Sex-specific nonlinear DNA methylation aging trajectories reveal biomarkers of cancer risk and inflammation.

SNITCH detected complex nonlinear methylation trajectories and disentangled shared from sex-divergent aging patterns in whole-blood methylomes.

• Applied to array-derived whole-blood methylomes from 252 females and 246 males aged 19–90 years
• The framework identifies convergent and divergent epigenetic aging pathways independent of immune cell composition
• SNITCH was designed to overcome the limitation of most studies that assume linear age relationships and analyze mixed-sex cohorts

Nonlinear DNA methylation trajectories are enriched for developmental transcription factor motifs with known oncogenic roles.

• Enriched motifs include NF1/CTF and REST
• Both NF1/CTF and REST have known oncogenic roles
• This enrichment was identified across the nonlinear trajectory clusters detected by SNITCH

A female-specific nonlinear DNA methylation cluster is prospectively associated with cancer onset in an independent cohort.

• The association was identified prospectively, suggesting predictive or preclinical relevance
• The cluster was specific to females, highlighting sex-divergent epigenetic aging programs
• This finding nominates clinically relevant biomarkers for cancer risk

A female-specific nonlinear DNA methylation cluster is prospectively associated with systemic inflammation in an independent cohort.

• The association with systemic inflammation was identified in the same female-specific nonlinear cluster linked to cancer onset
• The analysis was conducted in an independent cohort, supporting external validity
• Findings were described as nominating clinically relevant biomarkers

Nonlinear aging trajectories and their sex-specific patterns were replicated in an additional cohort.

• Replication analysis highlighted consistent nonlinear trajectories across cohorts
• Replication was performed independently of the discovery cohort of 252 females and 246 males
• Consistency of nonlinear trajectories across cohorts supports robustness of the SNITCH framework findings

Sex-specific nonlinear epigenetic aging programs capture dynamics of epigenetic change beyond what linear models detect.

• Most existing studies assume linear age relationships and analyze mixed-sex cohorts, which risks obscuring critical nonlinear transitions and sex-specific trajectories
• SNITCH reveals both convergent and divergent epigenetic aging pathways between sexes
• The results advance understanding of how aging trajectories diverge between sexes at the epigenomic level