🧬 Aging Wiki

type-i-interferon-signaling

Properties1
aliasestype I IFN signaling, IFN-α/β signaling, interferon alpha beta pathway, ISGF3 pathway, antiviral interferon response

20 min read

Type I Interferon Signaling pathway

The type I interferon (IFN-I) signaling pathway is the canonical innate immune response axis triggered by cytosolic pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). It runs in two linked phases: (1) IFN-I production — upstream sensors (cgas, RIG-I/MDA5, TLR3/7/9) detect cytosolic nucleic acids and activate tbk1/IKKε → irf3/irf7 → transcription of IFNA and IFNB genes; and (2) IFN-I receptor signaling — secreted IFN-α/β binds the heterodimeric receptor IFNAR1/IFNAR2 → jak1/tyk2 → stat1/stat2 phosphorylation → ISGF3 complex assembly with irf9 → nuclear translocation → binding of interferon-stimulated response elements (ISREs) → expression of hundreds of interferon-stimulated genes (ISGs). In aging, this pathway is chronically and tonically activated by self-derived nucleic acids — leaked mitochondrial DNA, cytosolic chromatin fragments from senescent cells, and reverse-transcribed LINE-1/ERV retrotransposon cDNA — making it the molecular integrator of upstream genomic and mitochondrial damage into the systemic inflammatory phenotype of aging (inflammaging).

Naming note: This page is the canonical [[type-i-interferon-signaling]] wikilink target. The upstream sensing page is [[cgas-sting]]. The downstream transcriptional relay is covered by [[jak-stat-pathway]]. Individual protein pages exist for [[cgas]], [[sting]], [[tbk1]], [[irf3]]; downstream nodes [[ifnar1]], [[ifnar2]], [[jak1]], [[tyk2]], [[stat1]], [[stat2]], [[irf9]], [[irf7]], [[ikbke]] are implicit stubs pending seeding.

Two-phase architecture

Phase 1: IFN-I production (sensor → TBK1 → IRF3/7 → IFNB/IFNA transcription)

Cytosolic dsDNA is sensed by cgas, which catalyzes synthesis of 2′3′-cGAMP → activates sting → recruits tbk1 and IKKε (encoded by IKBKE) → IRF3 phosphorylation at Ser386/Ser396 → dimerization → nuclear translocation → IFN-β transcription. Viral dsRNA and ssRNA activate RIG-I (DDX58) or MDA5 (IFIH1) → MAVS → same TBK1/IRF3 arm. irf7, expressed at low basal levels but strongly induced by IFN-I signaling itself, preferentially drives IFNA gene transcription and amplifies the response in a feed-forward loop 1.

SensorLigandAdaptorKinaseTFOutput
cGAScytosolic dsDNASTINGTBK1/IKKεIRF3, IRF7IFN-β, IFN-α
RIG-I5′-triphosphate ssRNA / short dsRNAMAVSTBK1/IKKεIRF3, IRF7IFN-β, IFN-α
MDA5long dsRNAMAVSTBK1/IKKεIRF3, IRF7IFN-β, IFN-α
TLR3dsRNA (endosomal)TRIFTBK1IRF3IFN-β
TLR7/8/9 (pDC)ssRNA / CpG DNAMyD88/IRAKIKKαIRF7IFN-α (bulk)

Phase 2: IFNAR → ISGF3 → ISG induction (receptor → JAK → STAT → ISGs)

Secreted IFN-α/β binds the heterodimeric surface receptor formed by IFNAR2 (high-affinity subunit) and IFNAR1 (signal-amplifying subunit). IFNAR2 is constitutively associated with JAK1; IFNAR1 is associated with TYK2 1. Ligand-induced receptor dimerization promotes:

  1. JAK1 transphosphorylates TYK2; TYK2 phosphorylates IFNAR1 (Tyr466)
  2. Phospho-IFNAR1 recruits STAT2; STAT2 is phosphorylated (Tyr689)
  3. JAK1 phosphorylates STAT1 (Tyr701)
  4. p-STAT1:p-STAT2 heterodimer releases from receptor and binds IRF9 via IRF9’s IRF association domain
  5. The trimeric ISGF3 complex (STAT1:STAT2:IRF9) translocates to the nucleus
  6. ISGF3 binds ISREs (5′-AGTTTCNNTTTCC-3′) in ISG promoters → transcriptional activation of hundreds of ISGs

A parallel branch: STAT1 homodimers (GAS-binding “GAF” complex) also form and drive a partially overlapping but distinct ISG subset. IFN-γ (type II IFN) signals exclusively through the GAF branch 1.

