🧬 Aging Wiki

R7

70 min read

log/R7.md — Round 7 entries

Sub-file of log — see parent for index.

[2026-05-04] verify | bcl2l13

Pages verified: 1 (partial scope — 3/6 sources verified against full PDFs; 2 failed download; 1 not_oa)

  • molecules/proteins/bcl2l13.md — verified: true (partial scope)
    • Sources checked against full PDFs: Murakawa 2015 (ncomms8527), Otsu 2015 (15548627.2015.1084459), Kataoka 2022 (fcell.2022.1065702, pp.1–15)
    • Sources unverifiable: Kataoka 2001 (jbc.m010520200) — hybrid OA, no PMC copy, download failed; Murakawa 2024 (celrep.2024.115001) — gold OA but Elsevier access block; Murakawa 2025 (15548627.2025.2465408) — not_oa
    • Corrections made:
      1. LIR motif residues: human 286–289 (WQQI) per Kataoka 2022 Fig. 4C — prior estimate 218–248 incorrect; needs-canonical-id closed
      2. BH domain fragmentation requirement: wiki said “BH1 and BH4” — Murakawa 2015 explicit: all BH1-4 required; corrected throughout
      3. Yeast complementation: partial rescue, not full rescue — Murakawa 2015 states “suggesting partial restoration”; orthology table updated
      4. Cell lines: MEFs removed from murakawa2015 footnote — paper used HEK293A and HeLa only
      5. BCL-2 family interactions: “weak sensitizer” / BCL-2/BCL-xL interaction claim removed — BCL2L13 does not interact with any anti- or pro-apoptotic BCL-2 family members (Murakawa 2015, Kataoka 2001/2022); BCL-2/BCL-xL relisted as non-interactors
      6. Yeast TAmito chimeric construct: BCL2L13 residues 1–407 + Gem1p tail-anchor (aa 618–662) — added
      7. BHNo domain nomenclature: added from Kataoka 2022
      8. Non-functional first WXXL/I motif: 147–150 (mouse) added to domain table
      9. Murakawa 2024 + 2025 cardiac section: flagged no-fulltext-access
    • Gap tags resolved: needs-canonical-id for LIR (closed)
    • Gap tags added: no-fulltext-access for Murakawa 2024 + 2025

Downstream pages to check (main agent — do not propagate here):

  • mitophagy — may carry “BH1 and BH4” fragmentation claim; check
  • bcl-2-family-signaling — if BCL2L13 listed as weak sensitizer, correct to non-interactor
  • ampk — AMPKα2/Ser272 cardiac claim from Murakawa 2024 is unverified against full PDF

[2026-05-04] verify | atg13

Pages verified: 1

  • molecules/proteins/atg13.md — Hosokawa 2009 MBC, Ganley 2009, Puente 2016, Suzuki 2015 primary PDFs all read end-to-end.

Corrections applied:

  1. Ser-224 kinase identity (central error): wiki had “AMPK pathway (indirect; mTORC1-regulated) / AMPK-mediated dephosphorylation” — corrected to “AMPK directly phosphorylates Ser-224 (inhibitory)”; Puente 2016 shows AMPK is the kinase, not a dephosphorylase
  2. Activation mechanism diagram: removed incorrect “AMPK activated → ATG13 dephosphorylated” framing; added note that AMPK activity actually decreases under amino acid starvation, which is how pSer-224 is released
  3. Phospho-site table: restructured; Ser-224, Ser-258, Ser-318 from Puente 2016; Ser-355/356/361 from UniProt (not characterized in Puente 2016)
  4. AMPK cross-reference: removed erroneous “but not ATG13 directly” clause; added accurate description
  5. AMPK added to interactors table as direct kinase relationship
  6. Suzuki 2015: corrected “seatbelt” → “WF finger (Trp/Phe loop)”; specified fission yeast as structural model (not mouse/human)
  7. Puente 2016 footnote: fully updated to PDF-verified citation
  8. Suzuki 2015 footnote: updated with 2-page punctum format, fission yeast, WF finger, local path
  9. Mercer 2009 + Hosokawa 2009b: “pending” → “permanently unverifiable — 0 URLs, Tandfonline paywall, no PMC”
  10. key-ptms frontmatter: added Ser224-phosphorylation-AMPK and Ser258-phosphorylation-mTOR
  11. Gap table: Ser-224 and HORMA entries updated with PDF-verified findings
  12. ⚠️ banner removed; verified: true flipped

Pages unverifiable (permanent access failure):

Downstream pages for main agent to propagate:

  • molecules/proteins/ulk1.md — verify Ser-224/AMPK framing matches corrected Puente 2016 reading
  • pathways/autophagy.md or equivalent — if activation diagram mirrors old AMPK/ATG13 framing
  • molecules/proteins/atg101.md — Suzuki 2015 WF finger terminology; confirm consistent with atg13.md

[2026-05-04] verify | xenophagy

Pages verified: 1 (partial — 4/6 sources verified against full PDFs; 2 not_oa)

  • processes/xenophagy.md — verified: true (partial scope)
    • Sources checked against full PDFs: Gutierrez 2004 (Cell), Thurston 2009 (Nat Immunol), Levine 2011 (Nature review), Tumbarello 2015 (PLoS Pathog)
    • Sources unverifiable (not_oa): Wild 2011 (Science 10.1126/science.1205405), Thurston 2012 (Nature 10.1038/nature10744) — tagged no-fulltext-access
    • Corrections made:
      1. Footnote model cell line: J774 → RAW 264.7 (Gutierrez 2004 used RAW 264.7, not J774; also validated in BMMs and human MDMs)
      2. ESX-1/EsxA/SNARE claim removed from [^gutierrez2004] attribution — Gutierrez 2004 does not mention ESX-1, EsxA, or SNARE disruption; body text corrected and tagged unsourced for the ESX-1/SNARE claim pending a primary source
      3. NDP52 ubiquitin-binding domain: “CLIR motif” → “zinc-finger domain” per Thurston 2009 (CLIR = LC3-interaction region, not ubiquitin-binding region)
      4. Thurston 2009 footnote: clarified that galectin-8 recruitment is from Thurston 2012, not Thurston 2009; corrected description of TBK1 recruitment mechanism (Nap1/Sintbad adaptors)
      5. TAX1BP1 table entry: corrected ubiquitin-chain specificity (ZF2 is primary K63-Ub binding domain; ZF1+ZF2 for myosin VI; K48-Ub and linear Ub also bound); corrected LC3 isoform binding (binds LC3B and LC3C equally, unlike NDP52 which is LC3C-selective); added TAX1BP1 dominant-vertebrate-paralogue context (NDP52 lost from Xenopus, truncated in mice)
      6. Myosin VI mechanism: “recycling endosomes” → “endosomal membrane components” (Tumbarello 2015 specifies endosomes, not specifically recycling endosomes); added key distinction that myosin VI loss causes bacteria inside LC3+ autophagosomes (late-stage defect) vs. receptor loss causes cytosolic ubiquitin-positive bacteria (early-stage defect)
      7. TAX1BP1/myosin VI receptor specificity section: corrected to distinguish TAX1BP1 siRNA (cargo-recognition defect) from myosin VI siRNA (maturation defect); corrected that myosin VI single KD causes stronger Salmonella hyper-proliferation than the triple receptor KD
      8. Listeria/ActA: added [^levine2011] as a verifiable source (confirmed against PDF); qualified the “galectin occlusion” framing as unresolved mechanism
      9. Tumbarello 2015 footnote: corrected model (HeLa + RPE + myosin VI KO MEFs); corrected claim from “maturation but not initial receptor recruitment” to accurate distinction between TAX1BP1 siRNA and myosin VI siRNA phenotypes
      10. Levine 2011 footnote: added all three author names (Levine B, Mizushima N, Virgin HW); DOI-BUG-2 mismatch note retained in streamlined form
      11. Receptor specificity text for NDP52: replaced “abolishes autophagic restriction” (overstatement vs. source which shows hyper-proliferation not complete abolition) + removed erroneous “CLIR” attribution for ubiquitin binding
    • Gap tags added: no-fulltext-access (Wild 2011, Thurston 2012), unsourced (ESX-1/SNARE disruption claim)
    • BUG-2 confirmed: task brief DOI 10.1016/j.cell.2010.12.024 is Chromatin Remodeling SnapShot; correct Levine 2011 DOI is 10.1038/nature09782 — already corrected in frontmatter of xenophagy.md

Downstream pages to check (main agent — do not propagate here):

  • ndp52 — may carry “CLIR = ubiquitin binding” error
  • optn — OPTN Ser177 claims sourced to Wild 2011 (not_oa); flag for future access
  • galectin-8 — if/when seeded, galectin-8 → NDP52 claim must cite Thurston 2012 not 2009
  • tbk1 — check if it credits Gutierrez 2004 for ESX-1/SNARE; correct if so

[2026-05-04] verify | atg101

Pages verified: 1 (partial)

  • molecules/proteins/atg101.md — Qi 2015 fully read (local PDF confirmed). Mercer 2009 and Hosokawa 2009 Crossref-metadata-only (Taylor & Francis paywall blocked PDF downloads). Suzuki 2015 closed-access (not_oa).

Corrections applied:

  1. HORMA domain boundaries: “aa ~4–214 by UniProt annotation” → “aa 1–198 by Qi 2015 structural boundaries; residues 199–218 form disordered C-terminal safety belt” (Figure 1A, Qi 2015)
  2. WF finger conformation: “constitutively open conformation” → corrected to O-conformation HORMA with WF finger in closed/inactive (“off”) conformation in human heterodimer, sequestered in hydrophobic pocket (Trp110/Phe112 packed against Ile117); Qi 2015 explicitly states binding partners “remain to be determined”
  3. WF finger binding partners: attribution of GABARAPL1/GABARAPL2/LC3C binding to Qi 2015 removed — Qi 2015 does NOT establish this; it derives exclusively from Suzuki 2015 (closed-access). Qualified throughout with no-fulltext-access
  4. WF-finger mutant experiment attribution: wiki said “fission yeast” — corrected to Qi 2015’s HEK293 pull-down assay system (17 mutants, GST/Strep HORMA fragments)
  5. Interface details added from Qi 2015: ATG13 Ser127–ATG101 His31 H-bond (2.8 Å); buried salt bridge ATG13 Arg133–ATG101 Asp54 (2.64 Å); 1,523 Ų buried surface; PDB 5C50; 1.6 Å resolution
  6. New content added: benzamidine pockets (five conserved hydrophobic sites; two animal-specific at subunit junction) and “interaction hub” framing from Qi 2015; gap tagged
  7. Mercer 2009 footnote: added Crossref-confirmed authors (Mercer CA, Kaliappan A, Dennis PB), pages (649–662), full citation; no-fulltext-access
  8. Hosokawa 2009 footnote: added Crossref-confirmed authors (Hosokawa N, Sasaki T, Iemura S, Natsume T, Hara T, Mizushima N), pages (973–979); no-fulltext-access
  9. Suzuki 2015 footnote: added Crossref-confirmed volume/pages (22:572–580), authors (Suzuki H, Kaizuka T, Mizushima N, Noda NN), 3.0 Å resolution
  10. Qi 2015 footnote: added PDB 5C50, resolution (1.6 Å), full author list, Structure 23:1848–1857, HEK293 system note
  11. DOI corrections confirmed correct:.8504→.8249 (Mercer) and nsmb.3162→nsmb.3036 (Suzuki) — wrong DOIs resolve to unrelated papers (rapamycin paper and m6A paper respectively)
  12. Three new gap entries added to Limitations: benzamidine pockets (#gap/no-mechanism), Mercer/Hosokawa unverified text (#gap/no-fulltext-access), WF-finger conformation trigger (#gap/no-mechanism)
  13. Key interactors table: GABARAPL1/GABARAPL2/MAP1LC3C rows now explicitly cite Suzuki 2015 as source and note closed-access status

Pages unverifiable (closed-access or download failure):

  • Suzuki 2015 (10.1038/nsmb.3036) — not_oa; tagged no-fulltext-access on all derived claims
  • Mercer 2009 (10.4161/auto.5.5.8249) — bronze OA but Taylor & Francis blocked download (failed); tagged no-fulltext-access
  • Hosokawa 2009 (10.4161/auto.5.7.9296) — hybrid OA but Taylor & Francis blocked download (failed); tagged no-fulltext-access

Downstream pages that may need updates (propagation for main agent):

  • qi-2015-human-atg13-atg101-horma — stub likely missing WF-finger-off-conformation finding and benzamidine pockets
  • suzuki-2015-atg101-atg13-horma — stub; cannot verify until OA access obtained
  • atg13 — may carry inherited claim that ATG101 “stabilizes ATG13 against proteasomal degradation” without noting the Mercer/Hosokawa quantitative data are unverified; also may need WF-finger conformation update
  • ulk1 — may carry WF-finger binding partner claims (GABARAPL1/LC3C attribution) that should be traced to Suzuki 2015 with no-fulltext-access

[2026-05-04] ingest | round-7d-followup

daf-2

  • added: molecules/proteins/daf-2.md
  • entity type: protein (C. elegans insulin/IGF-1 receptor; single worm ortholog of vertebrate INSR + IGF1R; founding longevity gene of modern aging research)
  • canonical IDs: UniProt Q967D7 (Q967D7, Swiss-Prot reviewed; length needs confirmation — NCBI Gene 175410 lists isoforms up to 1,604 aa; 1,846 aa figure from literature unconfirmed against current UniProt record, tagged needs-canonical-id), NCBI Gene 175410, WormBase WBGene00000898; HGNC null (worm gene)
  • historical prominence: Kenyon 1993 (Nature 366:461) is the founding paper of modern aging genetics; daf-2(e1370) LoF approximately doubles adult C. elegans lifespan; completely suppressed by daf-16 LoF — established that aging is genetically regulated. 3,379 citations (100th percentile impact); closed-access (not_oa; no local PDF; no-fulltext-access).
  • DOIs cited:
    • 10.1038/366461a0 (Kenyon 1993 Nature — founding paper; not_oa no-fulltext-access; confirmed via Crossref: title matches, 5 authors Kenyon/Chang/Gensch/Rudner/Tabtiang; 3,379 citations; 100th percentile)
    • 10.1126/science.277.5328.942 (Kimura 1997 Science — daf-2 cloning + INSR/IGF1R orthology; local PDF confirmed at ; 2,246 citations)
    • 10.1093/genetics/150.1.129 (Gems 1998 Genetics — Class I/II allele distinction; bronze OA; archive pending download; confirmed via Crossref: 16 alleles, 2 classes, Gems et al.; 715 citations)
    • 10.1101/gad.867301 (Pierce 2001 Genes & Dev — ~40 ins peptides, INS-1/INS-18 antagonists, DAF-28 agonist; diamond OA; archive pending download; confirmed via Crossref: Pierce SB et al.; 673 citations)
    • 10.1038/nature08980 (Kenyon 2010 Nature review — cross-species IIS-FOXO axis; local PDF confirmed at ; 2,671 citations; 100th percentile)
  • implicit stubs created: age-1, pdk-1, akt-1, akt-2, ins-1, daf-28, kenyon-1993-daf2-longevity, kimura-1997-daf2-cloning, gems-1998-daf2-alleles, pierce-2001-ins-ligands
  • schema escalation: wormbase-id field used (precedent from daf-16.md, verified-partial); organism field used (both also on daf-16.md); HGNC set to null with explanation. These fields are not in the CLAUDE.md type:protein schema but are established practice from daf-16.md. No new schema invention.
  • gaps surfaced: protein length discrepancy (#gap/needs-canonical-id); GenAge-models entry ID not confirmed (#gap/needs-canonical-id); Kenyon 1993 not_oa (#gap/no-fulltext-access); exact n and statistics from Kenyon 1993 cannot be verified; full agonist/antagonist classification of all ~40 ins peptides incomplete (#gap/needs-replication); atomic-resolution DAF-2 ligand-binding domain structure not solved (#gap/no-mechanism); tissue-specific contribution to longevity not quantitatively partitioned
  • verification priority: HIGH — Kenyon 1993 cannot be PDF-verified (closed-access); Kimura 1997 local PDF available (verify sequence-level INSR orthology claims and specific domain annotations); Kenyon 2010 local PDF available (verify cross-species magnitude table); Gems 1998 pending download (verify Class I/II allele table); Pierce 2001 pending download (verify ins peptide count and INS-1/DAF-28 functional assignments). Protein length (#gap/needs-canonical-id) is the top priority factual gap.
  • ROADMAP: daf-2 marked [x] (drafted, verified: false) under Round 7d-followup

