Elsevier

Experimental Eye Research

Volume 156, March 2017, Pages 103-111
Experimental Eye Research

Review
Lens glutathione homeostasis: Discrepancies and gaps in knowledge standing in the way of novel therapeutic approaches

https://doi.org/10.1016/j.exer.2016.06.018Get rights and content

Highlights

  • Glutathione is playing vital role in lens biology.

  • The lens GSH homeostasis is maintained via biosynthesis and transport.

  • The aqueous humor and gamma-glutamyl cycle continuously supplies constituent amino acids for GSH synthesis.

  • Aqueous and vitreous humor are providing glutathione for transporting into lens.

  • The mechanisms of lens GSH transport and nucleus GSH homeostasis are unknown.

Abstract

Cataract is the major cause of blindness worldwide. The WHO has estimated around 20 million people have bilateral blindness from cataract, and that number is expected to reach 50 million in 2050. The cataract surgery is currently the main treatment approach, though often associated with complications, such as Posterior Capsule Opacification (PCO)-also known as secondary cataract. The lens is an avascular ocular structure equipped with an unusually high level of glutathione (GSH), which plays a vital role in maintaining lens transparency by regulating lenticular redox state. The lens epithelium and outer cortex are thought to be responsible for providing the majority of lens GSH via GSH de novo synthesis, assisted by a continuous supply of constituent amino acids from the aqueous humor, as well as extracellular GSH recycling from the gamma-glutamyl cycle. However, when de novo synthesis is impaired, in the presence of low GSH levels, as in the aging human lens, compensatory mechanisms exist, suggesting that the lens is able to uptake GSH from the surrounding ocular tissues. However, these uptake mechanisms, and the GSH source and its origin, are largely unknown. The lens nucleus does not have the ability to synthesize its own GSH and fully relies on transport from the outer cortex by yet unknown mechanisms. Understanding how aging reduces GSH levels, particularly in the lens nucleus, how it is associated with age-related nuclear cataract (ARNC), and how the lens compensates for GSH loss via external uptake should be a major research priority. The intent of this review, which is dedicated to the memory of David C. Beebe, is to summarize our current understanding of lens GSH homeostasis and highlight discrepancies and gaps in knowledge that stand in the way of pharmacologically minimizing the impact of declining GSH content in the prevention of age-related cataract.

Introduction

The lens has evolved as an anaerobic biological system with millimolar concentrations of glutathione (GSH). The critical role of GSH in maintaining lens redox status and transparency is well recognized and has been, over the years, the subject of several excellent reviews (Giblin, 2000, Lou, 2000, Reddy, 1990, Truscott, 2005). While one could argue that nothing new was to be expected concerning the protective role of GSH in the lens, our interest in GSH homeostasis in the lens was rekindled with the unexpected finding that lenticular GSH levels were not completely suppressed in the LEGSKO mouse in spite of complete absence of γ-glutamylcysteine ligase (Fan et al., 2012). This issue, which is the subject of intense investigation in our laboratory, is closely linked to lenticular ascorbate metabolism and cataractogenesis and the work of David Beebe who has pioneered the importance of the vitreous as a source of oxidative stress to the lens (Beebe et al., 2014, Holekamp et al., 2005, Li et al., 2013b, Shui et al., 2009). These paradigm shifting studies inspired us to study lens biology in connection not only to the aqueous humor but also to the vitreous humor. Additionally, Dr. Beebe’s pioneer studies provide the mechanistic framework for a potential therapeutic treatment of high risk (>90%) and rapid (within two years) nuclear cataract formation after vitrectomy surgery (Petrash, 2013).

In order to provide a complete coverage of lens GSH homeostasis, we have to discuss the lenticular GSH dynamics from the perspective of both protein conjugated GSH and free GSH/oxidized GSH (GSSG). Since several excellent reviews have covered the protein glutathionylation (Lou, 2000, Lou, 2003, Lou and Dickerson, 1992, Lou et al., 1990, Lou et al., 1995), we will mainly focus on the roles of latter. Below we review the established mechanisms and pathways that are involved in lens GSH homeostasis. We also provide a brief summary of recent progress regarding lens nucleus GSH homeostasis, as well as the impact of aging on lens GSH homeostasis, since age-related nuclear cataract (ARNC) is often believed to be, in part, associated with declining nuclear GSH levels in the aging human lens (Giblin, 2000).

