Grx1/Grx2 Deficiency Leads to Low-grade Inflammation, resulting in Accelerated Senescence in Mouse Lens Epithelial Cells

Grx1/Grx2 Deficiency Leads to Low-grade Inflammation, resulting in Accelerated Senescence in Mouse Lens Epithelial CellsThis study investigates how glutaredoxin1 and glutaredoxin2 (Grx1/Grx2) deficiency promote premature senescence in mouse lens epithelial cells (LECs), aiming to clarify the molecular links between oxidative stress, chronic inflammation, and accelerated lens aging.Primary LECs were isolated from wild-type (WT) and Grx1/Grx2 double knockout (DKO) mice at 1 and 12 months of age.Senescence markers, including senescence-associated -galactosidase (SA--Gal), p53, p21, p16, and phospho-RB, and inflammatory cytokines such as IL-6, were assessed by SA--gal staining, western blot, RNA sequencing, and qPCR.DKO LECs showed significantly elevated -Gal activity in the WT 12-month and DKO groups, with markedly stronger staining in the DKO 12-month group.Age-related increases in senescence were observed in WT 12-month LECs, but to a lesser extent than in DKO counterparts.Western blot results revealed increased p21 expression alongside reduced phospho-RB levels in 12month DKO LECs (p < 0.001), indicating persistent cell cycle arrest.IL-6 protein and mRNA levels were significantly upregulated in DKO lenses (p < 0.05 and p < 0.001, respectively), suggesting heightened inflammatory signaling.RNA-sequencing analysis further revealed the enrichment of genes involved in oxidative stress responses, immune activation, extracellular matrix remodeling, and inflammation (p < 0.001), indicating that chronic inflammation, rather than oxidative stress alone, is a critical and previously underappreciated contributor to cataract pathogenesis.These findings demonstrate that Grx1/Grx2 deficiency disrupts redox balance, enhances chronic inflammation, and accelerates lens aging by driving early-onset and sustained cellular senescence in LECs.Elevated IL-6 supports a role for inflammaging, a persistent, low-grade, sterile inflammation, in contributing to lens dysfunction.This model offers a valuable platform for investigating aging and assessing therapeutic targets to delay cataract formation and age-related tissue decline.