sgk1

  • added: molecules/proteins/sgk1.md
  • entity type: protein (431 aa; AGC-family serine/threonine kinase; PDK1/mTORC2 substrate; parallel to AKT but no PH domain; short half-life ~30 min; transcriptionally glucocorticoid/mineralocorticoid/stress-inducible)
  • canonical IDs: UniProt O00141 (SGK1_HUMAN, confirmed via REST API 2026-05-04), NCBI Gene 6446, HGNC 10810
  • CRITICAL aging-narrative correction: Hertweck 2004 (10.1016/s1534-5807(04)00095-4; local PDF confirmed; verified on akt.md 2026-05-04) establishes sgk-1 single mutant as +63% C. elegans lifespan (14.7→24.0 d; p<0.0001; n=147), while akt-1 alone (p=0.1642 NS) and akt-2 alone (p=0.3717 NS) do not significantly extend lifespan. SGK-1 is the dominant IIS longevity kinase in C. elegans, not AKT-1/AKT-2. This corrects the long-standing narrative that attributed the daf-2 longevity signal primarily to the AKT orthologs.
  • DOIs cited: 10.1128/mcb.13.4.2031 (Webster 1993 — not_oa); 10.1093/emboj/18.11.3024 (Park 1999 — pending download); 10.1042/bj3390319 (Kobayashi 1999 — not_oa); 10.1016/s1534-5807(04)00095-4 (Hertweck 2004 — local PDF confirmed, VERIFIED on akt.md); 10.1152/physrev.00050.2005 (Lang 2006 — not_oa)
  • implicit stubs created: daf-2, daf-16, nedd4l
  • gaps surfaced: GenAge ID null; SGK2/SGK3 UniProt IDs not re-verified; no mammalian longevity experiment with SGK1 LoF; Brunet 2001 SGK-FoxO DOI not confirmed (excluded — BUG-2 risk); GSK650394 in-vivo aging data absent; mechanistic basis for SGK-1 dominance over AKT-1/2 in C. elegans unresolved
  • verification priority: HIGH — Hertweck 2004 numerics pre-verified; other sources not_oa; verifier should focus on UniProt O00141 canonical fields + Park 1999 phosphosite claims

foxo-transcription-factors

  • added: molecules/proteins/foxo-transcription-factors.md
  • entity type: protein (family overview page — covers FOXO1/3/4/6 mammalian paralogs + evolutionary origin; uniprot/ncbi-gene/hgnc all null by design; complex-subunits lists Q12778/O43524/P98177/A8MYZ6)
  • canonical IDs: null for family page; individual UniProt IDs in complex-subunits frontmatter and member table; FOXO6 A8MYZ6 flagged for lint-pass re-verification (#gap/needs-canonical-id)
  • CRITICAL BUG-2 correction — Paik 2007 DOI: Task brief specified 10.1016/j.cell.2007.01.034. DOI lookup resolves this to “The XIST Noncoding RNA Functions Independently of BRCA1 in X Inactivation” (80 citations) — confirmed BUG-2 DOI-title mismatch. Correct Paik 2007 triple-KO DOI: 10.1016/j.cell.2006.12.029 (“FoxOs Are Lineage-Restricted Redundant Tumor Suppressors,” Cell 128:309, 2007; 1,023 citations). Confirmed via Crossref + DOI lookup. Page and ROADMAP use corrected DOI.
  • Attribution resolution — Hosaka vs Paik vs Tothova: Hosaka 2004 (10.1073/pnas.0400093101) = three individual single germline KOs only. Triple conditional KO hemangiomas+thymic lymphomas = Paik 2007 (10.1016/j.cell.2006.12.029). Triple conditional KO HSC depletion via ROS = Tothova 2007 (10.1016/j.cell.2007.01.003). All three attributions documented explicitly on the page.
  • DOIs cited: 10.1016/s0092-8674(00)80595-4 (Brunet 1999, local PDF), 10.1073/pnas.0400093101 (Hosaka 2004, local PDF), 10.1016/j.cell.2006.12.029 (Paik 2007, pending), 10.1016/j.cell.2007.01.003 (Tothova 2007, pending), 10.1016/j.cell.2017.02.031 (Baar 2017, pending), 10.1073/pnas.0801030105 (Willcox 2008, local PDF), 10.1074/jbc.274.23.15982 (Nakae 1999, local PDF on foxo1.md), 10.1016/s0960-9822(00)00728-4 (Dijkers 2000, local PDF), 10.1038/nature01036 (Kops 2002, local PDF), 10.1016/j.cmet.2007.08.006 (Matsumoto 2007, local PDF), 10.1038/nature08980 (Kenyon 2010, local PDF), 10.1038/onc.2008.21 (Calnan & Brunet 2008, not_oa no-fulltext-access)
  • implicit stubs (net new): foxo6, paik-2007-foxo-triple-ko-tumor-suppressor, tothova-2007-foxo-hsc-rox, baar-2017-foxo4-dri-senolytic, hosaka-2004-foxo-single-kos, brunet-1999-akt-foxo3-14-3-3, willcox-2008-foxo3a-longevity
  • schema decisions: family overview uses complex-subunits field (established precedent) with null uniprot/ncbi-gene/hgnc; no new schema invented
  • gaps surfaced: FOXO6 aging biology absent (#gap/unsourced, needs-replication); MST1 Ser207 / CDK1/2 inhibitory phospho-FOXO citations needed (#gap/unsourced); FHRE ChIP-seq consensus citation needed (#gap/unsourced); rs2802292 mechanism (#gap/no-mechanism); FOXO4-DRI human efficacy (#gap/needs-human-replication); Calnan & Brunet 2008 not_oa (#gap/no-fulltext-access)
  • verification priority: MEDIUM — Brunet 1999, Hosaka 2004, Willcox 2008 local PDFs available for cross-check; Paik/Tothova/Baar PDFs pending download
  • ROADMAP: foxo-transcription-factors marked [x] (drafted, verified: false) under Round 7d FOXO family

growth-hormone

  • added: molecules/proteins/growth-hormone.md
  • entity type: protein (217 aa precursor → 191 aa mature; 22 kDa; four-helix bundle; somatotropic axis master regulator)
  • canonical IDs: UniProt P01241 (confirmed via REST API 2026-05-04), NCBI Gene 2688, HGNC 4261
  • DOIs cited: 10.1073/pnas.68.4.866 (Niall 1971 PNAS — GH sequence/evolution; 373 citations; archive pending, green OA PMC389061), 10.1093/nar/9.15.3719 (DeNoto 1981 NAR — GH cDNA + alternative splicing; 460 citations; archive pending, bronze OA), 10.1210/en.2003-0374 (Coschigano 2003 Endocrinology — GHR-/- ~40-55% lifespan extension; 509 citations; archive not_oa, no local PDF), 10.1038/384033a0 (Brown-Borg 1996 Nature — Ames dwarf longevity; 1,060 citations; archive pending, bronze OA), 10.1126/scitranslmed.3001845 (Guevara-Aguirre 2011 Sci Transl Med — Laron syndrome Ecuador cohort; 731 citations; DOI lookup failed, green OA PMC3357623)
  • PMID mismatch corrected: task brief cited PMID 5159922 for “Niall 1971 JBC GH sequence.” PubMed efetch of PMID 5159922 returns a Soviet pneumonia paper (Griskin 1971 Klin Med) — clear PMID error. Correct Niall 1971 GH paper identified as doi:10.1073/pnas.68.4.866 (confirmed via DOI lookup: “Sequences of pituitary and placental lactogenic and growth hormones: evolution from a primordial peptide by gene reduplication,” PNAS 1971, 373 cites). PMID not used; DOI used instead.
  • implicit stubs created: ghr, ames-dwarf-mouse, jak-stat-pathway
  • gaps surfaced: GenAge ID for GH1 not confirmed (longevity phenotype is GHR-/- receptor, not GH1 KO); sex-specific GH pulse pattern primary reference needed; 75% hepatic IGF-1 fraction needs citation (Liu 1998 / Sjögren 1999 liver Igf1 KO); bovine GH transgenic lifespan shortening quantitative values unsourced (Bartke lab refs needed)
  • schema decisions: genage-id: field omitted (not null) because GH1 is the ligand gene — the longevity phenotype belongs to GHR-/- — rather than marking it null and implying a data gap where the field simply does not apply. Escalated to schema: CLAUDE.md protein schema could benefit from a genage-id-note: free-text field for cases like this where the field semantics are ambiguous.
  • verification priority: MEDIUM-HIGH — Coschigano 2003 (~55% lifespan extension claim) is the most critical quantitative finding and is not_oa; Guevara-Aguirre 2011 download failed (but covered in depth on igf-1.md verified-partial); Brown-Borg 1996 pending. Verifier should attempt Coschigano 2003 via interlibrary access or publisher portal; Guevara-Aguirre 2011 available at PMC3357623.
  • ROADMAP: growth-hormone marked [x] drafted R7d 2026-05-04, verified: false

[2026-05-04] verify | molecules/proteins/foxo1.md

Pages verified: 1 (partial — Galili 1993 closed-access PDF inaccessible at runtime; canonical-DB IDs not live-re-verified)

PDFs read: Hosaka 2004 (10.1073/pnas.0400093101), Brunet 1999 (10.1016/s0092-8674(00)80595-4), Nakae 1999 (10.1074/jbc.274.23.15982 — downloaded during this pass), Nakae 2002 (10.1038/ng890), Matsumoto 2007 (10.1016/j.cmet.2007.08.006 — downloaded during this pass)

Corrections applied:

  1. Hosaka 2004 citation gap RESOLVED: Replaced provisional [^foxo1ko-note] with proper [^hosaka2004]; removed needs-canonical-id from Limitations section and footnotes. Confirmed: PNAS, not Cell; Hosaka T et al. 2004 is the correct attribution.
  2. CRITICAL — vasculogenesis → angiogenesis (Hosaka 2004): Wiki said “vasculogenesis defect.” Hosaka 2004 explicitly states Foxo1 “may not have a major role in the process of embryonic vasculogenesis” and attributes lethality to failure of embryonic angiogenesis (remodeling). Knockout phenotype section rewritten to accurately describe the angiogenesis defect, PECAM-1 findings, and lacZ expression pattern.
  3. CRITICAL — 14-3-3 binding sites corrected (Brunet 1999): Wiki table said Ser319 “cooperates with Ser256 in nuclear export.” Brunet 1999 demonstrates (for the analogous FOXO3/FKHRL1 sites) that S315A alone does not reduce 14-3-3 binding; only T32A+S253A double mutant abolishes it. Table corrected: Thr24+Ser256 are the 14-3-3 docking sites; Ser319 drives a distinct nuclear-export mechanism. Body text and [^14-3-3] interactor entry updated.
  4. CRITICAL — Brunet 1999 organism/cell type corrected: Footnote said “neurons, NIH3T3.” Actual cell lines are CCL39 fibroblasts (Chinese hamster lung), 293T cells, cerebellar granule neurons, and Jurkat T cells. NIH3T3 not used in this paper.
  5. CRITICAL — Nakae 1999 cell type corrected: Footnote said “CHO cells.” Actual system is SV40-transformed mouse hepatocytes. CHO cells not used.
  6. CRITICAL — Atrogin-1/MuRF1 attribution removed from [^nakae2002]: Nakae 2002 (Nat Genet) does not mention Atrogin-1, MuRF1, FBXO32, or TRIM63. The FOXO-muscle atrophy claim was incorrectly attributed to this paper. Body text tagged unsourced with correct primary sources identified (Sandri 2004, Stitt 2004).
  7. Foxa2/G6PC-PCK1 claim corrected (Nakae 2002): Wiki said “FOXO1 + Foxa2 axis in gluconeogenesis (G6PC, PCK1).” Nakae 2002 explicitly shows Foxa2 regulates Slc2a2 (Glut2), NOT G6pc/Pck1. Foxo1 and Foxa2 are parallel hepatic regulators of different targets. β-cell section rewritten.
  8. Matsumoto 2007 quantitative data added: Added specific numbers verified from PDF — 40% glucose reduction at birth, 30% after 48 hr fast, >50% HGP reduction under clamp, ~50% each glycogenolysis and gluconeogenesis, 2-4x blunting of G6pc/Pck1 mRNA. Cre line corrected to α1-antitrypsin-Cre (not albumin-Cre). Key mechanistic finding added: Foxo1 required for Pgc1α-induced gluconeogenesis and for both cAMP and insulin axes of HGP regulation.
  9. Discovery section: Clarified that Brunet 1999 characterizes FKHRL1/FOXO3a (not FOXO1); FOXO1 sites are analogous by homology. Nakae 1999 cell model corrected.
  10. Footnote nakae2002 corrected: Removed “Foxo1 activates Atrogin-1/MuRF1 in muscle”; added explicit note that these targets are not in this paper; corrected model description.
  11. Footnote matsumoto2007: Updated from “pending” to downloaded; added key quantitative numbers, Cre line, n range.

Claims confirmed correct from PDFs:

  • FOXO1 AKT phospho sites Thr24/Ser256/Ser319 correctly transposed from FOXO3 Thr32/Ser253/Ser315 (Brunet 1999)
  • Nakae 1999: Ser256/rat-Ser253 is the primary gatekeeper site; T24A and S316A reduce but do not abolish phosphorylation
  • Nakae 2002: G6pc (~75% lower with Foxo1 haploinsufficiency), Pck1, Igfbp1 as FOXO1 hepatic targets; Pdx1 suppression in β-cells; n=8-15/group; Foxa2→Slc2a2 axis confirmed distinct from Foxo1→G6pc/Pck1
  • Hosaka 2004: E10.5 lethality; hearts beating at E9.5; Foxo3a- and Foxo4-null viable and fertile; Foxo1 expressed in dorsal aorta, posterior cardinal vein, intersomitic/umbilical vessels
  • Matsumoto 2007: all quantitative values confirmed against figures and Table 1

Unverifiable claims:

  • Galili 1993 PAX3-FKHR translocation: PDF path ((stale local path) inaccessible in this environment (closed-access paper); claim consistent with archive title “Fusion of a fork head domain gene to PAX3 in the solid tumour alveolar rhabdomyosarcoma” and corroborated across all downstream papers citing FKHR discovery
  • Canonical-DB fields (UniProt Q12778, NCBI Gene 2308, HGNC 3819): not re-verified against live databases in this pass
  • SIRT1-FOXO1 deacetylation (Lys245/Lys248): no primary PDF read for this claim; retained with existing needs-replication tag
  • Cell-cycle and stress targets (p27, BIM, catalase, MnSOD): no new PDF verification this pass

Downstream pages that may need updates:

  • molecules/proteins/akt.md — already flagged S315/Ser319 in its foxo3 correction; foxo1-specific wording should be consistent — check “Thr32/Ser253 are 14-3-3 sites” claim propagated correctly
  • pathways/insulin-igf1.md — may describe Foxo1-/- as “vasculogenesis defect”; correct to angiogenesis
  • pathways/pi3k-akt-pathway.md — may contain Foxa2+Foxo1 gluconeogenesis claim; check
  • interventions/pharmacological/senolytics.md or diabetes intervention pages — may cite Nakae 2002 for Atrogin-1/MuRF1; check and remove incorrect attribution
  • studies/nakae-2002-foxo1-hepatic-gluconeogenesis.md — if seeded, confirm no Atrogin-1/MuRF1 content and that model is Insr+/- Foxo1+/- double heterozygotes

Newly downloaded: Nakae 1999 JBC (10.1074/jbc.274.23.15982), Matsumoto 2007 Cell Metabolism (10.1016/j.cmet.2007.08.006)

[2026-05-04] verify | molecules/proteins/insulin.md

Pages verified: 1 (partial — 4 of 9 cited sources verifiable from local PDFs; 4 are not_oa; Sanger/Ryle 1955 PDF inaccessible)

PDFs read: Bluher 2003 (10.1126/science.1078223), Holzenberger 2003 (10.1038/nature01298), Suh 2008 (10.1073/pnas.0705467105), Goeddel 1979 (10.1073/pnas.76.1.106 — downloaded during this pass). Sanger/Ryle 1955 (10.1042/bj0600541) downloaded but PDF contains only journal index volume, not article text.

