Development of the retinal senescence protein signature based on proteomics to evaluate the progression of diabetic retinopathy

Diabetic retinopathy (DR) is a leading cause of visual impairment, with biological aging implicated in its pathogenesis. However, how cellular senescence (CS) relates to DR's progression remains unclear. This study aimed to develop a senescence-associated proteomic signature to evaluate DR's progression. We performed a proteomic analysis of ocular fluid samples from Guangdong DR Multiple-Omics Study (GD-RMOS) patients across DR stages defined by clinical records and the International Classification of Diseases (10th Revision) (ICD-10). Multivariate linear regression identified 1,228 proteins significantly associated with DR severity from 6,379 candidates. Intersection with the CellAge and senescence-associated secretory phenotype (SASP) databases yielded 307 proteins defining the retinal senescence protein signature (RSPS). A weighted RSPS score was developed and then validated in the UK Biobank plasma proteomic cohort. Functional enrichment and subgroup analyses were conducted. The RSPS score was significantly associated with DR's progression and adverse outcomes; each standard deviation of increase was associated with a 35% higher risk of the composite endpoint (hazard ratio = 1.35, 95% confidence interval: 1.21–1.51) in the fully adjusted model. The RSPS score serves as a senescence-associated molecular signature linked to DR's progression, correlates with metabolic syndromes, inflammation, and SASP activation, as well as supporting molecular senescence monitoring and targeted therapeutic strategies.