🧬 Aging Wiki

2026-06-25

6 min read

[2026-06-25] log

ingest | Xu 2015 eLife senescence→adipogenesis paper + activin A node + human senescent-cell accumulation evidence

Triggered by two user-supplied papers: the Xu 2015 eLife senescence/adipogenesis paper, and two human-tissue senescence surveys (in answer to “do we have direct human accumulation data?”).

Added (4 new pages)

  • studies/xu-2015-senescent-cells-adipogenesis.md — Xu et al. 2015 eLife (doi:10.7554/eLife.12997). Senescent fat progenitors secrete activin A → paracrine inhibition of adipogenesis; INK-ATTAC clearance and ruxolitinib (60 mg/kg/day, 8 wk, ~22-mo mice) lower circulating activin A, preserve fat mass, cut hepatic TG + plasma FFA, improve insulin sensitivity. Companion to — and distinct from — the already-present Xu 2015 PNAS JAK/frailty paper (10.1073/pnas.1515386112 on senomorphics); page flags the disambiguation. verified:true (claude) — full OA cross-check; only AP20187 dosing-schedule phrasing corrected.
  • molecules/proteins/inhba.md — Activin A / INHBA (UniProt P08476, NCBI 3624, HGNC:6066, Ensembl ENSG00000122641, mouse Inhba). TGF-β-superfamily ligand; SASP factor; adipogenesis suppressor + muscle-catabolism driver; antagonized by follistatin/FSTL3. druggability-tier 1 (sotatercept FDA-approved 2024 PAH; garetosmab Phase 3). Closes long-standing dangling “activin A” plain-text references across ≥5 pages. verified:true (partial scope) — verifier corrected a fabricated n=80 (→ N=8–15/group), a MuRF1/p38-dependence overclaim, and a Prokopidis-2026 effect-direction error; gap/contradictory-evidence retained (meta-analysis finds no sarcopenic activin-A difference).
  • studies/idda-2020-senescent-markers-human-tissues.md — Idda et al. 2020 Aging (Albany NY) (doi:10.18632/aging.102903). Primary human p16/p21 IHC across 10 organs × 3 age groups (n=5/group); tissue-specific accumulation (endocrine pancreas p16 ~35% in elderly; lung no change; skeletal/cardiac muscle undetectable). verified:false (pending PDF figure-percentage cross-check).
  • studies/tuttle-2021-human-senescence-systematic-review.md — Tuttle et al. 2021 Ageing Research Reviews (doi:10.1016/j.arr.2021.101334). Systematic review, 103 studies / 9 organ systems / 27 age-related diseases; p16INK4a in 23/27 pathologies; marker standardization lacking. verified:false gap/no-fulltext-access (abstract-sourced; paywalled).

Updated (propagation)

  • processes/sasp.md — added [[inhba]] to key-proteins; activin A → adipogenesis arm added to the T2D inflammaging bullet (+ ^xu2015elife footnote).
  • hallmarks/cellular-senescence.md — new “Direct human cross-sectional accumulation evidence” paragraph citing Idda 2020 + Tuttle 2021 (+ footnotes), positioned against the SenNet heterogeneity consensus.
  • molecules/proteins/myostatin.md, interventions/gene-therapy/aav-follistatin.md — converted plain-text “activin A” to [[inhba|activin A]].

Gaps surfaced / next seeding candidates

  • Krishnamurthy 2004 (J Clin Invest, p16/Ink4a-Arf as pan-tissue aging biomarker) and Ressler 2006 (Aging Cell, p16INK4A robust in vivo human-skin biomarker) — foundational human anchors, currently bare-DOI only; high-priority study pages.
  • white adipose tissue (type: tissue) and adipogenesis (type: process) — genuine missing atomic pages underpinning the Xu 2015 mechanism; deferred pending user go-ahead.
  • Zaragosi 2010 (activin A in human adipose-progenitor differentiation) and Baker 2011 (foundational INK-ATTAC) also surfaced as candidates.

ingest (batch 2) | foundational p16 biomarker anchors + white adipose tissue + adipogenesis

Follow-on to the above, at user request (build the two foundational human-p16 anchors + the WAT tissue and adipogenesis process pages).

Added (4 new pages)

  • studies/krishnamurthy-2004-ink4a-arf-aging-biomarker.md — Krishnamurthy et al. 2004 J Clin Invest (doi:10.1172/JCI22475, PMID 15520862). Canonical rodent p16^INK4a^/Ink4a-Arf-as-aging-biomarker paper (~9.7-fold geometric-mean rise across 15 tissues; CR attenuates). verified:true — verifier fixed p16/Arf r 0.70→0.75, added the GHR-lung finding, flagged figure-derived fold-changes, corrected the rat-CR n.
  • studies/ressler-2006-p16-human-skin-biomarker.md — Ressler et al. 2006 Aging Cell (doi:10.1111/j.1474-9726.2006.00231.x, PMID 16911562). p16^INK4a^ as robust in-vivo marker of human-skin aging. **verified:false gap/no-fulltext-access (closed-access Wiley paywall; abstract-sourced).
  • tissues/white-adipose-tissue.md — type: tissue; parent-system endocrine-system (dual connective/endocrine identity documented); SAT/VAT, adipokine shifts, adipose senescence (Xu 2015 + Hickson 2019), lipotoxicity/ectopic fat. (verification pass run.)
  • processes/adipogenesis.md — type: process; PPARγ + C/EBP master cascade, pro/anti-adipogenic signals, aging decline (activin A paracrine block, CUGBP1). Banner removed after verification; verifier corrected the Rosen 2002 mechanism (PPARγ is the sufficient proximal effector; C/EBPα acts through it).

