Changes in SIRT1 Expression and Its Downstream Pathways in Age-Related Cataract in Humans

Purpose: SIRT1, the most well-known sirtuin family (class III histone deacetylases) member, is involved in many age-related diseases. However, no study has demonstrated its relationship with age-related cataract (ARC). This study was to investigate the expression of SIRT1 in human lens epithelial cells, and to observe the changes in SIRT1 expression and its downstream P53 and forkhead box class O (FOXO) proteins at the onset of ARC. Methods: The anterior lens capsule specimens from 360 normal human donor eyes (age 19-91 years) were divided into three groups: group A of young lens (younger than age 49 without cataract), group B of old but normal lens (older than age 50 without cataract), and group C of ARC lens (older than age 50 with ARC). Real-time quantitative reverse transcription of SIRT1 mRNA; Western blot analysis by anti-SIRT1, anti-p53, anti-p53 (acetyl K379), anti-FOXO3a, anti-FOXO4, anti-p27kip1, anti-p130, and anti-Bim; immunofluorescence of SIRT1; and TUNEL assay were performed in each group. Results: SIRT1 expression was significantly decreased in group B compared with group A, but increased in group C compared with group B. P53 expression increased with age and topped in group C; however, there was a decrease in active acetyl-P53 expression in group C compared with group B. The expression of both FOXO3a and FOXO4 decreased with age, but in group C, their expression level is equivalent to group A. Accordingly, the downstream p27kip1 and p130 showed the similar changes among three groups. In contrast, the expression of Bim was lowest in the ARC lens, and TUNEL assay showed significantly increased apoptosis incidence in group C. Conclusions: The expression of SIRT1 increased in ARC in humans. Its downstream p53 was inhibited, and FOXO pathway was activated, indicating that SIRT1 may play a protective role in ARC formation.