Metformin protects lens epithelial cells against senescence in a naturally aged mouse model

Mengmeng Chen,Xu Wang,Dongmei Su,Yushan Fu,Nan Zhou,Ruitong Wu,Yanhua Qi

doi:10.1038/s41420-021-00800-w

Abstract

The senescence of lens epithelial cells (LECs) is a major factor leading to age-related cataract (ARC). ARC results in visual impairment and severe vision loss in elderly patients. However, the specific mechanism of ARC remains unclear, and there are no effective therapeutic agents to halt the formation of ARC. This study aimed to assess the underlying mechanism of the formation of ARC and investigate the potential anti-ageing effect of metformin (MET) on ARC. Male C57BL/6 mice were divided into three groups: the control group having young mice (3 months old, n = 40), the naturally aged group (aged 20 months, n = 60) and the MET group (MET, 20 months, n = 60). Mice in the control and the naturally aged groups were fed a standard purified mouse diet ad libitum and water, whereas those in the MET group were fed chows supplemented with 0.1% MET for 10 months. The transparency of the lens and age-associated proteins p21 and p53 were analysed in the LECs of these three groups. Furthermore, we determined the expressions of the adenosine monophosphate (AMP)-activated protein kinase (AMPK) pathway and the effect of MET on this pathway in LECs during the ageing process of ARC. In addition, the relationship between autophagy and the senescence of LECs and the role of MET in the autophagy of LECs during the ageing process of ARC were examined. Our results indicated that age-related inactivation of the AMPK pathway and impairment of autophagy might contribute to the senescence of LECs and the occurrence of ARC. More importantly, these results demonstrated that MET effectively alleviated the senescence of LECs and the formation of ARC probably via inactivation of the AMPK pathway and augmentation of autophagy. These findings revealed that MET can be exploited as a potentially useful drug for ARC prevention. Our study will help in enlightening the development of innovative strategies for the clinical treatment of ARC.

Highlights

Lens epithelial cells (LECs) form a monolayer of cells lining the anterior capsule of the lens and extend to the equatorial lens bow [1, 2]
Haematoxylin and eosin (H&E) staining assay indicated that the LECs in the control group were round in shape and arranged regularly, and the density of the normal LECs was relatively high, whereas the LECs of the naturally aged mice were flat in shape and arranged unevenly, and the density of senescent LECs was markedly decreased (Fig. 1c)
We further discovered that the protein expression of p21 and p53 was higher in the lens capsules of naturally aged mice than in the lens capsules of young mice (Fig. 1g). These results suggested that the senescence of LECs was associated with Age-related cataract (ARC) in naturally aged mice

Summary

Introduction

Lens epithelial cells (LECs) form a monolayer of cells lining the anterior capsule of the lens and extend to the equatorial lens bow [1, 2]. The normal construction and function of LECs are essential for the maintenance of the transparency and metabolic homeostasis of the entire lens [3]. Increasing evidence indicates that the senescence of LECs may cause modification, denaturation and aggregation of lens proteins including enzymes and crystallins, thereby leading to lens opacification or even cataract [3,4,5]. Age-related cataract (ARC) remains the leading cause of visual impairment and blindness, which severely affects the quality of life of older individuals [6]. There are no effective strategies for the prevention of progression of ARC. It is necessary to develop a pharmacological intervention that can improve the transparency of the lens and delay ARC progression

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