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

Abstract

Purpose: To investigate the association between epigenetic age acceleration and glaucoma progression.

Design: Retrospective cohort study.

Participants: A total of 100 patients with primary open-angle glaucoma (POAG) with fast progression and 100 patients with POAG with slow progression.

Methods: Patients 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 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 age acceleration 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% confidence interval [CI], -1.28 to -0.85 dB/year) for fast progressors compared with -0.10 dB/year (95% CI, -0.16 to -0.04 dB/year) for slow progressors (P < 0.001). For RNFL thickness, corresponding values were -1.60 μm/year (95% CI, -1.97 to -1.23 μm/year) and -0.76 μm/year (95% CI, -1.04 to -0.48 μm/year), respectively (P < 0.001). Fast progressors demonstrated significantly greater age acceleration compared with slow progressors for the Horvath clock (mean difference, 2.93 years; 95% CI, 1.48-4.39 years; P < 0.001) and Hannum clock (mean difference, 1.24 years; 95% CI, 0.03-2.46 years; P = 0.045). In multivariable models, each year of Horvath age acceleration was associated with 15% higher odds of fast progression (odds ratio, 1.15; 95% CI, 1.07-1.23; P < 0.001). Hannum and GrimAge clocks also showed significant associations with fast progression. The association between age acceleration and fast progression was stronger in those with relatively low IOP during follow-up.

Conclusions: 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.

Financial disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Keywords: Aging; Epigenetics; Glaucoma; Glaucoma progression; Methylation.