Key ISGs in the aging context:

ISGFunctionAging relevance
IFIT1/2/3RNA-binding antiviral restrictionElevated in aged blood transcriptome
MX1/MX2GTPases blocking viral replicationAging biomarker (ISG score)
OAS1/2/3, RNASELRNase-L dsRNA destructionChronic activation damages cellular RNA
ISG15ISGylation (ubiquitin-like modifier)Secreted; amplifies paracrine IFN signaling
IFITM3Membrane-resident restriction factor; IFN-I-inducedMarks senescent T cell subset in aged humans (see below)
TRIM5, TRIM22, APOBEC3sRetrotransposon restrictionReduced in aged cells, enabling LINE-1 reactivation
BST2/TetherinVirion retentionElevated on senescent cells
CXCL10 (IP-10)Chemokine attracting T cells, NK cellsMajor SASP component; elevated in aged plasma

Aging-specific dysregulation

1. cGAS-STING-driven constitutive IFN-I in aging

The dominant mechanism of tonic IFN-I activation in aged tissues is chronic cGAS-STING engagement by self-derived DNA. Three sources converge:

Mitochondrial DNA leakage. mtDNA leaks from damaged mitochondria into the cytoplasm via VDAC1/2/3 oligomerization pores or during outer-membrane permeabilization events. This mtDNA — unmethylated at CpG and therefore recognized by cGAS as foreign-like — is a major source of chronic cGAS-STING activation in aged cells. Mitophagy normally degrades damaged mitochondria before mtDNA escape. In aged tissues where mitophagy efficiency declines (via mTOR-mediated suppression of ULK1; see mtor), mtDNA accumulates in the cytoplasm and drives cGAS activation. Pharmacological rescue: in aged C57BL/6J mice (24–26 months), treatment with urolithin A (UA, 2.3 mg/kg/day i.p. for 8 weeks) — a mitophagy inducer — significantly reduced cytosolic mtDNA accumulation and suppressed cGAS-STING-IFN-I activation, with attenuated IFNα, IFNγ, and TNFα transcriptional signatures in retinal pigment epithelium and neuroretina; mitophagy increase was also documented in brain (cerebellum). Mechanistically, PINK1/Parkin-dependent mitophagy was confirmed as required in the ARPE-19 cell line model (PINK1/PARK2-siRNA knockdown abrogated UA’s cytosolic DNA reduction) but the in-vivo pharmacological rescue used urolithin A directly, not genetic activation of PINK1/Parkin 2. These findings are also conserved in primary human normal dermal fibroblasts (NHDFs) from elderly donors (62 years) which showed elevated cGAS/STING pathway mediators and ISG expression vs. young (28 years). Pathway conserved in humans? yes (mtDNA leakage and cGAS-STING are conserved; the mitophagy decline and IFN-I elevation phenotype confirmed in human aged fibroblasts).

Cytosolic chromatin fragments (CCFs). Senescent cells generate cytoplasmic chromatin fragments from nuclear envelope rupture, micronuclei from lagging chromosomes, and cytoplasmic protrusions of nuclear material. These CCFs activate cGAS → STING → IFN-I → paracrine spread to bystander cells [^gluck2017 — see cgas-sting]. The IFN-I component of SASP creates a feed-forward senescence-amplifying loop: bystander IFN-I drives paracrine senescence via JAK-STAT-p21 signaling.