Intracellular GSH is synthesized by two ATP-dependent enzymes: γ-glutamylcysteine ligase (GCL) and glutathione synthase (GS) to produce γ-glutamylcysteine and GSH, respectively. The mammalian GCL is a heterodimer enzyme consisting of a 73-kDa catalytic subunit, Gclc, and a 28-kDa modulatory subunit, Gclm. The catalytic subunit, Gclc has the enzymatic activity and is regulated via a GSH feedback inhibition mechanism (Richman and Meister, 1975). Gclm has no enzymatic activity, but heterodimer formation of Gclm and Gclc significantly decreases the Km value for glutamate and increases the Ki value for the feedback inhibition by GSH (Chen et al., 2005).

Like other tissue systems, the lens has a functional GSH de novo synthesis machinery, which mostly lies in the epithelial and cortical layers, while mature fibers cells sit in inner layers of the lens that have lost cell organelles such as nucleus and mitochondria (Bassnett and Beebe, 1992). However, due to the avascularity of the lens, for GSH biosynthesis to take place, the constituent amino acids, glutamic acid, glycine and cysteine have to be transported to the epithelial and outer cortical fibers cells. Pioneering work from Reddy et al. has demonstrated that these amino acids are delivered to the lens from the plasma via the aqueous humor and the lens epithelium, from which they are delivered to the rest of the lenticular system (Reddy, 1973, Reddy, 1979) (Fig. 1). For GSH synthesis, the Km value of GCL for cysteine is ∼0.15 mM, while that for glutamate is ∼1.7 mM, and that of GS for glycine is ∼0.8 mM (McBean, 2012). In order for GSH biosynthesis to take place, the required intracellular concentration of these amino acids is thought to be close to their Km value. However, various studies suggest species-specific results regarding these amino acids levels in the lens epithelium and outer cortex. For example, Lim et al. (Lim et al., 2007) find that the concentration of the three amino acids in the rat lens cortex is lower than that required for the GCL and GS Km value of its proper constituent amino acids. In contrast, other studies in human, rabbit and bovine lens demonstrate much higher values than these required for the Km (Barber, 1968, Kern and Ho, 1973, Reddy, 1973). It has to be pointed out that these studies measured the total GSH from the homogenate of the lens tissue, and that this does not exclude the possibility that intracellular amino acid level might be much higher to fulfill the needs of GSH de novo synthesis. Nevertheless, similar to other body systems, such as the central nervous system (CNS) (Aoyama et al., 2012), cysteine level is relatively lower than glutamic acid and glycine. It is, therefore, the rate-limiting substance in lenticular de novo GSH synthesis and an adequate cysteine supply is essential wherever GSH de novo synthesis is taking place.

From the above considerations, it is clear that cellular cysteine and GSH synthesis are tightly linked. Multiple mechanisms have been postulated in terms of intracellular cysteine homeostasis in studies of the central nervous system (CNS) or hepatocytes (Lu, 1999, McBean and Flynn, 2001). The sodium independent cystine/glutamate exchanger (Xc) has been shown to take up cystine into cells, which is subsequently reduced into cysteine for GSH synthesis (Lewerenz et al., 2013, Lim and Donaldson, 2011). In one set of studies, the Xc exchanger was found present in the entire rat lens, predominantly in the cytoplasm in the outer cortex cells, while it was more membranous in the inner cortex region (Lim et al., 2005). In the human lens, Xc is present in the entire lens region at a young age, but no immunoreactivity is found in the central lens region of aged human lenses (Lim et al., 2013). In contrast, in other studies, Xc was reported to be predominately present in the membranes of outer cortex cells, and no detection was observed in the nuclear region of the dog lens(Lall et al., 2008). These studies provide evidence for the presence of Xc, but whether this exchanger is important for lens cysteine homeostasis is still not very clear. Several findings point to quite different research directions. In a vascular eye perfusion study in guinea pigs, radiolabeled cysteine, cystine and methionine were injected through the common carotid artery (Mackic et al., 1997). In this study, cysteine, but not cystine, was readily taken up by the lens epithelial and cortical fiber layers, while infused cystine failed to incorporate into GSH synthesis. Other evidence in support of cysteine rather than cystine uptake is that high levels of free cysteine, but not cystine, are found in human (Barber, 1968), monkey (Gaasterland et al., 1979) and calf (Kern and Ho, 1973) aqueous humor, though different results was reported in the aqueous humor of guinea pigs (Mackic et al., 1997). Furthermore, recent reports (Martis et al., 2015) indicate no impact on lens GSH level based on tests with Xc knockout mice.

