{
  "signature_set_id": "LACA-HOA12-TRANSCRIPTOME-v1",
  "framework_reference": {
    "title": "Hallmarks of aging: An expanding universe",
    "doi": "10.1016/j.cell.2022.11.001",
    "pmid": "36599349"
  },
  "scope": "Human transcriptomic proxy signatures for exploratory single-cell visualization. These are not direct functional assays or diagnostic scores.",
  "signatures": [
    {
      "id": "genomic_instability",
      "label": "Genomic instability",
      "layer": "Primary",
      "evidence_level": "indirect",
      "genes": [
        "ATM",
        "ATR",
        "CHEK1",
        "CHEK2",
        "TP53",
        "BRCA1",
        "BRCA2",
        "RAD50",
        "MRE11",
        "NBN",
        "RAD51",
        "XRCC5",
        "XRCC6",
        "PARP1",
        "GADD45A",
        "DDB2",
        "XPC",
        "FANCD2"
      ],
      "interpretation": "DNA-damage sensing and repair-response transcriptional proxy.",
      "limitation": "Does not measure mutation burden, chromosome abnormalities, DNA lesions, or repair capacity."
    },
    {
      "id": "telomere_attrition",
      "label": "Telomere attrition",
      "layer": "Primary",
      "evidence_level": "indirect",
      "genes": [
        "TERT",
        "TERC",
        "DKC1",
        "TINF2",
        "TERF1",
        "TERF2",
        "POT1",
        "ACD",
        "RTEL1",
        "CTC1",
        "STN1",
        "TEN1",
        "WRAP53",
        "PIF1"
      ],
      "interpretation": "Telomere-maintenance machinery expression proxy.",
      "limitation": "Does not measure telomere length, critically short telomeres, uncapping, or telomerase activity."
    },
    {
      "id": "epigenetic_alterations",
      "label": "Epigenetic alterations",
      "layer": "Primary",
      "evidence_level": "indirect",
      "genes": [
        "DNMT1",
        "DNMT3A",
        "DNMT3B",
        "TET1",
        "TET2",
        "TET3",
        "EZH2",
        "KMT2A",
        "KDM6A",
        "SIRT1",
        "SIRT6",
        "HDAC1",
        "HDAC2",
        "HAT1",
        "CHD4",
        "SMARCA4",
        "SETDB1",
        "SUV39H1"
      ],
      "interpretation": "Chromatin and epigenetic-maintenance machinery expression proxy.",
      "limitation": "Does not measure DNA methylation age, chromatin accessibility, histone marks, or epigenetic drift."
    },
    {
      "id": "loss_of_proteostasis",
      "label": "Loss of proteostasis",
      "layer": "Primary",
      "evidence_level": "moderate_proxy",
      "genes": [
        "HSPA1A",
        "HSPA1B",
        "HSPA5",
        "HSPA8",
        "HSP90AA1",
        "HSP90AB1",
        "HSPB1",
        "HSF1",
        "DNAJB1",
        "DNAJC3",
        "XBP1",
        "ATF4",
        "ATF6",
        "DDIT3",
        "ERN1",
        "EIF2AK3",
        "PSMA1",
        "PSMB5",
        "UBE2D1",
        "SQSTM1"
      ],
      "interpretation": "Chaperone, unfolded-protein response, and proteasome stress-response proxy.",
      "limitation": "Higher expression can indicate compensation rather than proteostasis failure and does not measure aggregate load or protein turnover."
    },
    {
      "id": "disabled_macroautophagy",
      "label": "Disabled macroautophagy",
      "layer": "Primary",
      "evidence_level": "moderate_proxy",
      "genes": [
        "ULK1",
        "ULK2",
        "ATG3",
        "ATG5",
        "ATG7",
        "ATG9A",
        "ATG12",
        "ATG13",
        "ATG14",
        "BECN1",
        "MAP1LC3B",
        "GABARAP",
        "SQSTM1",
        "LAMP1",
        "LAMP2",
        "TFEB",
        "TFE3",
        "WIPI1",
        "WIPI2"
      ],
      "interpretation": "Autophagy and lysosomal machinery expression proxy.",
      "limitation": "Direction is not equivalent to disabled flux; steady-state RNA cannot distinguish induction from blocked clearance."
    },
    {
      "id": "deregulated_nutrient_sensing",
      "label": "Deregulated nutrient sensing",
      "layer": "Antagonistic",
      "evidence_level": "moderate_proxy",
      "genes": [
        "IGF1R",
        "INSR",
        "IRS1",
        "IRS2",
        "PIK3CA",
        "AKT1",
        "MTOR",
        "RPTOR",
        "RHEB",
        "TSC1",
        "TSC2",
        "RPS6KB1",
        "PRKAA1",
        "PRKAA2",
        "SIRT1",
        "FOXO1",
        "FOXO3",
        "GSK3B"
      ],
      "interpretation": "Insulin/IGF-1, mTOR, AMPK, sirtuin, and FOXO transcriptional proxy.",
      "limitation": "Does not measure phosphorylation, nutrient availability, pathway flux, or whether pathway activity is beneficial."
