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The prevalence of presbyopia and nuclear cataracts (NUC) is reported to be higher in tropical areas than that in other regions, suggesting a potential influence of high temperatures on lens health. Transient receptor potential vanilloid (TRPV) channels play a crucial role in detecting ambient temperatures across various species, with TRPV1 and TRPV4 expressed in lens epithelial cells. In this study, we investigated whether ambient temperatures affect TRPV1 and TRPV4 activity in the lens, potentially contributing to the development of presbyopia and NUC. We conducted experiments using cultured human lens epithelial cell lines under different temperature conditions. Our results revealed that the mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) and p38 pathways, downstream molecules of TRPV1, were activated, while Src family kinase, a downstream molecule of TRPV4, was inhibited at 37.5 °C culture compared to 35.0 °C. Confocal microscope images demonstrated higher expression of TRPV1 in 3D-structured cells under high-temperature culture conditions. Additionally, in organ culture lenses, higher elasticity was observed at elevated temperatures compared to that at lower temperatures. These results suggest that high ambient temperatures may induce lens sclerosis via TRPV1 activation, potentially contributing to the development of presbyopia and NUC., (© 2024. The Author(s) under exclusive licence to The Japanese Society for Clinical Molecular Morphology.)

Aging proteins in the lens become increasingly aggregated and insoluble, contributing to presbyopia. In this study, we investigated the ability of aggrelyte-2 (N,S-diacetyl-L-cysteine methyl ester) to reverse the water insolubility of aged human lens proteins and to decrease stiffness in cultured human and mouse lenses. Water-insoluble proteins (WI) of aged human lenses (65-75 years) were incubated with aggrelyte-2 (500 μM) for 24 or 48 h. A control compound that lacked the S-acetyl group (aggrelyte-2C) was also tested. We observed 19%-30% solubility of WI upon treatment with aggrelyte-2. Aggrelyte-2C also increased protein solubility, but its effect was approximately 1.4-fold lower than that of aggrelyte-2. The protein thiol contents were 1.9- to 4.9-fold higher in the aggrelyte-2- and aggrelyte-2C-treated samples than in the untreated samples. The LC-MS/MS results showed N ε -acetyllysine (AcK) levels of 1.5 to 2.1 nmol/mg protein and 0.6 to 0.9 nmol/mg protein in the aggrelyte-2- and aggrelyte-2C-treated samples. Mouse (C57BL/6J) lenses (incubated for 24 h) and human lenses (incubated for 72 h) with 1.0 mM aggrelyte-2 showed significant decreases in stiffness with simultaneous increases in soluble proteins (human lenses) and protein-AcK levels, and such changes were not observed in aggrelyte-2C-treated lenses. Mass spectrometry of the solubilized protein revealed AcK in all crystallins, but more was observed in α-crystallins. These results suggest that aggrelyte-2 increases protein solubility and decreases lens stiffness through acetylation and disulfide reduction. Aggrelyte-2 might be useful in treating presbyopia in humans., (© 2023 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

With aging, human lenses lose the ability to focus on nearby objects due to decreases in accommodative ability, a condition known as presbyopia. An increase in stiffness or decrease in lens elasticity due to protein aggregation and insolubilization are the primary reasons for presbyopia. In this study, we tested aggrelyte-1 ( S , N -diacetyl glutathione diethyl ester) for its ability to promote protein solubility and decrease the stiffness of lenses through its dual property of lysine acetylation and disulfide reduction. Treatment of water-insoluble proteins from aged human lenses (58-75 years) with aggrelyte-1 significantly increased the solubility of those proteins. A control compound that did not contain the S-acetyl group (aggrelyte-1C) was substantially less efficient in solubilizing water-insoluble proteins. Aggrelyte-1-treated solubilized protein had significant amounts of acetyllysine, as measured by Western blotting and LC-MS/MS. Aggrelytes increased the protein-free thiol content in the solubilized protein. Aged mouse (7 months) and human (44-66 years) lenses treated with aggrelyte-1 showed reduced stiffness accompanied by higher free thiol and acetyllysine levels compared with those treated with aggrelyte-1C or untreated controls. Our results suggested that aggrelyte-1 reduced lens stiffness through acetylation followed by disulfide reduction. This proof-of-concept study paves the way for developing aggrelyte-1 and related compounds to reverse presbyopia.