On the other hand, earlier studies indicate that over 90% of cystine transport is actually processed by sodium-dependent high affinity glutamate transporters (XAG−), based on rat brain tissue uptake experiments (Flynn and McBean, 2000) and a cultured astrocytes study (Bender and Norenberg, 2000). Also, cysteine was found to be able to inhibit XAG-facilitated transport (McBean and Flynn, 2001). Altogether, five subtypes of high-affinity glutamate transporters (excitatory amino acid transporters 1–5 (EAAT1–5)) have been identified in mammalian tissues(Aoyama and Nakaki, 2013, Bridges and Esslinger, 2005). More recent studies demonstrate that EAAT3, also named “excitatory amino acid carrier 1” (EAAC1), is more functional in cysteine transport than the control of extracellular glutamate levels (Aoyama and Nakaki, 2013, Holmseth et al., 2012). The brain cysteine and GSH levels are significantly reduced in EAAC1-deficent mice, and this can be attenuated by the treatment with N-acetylcysteine (NAC), whose uptake proceeds via different uptake mechanisms than cysteine/cystine (Aoyama et al., 2006). All five types of EAATs are found present in rat lens based on RT-PCR and western-blot analysis (Lim et al., 2005). We therefore speculate that lenticular cysteine transport from aqueous humor occurs, most likely via a sodium-dependent transporter system, such as EAAC1, and that high cysteine transport activity occurs at the lens equator region, as reported by Truscott’s group (Sweeney et al., 2003).

The metabolic pathway transsulfuration can also supply cysteine from methionine via the transmethylation pathway (McBean, 2012). The transsulfuration pathway is also present in the lenticular system (Persa et al., 2004). Cystathionine-beta-synthase (CBS), one of the enzymes utilizing methionine to produce cysteine via transmethylation is elevated in human lens nucleus but decreased in the epithelial layer with aging. CBS expression can also be stimulated with oxidative stress, such as H2O2 in lens epithelial cell culture (Persa et al., 2004). In addition, the betaine-homocysteine S-methyltransferase 1(BHMT1), a remethylation enzyme that converts homocysteine to methionine, is found to be down-regulated in aged human lens nuclei (Zhou et al., 2015). This may explain the findings that the free cysteine levels are elevated in the lens nucleus under oxidative stress (Giblin et al., 1995, Lou, 2000). However, in a vascular eye perfusion study in guinea pigs (Mackic et al., 1997), methionine failed to produce cysteine and incorporate into GSH, suggesting minimal contribution of methionine in circulation to lenticular cysteine homeostasis (Mackic et al., 1997). Apparently, more study is needed to clarify whether the transsulfuration pathway plays a significant role in lens cysteine and GSH homeostasis.

As mentioned above, high affinity sodium-dependent glutamate transporters have been located in rat lenses (Lim et al., 2005), though no report exists so far about their expression level in the human lens. We anticipate that these transporters are also present in human lenses. Extensive studies and reviews have addressed their roles in the CNS (Divito and Underhill, 2014, Vandenberg and Ryan, 2013). On the other hand, it is well established that cellular glutamate originates from glutamine, which is readily taken up by the lens via a transport mechanism that is hundreds of times more efficient than that of glutamate. Glutamine was shown to convert into glutamate and be incorporated into GSH synthesis in ex vivo calf and rat lens culture systems (Kern and Ho, 1973). However, no in vivo confirmation of this in vitro finding was reported. Since the anterior, but not posterior, part of the lens is equipped with a monolayer of epithelial cells (Beebe, 2008), it is anticipated that the anterior will be more selective and specific for amino acid transport than the posterior of the lens. In that regard, it is our point of view that ex vivo lens culture systems using total immersion are convenient, but not suitable for lens transporter studies because lens anterior and posterior surfaces have completely different structures. More work is needed to test whether glutamine uptake and conversion to glutamate plays a significant role in lens GSH homeostasis. At least one neutral amino acid transporter, ASCT2, has been found present in rat lenses (Lim et al., 2006), and free glutamine measured in calf aqueous humor is more than double that of glutamate (Kern and Ho, 1973).

Intracellular glycine homeostasis, like other neurotransmitters, is mainly regulated by the high affinity sodium-dependent transporters GLYT1 and GLYT2, which belong to the solute transporter family (SLC6) (Chen et al., 2004). Both glycine transporters have been identified in rat lenses (Lim et al., 2006, Lim et al., 2007) (Fig. 1).

