Corneal Nerve Fiber Morphology and Biological Age in Healthy Adults

Background/Objectives: Corneal confocal microscopy (CCM) quantifies subbasal corneal nerve fibers noninvasively and may inform peripheral neuroaging. PhenoAge is a validated clinical measure of biological aging linked to morbidity and mortality risk and therefore provides a geriatric-relevant index of systemic aging. We aimed to assess corneal nerve morphology in clinically healthy adults and determine whether CCM-derived parameters are associated with biological age (PhenoAge) beyond chronological age. Methods: Eighty-four healthy volunteers (22-89 years) underwent CCM. PhenoAge was calculated using the Levine algorithm. Associations with chronological age and PhenoAge were tested using Spearman correlations (eye-specific and participant-level mean of both eyes). Paired inter-eye differences were assessed, and linear mixed-effects models (random intercept for participant; fixed effects for age/PhenoAge and eye) were fitted. Results: Mean chronological age was 50.8 ± 15.5 years, and mean PhenoAge was 47.1 ± 16.3 years. No systematic inter-eye differences were detected (all p > 0.05). Across analyses, older age and higher PhenoAge were associated with lower main corneal nerve fiber measures, most consistently for main-fiber density. Participant-level sensitivity analysis (mean of both eyes) confirmed inverse associations of both chronological age and PhenoAge with main-fiber length and density (all p ≤ 0.035). In mixed-effects models, main-fiber density was associated with chronological age (β = -0.020/year, p = 0.032) and PhenoAge (β = -0.019/year, p = 0.037). Conclusions: CCM-derived corneal nerve morphology demonstrates aging-related patterns in clinically healthy adults. The association between PhenoAge and main-fiber density may suggest a systemic biological aging component and warrants longitudinal validation.