoint 4) — no BLOCKER/HIGH/MEDIUM; confirmed inlining preserves no-network, const load-order safe, _historyImportGen correct; folded its example-validation-test suggestion + design-note rename note.
user request: export current settings to JSON (download or copy), re-loadable. Chose to EXTEND the history-bundle so one format does both directions.
discovery: the friendly bundle sections are date-based + require birthDate, and treatments are single-window (vs the app’s multi-knot) — a per-section retrofit would be lossy/awkward. Solution: a lossless top-level events[] passthrough of the app’s native age-based timeline events.
engine (model/engine.mjs, parseHistoryBundle): (1) birthDate optional — required only to convert dated friendly entries (toAge errors per-entry if a date is given with no birthDate); present-but-malformed still aborts. (2) optional currentAge → returned so the app restores “now” without a birthDate. (3) events[] passthrough — validates each native event vs ctx (kind∈input/treatment/lifestyle/intervention/operator/biomarker; id known; intervention finite startAge+efficacy∈[0,1]+endAge null|>startAge; operator non-empty finite ages[]+object scenario; step/point finite age+value/enum); counts report.loaded.events; carries lifestyle:extrinsic (which the friendly sections can’t).
Codex (gpt-5.5/high, checkpoint 5) caught a HIGH (oversized native operator ages[] bypassed the import-size cap) + MEDIUM (malformed scenario silently coerced, both native + friendly paths) + 2 LOW (round-trip test only compared channel names; privacy-banner wording) — ALL fixed: cap now counts operator ages, ages[] must be a non-empty finite array (no silent filter), scenario must be a non-array object, round-trip test compares full canonical payload, banner notes explicit user download/copy. Re-verified.