Abstract
Purpose :
This study aims to explore the new roles of glutaredoxin 1 (Grx1) and glutaredoxin 2 (Grx2) in cellular senescence and age-related pathologies. Using a Grx1/Grx2 double knockout (DKO) mouse model, we aim to identify the underlying molecular mechanisms contributing to the aging process and the resultant senescence phenotypes in the lens and various other tissues.
Methods :
Primary lens epithelial cells (LECs) from both wild-type (WT) and DKO mice underwent in vitro assessments, including analyses of cell cycle dynamics, apoptostic pathways, and senescence biomarkers. Systemic evaluations included body weight measurements, morphological examinations of major organs, and assessments of age-related cataract progression in both WT and DKO mice.
Results :
DKO-derived LECs displayed signs of accelerated senescence, such as altered morphology, reduced proliferation, dysregulated cell cycle distribution, and increased senescence-associated β-galactosidase activity (n=6; P<0.01). Resistance to apoptosis in these cells was suggested by elevated Bcl-2 expression and the absence of cleaved caspase-3 under serum deprivation stress (n=4; P<0.01). Scratch wound healing assays revealed diminished migratory and proliferative capacities in DKO LECs compared to WT counterparts (n=6; P<0.001). Histological analyses with hematoxylin and eosin staining confirmed morphological disruptions in DKO lenses. Systemically, DKO mice exhibited faster aging including a more rapid onset of age-related cataract development, lower body mass, diminished physical vigor, premature graying of the fur, cardiac hypertrophy, brain enlargement, and reduced fertility (n=6; P<0.001).
Conclusions :
Our findings revealed the critical involvement of Grx1 and Grx2 in maintaining lens epithelial cell homeostasis and preventing accelerated cellular senescence. The absence of these enzymes correlates with various systemic aging phenotypes, suggesting a broader role for glutaredoxin in the physiological aging process. These results highlight Grx 1 and Grx2 as potential targets for therapeutic strategies aimed at mitigating senescence-associated ocular and systemic diseases.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.