LINE-1 retrotransposon reactivation. This is the most aging-specific mechanism. Heterochromatin loss in aged cells (epigenetic derepression — see epigenetic-alterations) allows LINE-1 (L1) retrotransposons to be transcribed and reverse-transcribed, generating cytosolic RNA:DNA hybrids and cDNA that activate cGAS and RIG-I/MDA5. De Cecco et al. (2019) demonstrated that L1 elements become transcriptionally derepressed in senescent cells and old mouse tissues; L1 reverse-transcriptase inhibition with NRTIs (nucleoside reverse-transcriptase inhibitors, e.g., lamivudine, stavudine) suppressed the IFN-I signature in aged cells and extended healthspan in aged mice. L1 open reading frame 1 protein (ORF1p) and reverse-transcribed cDNA were detectable in old mouse tissues 3. This directly connects the genomic-instability and epigenetic-alterations hallmarks to chronic-inflammation via the type I IFN pathway. needs-replication — NRTI-in-aging results have not been confirmed in large mammal models or human RCTs.

Very recent work (2026) extends this: plasma EV LINE-1 RNA levels increase markedly with age in humans (n=185 aged 20–95; ~7.6-fold elevation in >65y vs. 20–45y group; strong correlation with neurofilament light chain as a brain aging biomarker); EVs from aged donors crossed the blood-brain barrier in mouse transfer experiments and activated cGAS-STING in microglia, causing neuroinflammation and cognitive dysfunction in young recipient mice 4. Targeting age-related LINE-1 activation in the heart (via lamivudine-equivalent NRTI) reduced cardiac fibrosis and improved cardiac function metrics in aged mice 5. These are very recent results (2026, low citation counts) that have not been independently replicated.

2. SASP IFN-I component

Senescent cells constitutively produce and secrete type I interferons as part of the SASP (see sasp). IFN-β secretion from senescent cells was first characterized alongside the cytokine/chemokine SASP components. The IFN-I SASP component acts in paracrine to:

  • Induce STAT1-dependent growth arrest in neighboring cells (bystander senescence)
  • Upregulate MHC-I expression → increased NK and CD8+ T cell recognition of senescent cells (potentially promoting immune clearance, but this is impaired in aged immune systems — see disabled-adaptive-immunity)
  • Amplify NF-κB-dependent SASP via IFNAR → JAK1 → STAT3 cross-talk 6

IFN-γ (type II IFN) synergizes with TNF-α to hyperactivate JAK/STAT1 in endothelial cells — TNF-α/IFN-γ co-stimulation substantially amplified SASP marker expression (IL-6, IL-8, CCL2, IL-1β) and increased ACE2/DPP4 expression (SARS-CoV-2 entry receptors) vs. either cytokine alone, in human umbilical vein endothelial cells (HUVECs) driven to a senescence-like state; ruxolitinib (1 µM JAKi) reversed ACE2/DPP4 upregulation and normalized SASP marker expression 6. This provides a molecular basis for aged individuals’ greater COVID-19 severity via senescent endothelial cells. needs-replication — the ACE2 upregulation link to clinical COVID-19 severity is mechanistic in a HUVEC model; causal human in-vivo evidence is not established.

3. IFITM3-positive senescent T cells

IFN-I signaling upregulates IFITM3 (Interferon-Induced Transmembrane Protein 3) on T cells. A subset of CD8+ T cells in aged humans exhibits a senescent phenotype (p16^INK4a^+, p21+, telomere-dysfunction foci) with high IFITM3 surface expression, interpreted as chronically IFN-I-exposed cells that have entered a dysfunctional senescent state. These IFITM3+ T cells accumulate with age and are impaired in antigen-specific responses. The causal directionality — whether chronic IFN-I drives T cell senescence, or whether senescent T cells upregulate IFITM3 — is not fully resolved. needs-replication — IFITM3 as a senescent T cell marker is described in early reports but has not been validated with large well-powered human cohorts.

Note: The Jin 2022 footnote below (7) documents a Down syndrome / Alzheimer’s disease model (DS iPSC-derived microglia in human microglial chimeric mice) where chronic IFN-I signaling caused microglial senescence — rescued by IFNAR1/2 shRNA knockdown, not by ruxolitinib. Ruxolitinib appears in this section’s footnotes via Kandhaya-Pillai 2022 (HUVEC model, different context). The IFITM3 senescent T cell population in aged humans is a distinct, parallel observation not directly sourced from Jin 2022.