Corrections applied:

  1. FIRKO background (CRITICAL — Bluher 2003): “C57BL/6 background” → “mixed genetic background” (paper explicitly states FIRKO mice have the same mixed background as their littermate controls; C57BL/6J is cited as a reference lifespan comparison only).
  2. FIRKO lifespan metric (Bluher 2003): “~18% median lifespan extension” → “~18% mean lifespan extension (134 days; 753→887 days)”; added quantitative detail including median +3.5 months and maximum +5 months.
  3. FIRKO footnote (Bluher 2003): Added n=250 total, both independent founder lines (line 1 n=131, line 2 n=119); replaced vague background descriptor with correct “mixed genetic background”; added fat mass reduction detail (50–70%).
  4. Holzenberger footnote: Replaced imprecise “~70 per genotype” with actual cohort breakdown (cohort 1: 32 Igf1r+/- + 33 WT lifespan animals; cohort 2/3 for metabolic/oxidative stress studies separately described).
  5. Sanger 1955 footnote author correction: “Sanger F & Tuppy H (1955)” → “Ryle AP, Sanger F, Smith LF & Kitai R (1955)” — the DOI 10.1042/bj0600541 resolves to the Ryle et al. paper on disulfide bond arrangement, not the Sanger & Tuppy amino acid sequence paper. Added no-fulltext-access note since article text was not accessible in downloaded PDF.
  6. FOXO3/Suh 2008 footnote conflation (CRITICAL): Line 104 used [^suh2008_ref] (dangling label) to cite “Willcox 2008” for FOXO3 SNPs — but there was no corresponding footnote definition and Suh 2008 is about IGF1R variants, not FOXO3. Fixed: replaced with cross-reference to foxo3 for the Willcox 2008 FOXO3 claim; retained [^suh2008] correctly for the IGF1R centenarian data.

Claims confirmed correct (against Bluher 2003, Holzenberger 2003, Suh 2008, Goeddel 1979):

  • FIRKO ~18% lifespan extension, both sexes (Bluher 2003 Fig. 2B)
  • IGF1R+/- 26% overall, 33% females, 15.9% males (NS), 129/Sv background (Holzenberger 2003 Fig. 2)
  • Suh 2008: n=79 centenarians + 161 controls; IGF1R variants Ala37Thr + Arg407His; elevated IGF-1; reduced AKT phosphorylation
  • Goeddel 1979: A- and B-chain synthesized separately, each fused to β-galactosidase, cleaved with CNBr, recombined by oxidative refolding

Unverifiable claims (not_oa):

  • Steiner 1967 (10.1126/science.157.3789.697): proinsulin discovery, 5% receptor affinity — tagged not_oa in footnote (already present)
  • Taguchi 2007 (10.1126/science.1142179): brain Irs2 KO lifespan data — tagged not_oa in footnote (already present)
  • Kenyon 1993 (10.1038/366461a0): daf-2 lifespan claim — tagged not_oa (already present)
  • Banting 1922 (10.1152/ajplegacy.1922.62.1.162): historical discovery — tagged not_oa (already present)
  • Sanger/Ryle 1955 (10.1042/bj0600541): disulfide bond positions — PDF is journal index only; no-fulltext-access added to footnote

Downstream pages that may need updates:

  • molecules/proteins/foxo3.md — already verified; Willcox 2008 attribution intact there
  • pathways/insulin-igf1.md — may repeat “C57BL/6 background” for FIRKO mice; check and correct
  • Any study page for Bluher 2003 if it exists — check background descriptor

[2026-05-04] verify | molecules/proteins/pdk1.md

Pages verified: 1 (partial — Mora 2004 closed-access)

PDFs read: Alessi 1997 (10.1016/s0960-9822(06)00122-9), Alessi 1996 (10.1002/j.1460-2075.1996.tb01045.x), Pullen 1998 (10.1126/science.279.5351.707), Lawlor 2002 (10.1093/emboj/cdf387). UniProt O15530 verified via REST API.

Corrections applied:

  1. CRITICAL — “improved insulin sensitivity” fabricated (Lawlor 2002): Lawlor 2002 shows insulin-stimulated PKB/S6K/RSK activation is NORMAL in hypomorphic mice (Figure 6), not improved. The paper’s conclusion is that PDK1 regulates cell size independently of its insulin-signaling role. Claim removed and replaced with the actual finding.
  2. Body size nuance (Lawlor 2002): PDK1fl/fl homozygous hypomorphs are ~30% smaller; the 40–50% figure applies to PDK1−/fl. Both lines now distinguished.
  3. Embryonic phenotype expanded (Lawlor 2002): Added lack of forebrain, branchial arches, heart; clarified embryos confirmed at E9.5 but absent E10+.
  4. Mouse strain footnote corrected (Lawlor 2002): Was “C57BL/6”; paper used chimeric ES → C57Black6 blastocysts → Balb/c crosses (mixed background).
  5. Aging-relevance paragraph corrected: Removed “preserved metabolic sensitivity” framing; clarified longevity inference is indirect and not tested in Lawlor 2002.
  6. PIF-pocket terminology clarified (Pullen 1998): Term “PIF-pocket” does not appear in Pullen 1998; named in Biondi 2001/Mora 2004. Noted in footnote.
  7. Mora 2004 gap added: no-fulltext-access in footnote and limitations for PIF-pocket detail, RSK contact-mode, substrate site completeness.
  8. DOI correction confirmed: Correct Alessi 1996 DOI is 10.1002/j.1460-2075.1996.tb01045.x (verified via PDF).

Claims confirmed correct:

  • UniProt O15530: 556 aa; kinase 82–342; PIF-pocket 113–157; PH 459–550 (all match UniProt REST API)
  • AKT Thr308 only (not Ser473) as PDK1 target (Alessi 1997 Fig. 5)

  • 30-fold AKT activation (Alessi 1997 Fig. 3a)

  • S6K1 Thr229 as PDK1 site (Pullen 1998)
  • PDK1 constitutively active, wortmannin-insensitive (Alessi 1997; Pullen 1998)
  • Embryonic lethality E9.5 (Lawlor 2002 Table I)

Pages unverifiable (closed-access):

Downstream pages that may need updates:

  • pathways/pi3k-akt-pathway.md — may describe PDK1 hypomorphs as “insulin sensitized”; check and correct
  • pathways/insulin-igf1.md — same risk
  • molecules/proteins/akt.md — may cross-reference Lawlor 2002; verify wording
  • molecules/proteins/s6k1.md — Pullen 1998 Thr229 attribution; verify consistency

[2026-05-04] verify | molecules/proteins/foxo3.md

Pages verified: 1 (partial — Castrillon 2003 remains closed-access; canonical DB identity fields not independently re-checked)

PDFs read: Brunet 1999 (10.1016/S0092-8674(00)80595-4), Willcox 2008 (10.1073/pnas.0801030105), Kops 2002 (10.1038/nature01036), Dijkers 2000 (10.1016/s0960-9822(00)00728-4), Mammucari 2007 (10.1016/j.cmet.2007.11.001; downloaded during this pass), Hosaka 2004 (10.1073/pnas.0400093101; downloaded during this pass)

Corrections applied:

  1. Willcox 2008 footnote n (CRITICAL): “n=3,584” → “n=615 total (213 cases, 402 controls)”; design corrected from “observational cohort” to “nested case-control”; OR and CI expanded to full form (GG vs TT: OR=2.75, 95% CI 1.51–5.02, P=0.0007; TG vs TT: OR=1.91, 95% CI 1.34–2.72, P=0.0003)
  2. Hosaka 2004 triple KO misattribution (CRITICAL): The wiki attributed “Foxo1/3/4 triple KO → hemangiomas and thymic lymphomas” to Hosaka 2004. Hosaka 2004 only covers three separate single knockouts (Foxo1-/-, Foxo3a-/-, Foxo4-/-). The triple-KO phenotype derives from Paik et al. 2007 (Cell) or Tothova et al. 2007 (Cell). The Foxo1/3/4 triple KO section was fully rewritten to accurately describe the Hosaka 2004 single-KO phenotypes, with an attribution note pointing to the correct triple-KO papers.
  3. Hosaka 2004 footnote: “conditional triple KO mouse” → “germline single KO mice (Foxo1, Foxo3a, Foxo4 separately)”; removed “not yet downloaded”
  4. Brunet 1999 footnote cell line: “Rat1 fibroblasts and primary neurons” → “CCL39 fibroblasts (Chinese hamster lung), 293T cells, cerebellar granule neurons, Jurkat T cells”; refined 14-3-3 binding site detail (T32+S253 required, S315 not required)
  5. Kops 2002 footnote model: “MEFs, DT40 cells, mouse” → “DL23, MEFs, 3T3-L6, 293T cells”; DT40 not in this paper; catalase claim qualified
  6. Kops 2002 catalase (body text): Added qualification that Kops 2002 directly demonstrates only MnSOD/SOD2 (by ChIP, luciferase, northern blot); catalase as direct target needs independent citation; needs-replication added
  7. MST1/Ser209 citation: Removed erroneous [^kops2002] citation; replaced with unsourced marker noting Lehtinen et al. 2006 as likely source
  8. Mammucari 2007 footnote: Removed “not yet downloaded”; updated target gene list to match paper’s actual primary findings (LC3, Bnip3, Bnip3l, Gabarapl1 as primary ChIP-confirmed targets; Beclin-1 and Atg12 as supplemental/secondary)
  9. Castrillon 2003 lymphadenopathy claim: Added no-fulltext-access flag; noted that Hosaka 2004 found no non-ovarian histological abnormalities across 30+ tissues in Foxo3a-null mice, which creates uncertainty about this claim

Claims confirmed correct from PDFs:

  • AKT phosphorylates FOXO3 (FKHRL1) at Thr32/Ser253/Ser315 — confirmed (Brunet 1999)
  • 14-3-3 binding via Thr32 and Ser253 (not Ser315) — confirmed (Brunet 1999 Fig. 4)
  • Kops 2002: FOXO3a-deficient cells accumulate ROS, hypersensitive to glucose deprivation; MnSOD/SOD2 direct transcriptional target — confirmed
  • Willcox 2008: rs2802292 GG genotype; OR=2.75 (95% CI 1.51–5.02), P=0.0007 — confirmed (matches pi3k-akt-pathway.md verified data exactly)
  • Dijkers 2000: FKHR-L1/FOXO3 transactivates BIM (BCL2L11); direct transcriptional regulation shown by cycloheximide experiment; Ba/F3 cells — confirmed
  • Mammucari 2007: constitutively active FoxO3 induces autophagy and atrophy in vivo; dn-FoxO3 blocks fasting-induced autophagy; LC3 direct target confirmed by ChIP and reporter — confirmed
  • Hosaka 2004: Foxo3a-/- females show premature ovarian failure (all oocytes degenerated by 12 weeks); Foxo4-/- grossly normal — confirmed

Pages unverifiable (closed-access):

  • Castrillon 2003 (10.1126/science.1086336) — not_oa; ovarian failure confirmed via Hosaka 2004; lymphadenopathy claim flagged no-fulltext-access

Downstream pages that may need updates:

  • pathways/pi3k-akt-pathway.md — the n=3,584 error may appear in body text; verified copy has n=615 per its own verified footnote, but body text “three somatic FOXO paralogs” triple-KO reference should be checked
  • Any page citing the Hosaka 2004 triple-KO phenotype (hemangiomas/lymphomas) — the correct citation is Paik 2007 or Tothova 2007; check index.md and interventions pages
  • studies/ pages for Brunet 1999, Kops 2002, Willcox 2008 if they exist — footnote corrections should propagate

Lin 2010 → Mammucari 2007 substitution assessment: CORRECT. Mammucari 2007 is the canonical in vivo paper demonstrating FoxO3-driven autophagy in skeletal muscle, is well-cited (1,868 citations per wiki), and directly demonstrates LC3/Bnip3/Gabarapl1 as direct FoxO3 targets by ChIP. Lin 2010 (likely a later paper) would be secondary to Mammucari 2007 for this specific claim. Substitution is appropriate.

[2026-05-04] verify | molecules/proteins/daf-16.md

Pages verified: 1 (partial — Kenyon 1993 and Hsu 2003 remain closed-access)

PDFs read: Lin 1997 (10.1126/science.278.5341.1319), Ogg 1997 (10.1038/40194), Tissenbaum 2001 (10.1038/35065638), Murphy 2003 (10.1038/nature01789), Apfeld 2004 (10.1101/gad.1255404), Kenyon 2010 (10.1038/nature08980)

Corrections applied:

  1. GFP::DAF-16 nuclear translocation misattribution (HIGH): wiki body text and original [^lin1997] footnote both claimed Lin 1997 demonstrated “GFP::DAF-16 nuclear translocation upon daf-2 RNAi.” Lin 1997 is exclusively a cloning paper (Tc1 transposon tagging) — it contains no GFP::DAF-16 reporter or translocation experiment. The nuclear translocation work is from Lin et al. 2001 (Nat Genet 28:139). Body text corrected; footnote updated to accurately describe Lin 1997’s actual content (cloning, 510/508 aa forms, HNF-3/forkhead identity, FKHR/AFX similarity).
  2. Isoform count context added: founding papers (Lin 1997: 2 spliced forms; Ogg 1997: 3 isoforms — daf-16a1, daf-16a2, daf-16b) do not support the “8 isoform” claim, which derives from subsequent WormBase curation reflected in UniProt. Identity section updated to clarify primary-source isoform count vs. current database annotation.
  3. Mouse lifespan “~16%” replaced with sourced range: Kenyon 2010 text gives “~15% to 40%” for mammalian IIS pathway mutants, not a specific 16% figure for Igf1r+/-. Corrected to the range with a gap tag noting the specific Holzenberger 2003 figure is not stated in the Kenyon 2010 review.
  4. [^ogg1997] footnote expanded with Ogg 1997’s specific findings: three isoforms named (daf-16a1, daf-16a2, daf-16b), daf-16a::GFP expression pattern (broad; not pharynx), forkhead domain identity percentages to FKHR/AFX.

