Data from a recent retrospective cohort study shows a significant association between epigenetic age acceleration and the rate of glaucoma progression. Researchers led by Felipe A. Medeiros, MD, PhD a professor of ophthalmology and vice-chair of research at the Bascom Palmer Eye Institute in Miami, found that primary open-angle glaucoma (POAG) patients with faster disease progression exhibited greater epigenetic aging, as measured by DNA methylation patterns, than those with slower progression.
“Faster biological aging, indicated by epigenetic age, has been linked to age-related diseases such as cardiovascular diseases, and neurodegenerative disease like Alzheimer and Parkinson’s,” said Alessandro Jammal, MD, PhD, of the Bascom Palmer Eye Institute, who presented the findings at the American Glaucoma Society’s 2025 meeting in Washington, DC. “We hypothesized that individuals with faster disease progression would demonstrate an accelerated biological age as indicated by a greater divergence between epigenetic and chronological age compared to those with slower progression.”
Epigenetic age, distinct from chronological age, reflects biological aging through DNA methylation patterns. It is calculated using epigenetic clocks such as the Horvath, Hannum, PhenoAge, and GrimAge clocks. These clocks assess specific cytosine-phosphate-guanine (CPG) sites that consistently undergo methylation or demethylation with aging. “Epigenetics is the study of alterations in gene expression without changes in the DNA sequence itself,” Jammal explained. “The epigenetic clocks sample some of these CPG sites and generate accurate biological age estimates."
The study examined 200 POAG patients, divided evenly between those with fast and slow progression. Fast progressors were identified based on significant declines in standard automated perimetry (SAP) mean deviation and retinal nerve fiber layer (RNFL) thickness. DNA methylation profiles from blood samples were used to calculate epigenetic age, and age acceleration (AgeAccel) was determined as the residual from a linear regression of epigenetic age on chronological age. Positive values indicated faster biological aging.
Results showed that fast progressors had significantly greater age acceleration than slow progressors when assessed with the Horvath (mean difference = 2.93 years, P<.001) and Hannum (mean difference = 1.24 years; P=.045) clocks. Multivariable logistic regression models revealed that each additional year of Horvath AgeAccel increased the odds of fast progression by 15% (P<.001), after adjusting for confounders such as sex, race, intraocular pressure (IOP), central corneal thickness, baseline disease severity, smoking status, and follow-up time.
“For the Horvath clock, the fast progressors had significantly greater age acceleration compared to those with slow progression, with a mean difference of 2.9 years,” Jammal said. “We also did a subanalysis on POAG patients who had no history of elevated IOP—defined as never having a clinic visit with IOP above 21 mmHg—and in these eyes, the mean age acceleration was almost five years for the Horvath clock.”
The findings suggest that biological aging may contribute to optic nerve susceptibility beyond IOP-related damage. The effect was particularly pronounced in patients who progressed despite relatively lower IOP, indicating that accelerated aging could play a role independent of traditional risk factors.The study also raises the possibility of incorporating epigenetic aging metrics into predictive models for glaucoma progression. “For practical applications, we see that predictive models incorporating epigenetic age may be able to identify fast progressors,” Jammal noted. “This still requires prospective validation. Therapies aimed at slowing aging or enhancing mitochondrial function may have neuroprotective potential in glaucoma.” Further research is necessary to establish causality and explore therapeutic interventions, he noted.
The study has been accepted for publication in Ophthalmology and is available online, noted Dr. Jammal. GP