4. Anti-IFN-I autoantibodies in elderly: COVID-19 vulnerability

Bastard et al. (2020) reported that ~10% of patients with life-threatening COVID-19 pneumonia (101/987) carry pre-existing autoantibodies that neutralize IFN-α and/or IFN-ω, but not IFN-β. These autoantibodies were present in blood collected before SARS-CoV-2 exposure and were absent from all 663 asymptomatic/mild COVID-19 individuals and from only 4/1,227 (0.33%) healthy controls 8. Within the life-threatening COVID-19 cohort, autoantibody prevalence was higher in patients aged ≥65 years (50/385, 13.0%) than in those <65 years (51/602, 8.5%) (Table 1, OR 1.61 [1.04–2.49], p=0.024). Population-level age-stratified prevalence (~1% in those <65 years; ~4% in those aged >70 years) was reported in the companion follow-up study Bastard et al. 2021 Science Immunology (not cited here — see below) 9. This is a distinct failure mode from the tonic IFN-I activation described above: in certain aged individuals, IFN-I production may be adequate but effector function is neutralized by autoantibody. Pathway conserved in humans? yes — observed in humans directly.

DimensionStatus
Pathway conserved in humans?yes
Phenotype conserved in humans?yes (aging-associated IFN-I dysregulation documented in human transcriptomic studies)
Anti-IFN autoantibody aging datayes — direct human epidemiology

Cross-talk with NF-κB and JAK-STAT

The IFN-I pathway does not operate in isolation. Key cross-talks:

  • NF-κB: Both IRF3 and NF-κB are co-activated downstream of TBK1/IKKε. The IFN-β promoter (IFNB1 enhancer, “enhanceosome”) requires a composite IRF3 + NF-κB + AP-1 binding. In aged cells, constitutive low-level NF-κB activity (from SASP, mitochondrial stress) lowers the threshold for full IFN-I induction. See nf-kb.
  • JAK-STAT (Type I IFN → STAT3): IFNAR signaling can activate STAT3 in addition to the canonical STAT1/STAT2/IRF9 arm. STAT3 is the primary mediator of IL-6/gp130 SASP amplification (see jak-stat-pathway). JAK1 is shared between IFNAR and IL-6 receptor complexes — JAK inhibitors targeting JAK1 suppress both arms.
  • IRF3 → p53 cross-talk: IRF3 can directly interact with p53 to modulate apoptosis decisions in virally infected / senescent cells. When IFN-I signaling is chronic, this may contribute to apoptosis resistance in senescent cells. no-mechanism — direct molecular mechanism of IRF3-p53 interaction in senescent (vs. virally infected) cells is incompletely characterized.
  • mTORC1 translational amplification: mTORC1 activity promotes cap-dependent translation of ISG mRNAs; in aged cells, paradoxically elevated mTORC1 activity (see mtor) may amplify ISG protein output beyond what the IFN-I transcriptional signal alone would predict. Conversely, rapamycin treatment reduces ISG expression in aged mouse tissues — a candidate mechanism for some of rapamycin’s anti-inflammaging effects (#gap/needs-replication — mechanistic link is inferred, not directly demonstrated with rapamycin-IFN-I epistasis experiments).

Interventions modulating type I IFN signaling in aging

JAK1/TYK2 inhibitors (JAKinibs)

JAK inhibitors targeting JAK1 (and/or TYK2) suppress the IFNAR → JAK1/TYK2 → STAT1/STAT2 arm, blocking ISG expression without affecting IFN-I production. In aging contexts:

  • Ruxolitinib (JAK1/JAK2 inhibitor): FDA-approved for myelofibrosis and graft-versus-host disease. Reduces circulating inflammatory markers in patients with myeloid disease. The NIA Interventions Testing Program is evaluating ruxolitinib in aged mice. Under investigation as a senomorphic agent because it suppresses both IFN-I ISG induction and the IL-6/STAT3 SASP arm via shared JAK1.
  • Baricitinib (JAK1/JAK2 inhibitor): FDA-approved for rheumatoid arthritis and atopic dermatitis. Reduced mortality in hospitalized COVID-19 patients — consistent with blocking hyperactivated IFN-I/JAK-STAT signaling contributing to immunopathology.
  • Tofacitinib (pan-JAK inhibitor): FDA-approved for RA, ulcerative colitis. Less selective; JAK3 inhibition adds lymphotoxicity risk.

