Accelerated Epigenetic Aging is Associated with Faster Glaucoma Progression: A DNA Methylation Study.

Purpose: To investigate the association between epigenetic age acceleration and glaucoma progression. Design: Retrospective cohort study. Participants: 100 primary open-angle glaucoma (POAG) patients with fast progression and 100 POAG patients with slow progression. Methods: Subjects were classified as fast or slow progressors based on rates of change in standard automated perimetry (SAP) mean deviation (MD) and retinal nerve fiber layer (RNFL) thickness. Epigenetic age was calculated using the Horvath, Hannum, PhenoAge, and GrimAge clocks from DNA methylation profiles obtained from blood samples. Age acceleration (AgeAccel) was defined as the residual from a linear regression of epigenetic age on chronologic age, with positive values suggesting faster biological aging. Multivariable logistic regression models estimated the association between AgeAccel and likelihood of fast progression, adjusting for confounders. Main Outcome Measures: Difference in epigenetic age acceleration between fast and slow glaucoma progressors. Results: The mean rate of SAP MD change in the fastest progressing eye was -1.06 dB/year (95% CI: -1.28 to -0.85) for fast progressors compared to -0.10 dB/year (95% CI: -0.16 to -0.04) for slow progressors (P<0.001). For RNFL thickness, corresponding values were -1.60 μm/year (95% CI: -1.97 to -1.23) and -0.76 μm/year (95% CI: -1.04 to -0.48), respectively (P<0.001). Fast progressors demonstrated significantly greater age acceleration compared to slow progressors for the Horvath clock (mean difference = 2.93 years, 95% CI: 1.48 to 4.39, P<0.001) and Hannum clock (mean difference = 1.24 years, 95% CI: 0.03 to 2.46, P=0.045). In multivariable models, each year of Horvath AgeAccel was associated with 15% higher odds of fast progression (OR 1.15, 95% CI 1.07-1.23, P<0.001), after adjusting for sex, race, intraocular pressure, central corneal thickness, baseline disease severity, smoking status and follow-up time. Hannum and GrimAge clocks also showed significant associations with fast progression. The association between AgeAccel and fast progression was stronger in subjects with relatively low IOP during follow-up. Conclusion: Accelerated epigenetic aging was associated with faster glaucoma progression. These findings suggest that faster biological age, as reflected in DNA methylation, may increase optic nerve susceptibility to damage, highlighting epigenetic age as a potential prognostic biomarker.