Claims confirmed correct from PDFs:

  • aak-2 LoF 12% shorter lifespan; aak-2 OE 13% longer; daf-16;aak-2 double 15% shorter than either single (Apfeld 2004 — exact)
  • sir-2.1 OE extends lifespan up to 50%; DAF-16-dependent (daf-16(mgDf50);geIn3 = 13.7d vs geIn3 = 27.5d; Tissenbaum 2001 — exact)
  • Murphy 2003 Class I/II gene classification and exemplar genes (sod-3, mtl-1, hsp-12.6, lys-7) — all confirmed in Tables 1 and 2
  • Kenyon 2010 JNK-1 phosphorylation promoting DAF-16 nuclear import confirmed (Fig. 2 legend)
  • DAF-16 parallel to AMPK (aak-2) confirmed as parallel not upstream

Pages unverifiable (closed-access):

  • Kenyon 1993 (10.1038/366461a0) — not_oa; daf-2 LoF ~2x lifespan and daf-16 epistasis claims retained with no-fulltext-access
  • Hsu 2003 (10.1126/science.1083701) — not_oa; HSF-1 cooperation claims retained with no-fulltext-access

Downstream pages that may need updates:

  • model-organisms/caenorhabditis-elegans.md — may contain the GFP translocation attribution to Lin 1997; verify
  • molecules/proteins/foxo3.md — cites Kenyon 2010 for mammalian extrapolation; check if “~16%” figure appears there
  • pathways/insulin-igf1.md (if seeded) — may cite Lin 1997 for nuclear translocation claim; check
  • studies/ pages for Lin 1997 and Ogg 1997 if they exist — footnote corrections may need propagation

[2026-05-04] verify | molecules/proteins/insr.md

Pages verified: 1 (partial — Brüning 2000 NIRKO and Belfiore 2009 are not_oa; activation loop Tyr coordinates not resolved against Hubbard 1994; canonical DB identity fields not re-checked against live databases)

PDFs read and downloaded: Ullrich 1985 (10.1038/313756a0), Accili 1996 (10.1038/ng0196-106), Brüning 1998 MIRKO (10.1016/s1097-2765(00)80155-0; downloaded this pass from bronze OA), Blüher 2003 FIRKO (10.1126/science.1078223), Frasca 1999 (10.1128/MCB.19.5.3278; downloaded this pass from PMC), Nakae 2002 (10.1038/ng890)

Corrections applied:

  1. CRITICAL — Precursor length (Ullrich 1985): “1,382 amino acids” → “1,370 amino acids.” Ullrich 1985 explicitly states “1,370-amino-acid sequence of the human insulin receptor precursor.” The 1,382-aa figure is erroneous throughout (also corrected in mature β-subunit endpoint: “763–1382” → “763–1370”; transmembrane residue range corrected to “~918–940” per Ullrich 1985).
  2. CRITICAL — frontmatter key-ptms: Removed specific Tyr numbers (Tyr1158/1162/1185/1189/1190/1163) since (a) precursor length was wrong, making all residue numbers unreliable, and (b) Ullrich 1985 does not report activation loop Tyr positions by number. Replaced with generic descriptor; added needs-canonical-id flag pending Hubbard 1994 structural paper verification.
  3. CRITICAL — INSR-A IGF-2 affinity (Frasca 1999): “~5 nM” → “~3 nM (EC50 for autophosphorylation; ~2.5 nM for binding competition).” Frasca 1999 Table 1 reports EC50 = 3.0 ± 0.4 nM for IR-A autophosphorylation by IGF-II; Figure 1A shows binding EC50 ~2.5 nM.
  4. CRITICAL — Insulin Kd claims: Removed unsupported “~0.2 nM” Kd claim from isoform table (Frasca 1999 reports insulin EC50 of 0.8–0.9 nM for autophosphorylation, not 0.2 nM; the 0.2 nM figure was unattributed). Replaced with EC50 values from Frasca 1999 Table 1.
  5. CRITICAL — Accili 1996 death timing and heterozygote phenotype: “within days of birth” → “within 48–72 hours of birth” (paper states “die as a result of diabetic ketoacidosis in 48–72 hours”). Glucose and acetoacetate levels added (24–37 mmol/l; 8–16 mmol/l). Heterozygote phenotype corrected from “mild glucose intolerance with age” → “normal glucose tolerance on IPGTT” (paper explicitly shows normal IPGTT curves for IR+/- at Fig. 4a,b).
  6. CRITICAL — mTORC1-S6K1→IRS serine phosphorylation misattributed to Nakae 2002: Nakae 2002 is entirely about FOXO1 and does not address S6K1 or mTOR. Citation removed; replaced with unsourced marker identifying Um et al. 2004 (Science) or Harrington et al. 2004 (Nat Cell Biol) as correct primary sources for this mechanism.
  7. Nakae 2002 model description corrected: “IRS-2 KO or ob/ob backgrounds” removed — primary model is Insr+/- Foxo1+/- double heterozygotes, not IRS-2 KO. Added quantitative rescue data (glucose ~25% lower, p<0.005; G6pc/Pck1 mRNA reduced). Gain-of-function Foxo1S253A transgenic result described (Pdx1 suppression → β-cell failure).
  8. Exon 11 residue mapping (Frasca 1999): Qualified as “residues 718–729 of the α subunit C-terminus” per Frasca 1999 (was vague “C-terminus”).
  9. MIRKO quantification (Brüning 1998): Added precise effect sizes — triglycerides ~70% elevated (p<0.01), FFAs ~20% elevated (p<0.05), epididymal fat pad ~40% increase (p=0.02); added glucose tolerance follow-up duration “up to 11 months.”
  10. Blüher 2003 FIRKO lifespan: Confirmed accurate (mean +134 days/+18%; 753→887 days; both sexes; both independent founder lines). No corrections needed.
  11. Brüning 1998 footnote: Updated download status from “pending (bronze OA)” to “downloaded.”
  12. Frasca 1999 footnote: Updated download status from “pending (green OA via PMC)” to “downloaded.”

Claims confirmed correct:

  • Blüher 2003: mean lifespan 753→887 days (+134 days, +18%); median +3.5 months; max +5 months; both sexes pooled; two independent founder lines; normal food intake; 15–25% lower body weight; 50–70% lower fat mass (Fig. 1A, 2B)
  • Brüning 1998: MCK-Cre; >95% muscle IR reduction; normal glucose and insulin levels; confirmed euglycemic up to 11 months; MIRKO via Molecular Cell Vol. 2 (not Cell) — DOI confirmed correct
  • Frasca 1999: exon 11 = 36 nt, residues 718–729; INSR-A expressed in fetal tissues, hematopoietic cells; INSR-B in adult metabolic tissues; INSR-B IGF-2 affinity very low (>30 nM autophosphorylation EC50)
  • Accili 1996: null allele = Δ306 premature stop (exon 4); visually indistinguishable from WT/het at birth; no major structural organ abnormalities other than fatty liver; insulin levels paradoxically high (7.1 ng/ml in IR-/- vs 1.2 in IR+/-; p<0.001)
  • Ullrich 1985: single insulin receptor gene (Southern blot); 22-exon transcript; α subunit 719 aa (mature), β subunit 620 aa (mature); precursor Mr 155,000 (unglycosylated); transmembrane segment 918–940 (23 aa); kinase domain homologous to src/EGF-R family

Pages unverifiable (not_oa):

  • Brüning 2000 NIRKO (10.1126/science.289.5487.2122) — not_oa; NIRKO claims (diet-sensitive obesity, elevated TG, reproductive dysfunction) retained without verification; footnote marked not_oa
  • Belfiore 2009 (10.1210/er.2008-0047) — not_oa; hybrid receptor and insulin resistance claims from this review retained without primary verification

Downstream pages that may need updates:

  • pathways/insulin-igf1.md — likely repeats INSR precursor length (1,382 or 1,370?), INSR-A IGF-2 affinity (~5 nM?), and Accili 1996 death timing; verify
  • studies/bluher-2003-firko-fat-insulin-receptor-longevity.md — if seeded, check background descriptor and lifespan numbers (cross-checked as correct here but study page may have separate errors)
  • studies/accili-1996-insr-knockout-neonatal-lethal.md — if seeded, death timing and heterozygote phenotype need correction
  • studies/nakae-2002-foxo1-hepatic-gluconeogenesis.md — if seeded, check that model is described as Insr+/- Foxo1+/- not IRS-2 KO background
  • molecules/compounds/ pages for rapamycin, metformin — may cite Nakae 2002 for mTOR-IRS feedback; check attribution

[2026-05-04] verify | akt.md

Pages verified: 1

  • molecules/proteins/akt.md — corrections: 4

Corrections applied:

  1. Hertweck 2004 misattribution (HIGH): wiki claimed “akt-1/akt-2 reduction extends lifespan” — corrected to reflect paper’s actual finding that SGK-1 loss (not akt-1/akt-2) is the critical longevity factor; akt-1 and akt-2 single KOs show no significant lifespan extension (p=0.1642 and p=0.3717 respectively); quantitative lifespan data added (sgk-1: 14.7→24.0d, ~63% extension, n=147, p<0.0001)
  2. FOXO3a S315 overstatement (Brunet 1999): wiki claimed all three sites (T32/S253/S315) “create 14-3-3 binding motifs” — corrected; Brunet 1999 explicitly shows S315 is not directly phosphorylated by Akt in vitro and does not drive 14-3-3 binding (only pT32 and pS253 do)
  3. FoxO body text: third bullet corrected to remove incorrect claim that “akt-1/akt-2 reduction” extends C. elegans lifespan; redirected to SGK-1 and broader IIS reduction
  4. Footnotes: Hertweck 2004 footnote updated with quantitative data and archive: downloaded status; Brunet 1999 footnote expanded with S315 caveat, cell models, and journal/page info

Pages unverifiable (closed-access): Coffer 1991, Bellacosa 1991, Alessi 1996, Sarbassov 2005 (Sarbassov 2005 cross-confirmed via verified rictor.md)

Downstream pages that may need updates:

  • molecules/proteins/foxo3.md — cites Brunet 1999 and may state S315 as a 14-3-3-binding site; check
  • molecules/proteins/foxo1.md — may inherit same S315 claim; check
  • pathways/pi3k-akt-pathway.md — may cite Hertweck 2004 in the IIS/lifespan context; check wording
  • model-organisms/caenorhabditis-elegans.md (if seeded) — may cite akt-1/akt-2 as longevity genes

[2026-05-04] verify | molecules/proteins/pi3k.md

Pages verified: 1 (partial — Bilanges 2019 not_oa; Samuels 2004 not_oa; canonical UniProt accessions for non-alpha isoforms not independently re-verified against UniProt database)

PDFs read: Engelman 2006 (10.1038/nrg1879), Vanhaesebroeck 2010 (10.1038/nrm2882), Manning & Toker 2017 (10.1016/j.cell.2017.04.001), Friedman & Johnson 1988 (10.1093/genetics/118.1.75 — downloaded during this pass), André 2019 SOLAR-1 (10.1056/NEJMoa1813904 — downloaded during this pass)

Corrections applied:

  1. Pik3ca+/- lifespan misattribution (CRITICAL): wiki attributed “~18% lifespan extension in female mice” to [^engelman2006]. Engelman 2006 does NOT report this result — germline p110α/β deletion is embryonic lethal; kinase-dead heterozygous knockin shows glucose intolerance, not lifespan extension. Claim rewritten with unsourced; footnote updated to accurately describe Engelman 2006’s actual mouse genetics content.
  2. age-1 lifespan quantification corrected: wiki footnote said “extend mean lifespan ~65%” — this is the 25°C result only. Primary 20°C result is ~40% mean and ~60% maximum lifespan extension (Table 1). Both temperatures now in footnote. Body text expanded to note fer-15 co-segregation confound flagged by original authors.
  3. André 2019 footnote verified: n=572 (341 PIK3CA-mutant: 169 + 172) confirmed exact; PFS 11.0 vs 5.7 months confirmed; HR 0.65 (95% CI 0.50–0.85), P<0.001 confirmed; grade 3/4 hyperglycemia 36.6% vs 0.7% confirmed (Table 3). Status changed to verified.
  4. Body text hyperglycemia “~37%” → “36.6%” (SOLAR-1 primary source); citation moved from [^vasan2022] to [
  5. BAD Ser136 site: removed unattributed Ser136 designation; replaced with note that Ser136 requires separate primary citation.
  6. Footnotes expanded: Engelman 2006, Vanhaesebroeck 2010, Manning 2017, André 2019 all updated with precise content scope and journal pagination.
  7. Gaps section: added age-1 fer-15 confound note; added Pik3ca+/- source identification need.

Claims confirmed correct:

  • Class I/II/III taxonomy (substrates, products, subcellular roles) — confirmed (Engelman 2006, Vanhaesebroeck 2010)
  • RTK activation via pYxxM → p85 SH2 → p110 disinhibition → PIP2→PIP3 — confirmed (Engelman 2006)
  • VPS34 complexes PI3KC3-C1 (ATG14L/barkor) and PI3KC3-C2 (UVRAG) — confirmed (Vanhaesebroeck 2010 Fig. 4b)
  • AKT Thr308/PDK1 and Ser473/mTORC2 dual phosphorylation — confirmed (Manning 2017)
  • SOLAR-1 primary endpoint and safety data — confirmed (André 2019)
  • age-1 = C. elegans PI3K ortholog (AGE-1/p110) — confirmed (Engelman 2006 Table 1)

Pages unverifiable (closed-access):

  • Bilanges 2019 (not_oa) — VPS34/mTORC1 mechanism claims unverified
  • Samuels 2004 (not_oa) — PIK3CA hotspot mutation frequency claims unverified

Newly downloaded: Friedman & Johnson 1988 (PMC1203268); André 2019 (Univ. Padua repository)

Downstream pages that may need updates:

  • pathways/pi3k-akt-pathway.md — may contain Pik3ca+/- lifespan claim attributed to Engelman 2006; check and remove incorrect attribution
  • interventions/pharmacological/senolytics.md — hyperglycemia figure “~37%” should be 36.6% per SOLAR-1 primary source
  • Any page citing age-1 as straightforward longevity gene should note fer-15 confound

[2026-05-04] ingest | round-7c-irs-foxo

foxo1

  • added: molecules/proteins/foxo1.md
  • entity type: protein (FOXO1; Forkhead Box Protein O1; formerly FKHR — Forkhead In Rhabdomyosarcoma)
  • canonical IDs confirmed: UniProt Q12778 (reviewed Swiss-Prot, FOXO1_HUMAN), NCBI Gene 2308, HGNC 3819
  • archive status:
    • Galili 1993 (doi:10.1038/ng1193-230) — downloaded, local PDF available
    • Brunet 1999 (doi:10.1016/s0092-8674(00)80595-4) — downloaded, local PDF available
    • Nakae 2002 (doi:10.1038/ng890) — downloaded, local PDF available
    • Nakae 1999 JBC (doi:10.1074/jbc.274.23.15982) — pending (hybrid OA)
    • Matsumoto 2007 (doi:10.1016/j.cmet.2007.08.006) — pending (bronze OA; corrected DOI from supplied 10.1016/j.cmet.2007.05.013)
    • Foxo1 KO embryonic lethal paper — DOI unresolved during seeding; needs-canonical-id on page
  • DOI note: supplied Matsumoto 2007 DOI (10.1016/j.cmet.2007.05.013) not found in archive → correct DOI confirmed via PubMed PMID 17767907 as 10.1016/j.cmet.2007.08.006 (“Impaired Regulation of Hepatic Glucose Production in Mice Lacking the Forkhead Transcription Factor Foxo1 in Liver,” Cell Metabolism, 605 citations)
  • gaps surfaced: needs-human-replication (hepatic gluconeogenesis mechanism; muscle atrophy via FOXO1 specifically), needs-replication (SIRT1-FOXO1 deacetylation flux in vivo), long-term-unknown (FOXO1 inhibitor safety in aging), unsourced (precise forkhead domain residue boundaries), needs-canonical-id (Foxo1 KO embryonic lethal paper DOI unresolved)
  • implicit stubs created (new wikilinks to non-existent pages): 14-3-3, pp2a, gluconeogenesis, muscle-atrophy-pathway, pax3
  • previously listed stubs now linked: foxo3 (existing), akt (R7a), sirt1 (existing or stub), insr (R7b)
  • schema gaps: none — standard protein frontmatter; CLAUDE.md protein schema covers all fields used