Fixed — three wrong cited-reference DOIs (all “second-hand DOI from memory” failures)

  • Ressler 2006: brief-supplied …2006.00216.x → unrelated d-serine paper; corrected to …2006.00231.x on idda-2020 + tuttle-2021 study pages.
  • Zaragosi 2010: xu-2015 page footnote had 10.1242/dev.048652 (a sea-urchin skeletogenesis paper) → corrected to 10.2337/db10-0013 (Diabetes 2010;59(10):2513–2521, PMID 20530742), Crossref-confirmed.
  • Tchkonia 2010: non-resolving 10.1007/s11357-010-9177-7 → correct 10.1111/j.1474-9726.2010.00608.x (Aging Cell; already correct on the xu page by final state).

Updated (propagation)

  • hallmarks/cellular-senescence.md — Krishnamurthy + Ressler added to the human-accumulation paragraph (+ footnotes).
  • pathways/p16-rb-pathway.md — Krishnamurthy footnote converted to study-page wikilink; grandfathered private-store annotation cleaned in passing.
  • molecules/proteins/inhba.md, phenotypes/obesity.md, phenotypes/type-2-diabetes.md — WAT + adipogenesis (+ activin A) inbound links.

Gaps surfaced / next seeding candidates

  • Master-regulator protein pages still stubs: pparg (high-value — TZD drug target), cebpa/cebpb/cebpd, srebp-1c; plus brown-adipose-tissue, adipocytes (cell-type), adipose-tissue-macrophages (cell-type). lipid-storage-capacity referenced in adipogenesis causes: — decide whether it warrants a node or should be prose-only.

ingest | Physionic VERVE-102 video — reference mining (Ference 2012 MR primary anchor)

Source: Physionic YouTube “The End of Heart Disease in a SINGLE Dose?” (video id REOJxcU5yoA) — a summary of the Vafai 2026 NEJM VERVE-102 PCSK9 base-editing Phase 1. Per scraping-youtube-references, the video is a discovery lead only. The centerpiece (VERVE-102 / Vafai 2026) was already ingested + verified 2026-06-08 (studies/vafai-2026-verve-102-pcsk9, interventions/gene-therapy/crispr-base-editing-pcsk9, methods/in-vivo-base-editing); the video adds nothing new there. Reference mining surfaced one real cross-page gap.

Added (1 new page)

  • studies/ference-2012-ldl-mr-lifetime.md — Ference BA et al. 2012 JACC (doi:10.1016/j.jacc.2012.09.017, PMID 23083789). MR meta-analysis, 9 polymorphisms / 6 genes, n=312,321: 54.5% (95% CI 48.8–59.5%) CHD reduction per 1 mmol/L lower lifelong LDL-C — ~3× the per-unit statin effect (p=8.43×10⁻¹⁹, I²=0.0%). The primary source for the “~3× lifetime LDL benefit” claim recurring across the wiki. **verified:false gap/no-fulltext-access (JACC closed-access; headline numerics abstract-confirmed with CI + p — far better than the prior secondary cite).

Fixed — re-anchored the wiki-wide “~3× lifetime LDL benefit” claim to the primary source

Previously the figure was sourced either to Ference 2024 NRC review (closed-access, #gap/no-fulltext-access, unverifiable) or, on the VERVE page, miscited to Cohen 2006 with an explicit standing gap-note (“this claim is from Ference et al. MR analysis; add that citation in a follow-up lint pass”). Both resolved:

  • interventions/gene-therapy/crispr-base-editing-pcsk9.md — replaced the Cohen miscitation + #gap/needs-replication note with [^ference2012] (now carries the 54.5%/CI/p numerics); Cohen retained as the lifelong-PCSK9-LOF instance. Cleaned a grandfathered private-store footnote annotation in passing.
  • molecules/proteins/apob.md — quantitative claim re-anchored to [[studies/ference-2012-ldl-mr-lifetime]]; Ference 2024 review demoted to context/framing cite; #gap/no-fulltext-access on the number cleared (now abstract-confirmed from the primary).
  • molecules/proteins/ldlr.md — cross-reference now points at the primary study page (+ the 54.5%/mmol/L figure).

Added (2nd page) — PESA subclinical-atherosclerosis anchor (video ref [3])

  • studies/ibanez-2021-pesa-subclinical-atherosclerosis.md — PESA cohort study page, keyed on the cited Ibanez 2021 JACC focus-seminar review (doi:10.1016/j.jacc.2021.05.011, PMID 34238438; n=4,184 asymptomatic middle-aged, serial multi-territory imaging, NCT01410318), with the primary cross-sectional finding from Fernández-Friera 2017 JACC (doi:10.1016/j.jacc.2017.10.024, PMID 29241485) as the load-bearing result: subclinical plaque/CAC in 49.7% of risk-factor-free middle-aged adults; LDL-C independently associated with plaque presence/extent even at “normal” levels (OR 1.14–1.18 per 10 mg/dL). The imaging counterpart to the Ference 2012 genetic evidence; empirical case for primordial LDL lowering. **verified:false gap/no-fulltext-access (both JACC papers closed-access; numerics abstract-confirmed).
    • Propagated to phenotypes/atherosclerosis.md — new “Subclinical onset” paragraph (+ [^pesa2021] footnote) linking PESA to the ference-2012-ldl-mr-lifetime lifetime-LDL framing.

Gaps surfaced / next seeding candidates

  • Both Ference 2012 and the PESA papers are JACC closed-access (abstract-confirmed only); flag for verifier full-PDF pass if access opens.

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