Egr1/Gc/vitamin transport axis mediates synergistic effect of macular thinning and underweight in age-related visual acuity decline

To investigate the associated risk factors and potential molecular mechanisms affecting visual acuity (VA) in the elderly, this cross-sectional, population-based study collected the general information, past medical history and ophthalmologic data of 841 Shanghai elderly residents (mean age 69.61 ± 5.70 years, range 52-92 years). Univariate and multivariate logistic regression analyses revealed that the presenting worse VA problem was significantly associated with being underweight (OR = 3.071, P = 0.002). Across nine distinct macular retinal regions, thinning within 0.5-3.0 mm of the fovea (excluding the superior inner retina) was significantly associated with worse VA (all P < 0.05). Mouse models demonstrated that, compared to the simple retinal thinning group, the retinal thinning combined with underweight group exhibited more severe structural damage and elevated cell apoptosis rates via hematoxylin and eosin (HE) and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining. Electroretinogram showed that combined retinal thinning and underweight synergistically exacerbated visual dysfunction. To further explore the molecular mechanism underlying the retinal thinning-underweight phenotype, bulk RNA-seq analysis revealed a significant downregulation of vitamin D-binding protein (Gc), which was positively regulated by the transcription factor, early growth response 1 (Egr1). Pathway analysis highlighted the involvement of vitamin transmembrane transporter activity. Consistent with bioinformatics predictions, Western blot confirmed a significant downregulation of both Gc and Egr1 in the retinal thinning-underweight group. Collectively, we identified underweight and retinal thinning as systemic and ocular risk factors for worse VA in the elderly. Their synergistic effect deteriorated VA through the Egr1/Gc/vitamin transport axis.