foxo3

  • added: molecules/proteins/foxo3.md
  • entity type: protein (FOXO3; Forkhead Box Protein O3; formerly FOXO3A / FKHRL1)
  • canonical IDs confirmed: UniProt O43524 (reviewed Swiss-Prot, FOXO3_HUMAN), NCBI Gene 2309, HGNC 3821, GenAge human entry 123
  • DOI corrections made at seeding:
    • Supplied DOI 10.1006/geno.1998.5402 (“Anderson 1998 FOXO3 cloning”) resolves to a KSP-cadherin cloning paper (41 citations) — wrong DOI; no correct FOXO3-cloning DOI identified; omitted from page
    • Supplied DOI 10.1073/pnas.0307303101 (“Hosaka 2004 FOXO triple KO”) resolves to a bacterial/viral invasion paper (20 citations) — wrong; correct DOI found via Crossref as 10.1073/pnas.0400093101 (“Disruption of forkhead transcription factor (FOXO) family members in mice reveals their functional diversification,” 674 citations, PNAS 2004)
    • Supplied DOI 10.1126/science.1188619 (“Lin 2010 FOXO autophagy Science”) not found in archive; replaced with Mammucari 2007 (10.1016/j.cmet.2007.11.001, 1,868 citations) which is the primary FOXO3-autophagy in-vivo paper
  • archive status:
    • Brunet 1999 (doi:10.1016/S0092-8674(00)80595-4) — downloaded, local PDF available
    • Willcox 2008 (doi:10.1073/pnas.0801030105) — downloaded, local PDF available (also on pi3k-akt-pathway page)
    • Kops 2002 (doi:10.1038/nature01036) — downloaded, local PDF available
    • Dijkers 2000 (doi:10.1016/s0960-9822(00)00728-4) — downloaded, local PDF available (also on bim page)
    • Hosaka 2004 (doi:10.1073/pnas.0400093101) — pending (green OA)
    • Castrillon 2003 (doi:10.1126/science.1086336) — not_oa; no-fulltext-access
    • Mammucari 2007 (doi:10.1016/j.cmet.2007.11.001) — pending (bronze OA)
  • gaps surfaced: no-mechanism (rs2802292 G allele functional effect), needs-human-replication (lifespan extension via FOXO3 activation), dose-response-unclear (beneficial vs. atrogene-driving FOXO3 activation threshold), contradictory-evidence (FOXO3 vs FOXO4 roles in senescent cells), unsourced (tissue-specific FOXO3 expression changes with human aging), long-term-unknown (no randomized trial of FOXO3-targeted intervention), no-fulltext-access (Castrillon 2003 Science)
  • implicit stubs created (new wikilinks to non-existent pages): 14-3-3 (if not already from foxo1), mst1, caenorhabditis-elegans (may exist), daf-16, daf-2, sirtuin (pathway page)
  • previously listed stubs now linked: akt (R7a), bim (R5a), beclin-1 (R6a), bnip3 (R6c), caloric-restriction (existing), insulin-igf1 (existing), pi3k-akt-pathway (existing), ampk (existing), sirt1 (existing or stub)
  • ROADMAP.md updated: foxo3 marked ✓ seeded R7c 2026-05-04 in Tier A table (was 13 inbound — highest in queue)

irs-1

  • added: molecules/proteins/irs-1.md
  • entity type: protein (IRS-1; IRS1; Insulin Receptor Substrate 1)
  • canonical IDs confirmed: UniProt P35568 (IRS1_HUMAN, reviewed Swiss-Prot), NCBI Gene 3667, HGNC 6125
  • GenAge entry ID: not confirmed at seeding (#gap/needs-canonical-id — IRS1 aging-relevant but GenAge models ID not found via API)
  • archive status:
    • Sun 1991 (doi:10.1038/352073a0) — not_oa (1,572 citations, 100th percentile FWCI)
    • Tamemoto 1994 (doi:10.1038/372182a0) — not_oa (1,084 citations)
    • Withers 1998 IRS-2 KO (doi:10.1038/36116) — not_oa (1,770 citations)
    • Um 2004 S6K1/IRS-1 (doi:10.1038/nature02866) — downloaded, local PDF available (870 KB)
    • Selman 2008 FASEB J (doi:10.1096/fj.07-9261com) — not_oa (#gap/no-fulltext-access; exact lifespan quantitative values unverifiable)
    • Boucher 2014 CSH Perspect (doi:10.1101/cshperspect.a009191) — pending (bronze OA)
  • DOI corrections made at seeding:
    • Supplied Withers 1998 DOI 10.1038/35624 resolves to “Three neural tubes in mouse embryos with mutations in the T-box gene Tbx6” (412 citations, wrong paper) — correct IRS-2 KO DOI is 10.1038/36116 (“Disruption of IRS-2 causes type 2 diabetes in mice”) confirmed via PubMed PMID 9495343 + DOI lookup. BUG-2 risk flagged in page.
    • Supplied “Selman 2008 Science” DOI 10.1126/science.1163725 not found in archive — correct paper is Selman 2008 FASEB J doi:10.1096/fj.07-9261com (confirmed via PubMed efetch PMID 22371226 + DOI lookup). Note: distinct paper from Selman 2009 Science (S6K1 KO; doi:10.1126/science.1177221) — do not conflate.
  • gaps surfaced: no-fulltext-access (Selman 2008 lifespan values unverifiable), needs-human-replication (all lifespan data from mice), needs-replication (sex-specificity of Irs1-/- longevity), contradictory-evidence (Ser-1101 site attribution uncertain; Rajan 2013 disputes Ser-307 as S6K1 target in human adipocytes), needs-canonical-id (GenAge ID), unsourced (IRS-1 vs SHC1 MAPK partitioning; CR → IRS-1 protein levels in aged tissue)
  • implicit stubs created (new wikilinks to non-existent pages): mapk-pathway, inflammaging, irs2, glut4 (may exist from akt.md)
  • previously listed stubs now linked: s6k1 (existing), akt (R7a), insr (R7b), igf1r (R7b), pi3k (R7a parallel), grb2 (from igf1r.md), foxo3 (seeded this batch)
  • schema gaps: none — standard protein frontmatter per CLAUDE.md; genage-id: null for absent entry
  • ROADMAP.md updated: irs-1 added under new Round 7c heading (seeded R7c 2026-05-04)

[2026-05-04] ingest | round-7b-iis-receptors-ligands

igf1r

  • added: molecules/proteins/igf1r.md
  • entity type: protein (IGF1R; Insulin-like Growth Factor 1 Receptor; CD221)
  • canonical IDs confirmed: UniProt P08069, NCBI Gene 3480, HGNC 5465, GenAge HAGRID 15
  • DOI corrections made at seeding:
    • Ullrich 1986: supplied DOI 10.1002/j.1460-2075.1986.tb04488.x resolves to an X-chromosome factor IX methylation paper (42 citations) — corrected to 10.1002/j.1460-2075.1986.tb04528.x (“Insulin-like growth factor I receptor primary structure,” 1,856 citations, EMBO J) confirmed via PubMed PMID 2877871 + DOI lookup.
    • Liu 1993: supplied DOI 10.1016/0092-8674(93)90680-O resolves to a separate Cell 1993 paper (“Role of insulin-like growth factors in embryonic and postnatal growth,” 647 citations) — correct DOI for the IGF1R/IGF1 null lethal mouse paper is 10.1016/s0092-8674(05)80084-4 (“Mice carrying null mutations of Igf-1 and Igf1r,” 2,866 citations) confirmed via Crossref + DOI lookup.
  • archive status: Holzenberger 2003 (downloaded — local PDF), Willcox 2008 (downloaded — local PDF), Suh 2008 (downloaded — local PDF), Ullrich 1986 (pending — bronze OA), Liu 1993 (not_oa no-fulltext-access)
  • gaps surfaced: needs-human-replication (all lifespan data from mice), needs-replication (Suh 2008 n=79; Holzenberger C57BL/6 congenic attenuation), no-mechanism (sex dimorphism in Igf1r+/- mice), dose-response-unclear (pharmacological IGF1R partial reduction for longevity), contradictory-evidence (elevated IGF-1 in centenarian variant carriers per Suh 2008 — paradoxical), no-fulltext-access (Liu 1993 Cell)
  • implicit stubs created (new wikilinks to non-existent pages): irs1, irs2, grb2, shc1, igf-1, insr, foxo3, growth-hormone-receptor
  • ROADMAP.md updated: igf1r added under new Round 7b heading (Receptors); also marked seeded on the Round 7 Receptors line

[2026-05-04] ingest | round-7a-pi3k-akt-kinases

akt

  • added: molecules/proteins/akt.md
  • entity type: protein (AKT1 / PKBα)
  • canonical IDs confirmed: UniProt P31749, NCBI Gene 207, HGNC 391
  • DOI corrections made at seeding:
    • Coffer & Woodgett 1991: supplied DOI 10.1111/j.1432-1033.1991.tb16275.x was wrong (lipoyl domain NMR paper) → corrected to 10.1111/j.1432-1033.1991.tb16305.x (molecular cloning novel serine kinase) via Crossref
    • Bellacosa 1991: supplied DOI 10.1126/science.1956407 not found in archive → resolved to 10.1126/science.254.5029.274 (retroviral akt oncogene) via PubMed PMID 1833819
    • Hertweck 2004: supplied DOI 10.1016/j.devcel.2004.04.001 was wrong (maternal control paper) → corrected to 10.1016/s1534-5807(04)00095-4 (SGK-1/AKT lifespan) via PubMed PMID 15068796
    • Alessi 1996: DOI 10.1093/emboj/15.23.6541 returns 404 from Crossref (pre-DOI-era EMBO); cited by PMID:8978681 (confirmed: “Mechanism of activation of protein kinase B by insulin and IGF-1”, EMBO J 15:6541)
  • archive status: Datta 1997 (downloaded), Brunet 1999 (downloaded), Sarbassov 2005 (not_oa), Bellacosa 1991 (not_oa), Coffer 1991 (not_oa), Hertweck 2004 (pending)
  • gaps surfaced: needs-human-replication (AKT reduction / lifespan in worms, no human equivalent), dose-response-unclear (mammalian AKT suppression vs aging benefit), unsourced (eNOS Ser1177, GSK3β Ser9 phospho claims, AKT1 E17K cancer prevalence)
  • implicit stubs created (new wikilinks to non-existent pages): foxo, glut4
  • ROADMAP.md updated: akt added to Proteins section (Tier A queue, Round 7a)

pdk1

  • added: molecules/proteins/pdk1.md
  • entity type: protein (PDPK1; 3-phosphoinositide-dependent protein kinase 1)
  • canonical IDs confirmed: UniProt O15530, NCBI Gene 5170, HGNC 8816
  • DOI corrections made at seeding:
    • Supplied Alessi 1996 DOI 10.1093/emboj/15.23.6541 returns 404 on Crossref (confirmed bad; same DOI noted as bad in akt log entry above) → corrected to 10.1002/j.1460-2075.1996.tb01045.x (Mechanism of activation of protein kinase B by insulin and IGF-1, EMBO J, 3017 citations) via Crossref
    • Supplied Lawlor 2002 DOI 10.1093/emboj/cdf421 not in archive → corrected to 10.1093/emboj/cdf387 (Essential role of PDK1 in regulating cell size and development in mice, 323 citations) via Crossref
    • Supplied Mora 2004 DOI 10.1016/j.semcdb.2004.02.002 resolves to wrong paper (beta-cell/stem-cell paper) → corrected to 10.1016/j.semcdb.2003.12.022 (PDK1, the master regulator of AGC kinase signal transduction, 820 citations) via PubMed PMID 15209375
  • archive status: Alessi 1997 (pending), Alessi 1996 (pending; green OA via PMC452479), Pullen 1998 (downloaded — local PDF available), Lawlor 2002 (pending; green OA), Mora 2004 (not_oa; not downloadable)
  • gaps surfaced: needs-human-replication (hypomorphic mouse phenotype, no human equivalent), needs-replication (RSK activation-loop mechanism), long-term-unknown (PDK1 inhibitors in aging), unsourced (S6K1 deletion lifespan extension claim deferred to s6k1 page)
  • implicit stubs created (new wikilinks to non-existent pages): foxo-transcription-factors (may already exist; check), rsk (RSK1/2 — no page yet), sgk1 (Tier B in ROADMAP Round 7), pkc or pkcz (PKC isoforms), pkn
  • schema note: disambiguation note for PDK1 vs PDHK1 added in aliases and body; no CLAUDE.md schema gap — protein naming convention already covers this case
  • ROADMAP.md updated: pdk1 marked as seeded R7a 2026-05-04 in Tier B list and Round 7 kinases line

pten

  • added: molecules/proteins/pten.md
  • entity type: protein (Phosphatase and Tensin Homolog; MMAC1/TEP1)
  • canonical IDs confirmed: UniProt P60484, NCBI Gene 5728, HGNC 9588, GenAge HAGRID 63
  • DOI corrections made at seeding:
    • Di Cristofano 1998 supplied DOI 10.1038/2516 not found in archive → correct DOI is 10.1038/1235 (“Pten is essential for embryonic development and tumour suppression”, 1,508 citations) confirmed via Crossref and DOI lookup
    • Garcia-Cao 2012 supplied DOI 10.1016/j.cell.2012.06.030 resolves to wrong paper (sperm recombination paper) in archive → correct DOI is 10.1016/j.cell.2012.02.030 (“Systemic Elevation of PTEN Induces a Tumor-Suppressive Metabolic State”, 398 citations) confirmed via PubMed PMID 22401813 + DOI lookup
  • archive status: Steck 1997 (downloaded — local PDF), Stambolic 1998 (downloaded — local PDF), Li 1997 (not_oa), Di Cristofano 1998 (not_oa), Maehama&Dixon 1998 (pending — hybrid OA), Ortega-Molina 2012 (pending — bronze OA), Garcia-Cao 2012 (pending — bronze OA)
  • gaps surfaced: needs-human-replication (Pten GOF longevity mouse→human), needs-replication (Pten+/− lifespan paradox claim — no well-powered standardized study identified), unsourced (protein phosphatase substrates, NEDD4-1 ubiquitination mechanism, Cys71-Cys124 disulfide model, nuclear PTEN DNA-repair function, cancer frequency statistics)
  • implicit stubs created (new wikilinks to non-existent pages): pi3k (R7a parallel), akt (R7a parallel — page exists), foxo (if not yet seeded — referenced in pathway context)
  • schema gaps: none — standard protein frontmatter; genage-id field used per CLAUDE.md schema
  • ROADMAP.md updated: pten added under Round 7a Proteins entry

[2026-05-04] ingest | round-7a-pi3k-akt-kinases

pi3k

  • added: molecules/proteins/pi3k.md
  • type: protein (family/category page)
  • scope: PI3K catalytic subunit family — Class I (p110α/β/γ/δ), Class II (PI3K-C2α/β/γ), Class III (VPS34); primary anchor on PI3Kα/PIK3CA (UniProt P42336, NCBI Gene 5290, HGNC 8975)
  • canonical IDs pulled: UniProt P42336 (confirmed Swiss-Prot reviewed, 1068 aa); isoform UniProt IDs for all 8 catalytic subunits listed in body table (not independently re-verified against UniProt — flagged needs-canonical-id)
  • sources checked: Engelman 2006 (nrg1879) locally downloaded; Vanhaesebroeck 2010 (nrm2882) locally downloaded; Manning & Toker 2017 (cell.2017.04.001) locally downloaded; Samuels 2004 (science.1096502) not_oa; André 2019 alpelisib SOLAR-1 (nejmoa1813904) download pending; Bilanges 2019 (s41580-019-0129-z) not_oa; Friedman & Johnson 1988 (genetics 118:75) archive not found (DOI 10.1093/genetics/118.1.75); Vasan & Cantley 2022 (s41571-022-00633-1) download failed (partially verified on pi3k-akt-pathway.md)
  • key DOIs cited in footnotes: 10.1038/nrg1879, 10.1038/nrm2882, 10.1038/s41580-019-0129-z, 10.1016/j.cell.2017.04.001, 10.1126/science.1096502, 10.1056/nejmoa1813904, 10.1093/genetics/118.1.75, 10.1038/s41571-022-00633-1
  • implicit stubs created: alpelisib (compound page, FDA-approved PI3Kα inhibitor), kras (protein), irs-1 (protein; already Tier D in ROADMAP), foxo3 (Tier A; already in ROADMAP), pten (Tier C; already in ROADMAP), vps34 (referenced as Class III VPS34 = PIK3C3; separate from beclin-1 interactors already noted)
  • gaps surfaced: needs-human-replication (lifespan extension via PI3K reduction is model-organism only); needs-replication (Pik3ca+/- mouse lifespan not ITP-validated); dose-response-unclear (optimal PI3K attenuation for geroprotection unknown); needs-canonical-id (Class II/III isoform UniProt IDs unverified; GenAge entry IDs not found); long-term-unknown (Class II PI3K aging roles unstudied); no-mechanism (net effect of pan-PI3K inhibition — opposing Class I vs Class III effects — in aging)
  • ROADMAP updated: pi3k marked ✓ seeded R7a 2026-05-04 in Round 7 Kinases line

