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Literature Review | Is Cataract Reversible? The Protective Effects of Metformin on Lens Epithelial Cells in Naturally Aged Mice

Introduction

At present, age-related cataract (ARC) remains a leading cause of visual impairment and blindness, significantly compromising the quality of life of older adults. 。 The normal structure and function of lens epithelial cells (LECs) are essential for maintaining the transparency of the entire lens and its metabolic homeostasis. Aging of lens epithelial cells may lead to the modification, denaturation, and aggregation of lens proteins, including enzymes and crystallins, ultimately resulting in lens opacification and even cataract formation. Metformin (MET) is one of the most extensively studied anti‑aging agents. Numerous studies have demonstrated that, across diverse animal model systems, MET can slow aging and extend healthspan. MET thus represents a promising therapeutic agent for the prevention of age‑related cataracts (ARC).

 

In 2022, a team from the Second Affiliated Hospital of Harbin Medical University published an article titled “Metformin protects lens epithelial cells against senescence in a naturally aged mouse model” in the journal Cell Death Discovery (IF = 4.114). The study results indicated that:

① Inactivation of the AMPK pathway and autophagy dysfunction may underlie lens epithelial cell senescence and the development of ARC.
②MET effectively attenuates lens epithelial cell senescence and the formation of ARC, likely by inhibiting the AMPK pathway and enhancing autophagy.
③MET may serve as a potentially useful therapeutic agent for the prevention of ARC.
The experimental protocol is as follows:

 

1. Senescence of lens epithelial cells in naturally aged mice is associated with ARC.
The lens transparency of naturally aged mice (old mice) was significantly reduced, with a cataract incidence rate of 95.23%.
H&E staining revealed that in the control group, lens epithelial cells were round and arranged in a regular pattern, with a high density of normal lens epithelial cells. In contrast, in the naturally aged group, the lens epithelial cells exhibited a flattened morphology, with irregular cell arrangement and a markedly reduced cell density.
SAβ‑Gal staining revealed an increased proportion of senescent lens epithelial cells in naturally aged mice. We also assessed the protein expression of senescence‑associated markers by immunohistochemical staining and Western blot analysis. Immunohistochemical staining showed elevated expression of P21 and P53 in the lens epithelial cells of naturally aged mice. Moreover, the protein levels of P21 and P53 were higher in the lens capsules of naturally aged mice compared with those of young mice.

Figure 1

 

2. Chronic administration of low-dose MET can enhance lens transparency and delay senescence of lens epithelial cells.

Lens transparency was significantly improved in the MET group. Morphological examination confirmed a reduction in the degree of lens opacification in this group. The incidence of cataracts was 95.23% in the natural aging group and 19.00% in the MET group.
H&E staining revealed that the density of lens epithelial cells in the MET group was significantly higher than that in the naturally aged group. Furthermore, the lens epithelial cells in the MET group exhibited a more rounded morphology.
SA-β-Gal staining revealed a significant reduction in the proportion of senescent lens epithelial cells in the MET group. Immunohistochemical analysis demonstrated that the expression levels of P21 and P53 in lens epithelial cells were markedly lower in the MET group compared with the naturally aged group. Similarly, Western blotting showed that the protein expression of P21 and P53 in the lens capsule was significantly reduced in the MET group.

Figure 2

 

3. Chronic low-dose MET delays senescence of lens epithelial cells in naturally aging mice by activating AMPK.

In contrast, Fas mRNA levels were decreased in the natural aging group but increased in the MET group. In the lens epithelial cells of naturally aged mice, the expression of phosphorylated AMPKα (Thr172) and phosphorylated ACC (Ser79) was reduced. By contrast, in the MET group, the expression of phosphorylated AMPKα (Thr172) and phosphorylated ACC (Ser79) was elevated in lens epithelial cells.
Furthermore, Western blot analysis revealed that in the lens capsule of naturally aged animals, the protein levels of phosphorylated AMPKα (Thr172) and phosphorylated ACC (Ser79) were significantly downregulated, whereas in the lens capsule of the MET‑treated group, the expression levels of these two proteins were elevated.

Figure 3

 

4. Chronic low-dose MET restores autophagic flux and delays senescence of lens epithelial cells in naturally aging mice.

Autophagy may play a crucial role in counteracting the adverse effects of aging. In the natural aging group, the relative expression level of P62 mRNA was significantly elevated, whereas in the MET group, the relative expression level of P62 mRNA was markedly reduced compared with the natural aging group.
Immunohistochemical staining revealed elevated levels of microtubule-associated protein 1 light chain 3 (LC3‑II/I) and p62 in the lens epithelial cells of naturally aged mice. Furthermore, in the MET‑treated group, the levels of LC3‑II/I and p62 in lens epithelial cells were significantly reduced. In the naturally aged group, the levels of LC3‑II and p62 proteins in the lens capsule were markedly increased.
In summary, we hypothesize that autophagic flux is impaired in the lens epithelial cells of naturally aging mice and can be restored by long-term administration of low-dose MET, thereby delaying cellular senescence in these cells.

Figure 4

 

Untreated cataracts are a leading cause of blindness worldwide, characterized by lens opacity, and the only effective treatment is surgical removal. However, aging of lens epithelial cells is a major contributing factor to age-related cataract (ARC).

AMPK serves as an integrator and mediator of several pathways and processes that link energy metabolism to longevity. Inactivation of AMPK is a hallmark of lens epithelial cells in naturally aging mice. Both AMPK inactivation and impaired autophagic function are associated with the senescence of lens epithelial cells and the anterior rat ciliary body (ARC). MET may protect lens epithelial cells against aging and inhibit lens opacity by activating AMPK and enhancing autophagy. In aged LECs, autophagic levels are markedly reduced, whereas MET reverses age‑related autophagic impairment. The anti‑aging molecular mechanisms of MET are attributed to AMPK’s central role in the cell, as it typically promotes autophagy through AMPK activation.

 

Bibliographic Reference Information: https://doi.org/10.21203/rs.3.rs-414664/v1

 

 

Aniphe BioLab can provide you with aging animal models:

→ Naturally aged mice and rats, available from 7 to 18 months of age. Customization and pre‑orders are welcome; a formal contract is signed to safeguard your rights, with door-to-door delivery nationwide!
→ SAMP8 mice, a rapid‑aging model, and their control strain SAMR1 mice are available in single‑sex cohorts from 3 to 8 weeks of age, with nationwide door‑to‑door delivery!
→We also offer genetically edited animals and tool mice, with a wide range of animal models available—please feel free to inquire!
Aniphe BioLab also offers custom disease animal models and comprehensive CRO services:
→ Models of mental and neurological disorders; models of circulatory system diseases; models of endocrine system disorders; models of digestive system diseases; models of respiratory and urinary system diseases; bone-related disease models, etc.
→ Research services; comprehensive study design; preclinical CRO services; bio‑cleaning and animal breeding—welcome to inquire!

 

 

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