Hypothesis

Age‑associated mosaic chromosomal alterations (mCAs), particularly large losses, are not merely passive markers of genomic instability but actively promote organismal aging by triggering a chronic innate immune response in the hematopoietic niche. We propose that haploinsufficiency of dosage‑sensitive tumor‑suppressor and DNA‑repair genes on lost chromosome segments increases replication stress and micronucleus formation in hematopoietic stem cells (HSCs). The resulting cytosolic DNA activates the cGAS‑STING pathway in HSCs and their progeny, leading to sustained type‑I interferon (IFN) signaling, inflammasome activation, and the release of pro‑inflammatory cytokines that propagate systemic inflammaging and accelerate non‑cancer aging phenotypes (e.g., frailty, cognitive decline). This mechanism predicts that individuals with expanded mosaic losses (≥10% cell fraction) will exhibit elevated circulating cell‑free DNA (cfDNA), heightened cGAS‑STING activity biomarkers, and faster accumulation of aging‑related clinical deficits, independent of traditional cancer risk.

Mechanistic Rationale

1. Dosage‑sensitive haploinsufficiency → replication stress – Losses affecting genes such as TP53, ATM, or BRCA1/2 (commonly observed in mCA datasets) reduce DNA‑damage checkpoint fidelity, increasing stalled forks and micronuclei [2]. Micronuclei are prone to envelope rupture, exposing DNA to the cytosol.
2. Cytosolic DNA → cGAS‑STING activation – Cytosolic DNA is a potent agonist of the cyclic GMP‑AMP synthase (cGAS)‑stimulator of interferon genes (STING) pathway, driving IFN‑β production and NF‑κB‑mediated inflammation [3]. In HSCs, low‑grade STING signaling biases differentiation toward myeloid lineages and promotes senescence‑associated secretory phenotype (SASP).
3. Paracrine inflammaging – SASP factors (IL‑6, TNF‑α, IFN‑α) enter circulation, stimulating stromal and epithelial tissues, thereby propagating low‑grade inflammation that contributes to sarcopenia, neuroinflammation, and vascular stiffening.
4. Ancestry‑specific modulation – Epigenetic landscapes influencing chromatin accessibility at lost loci differ across populations (e.g., higher chromosome X mCAs in African/Hispanic XX individuals) [3], potentially altering the threshold for cGAS‑STING activation and explaining variability in inflammaging trajectories.

Testable Predictions

• Biomarker correlation: In longitudinal cohorts (e.g., UK Biobank, ACCORD), participants with expanded mosaic losses will show higher plasma cfDNA levels, increased phosphorylated STING (p-STING) in peripheral blood mononuclear cells, and elevated serum IFN‑α/IFN‑β compared with age‑matched controls lacking such mCAs.
• Functional linkage: Experimental induction of chr7p11.2 or chr20q13.33 loss in human HSCs (via CRISPR‑Cas9‑mediated chromosome engineering) will increase micronucleus frequency, cytosolic DNA, and STING‑dependent transcription, which can be rescued by pharmacological STING inhibition (e.g., H‑151).
• Phenotypic outcome: Individuals harboring both high polygenic risk scores for lung cancer and expanded mosaic losses will exhibit accelerated frailty index accumulation over 5 years, surpassing the risk predicted by either factor alone (synergistic HR >3.75 as reported for cancer) [4].
• Ancestry interaction: Stratified analysis will reveal a stronger cfDNA‑STING‑inflammaging axis in populations with higher baseline mCA rates on specific chromosomes (e.g., chromosome X in African/Hispanic XX), after adjusting for age and sex.

Experimental Approach

1. Cohort phenotyping – Obtain whole‑genome sequencing data from blood DNA to quantify mCA burden and size; measure plasma cfDNA, p‑STING, and cytokine panels.
2. Single‑cell multi‑omics – Perform scDNA‑seq + scRNA‑seq on sorted HSCs to link specific loss events with transcriptional signatures of DNA damage response and STING pathway activation.
3. Intervention studies – Treat mCA‑positive HSC cultures with STING inhibitors; assess reduction in SASP cytokine secretion and improvement in proliferative capacity.
4. In vivo validation – Engraft edited HSCs with defined mosaic losses into immunodeficient mice; monitor systemic inflammation markers and age‑related functional decline versus controls.

If validated, this hypothesis reframes mCAs as active drivers of inflammaging, offering a mechanistic bridge between somatic mosaicism, cancer predisposition, and broader age‑related decline, and suggests STING pathway modulation as a potential intervention to mitigate non‑cancer aging trajectories.