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

<b>Purpose. </b>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.<b>Methods</b>. 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.<b>Results. </b>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., <i>CXCL1/2</i>) and matrix remodeling genes (e.g., <i>LOX</i>). Conserved aging hallmarks included mitochondrial dysfunction (e.g., <i>MT-ND4/5/6</i> 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., <i>BHLHE40</i>) alongside cell-type-specific dysregulation.<b>Conclusions.</b> 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.