D94-09 Dietary Modulation of Epigenetic Aging Related Pathways in World Trade Center-Exposed Firefighters

Rationale

Environmental exposures may cause multi-organ morbidity. While we have identified diverse circulating biomarkers related to World Trade Center (WTC) site disease the methylome has not been explored. DNA methylation captures changes in pathways regulating cell-cycle control, genome stability and cellular maintenance, many of which may be involved in aging. WTC exposed first responders exhibit biomarkers of inflammation that may intersect with epigenetic changes. Therefore, in a subset of the WTC cohort we explored their methylome curated for sequences related to validated age-related mediators.

Methods

WTC-exposed firefighters with lung injury (FEV1<LLN) were randomized to either a low-calorie Mediterranean diet (LoCalMed) or usual care (UC). Genome-wide methylation profiling was performed on available paired high-quality samples (baseline vs. 6-month, LoCalMed;n=34 or UC;n=33 -Illumina EPIC array). Analyses focused on CpGs utilized in Horvath’s epigenetic clock;n=353. Within-group methylation changes evaluated using paired t-tests comparing baseline and 6-month β-values at each CpG. CpGs demonstrating statistically significant changes (p < 0.05) were annotated to genomic features and nearest genes using the Illumina EPIC array manifest implemented in R (Bioconductor). Enrichment analyses were conducted using the Reactome (www.reactome.org) and Ingenuity Pathway Analysis (IPA; Qiagen) allowing us to identify significant bioactive molecular pathways, disease associations and predict upstream regulators.

Results

Baseline characteristics were comparable between groups, including age (55.9 vs. 52.7 years at baseline; LoCalMed vs. UC), race distribution, spirometry (FEV₁ and FVC), and exposure characteristics. Distinct epigenetic trajectories were observed. Compared with UC, LoCalMed demonstrated predominant hypomethylation within promoter regions (p < 0.001), consistent with increased transcriptional potential, whereas UC showed a predominance of hypermethylation, Figure 1A.

IPA predicted tumor inhibition and increased survival in LoCalMed, Figure 1B, while UC showed only isolated retinoic acid receptor activation, data not shown.

Reactome pathway analysis further characterized these findings, with LoCalMed-associated genes showing coordinated enrichment across interconnected biological processes related to centrosome organization, cilium assembly, and mitochondrial biogenesis, reflected by higher gene ratios and overlap, Figure1C-E, In contrast, UC demonstrated heterogeneous enrichment, with functionally diverse pathways, Figure-1F, variable gene ratios across functionally distinct pathways spanning multiple biological domains, Figure-1G, and a Reactome overview map dominated by a localized MITF-M-regulated transcriptional module lacking broader pathway integration, Figure-1H.

Conclusion

A six-month LoCalMed intervention was associated with coordinated epigenetic change across aging-related pathways in WTC-exposed firefighters. These findings support diet as a modifiable factor influencing epigenetic mechanisms relevant to biological aging. Longer follow-up and integrative multi-omics studies are warranted.

This abstract is funded by: CDC/NIOSH U01-OH011300