Aging-context druggability tier rationale: JAK inhibitors are FDA-approved (Tier 1 criteria met by indication) but no aging-specific JAK inhibitor trial with primary lifespan/healthspan endpoints has been completed in humans. Tier 2 is applied per the aging-context convention — high-quality probes (ruxolitinib, baricitinib) exist and are mechanistically tractable for aging indications, but aging-validation is preclinical/pilot only. See jak-stat-pathway for full JAK inhibitor class discussion.

STING antagonists

Small-molecule STING antagonists (e.g., H-151, SN-011, MSA-2) block STING activation, preventing IFN-I production from the cGAS-STING arm. H-151 reduced IFN-I and IL-6 in aged mice and ameliorated age-associated inflammation in a mouse model of SAVI (STING gain-of-function disease). Aging-specific trials are preclinical. See cgas-sting for the full STING antagonist landscape.

STING + TLR4 dual-PAMP nanoparticle adjuvants (the inverse modality)

In cancer-vaccine contexts, the opposite therapeutic direction — acute amplification of IFN-I via dual-PRR agonism — is being explored. Kane et al. (2025) co-encapsulated cdGMP (STING agonist) and MPLA (TLR4 agonist) on the same ~30–60 nm lipid NP at a 2.5:1 mole ratio 10. In vitro, dual-agonist NPs drove >4-fold higher IFN-α/β in mouse macrophages, primary mouse splenic CD11c⁺ DCs, and primary human DCs (3 donors) vs single-agonist or empty NP controls; the synergy required IRF3, IRF5, and IRF7 (KO studies). In vivo IFNAR antibody blockade fully abolished tumor protection across multiple syngeneic models (B16F10 melanoma, Panc02 PDAC, 4T1 TNBC), confirming type I IFN signaling as the necessary effector axis. This is a clean preclinical mechanistic demonstration of the acute pro-IFN-I axis of the dual-edged IFN-I-in-aging biology this wiki tracks — useful for the same reason: STING + TLR4 dual-PRR engagement amplifies shared IRF-driven IFN-I output through coordinated activation of IRF3/IRF5/IRF7. Aged-host efficacy is the open question (paper used young immunocompetent mice). The same Atukorale group’s earlier Chibaya 2024 paper combined this NP platform with therapy-induced senescence (trametinib MEK + palbociclib CDK4/6) in PDAC — using SASP biology to remodel immune-cold tumor microenvironments — the most direct cancer-aging-IFN-I-interface published to date 11. See kane-2025-super-adjuvant-nanoparticles, nanoparticle-immunoadjuvants (class page), and cgas-sting § STING agonists for cancer immunotherapy.

NRTIs as retroelement suppressors

Nucleoside reverse-transcriptase inhibitors (lamivudine, stavudine, tenofovir) suppress LINE-1 reverse transcription, reducing cytosolic LINE-1 cDNA and the associated IFN-I induction. De Cecco et al. (2019) showed that lamivudine treatment reduced the IFN-I signature in old mice and in senescent human cells 3. Yang et al. (2026) showed NRTIs alleviated cardiac aging phenotypes in old mice via this mechanism 5. Human aging trials with NRTIs are not yet registered. needs-human-replication

Anti-IFN-I biologics

Anifrolumab (anti-IFNAR1 monoclonal antibody; FDA-approved for systemic lupus erythematosus) blocks IFN-I signaling by occupying IFNAR1. Sifalimumab and rontalizumab (anti-IFN-α mAbs) reduce ISG scores in SLE patients. These are not yet evaluated in aging-context trials but represent a mechanistically coherent intervention class for aging-associated IFN-I overactivation. needs-human-replication

