ABSTRACT

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.

Competing Interest Statement

F.A.M.: AbbVie (C), Annexon (C); Carl Zeiss Meditec (C), Galimedix (C); Google Inc. (F); Heidelberg Engineering (F), nGoggle Inc. (P), Novartis (F); Stealth Biotherapeutics (C); Stuart Therapeutics (C), Thea Pharmaceuticals (C), Reichert (C, F). A.V.: None. A.A.J.: None. H.T.: Novartis (F). W.K.S.: None.

Funding Statement

Supported in part by National Institutes of Health/National Eye Institute grant EY029885 (F.A.M), Aging Team Science Grant from the University of Miami (F.A.M), Shaffer Grant from the Glaucoma Research Foundation (F.A.M). The funding organizations had no role in the design or conduct of this research.

Author Declarations

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The Duke University and the University of Miami Institutional Review Boards approved this study. Informed consent was obtained from all participants. All methods adhered to the tenets of the Declaration of Helsinki for research involving human subjects and were conducted in accordance with regulations of the Health Insurance Portability and Accountability Act.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

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I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

Data Availability

All data produced in the present study are available upon reasonable request to the authors.

AbbreviationsAgeAccelAge accelerationCCTcentral corneal thicknessCpGcytosine-phosphate-guanineDGRDuke Glaucoma RegistryGATGoldmann applanation tonometryIOPintraocular pressureICDinternational classification of diseasesMDmean deviationPOAGprimary open-angle glaucomaRNFLretinal nerve fiber layerSAPstandard automated perimetrySITASwedish Interactive Thresholding Algorithm