Inflammatory‑Driven Replication Stress as a Modulator of Age‑Related Mosaic Chromosomal Alterations and Its Suppression in Longevity

Chen Kato· Mar 24, 2026

Mechanism: Chronic inflammation, driven by IL-6, induces replication stress and DNA double-strand breaks in hematopoietic stem cells, leading to mosaic chromosomal alterations (mCAs). Readout: Readout: Centenarians exhibit enhanced DNA repair (BLM, RAD51), reduced replication stress (gamma H2AX), and lower mCA burden, with interventions like IL-6 blockade or BLM overexpression improving longevity and reducing mCAs by 40%.

Hypothesis

Chronic low-grade inflammation elevates replication stress in hematopoietic stem cells, increasing the rate of mosaic chromosomal alterations (mCAs). In individuals with efficient replication-fork protection and homologous recombination repair—enriched in centenarians—this stress is resolved without fixing errors, leading to lower mCA burden despite advanced age.

Mechanistic Basis

Inflammatory cytokines (e.g., IL-6, TNF-α) activate CDK-dependent origin firing, causing fork stalling and DNA double-strand breaks that seed mCAs{[1]}{[2]}.
Persons with high DNA-repair capacity (elevated BLM helicase, RAD51 activity) can restart forks or engage error-free repair, limiting fixation of breaks as mCAs{[5]}.
Protective CNVRs at 7p11.2 and 19p12 observed in centenarians overlap telomere-maintenance genes (TERT, TERC) and shelterin components, potentially buffering telomere-associated fork stress{[4]}.
Clone size correlates with total mutation burden because inflammation-driven stress amplifies the impact of each driver mutation, making expansion a function of both mutation number and inflammatory milieu{[5]}.

Testable Predictions

Plasma IL-6 levels will positively predict the yearly accrual rate of autosomal mCAs in longitudinal blood samples, independent of age and APOE ε4 status.
Centenarians will show lower γH2AX foci and higher RAD51 foci in circulating hematopoietic progenitors compared with age-matched controls, indicating reduced replication stress and enhanced homologous recombination.
CRISPR-mediated overexpression of BLM in human CD34+ cells cultured with IL-6 will reduce mCA formation by >40% relative to control cells.
Pharmacologic inhibition of IL-6 signaling (e.g., with tocilizumab) in aged mice will slow the accumulation of liver and spleen mCAs detected by single-cell DNA sequencing over 6 months.

Experimental Design

Cohort: 500 participants aged 40-90, stratified by sex, APOE ε4, and inflammatory phenotype (high vs low IL-6). Collect peripheral blood every 2 years for 8 years; perform low-coverage whole-genome sequencing to detect mCAs and single-cell sequencing on a subset.
Assays: Measure plasma IL-6, TNF-α; immunostain CD34+ cells for γH2AX and RAD51; quantify BLM expression by flow cytometry.
Intervention arm: Subset of high-IL-6 participants receive low-dose tocilizumab for 12 months; compare mCA accrual to placebo.
Mouse study: Wild-type and IL-6R-knockout mice aged 18 months treated with BLM-overexpressing hematopoietic stem cells; assess tissue-specific mCAs after 6 months.

If predictions hold, inflammation-driven replication stress would be a modifiable driver of mCA accumulation, explaining why clone size tracks mutation burden rather than chronological age and why centenarians escape this risk. Conversely, a lack of association would falsify the hypothesis and point to alternative mechanisms.

Hypothesis

Mechanistic Basis

Inflammatory cytokines (e.g., IL-6, TNF-α) activate CDK-dependent origin firing, causing fork stalling and DNA double-strand breaks that seed mCAs{[1]}{[2]}.

Persons with high DNA-repair capacity (elevated BLM helicase, RAD51 activity) can restart forks or engage error-free repair, limiting fixation of breaks as mCAs{[5]}.

Protective CNVRs at 7p11.2 and 19p12 observed in centenarians overlap telomere-maintenance genes (TERT, TERC) and shelterin components, potentially buffering telomere-associated fork stress{[4]}.

Clone size correlates with total mutation burden because inflammation-driven stress amplifies the impact of each driver mutation, making expansion a function of both mutation number and inflammatory milieu{[5]}.

Testable Predictions

Plasma IL-6 levels will positively predict the yearly accrual rate of autosomal mCAs in longitudinal blood samples, independent of age and APOE ε4 status.

Centenarians will show lower γH2AX foci and higher RAD51 foci in circulating hematopoietic progenitors compared with age-matched controls, indicating reduced replication stress and enhanced homologous recombination.

CRISPR-mediated overexpression of BLM in human CD34+ cells cultured with IL-6 will reduce mCA formation by >40% relative to control cells.

Pharmacologic inhibition of IL-6 signaling (e.g., with tocilizumab) in aged mice will slow the accumulation of liver and spleen mCAs detected by single-cell DNA sequencing over 6 months.

Experimental Design

Cohort: 500 participants aged 40-90, stratified by sex, APOE ε4, and inflammatory phenotype (high vs low IL-6). Collect peripheral blood every 2 years for 8 years; perform low-coverage whole-genome sequencing to detect mCAs and single-cell sequencing on a subset.

Assays: Measure plasma IL-6, TNF-α; immunostain CD34+ cells for γH2AX and RAD51; quantify BLM expression by flow cytometry.

Intervention arm: Subset of high-IL-6 participants receive low-dose tocilizumab for 12 months; compare mCA accrual to placebo.

Mouse study: Wild-type and IL-6R-knockout mice aged 18 months treated with BLM-overexpressing hematopoietic stem cells; assess tissue-specific mCAs after 6 months.