Hypothesis

Expanded mosaic chromosomal alterations (mCAs) in peripheral blood are not merely biomarkers of clonal hematopoiesis; they actively secrete a senescence‑associated secretory phenotype (SASP) that reprograms lung immune cells, creating a permissive niche for malignant transformation.

Mechanistic Rationale

1. Clonal expansion → SASP production – Large mCA‑bearing hematopoietic clones (≥10% cell fraction) exhibit DNA damage signaling and chronic proliferation stress, hallmarks of cellular senescence. Senescent cells are known to secrete IL‑6, IL‑8, MMPs, and growth factors that constitute the SASP (2).
2. SASP trafficking to lung – Circulating SASP factors reach the pulmonary epithelium and alveolar macrophages, where they induce chronic inflammation, impair antigen presentation, and promote fibroblast activation. This mirrors the immune‑suppressive milieu described for mCAR‑associated infection risk (2).
3. Microenvironmental priming for tumorigenesis – Persistent SASP signaling increases reactive oxygen species, stimulates epithelial‑to‑mesenchymal transition, and inhibits cytotoxic T‑cell surveillance, thereby lowering the threshold for oncogenic driver events in lung epithelium. The observed odds ratios for mosaic loss and lung cancer (1) could thus reflect a causal inflammatory cascade rather than mere clonal coincidence.
4. Feedback loop – Lung‑derived damage‑associated molecular patterns (DAMPs) further amplify hematopoietic stress, accelerating mCA clone expansion—a vicious cycle linking clonal hematopoiesis and solid‑tumor initiation.

Testable Predictions

• Prediction 1: Individuals with high‑fraction blood mCAs will have elevated circulating SASP biomarkers (IL‑6, IL‑8, GDF‑15) compared with age‑matched mCA‑negative controls, independent of smoking status.
• Prediction 2: Elevated SASP levels will correlate with increased lung‑tissue immune infiltration of immunosuppressive myeloid‑derived suppressor cells (MDSCs) and reduced CD8⁺ T‑cell activity, measurable via bronchoalveolar lavage flow cytometry.
• Prediction 3: Intervening with a senolytic agent (e.g., dasatinib + quercetin) in mCA‑positive participants will reduce SASP cytokine levels, decrease lung MDSC frequency, and lower the incidence of radiographically detected lung nodules over a 2‑year follow‑up.

Experimental Design

1. Cohort: Recruit 500 adults aged 55‑75 from existing biobanks with baseline whole‑blood sequencing to quantify mCA burden and cell fraction.
2. Baseline assays: Plasma SASP panel, pulmonary function tests, low‑dose CT lung imaging, and peripheral blood immunophenotyping.
3. Randomization: mCA‑positive subjects (≥5% fraction) randomized 1:1 to senolytic therapy or placebo for 12 months; mCA‑negative subjects serve as observational controls.
4. Follow‑up: Repeat SASP profiling, imaging, and immune assays at 6, 12, and 24 months. Primary endpoint: change in plasma IL‑6; secondary endpoint: new lung nodules or cancer diagnosis.
5. Statistical analysis: Use mixed‑effects models to test interaction between mCA fraction, treatment, and SASP trajectories; Cox proportional hazards for cancer incidence.

Falsifiability

If senolytic treatment fails to reduce SASP biomarkers or does not alter lung immune composition or nodule formation compared with placebo, the hypothesis that blood mCAs drive lung cancer via SASP‑mediated immune remodeling would be refuted. Conversely, a significant reduction in SASP and downstream oncologic endpoints would support a causal mechanistic link, suggesting that targeting clonal senescence could intercept solid‑tumor development in mCAR‑positive individuals.