Gamma-glutamyl transpeptidase (GGT), also known as gamma-glutamyl transferase, a glycoprotein, is localized at the cell surface and anchored to the cell membrane via a single N-terminus transmembrane domain. It cleaves only the extracellular GSH, oxidized GSH (GSSG), as well as glutathione S-conjugates (Ikeda et al., 1995, Wickham et al., 2012), therefore providing the cells with the amino acids necessary for intracellular GSH synthesis (Hanigan, 2014). GGT was reported present in the lens, ciliary body and cornea over 40 years ago in two independent studies (Reddy and Unakar, 1973, Ross et al., 1973) (Fig. 1). GGT activity enables the cells to maintain their intracellular GSH levels, thus coping with reactive oxygen species (ROS) attack. Both GGT knockout and mutant mice develop cataract in a very short time period after birth (Chevez-Barrios et al., 2000, Yamada et al., 2013). GGT deficient mice were found to have severe cysteine deficiency (∼20% of WT plasma cysteine level) (Lieberman et al., 1996). Interestingly, despite high plasma GSH level in GGT deficient mice, eye and lens GSH levels are markedly reduced (∼5% of WT) (Chevez-Barrios et al., 2000). The drastic reduction of lens GSH content in GGT KO mice cannot simply be explained by impaired GSH de novo synthesis due to cysteine deficiency. The lens Gclc conditional knockout mouse (LEGSKO mouse) recently created by our group (Fan et al., 2012) is able to maintain ∼50% GSH levels (1–2 mM) relative to wild type (WT) mice on the C57BL/6 background (unpublished), while levels were lower in the FVB/B6 hybrid strain (Fan et al., 2012). We believe that both low cysteine and GSH supply to the lens are necessary for drastic GSH reduction. In other words, lenses lacking efficient de novo GSH synthesis may take up either GSH or GSSG from surrounding ocular structures, i.e. the aqueous humor or the vitreous humor. We will discuss this aspect in the following section. Needless to say, the gamma-glutamyl cycle is an important amino acid recycling mechanism for maintenance of lens GSH homeostasis, particularly in the metabolically active regions of the lens.

Section snippets

Lens GSH/GSSG uptake

An in situ vascular eye perfusion study in guinea pig has come to a very surprising conclusion that the de novo GSH synthesis from circulating and aqueous sulfur amino acids, such as cysteine, cystine or methionine can be only a minor source of the millimolar concentration of GSH in the epithelium (Mackic et al., 1997). A t1/2 of 5480 h was estimated for lens epithelium GSH to be replaced entirely if solely based on circulating sulfur amino acids, the limiting amino acids in intracellular GSH

Lens nucleus GSH homeostasis

From the inner core to the periphery, the lens nucleus is constituted by an embryonic nucleus, a fetal nucleus, and an adult nucleus formed by differentiated fiber cells. Each of these can be delicately peeled off the human lens using simple tweezers (Beebe, 2008). These mature fibers cells have no capacity for protein or small molecule synthesis, including that of GSH. However, the lens nucleus still contains substantial level of GSH for maintenance of lens nucleus redox status (Giblin, 2000,

Aging impact on lens GSH homeostasis

The GSH level declines with age in the lens, particularly in the lens nucleus, and this is widely believed to be a major mechanism for age-related nuclear cataract formation (Giblin, 2000, Lou, 2003, Truscott, 2005). Multiple causes have been proposed for this decrease:

  • 1)

    The age-related loss of synthetic enzymes for de novo GSH synthesis is considered one of the major mechanisms. GCL, the GSH de novo synthesis rate limiting enzyme, has a 16-fold decrease in activity over a 83-year time frame (

Concluding remarks and perspectives

The lens is an avascular ocular tissue equipped with an unusually high level of GSH. The high concentration of GSH works with its antioxidant partners to keep the lens redox system in check and maintain lens transparency for several decades in humans. In addition to GSH de novo synthesis that only occurs in the epithelium and outer cortex, the lens is believed to also take up large portions of GSH from surrounding ocular tissues, i.e. the aqueous humor and the vitreous humor. However, more

Acknowledgment

We thank the National Eye Institute (Grant EY024553 to XF, and EY 07099 to VMM), and the Case Western Reserve University Visual Science Research Center (NEI P30EY-11373) for supporting our research.

References (112)

  • J. Flynn et al.

    Kinetic and pharmacological analysis of L-[35S]cystine transport into rat brain synaptosomes

    Neurochem. Int.