    },
    {
      "id": "mitochondrial_dysfunction",
      "label": "Mitochondrial dysfunction",
      "layer": "Antagonistic",
      "evidence_level": "moderate_proxy",
      "genes": [
        "PPARGC1A",
        "TFAM",
        "NRF1",
        "NFE2L2",
        "SOD2",
        "PRDX3",
        "LONP1",
        "CLPP",
        "HSPD1",
        "HSPE1",
        "ATF5",
        "OPA1",
        "MFN1",
        "MFN2",
        "DNM1L",
        "PINK1",
        "PRKN",
        "BNIP3",
        "NIX"
      ],
      "interpretation": "Mitochondrial biogenesis, dynamics, quality-control, and stress-response proxy.",
      "limitation": "Does not measure respiration, membrane potential, ATP production, redox state, morphology, or mtDNA integrity."
    },
    {
      "id": "cellular_senescence",
      "label": "Cellular senescence",
      "layer": "Antagonistic",
      "evidence_level": "stronger_proxy",
      "genes": [
        "CDKN2A",
        "CDKN1A",
        "TP53",
        "RB1",
        "GLB1",
        "SERPINE1",
        "GDF15",
        "IGFBP3",
        "IGFBP7",
        "IL6",
        "IL1A",
        "IL1B",
        "CXCL8",
        "CCL2",
        "MMP3",
        "MMP9",
        "HMGB1",
        "BCL2L1"
      ],
      "interpretation": "Multi-component arrest, lysosomal, anti-apoptotic, and SASP-associated expression proxy.",
      "limitation": "No universal senescence marker exists; inflammatory, cycling, damaged, and differentiated states can share parts of this signature."
    },
    {
      "id": "stem_cell_exhaustion",
      "label": "Stem cell exhaustion",
      "layer": "Integrative",
      "evidence_level": "indirect",
      "genes": [
        "SOX2",
        "POU5F1",
        "NANOG",
        "KLF4",
        "MYC",
        "BMI1",
        "TERT",
        "PROM1",
        "KIT",
        "LMO2",
        "GATA2",
        "RUNX1",
        "MKI67",
        "TOP2A",
        "CDKN1A",
        "CDKN2A"
      ],
      "interpretation": "Stem/progenitor identity, proliferative capacity, and arrest-associated expression proxy.",
      "limitation": "A universal cross-tissue stem-cell exhaustion score is not established; interpretation requires lineage-specific stem/progenitor annotation."
    },
    {
      "id": "altered_intercellular_communication",
      "label": "Altered intercellular communication",
      "layer": "Integrative",
      "evidence_level": "indirect",
      "genes": [
        "IL6",
        "IL1B",
        "TNF",
        "TGFB1",
        "TGFB2",
        "CXCL8",
        "CCL2",
        "CCL5",
        "CXCL10",
        "IFNG",
        "VEGFA",
        "EGF",
        "FGF2",
        "PDGFA",
        "PDGFB",
        "JAG1",
        "DLL4",
        "WNT5A",
        "HMGB1"
      ],
      "interpretation": "Cytokine, chemokine, growth-factor, and damage-signal expression proxy.",
      "limitation": "Does not establish ligand-receptor pairing, signaling direction, spatial proximity, or functional communication."
    },
    {
      "id": "chronic_inflammation",
      "label": "Chronic inflammation",
      "layer": "Integrative",
      "evidence_level": "stronger_proxy",
      "genes": [
        "IL1B",
        "IL6",
        "TNF",
        "NFKB1",
        "RELA",
        "NFKBIA",
        "PTGS2",
        "CCL2",
        "CCL5",
        "CXCL8",
        "CXCL10",
        "NLRP3",
        "PYCARD",
        "CASP1",
        "S100A8",
        "S100A9",
        "STAT1",
        "IRF7",
        "ISG15"
      ],
      "interpretation": "NF-kB, inflammasome, cytokine, and interferon-associated inflammatory expression proxy.",
      "limitation": "Cross-sectional expression cannot establish chronicity and may reflect infection, acute injury, composition, or technical effects."
    },
    {
      "id": "dysbiosis",
      "label": "Dysbiosis",
      "layer": "Integrative",
      "evidence_level": "host_response_only",
      "genes": [
        "TLR2",
        "TLR4",
        "TLR5",
        "TLR9",
        "MYD88",
        "NOD1",
        "NOD2",
        "MUC2",
        "TJP1",
        "OCLN",
        "CLDN1",
        "DEFA5",
        "DEFA6",
        "REG3A",
        "LYZ",
        "IL22",
        "IL17A",
        "AHR"
      ],
      "interpretation": "Host microbial sensing, epithelial barrier, and antimicrobial-response proxy.",
      "limitation": "No microbiome measurements are present; this score must not be interpreted as microbial community dysbiosis."
    }
  ]
}