Limitations and knowledge gaps

  • Tonic vs. acute IFN-I in aging: The same pathway mediates beneficial antiviral responses and harmful chronic-inflammation. Blanket JAK inhibition or STING antagonism impairs acute antiviral immunity — the therapeutic window for aging-specific suppression without infection vulnerability is not established. dose-response-unclear
  • Causal vs. correlative evidence: Most aging data linking IFN-I to inflammaging are correlative (ISG scores elevated in aged blood) or mouse genetic interventions. Prospective human causal evidence (e.g., Mendelian randomization using IFN-I pathway SNPs → aging outcomes) is sparse. needs-replication
  • IFITM3+ T cell biology: The IFITM3-positive senescent T cell population requires larger cross-sectional and longitudinal human datasets to characterize its contribution to immunosenescence. needs-replication
  • NRTI aging trials: Lamivudine and related drugs are safe (HIV/hepatitis treatment profile over decades), but no aging-endpoint RCT has been run. Retroelement-IFN-I axis as an aging target needs human translation. needs-human-replication
  • IFN-I tissue heterogeneity: ISG signatures differ substantially across tissues in aging. Brain microglia, cardiac fibroblasts, and peripheral blood mononuclear cells show different IFN-I activation trajectories with age. A tissue-resolved understanding of when and where IFN-I drives vs. is driven by the aging program is missing. no-mechanism (tissue-specific regulatory logic)
  • Anti-IFN autoantibody clinical implications: Whether screening for anti-IFN-I autoantibodies in elderly individuals should inform vaccination or antiviral prophylaxis decisions is unresolved. needs-replication

Footnotes

Footnotes

  1. doi:10.1016/j.immuni.2012.03.013 · Stark GR, Darnell JE Jr · Immunity 2012 · n=not applicable · review · model: human (canonical review); covers JAK-STAT pathway 20-year landmark review; ISGF3 mechanism confirmed: STAT1/STAT2/IRF9 trimeric complex; ISRE motif (5′-AGTTTCNNTTTCC-3′ confirmed); IFN-α/β receptor subunit assignments confirmed (JAK1 constitutively associated with IFNAR2; TYK2 with IFNAR1); STAT1 Tyr701 and STAT2 Tyr689 phosphorylation; IRF7 feed-forward amplification of IFNA genes; IFN-γ signals exclusively through STAT1 homodimer (GAF/GAS branch, not ISGF3) — all confirmed against PDF · PDF verified against primary source · cited >1,400 times · PDF locally available: ↩ ↩2 ↩3

  2. doi:10.1038/s41467-024-45044-1 · Jiménez-Loygorri JI et al. · Nature Communications 2024 · n=5–9 mice per group (in-vivo, C57BL/6J mito-QC reporter); n=45–57 cells (NHDF in-vitro) · in-vivo + in-vitro · model: old (24–26 months) vs. young (6–8 months) C57BL/6J mito-QC mice; ARPE-19 cells; primary human normal dermal fibroblasts (NHDFs) from 28-year-old and 62-year-old donors · UA (urolithin A, 2.3 mg/kg/day i.p. × 8 weeks) reduced cytosolic mtDNA and suppressed cGAS-STING-IFN-I activation in aged retina (RPE + neuroretina) and brain; ISG expression reduced; improved neurological function (clasping score, NOR, ERG); PINK1/Parkin knockdown in ARPE-19 cells abrogated UA’s effect on cytosolic DNA, confirming PINK1/Parkin-dependent mitophagy as the mechanism in vitro · PDF verified against primary source · cited 211 times (FWCI 101.0) · PDF locally available: ↩

  3. doi:10.1038/s41586-018-0784-9 · De Cecco M, Ito T, Petrashen AP, et al. · Nature 2019 · n=not stated per group; multiple cohorts (senescent human cells, aged mouse tissues) · observational + genetic-intervention · model: IMR90 human fibroblasts; C57BL/6J mice (24 months vs. 3 months) · L1 elements transcriptionally derepressed in senescent cells and old mouse tissues; L1 ORF1p detectable in old tissues; NRTIs (lamivudine, stavudine) reduced IFN-I ISG signature in old mice; NRTI treatment improved healthspan metrics · cited >1,100 times (FWCI 94.5) · no-fulltext-access — archive status: closed-access (not_oa); quantitative claims (n per group, exact fold-changes, specific healthspan endpoints) unverified against full PDF; abstract-level claims only. ↩ ↩2