    (2000)
  • F.J. Giblin et al.

    Nuclear light scattering, disulfide formation and membrane damage in lenses of older guinea pigs treated with hyperbaric oxygen

    Exp. Eye Res.

    (1995)
  • H.J. Gukasyan et al.

    Glutathione and its transporters in ocular surface defense

    Ocular Surf.

    (2007)
  • M.H. Hanigan

    Gamma-glutamyl transpeptidase: redox regulation and drug resistance

    Adv. Cancer Res.

    (2014)
  • K.R. Heys et al.

    The stiffness of human cataract lenses is a function of both age and the type of cataract

    Exp. eye Res.

    (2008)
  • N.M. Holekamp et al.

    Vitrectomy surgery increases oxygen exposure to the lens: a possible mechanism for nuclear cataract formation

    Am. J. Ophthalmol.

    (2005)
  • R. Kannan et al.

    Evidence for the existence of a sodium-dependent glutathione (GSH) transporter. Expression of bovine brain capillary mRNA and size fractions in Xenopus laevis oocytes and dissociation from gamma-glutamyltranspeptidase and facilitative GSH transporters

    J. Biol. Chem.

    (1996)
  • H.L. Kern et al.

    Transport of L-glutamic acid and L-glutamine and their incorporation into lenticular glutathione

    Exp. Eye Res.

    (1973)
  • B. Li et al.

    Dynamic regulation of GSH synthesis and uptake pathways in the rat lens epithelium

    Exp. Eye Res.

    (2010)
  • J. Lim et al.

    Molecular identification and characterisation of the glycine transporter (GLYT1) and the glutamine/glutamate transporter (ASCT2) in the rat lens

    Exp. Eye Res.

    (2006)
  • J.C. Lim et al.

    Focus on molecules: the cystine/glutamate exchanger (System x(c)(-))

    Exp. Eye Res.

    (2011)
  • J.C. Lim et al.

    Molecular identification and cellular localization of a potential transport system involved in cystine/cysteine uptake in human lenses

    Exp. Eye Res.

    (2013)
  • M.F. Lou

    Redox regulation in the lens

    Prog. Retin. Eye Res.

    (2003)
  • M.F. Lou et al.

    Protein-thiol mixed disulfides in human lens

    Exp. Eye Res.

    (1992)
  • M.F. Lou et al.

    The role of protein-thiol mixed disulfides in cataractogenesis

    Exp. Eye Res.

    (1990)
  • X. Lumi et al.

    Ageing of the vitreous: from acute onset floaters and flashes to retinal detachment

    Ageing Res. Rev.

    (2015)
  • J.B. Mackic et al.

    Low de novo glutathione synthesis from circulating sulfur amino acids in the lens epithelium

    Exp. Eye Res.

    (1997)
  • J.M. May et al.

    Mechanisms of ascorbic acid recycling in human erythrocytes

    Biochim. Biophys. Acta

    (2001)
  • M.J. Nozal et al.

    Determination of glutathione, cysteine and N-acetylcysteine in rabbit eye tissues using high-performance liquid chromatography and post-column derivatization with 5,5’-dithiobis(2-nitrobenzoic acid)

    J. Chromatogr. A

    (1997)
  • H. Pau et al.

    Glutathione levels in human lens: regional distribution in different forms of cataract

    Exp. Eye Res.

    (1990)
  • C. Persa et al.

    The presence of a transsulfuration pathway in the lens: a new oxidative stress defense system

    Exp. Eye Res.

    (2004)
  • W.B. Rathbun et al.

    Age-related cysteine uptake as rate-limiting in glutathione synthesis and glutathione half-life in the cultured human lens

    Exp. Eye Res.

    (1991)
  • V.N. Reddy

    Transport of organic molecules in the lens

    Exp. Eye Res.

    (1973)
  • V.N. Reddy

    Glutathione and its function in the lens–an overview

    Exp. Eye Res.

    (1990)
  • V.N. Reddy et al.

    Localization of gamma-glutamyl transpeptidase in rabbit lens, ciliary process and cornea

    Exp. Eye Res.

    (1973)
  • P.G. Richman et al.

    Regulation of gamma-glutamyl-cysteine synthetase by nonallosteric feedback inhibition by glutathione

    J. Biol. Chem.

    (1975)
  • N. Slavi et al.

    Connexin 46 (cx46) gap junctions provide a pathway for the delivery of glutathione to the lens nucleus

    J. Biol. Chem.

    (2014)
  • M.H. Sweeney et al.

