2026-08-02

[2026-08-02] ingest | Lombardo 2026 D+Q oligodendrocyte safety signal

User-supplied paper incorporated through the seeder → independent verifier → propagation workflow: Lombardo et al., “Senolytic treatment induces oligodendrocyte dysfunction and demyelination in the corpus callosum,” PNAS (2026), doi:10.1073/pnas.2524897123, PMID 41843680.

Added

• studies/lombardo-2026-senolytic-demyelination.md — verified against the complete 10-page main article. Records the healthy young/aged mouse D+Q regimen, corpus-callosum TEM and histology, primary rat oligodendrocyte assays, cell-death null results, rapid process retraction, and UPR-associated transcript/staining results.
• Verification scope excludes the unavailable supporting information. The assigned PMC manuscript (PMC13012039) is embargoed until 2026-09-17; sex, sequencing replicate/QC detail, and study-wide animal accounting remain unresolved.

Propagated

• cell-types/oligodendrocytes.md — replaced the stale statement that no OL-specific senolytic study existed with the D+Q safety signal, cross-species table, and explicit evidence limits.
• interventions/pharmacological/senolytics.md — added the finding as a D+Q-specific off-target CNS safety concern, not a senolytic-class effect.
• molecules/compounds/dasatinib.md and molecules/compounds/quercetin.md — upgraded earlier abstract-only summaries to full-article evidence, linked the atomic study page, and removed unsupported single-agent attribution.
• hallmarks/cellular-senescence.md — corrected the prior phrase “vulnerable to D+Q senolysis”: no brain senescent-cell burden or target engagement was measured.
• processes/unfolded-protein-response.md — added the oligodendrocyte pharmacological-stress example while withholding a causal PERK/ISR edge.

Verifier-caught corrections and evidence judgment

• The primary g-ratio P values use 1,500–2,000 axons/group nested within only three mice/group; no mouse-level effect estimate or confidence interval was reported.
• Luxol-fast-blue evidence is qualitative: the main article reports no sample size, quantification, or statistical test for those images.
• Results text places the cell-death analysis in corpus callosum, while the Figure 2 legend says hippocampus; the article does not resolve the location conflict.
• UPR language was narrowed to an associated signature. There was no rescue/pathway blockade, direct PERK/eIF2α measurement, or XBP1-splicing assay.
• Only D+Q was tested in vivo. Dasatinib and quercetin each retracted oligodendrocyte processes in vitro, so neither single drug can be assigned the mouse phenotype.
• No senescent-cell burden or brain target-engagement assay was performed. The paper is evidence for off-target toxicity of this D+Q regimen, not evidence that senolysis caused injury or that all senolytics share the risk.
• No correction, retraction, expression of concern, or direct material replication was found as of 2026-08-02.

Remaining gaps

• Independent animal-level replication with prespecified mouse-level statistics, quantitative regional myelin measures, dose–response and pharmacokinetics.
• Recovery/remyelination, conduction, imaging, cognitive, and behavioral endpoints.
• Direct pathway perturbation to test whether UPR activation mediates the phenotype.
• Human CNS safety data; existing D+Q trials did not test dedicated white-matter imaging or myelin-injury endpoints.

---

[2026-08-02] ingest | Oppezzo 2026 telomeric-DDR suppression and hematopoietic function

User-supplied paper incorporated through the seeder → independent verifier → propagation workflow: Oppezzo et al., “Therapeutic inhibition of telomeric DNA damage response rescues hematopoietic dysfunction driven by telomere shortening and aging,” Nature Aging (2026), doi:10.1038/s43587-026-01136-9, PMID 42380622, PMCID PMC13375536.

Added

• studies/oppezzo-2026-telomeric-ddr-hematopoiesis.md — verified against the complete 33-page version of record and four-page Reporting Summary. Records G3 Terc−/−, aged wild-type, competitive-transplant, vaccine, safety, and two-donor human ex-vivo experiments.
• interventions/pharmacological/telomeric-antisense-oligonucleotides.md — verified intervention page for anti-TeloG/anti-TeloC; human-evidence-level: preclinical-only, clinical-stage: preclinical, zero active trials as of 2026-08-02.
• frameworks/intervention-classes.md — registered telomeric-rna-steric-blockade and telomeric-ddr-inhibition as a distinct class, separate from RNase-H gapmers, RNAi, splice modulation, allele-selective degradation, and telomerase activation.

Propagated

• hallmarks/telomere-attrition.md — added tDDR suppression without elongation, retained low tractability, and separated the checkpoint-suppression safety problem from telomerase-mediated cancer risk.
• pathways/dna-damage-response.md — added telomeric-RNA-dependent DDR assemblies and narrowed the preserved-global-DDR claim to one acute irradiation assay.
• cell-types/hematopoietic-stem-cells.md and hallmarks/stem-cell-exhaustion.md — added functional rescue with unchanged LSK abundance, the anti-TeloG-only competitive-repopulation result, and human-ex-vivo limits.
• molecules/proteins/terc.md — distinguished downstream phenotypic rescue from restoration of TERC or telomere maintenance.
• Intervention and causal-graph overlays — updated telomere/stem-cell coverage and linked the verified intervention evidence to the relevant hallmark edges.

Verifier-caught corrections and evidence judgment

• Most efficacy analyses pool anti-TeloG with anti-TeloC and untreated with control ASO; those data establish a pooled class effect, not efficacy of each sequence.
• Only anti-TeloG significantly rescued long-term competitive peripheral-blood, LSK, and multilineage repopulation when the active sequences were separated.
• Telomere length did not increase. tASO suppresses telomeric noncoding-RNA-dependent DDR signaling; it is not telomerase activation or reversal of telomere attrition.
• The irradiation result supports preserved γH2AX/pKAP1 induction one hour after 4.5 Gy in mouse marrow/spleen. It does not establish intact genome-wide repair across lesions, tissues, or time.
• In aged wild-type mice, LSK γH2AX-high and double-positive fractions fell, but pKAP1-high alone did not; lower Cdkn2a/p16 was measured in bulk marrow.
• Human evidence consists of CD34+ cells from two healthy, non-frail male donors ex vivo. Pooled tASO colony means increased, but individual sequence responses were nonuniform and no donor-level inference was possible.
• No correction, retraction, independent replication, human trial, or superseding synthesis was found through 2026-08-02.

Remaining gaps

• Independent sequence-separated replication and product selection, especially anti-TeloG versus anti-TeloC.
• Pharmacokinetics, biodistribution, dose response, scalable marrow/HSPC delivery, repeat dosing, and recovery.
• Cytogenetics, chromosome-fusion assays, mutation burden, clonal-hematopoiesis tracking, and adequately powered long-duration tumor surveillance.
• Large-animal toxicology before human testing; eventual in-vivo human target engagement, safety, and hematopoietic-function endpoints.