  4. doi:10.1111/acel.70350 · Yu S et al. · Aging Cell 2026 · n=185 humans (aged 20–95 years, stratified young n=58, middle-aged n=59, old n=68) for human plasma EV LINE-1 mRNA quantification; plus mouse EV transfer experiments · observational (human cohort) + in-vivo (mouse EV transfer) · model: human plasma cohort; C57BL/6J mice (EV transfer from aged to young recipients); pharmacological interventions with 3TC (LINE-1 reverse transcription inhibitor) and H151 (STING inhibitor) · plasma EV LINE-1 RNA levels markedly increased with age in humans (ORF1 mRNA: ~7.6-fold higher in >65y vs. 20–45y; p<0.001); correlated with NFL (brain aging biomarker); EVs from aged donors crossed BBB and activated cGAS-STING in microglia of young recipients; caused neuroinflammation and cognitive dysfunction; both 3TC and H151 reversed these deficits · PDF verified against primary source — the human cohort (n=185) and the 3TC/H151 pharmacological intervention data were not reflected in the original wiki footnote · gold OA PDF locally available: · Very recent publication (2026); citation count not yet meaningful; treat as preliminary. ↩

  5. doi:10.1038/s43587-025-01056-0 · Yang C et al. · Nature Aging 2026 · n=aged C57BL/6J mice (18–22 months) · in-vivo · model: aged mouse heart · LINE-1 activation in aged cardiac tissue; NRTI treatment (lamivudine) suppressed LINE-1-driven cGAS-STING-IFN-I activation; reduced cardiac fibrosis and improved systolic function · archive status: closed-access (not_oa); quantitative details unverified. Very recent publication (2026); citation count not yet meaningful; treat as preliminary. ↩ ↩2

  6. doi:10.1111/acel.13646 · Kandhaya-Pillai R et al. · Aging Cell 2022 · n=multiple independent experiments (2–3 independent replicates per condition) · in-vitro · model: human umbilical vein endothelial cells (HUVECs; Lonza CC-2519; senescence induced by serial passaging to passage 11–14); also preadipocytes from healthy donors · TNF-α (20 ng/ml) + IFN-γ (20 ng/ml) synergy hyperactivated JAK/STAT1; amplified SASP outputs (IL-6, IL-8, CCL2, IL-1β, NLRP3, CASP1) substantially above single-cytokine baselines; upregulated ACE2 and DPP4 (not TMPRSS2 — the paper does not mention TMPRSS2 as a finding) in senescent HUVECs; senescence-like proliferative arrest; all effects suppressible by ruxolitinib (1 µM) or remdesivir (2 µM) · PDF verified against primary source — cell model is HUVECs, not IMR90/WI-38 fibroblasts · cited 104 times (FWCI 11.8) · PDF locally available: ↩ ↩2

  7. doi:10.1016/j.stem.2022.06.007 · Jin M et al. · Cell Stem Cell 2022 · n=3 control + 3 DS hiPSC lines; chimeric mice (Rag2−/−hCSF1 immunodeficient); 7,790 human microglial cells recovered for scRNA-seq · in-vivo (human microglial chimeric mouse brains) + human iPSC model · model: Down syndrome (DS) and control hiPSC-derived microglia in organoids and chimeric mice; DSAD postmortem brain tissue · hyperactivated type I IFN signaling drove DS microglial senescence and excessive synaptic pruning (both in organoids and in chimeras); senescence rescue achieved by IFNAR1/2 shRNA knockdown (not ruxolitinib — the paper does not use ruxolitinib; ruxolitinib is a separate result in Kandhaya-Pillai 2022); DSAD brain-tissue-derived pathological tau additionally induced microglial senescence with elevated ISG signatures; IFNAR1/2 knockdown also rescued tau-induced senescence · PDF verified against primary source — ruxolitinib was NOT used in this paper · cited 146 times (FWCI 21.4) · PDF locally available: ↩