    Movement of cysteine in intact monkey lenses: the major site of entry is the germinative region

    Exp. Eye Res.

    (2003)
  • M.H. Sweeney et al.

    An impediment to glutathione diffusion in older normal human lenses: a possible precondition for nuclear cataract

    Exp. Eye Res.

    (1998)
  • K. Aoyama et al.

    Neuroprotective properties of the excitatory amino acid carrier 1 (EAAC1)

    Amino Acids

    (2013)
  • K. Aoyama et al.

    Neuronal glutathione deficiency and age-dependent neurodegeneration in the EAAC1 deficient mouse

    Nat. Neurosci.

    (2006)
  • K. Aoyama et al.

    Modulation of neuronal glutathione synthesis by EAAC1 and its interacting protein GTRAP3-18

    Amino Acids

    (2012)
  • G.W. Barber

    Free amino acids in senile cataractous lenses: possible osmotic etiology

    Investig. Ophthalmol.

    (1968)
  • K.A. Barton et al.

    Comment on: the Stokes-Einstein equation and the physiological effects of vitreous surgery

    Acta Ophthalmol. Scand.

    (2007)
  • S. Bassnett et al.

    Coincident loss of mitochondria and nuclei during lens fiber cell differentiation

    Dev. Dyn. Official Publ. Am. Assoc. Anatomists

    (1992)
  • D.C. Beebe et al.

    Oxidative damage and the prevention of age-related cataracts

    Ophthalmic Res.

    (2010)
  • D.C. Beebe et al.

    Vitreoretinal influences on lens function and cataract

    Philos. Trans. R. Soc. Lond. Ser. B Biol. Sci.

    (2011)
  • D.C. Beebe et al.

    Preserve the (intraocular) environment: the importance of maintaining normal oxygen gradients in the eye

    Jpn. J. Ophthalmol.

    (2014)
  • E.R. Berman

    Biochemistry of the Eye

    (1991)
  • N.H. Chen et al.

    Synaptic uptake and beyond: the sodium- and chloride-dependent neurotransmitter transporter family SLC6

    Pflugers Arch.

    (2004)
  • Cited by (51)

    • A tamoxifen-inducible Cre knock-in mouse for lens-specific gene manipulation

      2023, Experimental Eye Research
      Citation Excerpt :

      However, the quiescent lens epithelial cells can also rapidly convert to mitotically active cells to repair neighboring wounded cells (Wei et al., 2021b). The lens epithelium is essential for maintaining lens homeostasis and transparency by providing nutrients and regulating lens function through ion channels, transporters, and chaperone protein synthesis (Andley, 2008; Donaldson et al., 2001; Fan et al., 2006, 2017; Kiel, 2010; Merriman-Smith et al., 1999). For example, amino acids are delivered to the lens from the aqueous humor by epithelial cells and then delivered to the lens fibers (Reddy, 1973, 1979).

    • Thiol antioxidants protect human lens epithelial (HLE B-3) cells against tert-butyl hydroperoxide-induced oxidative damage and cytotoxicity

      2022, Biochemistry and Biophysics Reports
      Citation Excerpt :

      GSH levels were also increased in cells that were treated with exogenous GSH, which were washed carefully prior to analysis. While GSH generally does not diffuse across cell membranes [11,12], lens epithelial cells may express transporters for GSH [69]. MPG increased GSH levels, but not significantly.

    • The aging mouse lens transcriptome

      2021, Experimental Eye Research
      Citation Excerpt :

      As fiber cells are produced from epithelial cells throughout the lifespan, it has been hypothesized that cortical cataract could result from acquired genetic or age-related changes in the lens epithelium which would then propagate into fiber cells (Mesa et al., 2016; Pendergrass et al., 2001; Wang et al., 2020; Worgul et al., 1989). Further, as the lens has an internal circulation that delivers anti-oxidants and other protective molecules to the lens nucleus and removes their “spent” derivatives (Mathias et al., 2007), age-related changes in the biology of the lens epithelium have been hypothesized to have indirect effects on the transparency of the lens cortex and nucleus (Fan et al., 2017; Wang et al., 2017). While many laboratories have explored the idea that lens epithelial cells change their biology with age, upon oxidative stress, or coincident with ARC via “candidate gene” investigations (Periyasamy and Shinohara, 2017), the effect of aging on global gene expression in the lens is understudied.

    View all citing articles on Scopus
    View full text