(OR20-05-26) Blueberry Supplementation in Older Adults Alters the Epigenomic Landscape With Enrichment Across Neuronal, Cardiovascular, and Metabolic Gene Networks

Objectives: To determine whether wild blueberry (Vaccinium angustifolium); BB) supplementation in older adults is associated with differential DNA methylation and to evaluate whether differentially methylated genes are enriched in pathways related to neuronal, cardiovascular, and metabolic function.

Methods: Older adults (≥65 years) were enrolled in a randomized double-blind clinical trial and consumed either placebo powder or freeze-dried wild BB powder (equivalent to 2 cup/day; N=6/group) for 12 weeks. Buffy coat was collected for DNA extraction and Reduced Representation Bisulfite Sequencing. Methylation differences ≥10% were considered biologically significant. Enrichment analyses (p < 0.05) were performed on RRBS-derived differentially methylated genes. In silico docking energies ≤ -7 kcal/mol were defined as favorable binding to epigenetic enzymes.

Results: Wild BB treatment resulted in differential methylation of 798 mRNA genes, 655 miRNA genes, and 1,131 lncRNA genes. Genome-wide methylation changes ≥10% showed 52% hypermethylation and 48% hypomethylation. Enrichment analysis demonstrated significant enrichment by BB treatment in neuronal pathways, including axon guidance, oxytocin signaling, brain-derived neurotrophic factor signaling, and gap junction. Cardiovascular pathways enriched included VEGFA-VEGFR2 signaling, platelet activation, and lipid and atherosclerosis pathways. Metabolic pathways enriched included circadian entrainment, insulin signaling, and insulin secretion. Disease enrichment identified nervous system disease, cardiovascular disease, gastrointestinal disease, and diabetes mellitus among the top categories. In silico docking of parent flavonoids (malvidin-3-glucoside, delphinidin-3-O-glucoside, malvidin-3-galactose, and petunidin-3-O-glucoside) demonstrated favorable binding (-7 to -9 kcal/mol) across multiple epigenetic enzymes, including DNMT1, EZH2, FTO, HDAC4, and KDM6B.

Conclusions: The BB treatment altered the epigenome, with enrichment in genes and pathways relevant to cognitive, cardiovascular, and metabolic health. These pathways align with previously reported benefits of BB consumption and suggest epigenomic modification as a potential mechanism of action for polyphenolic bioactives.

Funding Sources: RO1AG084660