[2026-05-04] ingest | round-7b-iis-receptors-ligands

igf-1

  • added: molecules/proteins/igf-1.md
  • type: protein
  • scope: IGF-1 peptide hormone — precursor structure, GH–IGF-1 axis, IGFBP carrier system, receptor binding (IGF1R Kd ~0.1–1 nM primary; INSR-A secondary), postnatal growth KO genetics, aging/longevity evidence (GHR-/- mice, IGF1R+/- Holzenberger 2003, Laron syndrome human cohort), the centenarian paradox (Suh 2008: elevated IGF-1 as compensatory response to partial IGF1R LOF), pharmacology (mecasermin)
  • canonical IDs pulled: UniProt P05019 (confirmed Swiss-Prot reviewed, 195 aa precursor, mature 49–118); NCBI Gene 3479; HGNC 5464; GenAge ID 28 (confirmed via GenAge web API)
  • sources checked:
    • Rinderknecht & Humbel 1978 (10.1016/s0021-9258(17)40889-1) — confirmed in archive (pending download; 1,542 citations; citation_percentile 100)
    • Liu et al. 1993 Cell (10.1016/s0092-8674(05)80085-6) — confirmed in archive (not_oa; 2,377 citations; citation_percentile 100); separate DOI variant 10.1016/0092-8674(93)90680-o also confirmed same paper
    • Holzenberger 2003 (10.1038/nature01298) — local PDF available
    • Suh 2008 (10.1073/pnas.0705467105) — local PDF available; previously verified on insulin-igf1.md
    • Guevara-Aguirre 2011 (10.1126/scitranslmed.3001845) — confirmed in archive (pending download; 731 citations; green OA via PMC3357623; citation_percentile 100)
  • key DOIs cited in footnotes: 10.1016/s0021-9258(17)40889-1, 10.1016/s0092-8674(05)80085-6, 10.1038/nature01298, 10.1073/pnas.0705467105, 10.1126/scitranslmed.3001845
  • implicit stubs created: igf1r (R7b parallel seed; primary receptor), insr (insulin receptor; Round 7 target), igfbp3 (IGFBP-3 carrier protein), als (acid-labile subunit; ternary complex partner), growth-hormone (upstream regulator), irs1 / irs2 (IIS adapters), foxo3 (Tier A — already in ROADMAP queue)
  • gaps surfaced: needs-human-replication (all longevity data model-organism or correlational); contradictory-evidence (circulating IGF-1 vs tissue IIS signalling direction; frailty confounding); needs-replication (Guevara-Aguirre 2011 Laron single cohort; cardiac IGF-1 OE lifespan); dose-response-unclear (optimal IGF-1 reduction for healthspan); unsourced (reference range 100–300 ng/mL; extrahepatic IGF-1 tissue fraction); long-term-unknown (safety of pharmacological IGF-1 reduction in humans)
  • schema note: known-interactors frontmatter field used (present in p53.md prototype but not listed in CLAUDE.md protein schema — consistent with existing usage, not a new convention)
  • ROADMAP updated: igf-1 marked ✓ drafted R7b 2026-05-04 in Round 7 Receptors line

insulin

  • added: molecules/proteins/insulin.md
  • type: protein
  • scope: INS gene product — preproinsulin (110 aa) processing cascade (signal peptide → proinsulin 86 aa → C-peptide removal → mature insulin 51 aa A+B chains); 3 disulfide bonds (A7-B7, A20-B19, A6-A11 intrachain); β-cell glucose-stimulated secretion (KATP channel → Ca²⁺ → exocytosis); INSR-B binding Kd ~0.2 nM; IRS-1/2 → PI3K → AKT downstream; aging context (FIRKO mice ~18% lifespan, Bluher 2003; brain IRS-2 KO ~18%, Taguchi 2007; chronic hyperinsulinemia as pro-aging; centenarian IGF-1 paradox from Suh 2008); pharmacology (Banting & Best 1922 isolation; Sanger 1955 sequence; Steiner 1967 proinsulin; Goeddel 1979 recombinant; analogue design principles); IIS-aging paradox framed
  • canonical IDs pulled: UniProt P01308 (confirmed Swiss-Prot reviewed, 110 aa precursor, 51 aa mature); NCBI Gene 3630; HGNC 6081; GenAge ID: null (INS not in GenAge — classified as ligand, not longevity gene)
  • DOI corrections / notes at seeding:
    • Taguchi 2007 supplied DOI 10.1016/j.cell.2007.01.001 resolves to wrong paper (SnapShot: Molecular Chaperones) → corrected to 10.1126/science.1142179 (Brain IRS2 Signaling Coordinates Life Span and Nutrient Homeostasis, Science 317:369) confirmed via PubMed PMID 17641201
    • PMID 14367796 cited in brief as “Sanger 1955” resolves to wrong paper (Fontana 1767 history of medicine article) — not used; Sanger 1955 cited via DOI 10.1042/bj0600541 (disulfide bonds of insulin, Biochem J 60:541, confirmed in archive)
    • Banting & Best 1922 cited via AJP legacy DOI 10.1152/ajplegacy.1922.62.1.162 (confirmed in archive, not_oa)
  • archive status:
    • 10.1126/science.157.3789.697 (Steiner 1967) — not_oa
    • 10.1073/pnas.76.1.106 (Goeddel 1979) — pending (green OA PMC:382885)
    • 10.1042/bj0600541 (Sanger 1955 disulfide bonds) — pending (bronze OA)
    • 10.1038/nature01298 (Holzenberger 2003) — downloaded (local PDF)
    • 10.1073/pnas.0705467105 (Suh 2008) — downloaded (local PDF)
    • 10.1126/science.1142179 (Taguchi 2007) — not_oa
    • 10.1126/science.1078223 (Bluher 2003 FIRKO) — downloaded (local PDF)
    • 10.1038/nature08980 (Kenyon 2010 review) — downloaded (local PDF; not cited as footnote this page but cross-referenced via insulin-igf1 page)
    • 10.1152/ajplegacy.1922.62.1.162 (Banting & Best 1922) — not_oa
    • 10.1038/366461a0 (Kenyon 1993) — not_oa
  • key DOIs cited in footnotes: 10.1126/science.157.3789.697, 10.1042/bj0600541, 10.1073/pnas.76.1.106, 10.1152/ajplegacy.1922.62.1.162, 10.1038/nature01298, 10.1126/science.1078223, 10.1126/science.1142179, 10.1073/pnas.0705467105, 10.1038/366461a0
  • implicit stubs created: insr (R7b parallel seed; primary receptor — listed as already drafted in ROADMAP), igf1r (cross-ref; R7b), irs1 / irs2 (adapters), foxo-transcription-factors (FOXO longevity arm), glut4 (glucose transport effector), pcsk1 / pcsk2 (proinsulin cleavage enzymes), glp1r (incretins), type-2-diabetes (R8 planned), alzheimers-disease (planned R8), nf-kb (already seeded), sasp (already seeded)
  • gaps surfaced: needs-human-replication (FIRKO mouse lifespan → human); no-mechanism (hyperinsulinemia → senescence direct link); contradictory-evidence (centenarian IGF-1 paradox — elevated not reduced; brain-IRS2 KO overweight but long-lived); unsourced (Ensembl ID not cross-verified); GenAge null for INS noted in frontmatter
  • schema gaps: none — standard protein frontmatter; key-ptms field used for disulfide bonds (unusual for a non-phospho PTM but precedented by disulfide-dependent function)
  • ROADMAP updated: insulin marked ✓ drafted R7b 2026-05-04 in Round 7 Receptors line

insr

  • added: molecules/proteins/insr.md
  • entity type: protein (Insulin Receptor; IR; CD220)
  • scope: 1382 aa α₂β₂ heterotetramer; two splice isoforms (INSR-A/INSR-B exon 11); domain organization (L1/CR/L2 + FN-III-1/2/3 + TM 957–979 + kinase 1023–1298); activation loop autophosphorylation (Tyr1158/1162 per UniProt; Tyr1163 discrepancy flagged); IRS-1/2 pYxxM scaffolding → PI3K; INSR/IGF1R hybrid receptors; tissue-specific KO series (Accili 1996 whole-body lethal; Brüning 1998 MIRKO metabolic syndrome; Brüning 2000 NIRKO obesity/reproduction; Blüher 2003 FIRKO +18% lifespan); FOXO1 hepatic gluconeogenesis axis (Nakae 2002); insulin resistance in aging; Donohue/Rabson-Mendenhall/Type-A syndromes; pharmacology (insulin therapy, metformin indirect); Laron syndrome distinguished
  • canonical IDs pulled: UniProt P06213 (confirmed Swiss-Prot reviewed, 1382 aa; kinase 1023–1298; TM 957–979; α 28–758; β 763–1382; activation loop Tyr1158/Tyr1162); NCBI Gene 3643; HGNC 6091
  • DOI corrections at seeding:
    • Ebina 1985 Cell: task-supplied 10.1016/s0092-8674(85)80035-2 not in archive → corrected DOI 10.1016/0092-8674(85)90334-4 (1,483 cit) via Crossref; omitted from draft footnotes (not_oa; Ullrich 1985 Nature used instead — downloaded). Verifier should confirm Ebina vs Ullrich attribution.
    • Bruning 1998 MIRKO: task-supplied 10.1126/science.282.5394.2102 not found → corrected to 10.1016/s1097-2765(00)80155-0 (Mol Cell; 1,188 cit; bronze OA) via PubMed PMID 9844629
    • Bluher 2003 FIRKO: task-supplied 10.1172/JCI200317444 not found → corrected to 10.1126/science.1078223 (Science; 1,334 cit) via PubMed PMID 12543978
  • archive status: Ullrich 1985 (downloaded), Accili 1996 (downloaded), Blüher 2003 (downloaded), Nakae 2002 (downloaded); Brüning 1998 (pending bronze OA), Brüning 2000 (not_oa), Frasca 1999 (pending green OA PMC84122), Belfiore 2009 (not_oa)
  • key DOIs in footnotes: 10.1038/313756a0, 10.1038/ng0196-106, 10.1016/s1097-2765(00)80155-0, 10.1126/science.289.5487.2122, 10.1126/science.1078223, 10.1128/MCB.19.5.3278, 10.1038/ng890, 10.1210/er.2008-0047
  • gaps surfaced: needs-canonical-id (Tyr1158/1162/1163 activation loop numbering discrepancy vs structural literature), contradictory-evidence (INSR expression in aged tissue — mixed), unsourced (muscle INSR deletion + aging phenotype; INSR-A:B ratio in aging; TZD INSR upregulation), needs-replication (INSR-A cancer re-expression; S6K1→IRS-1 serine quantitation), needs-human-replication (FIRKO lifespan; muscle aging claims)
  • implicit stubs created: foxo1 (hepatic gluconeogenesis; Tier A ROADMAP), shc1 (new), grb2 (new), sos (new), sarcopenia (may be stub already)
  • schema note: known-interactors field used — consistent with existing protein page convention; not escalated
  • verification priority: HIGH — 4 local PDFs available; focus: activation loop Tyr numbering; FIRKO +134 days/+18% exact values; Nakae 2002 FOXO1 mechanism; MIRKO phenotype
  • ROADMAP updated: insr marked ✓ drafted R7b 2026-05-04 in Round 7 Receptors line

[2026-05-04] ingest | round-7c-irs-foxo

daf-16

  • added: molecules/proteins/daf-16.md
  • entity type: protein (DAF-16; abnormal DAuer Formation 16; C. elegans FOXO transcription factor)
  • canonical IDs confirmed: UniProt O16850 (Swiss-Prot reviewed; 541 aa canonical; function/domain/phosphosite data pulled); NCBI Gene 172981; WormBase WBGene00000912; HGNC null (worm gene); GenAge null (longevity effect captured via daf-2 entry and IIS pathway)
  • archive status:
    • 10.1038/366461a0 (Kenyon 1993) — not_oa; tagged no-fulltext-access
    • 10.1126/science.278.5341.1319 (Lin 1997) — local PDF available
    • 10.1038/40194 (Ogg 1997) — local PDF available
    • 10.1038/35065638 (Tissenbaum 2001) — local PDF available (pre-verified on caenorhabditis-elegans.md)
    • 10.1038/nature01789 (Murphy 2003) — local PDF available
    • 10.1126/science.1083701 (Hsu 2003) — not_oa; tagged no-fulltext-access
    • 10.1101/gad.1255404 (Apfeld 2004) — local PDF available (pre-verified on caenorhabditis-elegans.md)
    • 10.1038/nature08980 (Kenyon 2010) — local PDF available
  • key DOIs cited in footnotes: 10.1038/366461a0, 10.1126/science.278.5341.1319, 10.1038/40194, 10.1038/35065638, 10.1038/nature01789, 10.1126/science.1083701, 10.1101/gad.1255404, 10.1038/nature08980
  • gaps surfaced: needs-human-replication (all causal longevity data from C. elegans / model organisms); needs-canonical-id (isoform-specific sequence lengths; canonical isoform 516 vs 541 aa discrepancy); no-fulltext-access (Kenyon 1993, Hsu 2003 — closed-access); needs-replication (PPTR-1 dephosphorylation mechanism; full phosphosite atlas across all 8 isoforms); no-mechanism (Class I vs Class II target gene discrimination at chromatin level)
  • implicit stubs created: daf-2 (IIS receptor; founding longevity mutant), age-1 (PI3K ortholog; AGE-1 downstream of DAF-2), sir-2.1 (sirtuin; longevity requires DAF-16), aak-2 (AMPK ortholog; parallel to DAF-16), hsf-1 (heat-shock factor; cooperates with DAF-16), akt-1 (worm AKT-1; phosphorylates DAF-16), akt-2 (worm AKT-2), sgk-1 (serum/glucocorticoid kinase; DAF-16 Ser319 phosphorylation), jnk-1 (stress-activated kinase; promotes DAF-16 nuclear import), pptr-1 (PP2A regulatory subunit; opposes AKT-1)
  • schema gaps escalated:
    1. organism: field used in frontmatter — not in CLAUDE.md protein schema (human assumed); needed for non-human protein pages; recommend adding as optional field
    2. wormbase-id: field used in frontmatter — not in CLAUDE.md schema; WormBase is canonical DB for C. elegans genes (analogous to Ensembl for human); recommend adding as optional field alongside ensembl:
  • ROADMAP updated: daf-16 marked ✓ seeded R7c 2026-05-04 in both Round 7 FOXO family line and Tier D stub tracker line
  • verification priority: MEDIUM-HIGH — 6 of 8 source PDFs locally available; Tissenbaum 2001 and Apfeld 2004 already verified on caenorhabditis-elegans.md; priority targets: Lin 1997 (daf-16 cloning; GFP translocation specifics), Ogg 1997 (epistasis quantitation), Murphy 2003 (Class I/Class II gene list; sod-3/lys-7 confirmation); Kenyon 1993 and Hsu 2003 remain unverifiable (closed-access)

[2026-05-05] verify | pten

  • verified: molecules/proteins/pten.md
  • sources checked (5 local PDFs):
    • 10.1038/ng0497-356 (Steck 1997, Nat Genet) — local PDF, verified
    • 10.1016/s0092-8674(00)81780-8 (Stambolic 1998, Cell) — local PDF, verified
    • 10.1074/jbc.273.22.13375 (Maehama & Dixon 1998, J Biol Chem) — downloaded + verified
    • 10.1016/j.cmet.2012.02.001 (Ortega-Molina 2012, Cell Metab) — downloaded + verified
    • 10.1016/j.cell.2012.02.030 (Garcia-Cao 2012, Cell) — downloaded + verified
  • sources unverifiable (not_oa):
    • 10.1126/science.275.5308.1943 (Li 1997) — not_oa; claims remain from prior extraction
    • 10.1038/1235 (Di Cristofano 1998) — not_oa; claims remain from prior extraction
  • corrections made:
    • G129E attribution: removed [^maehama1998] → corrected to [^stambolic1998]; Maehama 1998 only uses C124S mutant, does not characterize G129E
    • Garcia-Cao 2012 body text: removed implication that Super-PTEN mice “extend lifespan” — paper reports NO lifespan measurement; corrected to “cancer-resistant metabolic phenotype”; added PTEN expression level range (1.1–3.5×) and mechanism detail (PFKFB3/GLS via APC/Cdh1)
    • Stambolic 1998 footnote: removed incorrect E6.5–E9.5 range (that is Di Cristofano’s range); corrected to “die by E9.5” per Stambolic paper; expanded to note exon 3–5 deletion model and MEF findings
    • Ortega-Molina 2012: added quantitative lifespan data — males +12% (n=49 wt/32 tg, p<0.005), females +9% (n=63 wt/32 tg, p<0.01), cancer-free +30%; footnote updated with sample sizes and Foxo1→Ucp1 axis
    • Maehama 1998 footnote: corrected expression system from “baculovirus” to E. coli; G129E mutant removed; C124S confirmed; added Km value (98.9 µM for Ins(1,3,4,5)P4)
    • Steck 1997 footnote: expanded with LOH frequencies from primary tumors
  • gaps surfaced: no-fulltext-access for Li 1997 and Di Cristofano 1998
  • downstream pages potentially affected:

[2026-05-04] verify | molecules/proteins/irs-1.md

Pages verified: 1 (partial — four of six cited sources are closed-access)

PDFs read: Um 2004 (10.1038/nature02866, including the published corrigendum in Nature 431:485); Boucher 2014 (10.1101/cshperspect.a009191, downloaded during this pass — bronze OA). Sun 1991, Tamemoto 1994, Withers 1998, Selman 2008: all not_oa (closed-access), claims attributed to these not verified from full text.

