**Background:** Bloom syndrome (BSyn) is a rare autosomal recessive disorder caused by biallelic null variants in the BLM gene, which encodes a RecQ DNA helicase essential for replication fork stability. Patients exhibit a 10-fold increase in sister chromatid exchanges, short stature, telangiectatic erythema, immunodeficiency, and a high predisposition to cancers such as leukemia, lymphoma, and colorectal cancer. While persistent DNA damage is thought to drive aging, it was unknown whether BSyn leads to measurable molecular aging. Epigenetic clocks, which estimate biological age from DNA methylation patterns, are robust predictors of health and mortality. This study hypothesized that BSyn patients and a mouse model would show accelerated epigenetic aging.
**Methods:** The study analyzed blood samples from 18 BSyn patients (age 1–38 years) and 30 carriers (age 23–69 years) from the Bloom Syndrome Registry, Jscreen, and UCLA. DNA methylation was profiled using the Illumina Infinium Methylation EPIC v2.0 kit (866k CpG sites). Epigenetic age was calculated using five clocks: pan-tissue (Horvath), skin and blood, Hannum, GrimAge, and PhenoAge. DNA methylation-based telomere length (DNAmTL) was also estimated. For the mouse model, brain, heart, kidney, liver, skin, and blood were collected from four wildtype (Blm^+/+^), four heterozygous (Blm^+/m3^), and four homozygous (Blm^m3/m3^) mice aged 70–73 days. Methylation was measured using the HorvathMammalMethylChip320 array. Mouse clocks included pan-tissue, tissue-specific, and brain clocks. Epigenome-wide association studies (EWAS) and GREAT enrichment analyses were performed to identify differentially methylated regions and biological pathways.
**Key Results:** In humans, BSyn patients showed significantly increased epigenetic age compared to carriers across all clocks: pan-tissue (p < 0.05), skin and blood (p < 0.05), Hannum (p < 0.05), GrimAge (p < 0.05), and PhenoAge (quadratic regression, p < 0.05). DNAmTL was significantly shorter in BSyn patients (p < 0.05). In mice, the pan-tissue clock did not detect significant age acceleration in Blm^m3/m3^ mice. However, the tissue-specific brain clock showed significantly increased DNAm age in brain (p < 0.0021), but not in heart, kidney, liver, skin, or blood. The murine brain clock applied to other tissues revealed increased DNAm age in brain, heart, kidney, skin, and blood (p < 0.0021 to p < 0.0002). EWAS identified hypermethylated regions enriched in DNA packaging, chromatin assembly, and remodeling pathways, and hypomethylated regions in immune-related genes (C-type lectin, Ly49-like N-terminal). GREAT analyses highlighted hypermethylated regions associated with Th1 cell upregulation, post-radiation tumor escape, breast cancer invasiveness, and acute myeloid leukemia stem cells.
**Clinical Implications:** This study provides the first molecular evidence of accelerated epigenetic aging in Bloom syndrome, detectable in both humans and a mouse model. The consistent acceleration across multiple clocks suggests that epigenetic age could serve as a biomarker for cancer risk and other clinical outcomes in BSyn. The finding that carriers do not show accelerated aging may inform genetic counseling. The tissue-specific effects in mice, particularly the brain clock, warrant further investigation into neurological involvement. The identified pathways (chromatin remodeling, immune function) offer potential targets for therapeutic intervention. Limitations include small sample size, lack of data on confounders like smoking, and the hypomorphic nature of the mouse model. Future studies should explore whether epigenetic age acceleration correlates with cancer development and other clinical features in BSyn.