  8. doi:10.1126/science.abd4585 · Bastard P et al. · Science 2020 · n=987 patients with life-threatening COVID-19; 663 with asymptomatic/mild COVID-19; 1,227 healthy controls · observational (case-control) · model: humans · 101/987 (10.2%) of patients with life-threatening COVID-19 pneumonia carried neutralizing IgG anti-IFN-α2 and/or anti-IFN-ω autoantibodies; present in only 4/1,227 (0.33%) healthy pre-pandemic controls (Fisher exact p<10⁻¹⁶); absent in all 663 asymptomatic/mild cases; male predominance (95/101 = 94%); age distribution within the life-threatening cohort: 51/602 (8.5%) in those <65 years vs. 50/385 (13.0%) in those ≥65 years (OR 1.61 [1.04–2.49], p=0.024) — NOTE: the fine-grained age-stratified population-level prevalence figures (~4% at age >70 in healthy uninfected individuals) are from the companion paper Bastard 2021 Science Immunology (doi:10.1126/sciimmunol.abl4340; PMID 34413139; see bastard-2021-anti-ifn-autoantibody-age-prevalence), NOT this 2020 paper; the abl4247 DOI cited in earlier drafts was incorrect — corrected 2026-05-13 · PDF verified against primary source · cited 2,785 times (FWCI 64.2; percentile 100) · PDF locally available: ↩

  9. bastard-2021-anti-ifn-autoantibody-age-prevalence · doi:10.1126/sciimmunol.abl4340 · PMID 34413139 · Bastard P et al. · Science Immunology 2021 · n=34,159 uninfected general population (prevalence cohort) + ~3,595 critical COVID-19 patients · observational (multi-cohort cross-sectional) · model: humans · anti-IFN-α/ω autoantibodies (high-concentration assay: 10 ng/mL, plasma 1:10) present in 0.18% of uninfected individuals aged 18–69, 1.1% aged 70–79, and 3.4% aged >80; sensitive assay (100 pg/mL) finds ~1%, ~2.3%, and ~6.3% in the same age bands respectively; autoantibodies predated SARS-CoV-2 infection; account for ~20% of COVID-19 deaths; anti-IFN-β autoantibodies did not increase with age · study page seeded 2026-05-13 · PDF locally available: · NOTE: the seeder brief cited DOI abl4247 (wrong) — correct DOI is abl4340; corrected on 2026-05-13. ↩

  10. kane-2025-super-adjuvant-nanoparticles · doi:10.1016/j.xcrm.2025.102415 · PMID:41072409 · PMC:PMC12629812 · in-vitro+in-vivo · “Super-adjuvant nanoparticles for platform cancer vaccination” · Kane GI et al. · Cell Reports Medicine 6(10):102415 · 2025 · n=3–4 biological replicates in vitro; 5–13 mice per group in vivo; 3 human DC donors · model: RAW 264.7 + iBMDMs (Irf3/Irf5/Irf7 KO) + primary mouse splenic CD11c⁺ DCs + primary human DCs (3 donors); in vivo C57BL/6 (B16F10, Panc02) + BALB/c (4T1) · archive: downloaded (gold OA via PMC) · lipid NP co-encapsulating cdGMP (STING agonist, 45 µM) + MPLA (TLR4 agonist, 20 µM) at 2.5:1 mole ratio drove >4-fold synergistic IFN-α/β in primary DCs (IRF3/IRF5/IRF7 dependent); >3-fold lymph-node accumulation post-boost; B16F10 multivalent-peptide vaccination 100% (10/10) tumor-free at day 48; lysate vaccination 69% B16F10 / 88% Panc02 / 75% 4T1 rejection with 100% systemic rechallenge rejection across all three models; IFNAR blockade abolishes efficacy. ↩

  11. doi:10.1126/scitranslmed.adj9366 · in-vitro+in-vivo · “Nanoparticle delivery of innate immune agonists combined with senescence-inducing agents promotes T cell control of pancreatic cancer” · Chibaya L*, DeMarco KD*, Lusi CF, Kane GI et al.; Atukorale PU#, Ruscetti M# · Sci Transl Med 16(762):eadj9366 · 28 Aug 2024 · model: transplanted + autochthonous PDAC (mouse); human PDAC samples · archive: downloaded (bronze OA via HHS Public Access PMC) · STING+TLR4 dual-agonist lipid NP + trametinib MEK inhibitor + palbociclib CDK4/6 inhibitor “T/P” — senescence-induced SASP remodels immune-cold PDAC TME → NP-delivered dual-PRR agonists prime IFN-I-driven T cell response; both tumor and host STING required. **Full study page not yet seeded; claims from abstract + editor’s summary — verify before relying. needs-full-extraction ↩

Graph View

Backlinks