Corrections applied:

  1. CRITICAL — Mouse IRS-1 serine site corrected (Um 2004 corrigendum): The wiki listed the S6K1-phosphorylated IRS-1 mouse site as “Ser-636” (matching the original Um 2004 figure labels). The published Um 2004 corrigendum (Nature 431:485, 23 Sep 2004) corrects the mouse sites to S632/S635 (not S636/S639 as the original western blot labels read). Human sites remain S312 + S636/S639. Corrected in: inhibitory serine table, step-2 of negative-feedback mechanism description, footnote [^um2004], and frontmatter key-ptms list.
  2. Corrigendum note added to body: Explicit note inserted explaining the original vs corrected mouse site numbering and citing the corrigendum location.
  3. Ser-1101 qualification updated: Previously attributed to “some reviews” without specifics; now notes that Boucher 2014 Figure 3 lists it in a schematic without kinase attribution, while Um 2004 does not support it as an S6K1 site. contradictory-evidence retained.
  4. Boucher 2014 footnote updated: Archive status corrected from “pending” to “downloaded”; scope description added noting the review covers IR signaling and insulin resistance mechanisms but does NOT contain IRS-1 KO lifespan data.
  5. CR → IRS-1 citation corrected: Removed [^boucher2014] citation from the caloric restriction paragraph (Boucher 2014 reviews the mTOR/S6K1 feedback mechanism but does not cite CR-specific IRS-1 protein preservation data); unsourced marker expanded with explanation.
  6. Um 2004 footnote updated: Added mouse strain (C57BL/6J, male) and explicit corrected site numbering.
  7. Banner removed; verified flag flipped to true with partial scope.

Claims confirmed supported by verified sources:

  • S6K1 → IRS-1 negative feedback loop mechanism (Um 2004, directly demonstrated via siRNA knockdown in HeLa + S6K1-/- mouse adipose/muscle/liver)
  • Mouse IRS-1 sites S307 confirmed (Um 2004 Fig. 3e, 4b, 4c; corrigendum retains S307)
  • Human IRS-1 sites S312 + S636/S639 confirmed (Um 2004 corrigendum)
  • JNK and IKKβ phosphorylate Ser-312/Ser-307 under inflammatory conditions (Boucher 2014, Figure 2 and “Regulation by Inhibitory Serine and Threonine Phosphorylation” section)
  • IRS-1 KO: growth retardation + insulin resistance without diabetes; IRS-2 KO → T2D (Boucher 2014 p.3, citing Araki 1994 = Tamemoto 1994 and Withers 1998)
  • IRS-1 dominant in muscle/adipose; IRS-2 dominant in liver/β-cells (Boucher 2014 p.3)
  • p85 SH2 docking to phospho-YxxM motifs → PI3K activation (Boucher 2014; Myers 1992 cited therein)

Unverifiable claims (closed-access sources):

  • Sun 1991: IRS-1 domain boundaries (PH 12-115, PTB 159/160-264), YXXM motif count and positions, disordered scaffold architecture
  • Tamemoto 1994: ~50% body weight figure, Mendelian viability, β-cell hyperplasia compensation
  • Withers 1998: specific IRS-2 vs IRS-1 tissue-specialization mechanistic details
  • Selman 2008: lifespan extension magnitude in Irs1-/- females (exact % and median values remain unconfirmable); sex-specificity of longevity phenotype

Downstream pages that may need attention:

  • molecules/proteins/s6k1.md — already corrected for mouse IRS-1 sites (S307/Ser-636 per Um 2006, which is a review citing Tremblay et al. 2005 and Harrington 2004 — s6k1.md has its own verified scope); the corrigendum mouse site Ser-632/Ser-635 should be noted there if not already
  • studies/um-2004-s6k1-irs1-feedback.md — if this study page exists, it should note the corrigendum and the corrected mouse site numbering
  • Any page citing Selman 2008 for lifespan numbers — quantitative values remain unverified

[2026-05-04] verify | molecules/proteins/igf1r.md

Pages verified: 1 (partial scope — Liu 1993 not_oa; canonical-database identity fields not independently re-verified)

  • molecules/proteins/igf1r.md — 8 corrections; verified: true (partial scope)

Sources checked:

  • 10.1002/j.1460-2075.1986.tb04528.x (Ullrich 1986, EMBO J) — DOWNLOADED and VERIFIED during this pass (bronze OA via PMC1167146). Primary structure / cDNA cloning of human IGF1R.
  • 10.1038/nature01298 (Holzenberger 2003, Nature) — local PDF. VERIFIED end-to-end.
  • 10.1073/pnas.0801030105 (Willcox 2008, PNAS) — local PDF. VERIFIED end-to-end.
  • 10.1073/pnas.0705467105 (Suh 2008, PNAS) — local PDF. VERIFIED end-to-end.
  • 10.1016/s0092-8674(05)80084-4 (Liu 1993, Cell) — not_oa. no-fulltext-access retained.

Corrections applied:

  1. Kinase domain boundaries CORRECTED: “999–1,274” → “~1,003–1,259” (precursor numbering). Ullrich 1986 gives tyrosine kinase features between proreceptor residues 973–1,229 (= precursor ~1,003–1,259); ATP-binding Lys is proreceptor Lys1003 (precursor Lys1033). The upper boundary 1,274 was unsourced in Ullrich 1986.
  2. Activation-loop phosphotyrosine citation CORRECTED: The wiki cited Ullrich 1986 for “Tyr1165, Tyr1161, Tyr1166” sequential autophosphorylation. Ullrich 1986 identifies the kinase domain region and ATP-binding motif but does NOT enumerate individual activation-loop phosphotyrosines by position. A sourcing note was added clarifying these residue assignments are the UniProt/biochemical literature consensus from subsequent kinetic studies; needs-replication added for phosphorylation order in intact cells vs isolated kinase.
  3. Willcox 2008 cohort sex ADDED: The HHP/HAAS cohort is male-only. “Japanese-American” → “Japanese-American men only” in body text and footnote. The OR=2.75 finding applies specifically to men.
  4. Suh 2008 P value CORRECTED: “P=0.04” → “P=0.02” for the combined rare functional variant enrichment. P=0.04 is the IGF-1 level difference in variant carriers vs noncarriers; these were conflated in the original text.
  5. Suh 2008 variant table CORRECTED: Individual variant frequencies (~1.3% and ~1.0%) derived from the pilot n=79 female centenarian screen. Full-cohort (n=384) numbers are: Ala-37-Thr 2/384 (0.52%), Arg-407-His 7/384 (1.82%), combined 9/384 (2.3%) vs 1/312 controls (0.3%), P=0.02. Table rewritten with full-cohort figures as primary.
  6. Suh 2008 footnote n CORRECTED: “n=79 female centenarians” → “n=384 centenarians (286 female + 98 male) + 312 controls” reflecting the full-cohort primary result.
  7. Suh 2008 functional follow-up EXPANDED: Added precise numbers — carriers n=6 (female centenarian carriers); IGF-1 levels 165±21 vs 121±6 ng/mL, P=0.04; compared to 10 noncarrier centenarian lymphocyte controls.
  8. Ullrich 1986 footnote UPDATED: Changed from “pending (bronze OA)” to “downloaded (bronze OA via PMC)”; replaced vague description with accurate content (1,367 aa precursor; 30 aa signal peptide; β chain from Asp-711; kinase domain proreceptor 973–1,229; ~84% kinase-domain identity with INSR; chromosome 15q).

Claims confirmed correct from PDFs:

  • 1,367 aa precursor; 30 aa signal peptide (Ullrich 1986 abstract + Fig. 2c)
  • α₂β₂ heterotetramer; α chain extracellular, β chain transmembrane + cytoplasmic (Ullrich 1986)
  • ~84% kinase-domain identity with INSR (Ullrich 1986 discussion; Fig. 3a domains)
  • Holzenberger 2003: 129/Sv background; female +33% (756±46 vs 568±49 days, P<0.001 t-test, P<0.001 Cox); male +15.9% (679±80 vs 585±69 days, NS); combined +26%, P<0.02 Cox — all confirmed (Fig. 2, methods)
  • Holzenberger 2003: metabolic phenotype — normal body weight and food intake; improved oxidative stress resistance — confirmed (text and Fig. 4)
  • Willcox 2008: n=615 (213 cases ≥95y, 402 controls); FOXO3A rs2802292 GG vs TT OR=2.75 (95% CI 1.51–5.02, P=0.0007) — confirmed (Table 3, abstract)
  • Suh 2008: two nonsynonymous variants Ala-37-Thr (244G>A) and Arg-407-His (1355G>A) in alpha-chain; reduced IGFR levels and reduced AKT phosphorylation in carriers (Fig. 1C, D, E) — confirmed
  • Liu 1993: perinatal lethality at birth; ~45% normal birth weight — cited in Holzenberger 2003 reference 16 and confirmed as field-standard; primary PDF not_oa

Unverifiable claims (closed-access source):

  • Liu 1993: exact Mendelian ratios, respiratory failure phenotype details, body weight quantification (all well-established in field; corroborated by Holzenberger 2003 citing Liu 1993 for the same facts)

Downstream pages that may need updates:

  • molecules/proteins/foxo3.md — Willcox 2008 is cited there; the male-only cohort is already noted in that page’s verified footnote (verified separately); cross-check that consistency is maintained
  • pathways/insulin-igf1.md — may cite Suh 2008 with the incorrect P=0.04; check footnote
  • pathways/pi3k-akt-pathway.md — carries verified Willcox 2008 footnote; check male-only cohort is already specified (should be, per foxo3 verify pass)

[2026-05-04] verify | molecules/proteins/igf-1.md

Pages verified: 1 (partial — Rinderknecht 1978 structural claims cross-confirmed via UniProt P05019 only; Liu 1993 abstract-only via PubMed; both PDFs unavailable)

PDFs read: Holzenberger 2003 (10.1038/nature01298) — local PDF; Suh 2008 (10.1073/pnas.0705467105) — local PDF; Guevara-Aguirre 2011 (10.1126/scitranslmed.3001845) — full text via PMC3357623 (web). Rinderknecht 1978: hybrid OA but download failed; structural claims cross-checked against UniProt P05019. Liu 1993: not_oa; abstract retrieved via PubMed PMID 8402901.

Corrections applied:

  1. Liu 1993 double-KO table (CRITICAL): wiki attributed ~30% birth weight to “Igf1-/-; Igf1r-/-” double KO. Per Liu 1993 abstract (PMID 8402901), Igf1-/-;Igf1r-/- phenotype is the same as Igf1r-/- alone (~45%). The ~30% figure applies to the Igf2-/-;Igf1r-/- double KO (and the phenotypically identical Igf1-/-;Igf2-/- double KO). Table corrected: Igf1-/-;Igf1r-/- → ~45%; added Igf2-/-;Igf1r-/- row at ~30%. Body text also corrected.
  2. Suh 2008 carrier height p-value (CRITICAL): wiki stated “~2.5 cm shorter on average (P<0.001)” for IGF1R mutation carriers vs noncarriers. Suh 2008 Table 2 shows P=0.41 (NS) for this comparison (162±2.8 vs 165±0.8 cm, n=6 carriers vs n=163 noncarriers). The P<0.001 applies to the female offspring vs control height comparison in Fig. 1B (broader cohort). Corrected to: P=0.41, NS; Fig. 1B distinction noted.
  3. Guevara-Aguirre 2011 cancer stats (CRITICAL): wiki said “17% cancer mortality in controls (P<0.05 by Fisher’s exact test).” Paper reports 20% of deaths in controls were cancer (17% of all diseases); statistical test was exact hypergeometric distribution, P=0.003 (not Fisher’s exact, not P<0.05). Corrected throughout.
  4. Guevara-Aguirre 2011 cohort sizes: “~100 Laron syndrome subjects and ~1600 controls” → exact numbers 99 GHRD subjects + 1,606 controls; 70% of GHRD deaths attributed to accidents/alcohol/convulsive disorders (quantified from paper).
  5. Suh 2008 offspring IGF-1 sample sizes added: n=105 female offspring vs n=67 female controls (P<0.01); male offspring (n=92) showed no difference — gender-specificity noted.
  6. Holzenberger 2003 serum IGF-1 elevation added: Igf1r+/- mice show paradoxically elevated serum IGF-1 (males 795±64 vs 625±30 ng/mL P<0.01; females 716±39 vs 516±14 ng/mL P<0.001) — added to body text bullet and footnote; directly parallels Suh 2008 centenarian finding.
  7. Suh 2008 cohort description clarified: n=79 was the initial discovery subset (short-statured female centenarians); full genotyping cohort was 384 centenarians + 312 controls (mean age 97.7 and 79.5 respectively). Both now stated.
  8. Footnotes updated: all four footnotes expanded with verified quantitative data; Guevara-Aguirre 2011 archive status changed to “download failed (green OA PMC3357623; URL filter blocked).”

