Interpretable Aging Signatures in Human Retinal Cell Types Revealed by Single-Cell RNA Sequencing and Sparse Logistic Regression

Purpose. This study aims to characterize the age-dependent transcriptional and cellular landscape of the human retina using single-cell RNA sequencing (scRNA-seq) in a Chinese cohort, with a focus on identifying conserved and cell-type-specific aging signatures. Additionally, it investigates how diabetic retinopathy (DR) accelerates or modifies normal aging processes in retinal tissues.Methods. Our cohort comprised 18 retinal samples from 13 Chinese donors (8 male, 5 female, ages 34–92 years), stratified into young (34-55 years) and old (68-92 years) groups. Samples were collected from both living donors and cadaveric sources without frozen, with balanced representation of diabetic status (7 DR, 3 diabetics without retinopathy, 8 non-diabetic). The whole retinal tissue without selective regional dissection was used to avoid sampling bias, with subsequent analysis focusing on photoreceptors, interneurons, and glial cells.Results. Aging was associated with shifts in retinal cellular composition, including a decreased rod-to-cone ratio, reduced bipolar cell proportions among interneurons, and increased astrocyte proportions within glial populations. Müller glial cells exhibited the most pronounced transcriptional changes, with upregulation of inflammatory mediators (e.g., CXCL1/2) and matrix remodeling genes (e.g., LOX). Conserved aging hallmarks included mitochondrial dysfunction (e.g., MT-ND4/5/6 downregulation) and inflammatory activation across multiple cell types. DR amplified these changes, particularly in synaptic signaling and inflammatory pathways. Transcriptional regulatory analysis revealed conserved activation of stress-responsive regulators (e.g., BHLHE40) alongside cell-type-specific dysregulation.Conclusions. This study provides a comprehensive characterization of age-related transcriptional and cellular changes in the human retina, revealing both conserved molecular hallmarks and unique cell-type-specific vulnerabilities. By including a Chinese cohort and stratifying by disease status, we highlight how DR amplifies aging-related inflammatory signaling and synaptic remodeling, offering critical insights into potential therapeutic targets for mitigating retinal degeneration across diverse populations.