Claims confirmed correct:

  • UniProt P05019: 195 aa precursor; signal peptide 1–21; mature IGF-1 residues 49–118 (70 aa); MW ~7,649 Da; three disulfide bonds (Cys54–Cys96, Cys66–Cys109, Cys95–Cys100) — confirmed via UniProt REST API
  • Holzenberger 2003: 26% overall lifespan extension (P<0.02, Cox’s test); females 33% (P<0.001), males 15.9% (NS); 129/Sv background — all confirmed
  • Suh 2008: Ala-37-Thr (244G>A) + Arg-407-His (1355G>A); 9/384 centenarians (2.3%) vs 1/312 controls (0.3%), P=0.02; reduced IGF1R levels (P<0.03) — confirmed
  • Liu 1993: Igf1-/- ~60% birth weight (viable), Igf1r-/- ~45% (perinatal lethal) — confirmed via abstract
  • Guevara-Aguirre 2011: 0 cancer deaths in GHRD; 0/90 T2D (p=0.02); serum IGF-1 ≤20 ng/mL (all GHRD) vs 29–310 ng/mL controls — confirmed

Unverifiable claims:

  • Rinderknecht 1978: disulfide bond positions and insulin-family structural homology claims are consistent with UniProt P05019 but not directly verified against primary paper; no-fulltext-access added to footnote
  • Liu 1993: Mendelian ratios, respiratory failure mechanism details — not_oa; abstract confirms birth weight and lethality data

Downstream pages that may need updates:

  • molecules/proteins/igf1r.md — may repeat the Suh 2008 cohort as “n=79 centenarians”; check and align with corrected description (n=384 full genotyping cohort; n=79 was discovery subset); the carrier height P<0.001 error may also appear there
  • pathways/insulin-igf1.md — may cite Holzenberger 2003 without the paradoxical IGF-1 elevation finding; may cite Suh 2008 with incorrect cohort n; check and correct
  • studies/ pages for Holzenberger 2003 and Suh 2008 if they exist — ensure corrected figures are propagated

[2026-05-04] round-7 summary

Round 7 (PI3K/AKT/IIS expansion) — 12 new pages drafted + verified. Sub-rounds:

  • R7a (kinases): akt, pdk1, pi3k, pten
  • R7b (receptors + ligands): igf1r, insr, insulin, igf-1
  • R7c (substrates + FOXOs): irs-1, foxo3, foxo1, daf-16

Major corrections (this round was particularly correction-rich — many systemic errors caught):

  • Hertweck 2004 misattributed: wiki claimed akt-1/akt-2 LoF extends C. elegans lifespan via DAF-16. Paper actually shows SGK-1 (not AKT-1/AKT-2) is the critical longevity kinase — sgk-1 loss extends lifespan ~63% (14.7→24.0d, p<0.0001); akt-1 and akt-2 alone show NO significant extension. Major reframing on akt.md.
  • Brunet 1999 14-3-3 binding sites: Only Thr32 + Ser253 (NOT Ser315) create 14-3-3 binding motifs in FOXO3a. Ser315 drives CRM1-mediated nuclear export, not 14-3-3 interaction. T32A+S253A double mutant abolishes binding; S315A alone does not. Same correction propagated to FOXO1 Thr24/Ser256/Ser319 sites. Multiple pages corrected.
  • Lawlor 2002 PDK1 hypomorph ‘improved insulin sensitivity’ was fabricated: paper Fig 6 shows PKB/S6K/RSK insulin-stimulated activation is ENTIRELY NORMAL in PDK1−/fl mice. Paper conclusion: PDK1 regulates cell size INDEPENDENTLY of its insulin-signaling role. Removed from pdk1.md.
  • Engelman 2006 Pik3ca+/- ‘lifespan extension’ was unsourced: paper does not report this finding. Removed; unsourced added; original primary source unidentified.
  • Hosaka 2004 has only single KOs, NOT triple KO: wiki described ‘Foxo1+3+4 triple KO hemangiomas/lymphoma’ attributed to Hosaka 2004 — wrong. Hosaka 2004 reports three separate single KOs (Foxo1-/- E10.5 lethal angiogenesis defect, Foxo3-/- POF, Foxo4-/- normal). The triple-KO with hemangiomas/lymphomas comes from Paik 2007 or Tothova 2007 (Cell). Critical correction on foxo3.md.
  • Hosaka 2004 IS the Foxo1-/- E10.5 lethality citation — verified, resolving the foxo1.md needs-canonical-id flag. Phenotype is angiogenesis defect (NOT vasculogenesis); primitive vessels form but fail to remodel.
  • Lin 1997 is daf-16 cloning paper only: wiki claimed Lin 1997 characterized GFP::DAF-16 nuclear translocation; that’s actually Lin 2001 (Nat Genet 28:139). Corrected on daf-16.md.
  • Suh 2008 carrier height P=0.41 NS (not P<0.001): wiki had IGF1R-variant carriers ~2.5 cm shorter at ‘P<0.001’ — paper reports P=0.41 (NS, n=6 vs n=163). Corrected on igf-1.md and igf1r.md.
  • Suh 2008 cohort sizes corrected: full genotyping cohort is 384 centenarians (286F + 98M) + 312 controls; n=79 was the height-selected discovery subset. Variant frequency 9/384 (2.3%) vs 1/312 (0.3%), P=0.02 (NOT P=0.04, which is IGF-1 level comparison).
  • Willcox 2008 Japanese-American HHP/HAAS cohort is MEN ONLY: not previously specified.
  • Holzenberger 2003 IGF-1 PARADOXICALLY ELEVATED in Igf1r+/- mice: males 795±64 vs 625±30 ng/mL (P<0.01); females 716±39 vs 516±14 ng/mL (P<0.001) — directly parallels Suh 2008 centenarian finding. Previously omitted on multiple pages.
  • Goldstein 2000 / Schweers 2007 / etc. — multiple BUG-2 DOI mismatches caught.
  • INSR length 1382 → 1370 aa per Ullrich 1985 (wrong on insr.md, corrected).
  • Blüher 2003 FIRKO background is MIXED, not C57BL/6 — multiple pages corrected.
  • Frasca 1999 INSR-A IGF-2 EC50 ~3 nM (~2.5 nM Kd) — not ‘5 nM’ as cited.
  • Liu 1993 double-KO table inverted: Igf1-/-;Igf1r-/- ~45% (resembles Igf1r-/- alone); Igf2-/-;Igf1r-/- ~30%. Wiki had Igf1-/-;Igf1r-/- at 30% — wrong.
  • Um 2004 corrigendum: mouse IRS-1 inhibitory sites are Ser632/Ser635 (NOT Ser636/Ser639) — published corrigendum Nature 431:485. Human sites Ser312/Ser636/Ser639 unchanged. Propagation needed to s6k1.md.
  • Foxo1-/- ‘vasculogenesis defect’ → ‘angiogenesis defect’: per Hosaka 2004 Discussion, primitive vessels form at E9.5; remodeling fails (angiogenesis).
  • Brunet 1999 cell models corrected: actual cells are CCL39 (Chinese hamster lung), 293T, cerebellar granule neurons, Jurkat — NOT ‘Rat1 fibroblasts and primary neurons’ as wiki stated.
  • Nakae 2002 misattributions corrected: paper does NOT cover Atrogin-1/MuRF1 (those are Sandri 2004 + Stitt 2004); does NOT cover S6K1/IRS-1 feedback. β-cell finding is via Pdx1 suppression (not Foxa2/G6pc/PCK1).
  • age-1 lifespan ~40%/~60% (mean/max) at 20°C; ~65%/~110% at 25°C — wiki had ~65% without temperature qualifier.
  • André 2019 SOLAR-1 hyperglycemia 36.6% (not ~37% from secondary citation).
  • Lin 1997 daf-16 cloning isoform count: 2 splice forms (Lin) / 3 named isoforms (Ogg); ‘8 isoforms’ is later WormBase curation.
  • Kuang 2016 ITC values corrected on FUNDC1 (Round 6 carryover): no Ser17 affinity measured.

Schema observations:

  • daf-16 verifier flagged that the protein schema needs optional organism: and wormbase-id: fields for non-human protein pages (currently human-implicit).
  • IRS-1 verifier surfaced the Um 2004 corrigendum should be propagated to s6k1.md (Ser636 → Ser632/635 in mouse numbering).

Coverage delta after Round 7:

  • 12 new proteins added in IIS/PI3K/AKT cluster — closes major Tier A items including foxo3 (13 inbound — highest in queue), akt (8), pi3k (5), pdk1 (4), pten (3), igf1r/insr/irs-1.
  • IIS pathway substantially complete from receptor to downstream FOXO transcription factors.
  • 40 pages drafted + verified across Rounds 5–7 in this session.

[2026-05-04] ingest | round-7d-followup

irs2

  • added: molecules/proteins/irs2.md
  • entity type: protein (IRS-2; Insulin Receptor Substrate 2; IRS2_HUMAN)
  • canonical IDs: UniProt Q9Y4H2 (Swiss-Prot curated), NCBI Gene 8660, HGNC 6126, Ensembl ENSG00000185950 — not independently live-verified against databases; recommend lint-pass re-check
  • length: 1,338 aa (canonical human isoform; longer than IRS-1 at 1,242 aa)
  • DOIs cited:
    • 10.1038/377173a0 (Sun et al. 1995 Nature — IRS-2 cloning + KRLB motif; LOCAL PDF available at ; 849 citations, 100th percentile FWCI)
    • 10.1038/36116 (Withers et al. 1998 Nature — Irs2-/- T2D phenotype; not_oa; 1,770 citations, 100th percentile FWCI; same paper cited on irs-1.md)
    • 10.2337/diabetes.49.11.1880 (Kubota et al. 2000 Diabetes — beta-cell characterization; bronze OA, download pending; 524 citations)
    • 10.1126/science.1142179 (Taguchi et al. 2007 Science — brain-specific Irs2-/- lifespan extension; not_oa; 518 citations, 100th percentile FWCI)
    • 10.1101/cshperspect.a009191 (Boucher et al. 2014 — review; local PDF confirmed; same paper cited on irs-1.md verified)
  • key aging finding (CRITICAL — brain-IIS-longevity paradox): Taguchi 2007 (Science) showed that brain-specific deletion of Irs2 (Nestin-Cre) extends female mouse lifespan ~18% despite peripheral obesity + hyperinsulinemia. This is the paradigm-shifting finding that tissue-specific, rather than systemic, IIS reduction is required to separate longevity benefit from metabolic disease risk in mammals. Quantitative details (exact medians, n per group, p-values) are unverifiable from abstract alone — Taguchi 2007 is not_oa (#gap/no-fulltext-access).
  • implicit stubs created: none new (all wikilinks point to existing pages: insulin-igf1, pi3k-akt-pathway, mtor, insr, igf1r, pi3k, s6k1, akt, grb2, foxo1, foxo3, irs-1, daf-2, chronic-inflammation, deregulated-nutrient-sensing)
  • gaps surfaced:
    • Taguchi 2007 not_oa — lifespan quantitative details unverifiable no-fulltext-access
    • Withers 1998 not_oa — beta-cell mass ~50% reduction + diabetes progression rate not verified from PDF no-fulltext-access
    • Human IRS-2 inhibitory serine phosphorylation sites not mapped from primary biochemistry papers needs-canonical-id
    • GenAge models entry ID for Irs2 not confirmed — Taguchi 2007 brain-KO is a strong candidate needs-canonical-id
    • Human aging IRS-2 protein level trajectory in liver/beta-cells not sourced no-mechanism
    • Male brain-Irs2-KO lifespan effect unclear from abstract needs-replication
    • IRS-2 vs IRS-1 relative contribution to beta-cell aging unresolved needs-replication
  • schema decisions: standard protein frontmatter used; no schema gaps encountered; complex-subunits: field not applicable (IRS-2 is a scaffold, not a complex)
  • ROADMAP: irs2 marked [x] (drafted, verified: false) under Round 7d

Suggested verification priority for wiki-verifier:

  • CRITICAL: Taguchi 2007 (10.1126/science.1142179) — brain-IIS-longevity paradox; all lifespan quantitative claims (median values, n per group, p-values, sex breakdown) unverified; not_oa; obtain PDF and verify
  • High: Withers 1998 (10.1038/36116) — beta-cell mass ~50% reduction, diabetes progression timeline; not_oa; core knockout phenotype claims
  • High: Sun 1995 (10.1038/377173a0) — local PDF available; KRLB motif characterization + phosphorylation site mapping; most domain/activation mechanism claims trace here
  • Medium: Kubota 2000 (10.2337/diabetes.49.11.1880) — bronze OA, downloadable; beta-cell replication and apoptosis data
  • Low: Boucher 2014 (10.1101/cshperspect.a009191) — local PDF confirmed; review only; already cited and verified on irs-1.md

[2026-05-04] ingest | round-7d-followup

foxo4

  • added: molecules/proteins/foxo4.md
  • entity type: protein (FOXO4; Forkhead Box Protein O4; formerly AFX, AFX1, MLLT7)
  • canonical IDs confirmed: UniProt P98177 (reviewed Swiss-Prot, FOXO4_HUMAN; 505 aa), NCBI Gene 4303, HGNC 7138
  • GenAge: no human or models entry found for FOXO4; genage-id: null in frontmatter; tagged needs-canonical-id
  • archive status:
    • Baar 2017 (doi:10.1016/j.cell.2017.02.031) — pending download (bronze OA; 1,365 citations, 100th percentile FWCI; CRITICAL — all Baar 2017 quantitative claims unverified against PDF)
    • Borkhardt 1997 (doi:10.1038/sj.onc.1200814) — not_oa; no-fulltext-access (closed-access Oncogene paper)
    • Hosaka 2004 (doi:10.1073/pnas.0400093101) — local PDF available at (local PDF)
    • Tothova 2007 (doi:10.1016/j.cell.2007.01.003) — pending download (bronze OA; 1,533 citations, 100th percentile FWCI)
    • Brunet 1999 (doi:10.1016/s0092-8674(00)80595-4) — local PDF available (confirmed on foxo1.md and foxo3.md)
  • DOI correction (task brief): brief cited “Borkhardt 1997 Blood DOI 10.1182/blood.V90.10.4063” — this DOI not found in archive; Europe PMC identifies the correct paper as Oncogene 1997 doi:10.1038/sj.onc.1200814 (“Cloning and characterization of AFX, the gene that fuses to MLL in acute leukemias with a t(X;11)(q13;q23)”). Page uses corrected Oncogene DOI.
  • CRITICAL data correction (task brief): brief stated AKT phospho-sites as Thr28/Ser193/Ser258; UniProt P98177 feature table gives Thr32/Ser197/Ser262. Discrepancy flagged in auto-extraction banner and in Limitations section; must be resolved against primary literature (Baar 2017 supplementary data) during verification.
  • gaps surfaced: needs-human-replication (all FOXO4-DRI in-vivo data from mice), needs-replication (Baar 2017 single landmark study; FOXO4-p53 mechanism needs independent replication), unsourced (phospho-site residue numbering discrepancy; FOXO4-specific target gene ChIP-seq; USP7-FOXO4 interaction primary citation; SIRT1-FOXO4 specific site), needs-canonical-id (GenAge entry absent), long-term-unknown (FOXO4-DRI safety long-term), dose-response-unclear (optimal DRI dosing regimen), no-fulltext-access (Borkhardt 1997 Oncogene)
  • implicit stubs created (new wikilinks to non-existent pages): sasp, hematopoietic-stem-cells, navitoclax, dasatinib, quercetin, foxo-transcription-factors
  • previously listed stubs now linked: foxo1, foxo3, daf-16, p53, akt, 14-3-3, sirt1, usp7, bim, insulin-igf1, pi3k-akt-pathway, cellular-senescence, fisetin
  • schema gaps: none — standard protein frontmatter per CLAUDE.md; all fields used are defined; genage-id: null consistent with foxo1.md and irs-1.md precedent
  • ROADMAP: foxo4 marked [x] drafted R7d 2026-05-04

Suggested verification priority for wiki-verifier:

  • CRITICAL: Baar 2017 (10.1016/j.cell.2017.02.031) — pending download (bronze OA URL available: https://www.cell.com/article/S0092867417302465/pdf); verify all in-vivo endpoint quantitative values (hair density % change, creatinine clearance improvement, running capacity, grip strength, senescence marker reductions); confirm FOXO4-DRI peptide design residues and mechanism; resolve Thr32/Ser197/Ser262 vs. Thr28/Ser193/Ser258 phospho-site discrepancy against supplementary data
  • High: Hosaka 2004 (10.1073/pnas.0400093101) — local PDF available; verify Foxo4-/- “grossly normal” claim and confirm no tissue histology abnormalities were reported; note this PDF also covers foxo1.md and foxo3.md Hosaka claims already logged
  • High: Tothova 2007 (10.1016/j.cell.2007.01.003) — pending download (bronze OA); verify HSC triple-KO ROS accumulation and myeloproliferation claims; confirm Mx1-Cre driver and n values

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