Presbyopia is characterized by a decline in the ability to accommodate the lens. The most commonly accepted theory for the onset of presbyopia is an age-related increase in the stiffness of the lens. However, the cause of lens sclerosis remains unclear. With age, water microcirculation in the lens could change because of an increase in intracellular pressure. In the lens, the intracellular pressure is controlled by the Transient Receptor Potential Vanilloid (TRPV) 1 and TRPV4 feedback pathways. In this study, we tried to elucidate that administration of α-glucosyl-hesperidin (G-Hsd), previously reported to prevent nuclear cataract formation, affects lens elasticity and the distribution of TRPV channels and Aquaporin (AQP) channels to meet the requirement of intracellular pressure. As a result, the mouse control lens was significantly toughened compared to both the 1% and 2% G-Hsd mouse lens treatments. The anti-oxidant levels in the lens and plasma decreased with age; however, this decrease could be nullified with either 1% or 2% G-Hsd treatment in a concentration- and exposure time-dependent manner. Moreover, G-Hsd treatment affected the TRPV4 distribution, but not TRPV1, AQP0, and AQP5, in the peripheral area and could maintain intracellular pressure. These findings suggest that G-Hsd has great potential as a compound to prevent presbyopia and/or cataract formation.

The chaperone activity of α-crystallin is important for maintaining the transparency of the human lens. αB-crystallin (αBC) is a long-lived protein in the lens that accumulates chemical modifications during aging. The formation of advanced glycation end products (AGEs) through glycation is one such modification. αBC is a small heat shock protein that exhibits chaperone activity. We have previously shown that αBC-client protein complexes can undergo AGE-mediated interprotein cross-linking. Here, we demonstrate that short-term (1 h) exposure to elevated temperatures and methylglyoxal (MGO) during the chaperoning of client proteins by αBC promotes AGE-mediated interprotein cross-linking. Liquid chromatography/mass spectrometry (LC-MS/MS) analyses revealed the rapid formation of AGEs by MGO. Interestingly, we found that despite protein cross-linking, the chaperone activity of αBC increased during the transient elevation of temperature in the presence of MGO. Together, these results imply that transient and subtle elevation of temperature in the lens of the eye can promote protein cross-linking through AGEs, and if this phenomenon recurs over a period of many years, it could lead to early onset of presbyopia and age-related cataracts., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest with the content of this work., (Copyright © 2020 Elsevier Inc. All rights reserved.)

A new class of diffraction-based corneal inlays for treatment of presbyopia is described. The inlay is intended to achieve an improvement of the near focus quality over previous designs. Our proposal is a two-zone hybrid device with separated amplitude and phase areas having a central aperture and no refractive power. An array of micro-holes is distributed on the surface of the inlay conforming a binary photon sieve. In this way, the central hole of the disk contributes to the zero order of diffraction, and the light diffracted by the micro-holes in the peripheral photon sieve produces a real focus for near vision. We employed ray-tracing software to study the performance of the new inlay in the Liou-Brennan model eye. The modulation transfer functions (MTFs) at the distance and near foci, and the area under the MTFs for different object vergences, were the merit functions used in the evaluation. The results were compared with those obtained with previous pure amplitude designs. Additionally, image simulations were performed with the inlays in the model eye to show the good performance of our proposal in improving the quality of the near vision.

Lens proteins become increasingly cross-linked through nondisulfide linkages during aging and cataract formation. One mechanism that has been implicated in this cross-linking is glycation through formation of advanced glycation end products (AGEs). Here, we found an age-associated increase in stiffness in human lenses that was directly correlated with levels of protein-cross-linking AGEs. α-Crystallin in the lens binds to other proteins and prevents their denaturation and aggregation through its chaperone-like activity. Using a FRET-based assay, we examined the stability of the αA-crystallin-γD-crystallin complex for up to 12 days and observed that this complex is stable in PBS and upon incubation with human lens-epithelial cell lysate or lens homogenate. Addition of 2 mm ATP to the lysate or homogenate did not decrease the stability of the complex. We also generated complexes of human αA-crystallin or αB-crystallin with alcohol dehydrogenase or citrate synthase by applying thermal stress. Upon glycation under physiological conditions, the chaperone-client complexes underwent greater extents of cross-linking than did uncomplexed protein mixtures. LC-MS/MS analyses revealed that the levels of cross-linking AGEs were significantly higher in the glycated chaperone-client complexes than in glycated but uncomplexed protein mixtures. Mouse lenses subjected to thermal stress followed by glycation lost resilience more extensively than lenses subjected to thermal stress or glycation alone, and this loss was accompanied by higher protein cross-linking and higher cross-linking AGE levels. These results uncover a protein cross-linking mechanism in the lens and suggest that AGE-mediated cross-linking of α-crystallin-client complexes could contribute to lens aging and presbyopia., (© 2020 Nandi et al.)

Purpose: To assess and compare the effect of the corneo-scleral lenses (C-ScL) and scleral lenses (ScL) on tear film parameters and central corneal thickness (CCT) in healthy presbyopic subjects., Methods: Thirty subjects wore two contact lenses (CLs), randomly assigned, of neutral power, but of different diameters, 12.7mm (C-ScL) and 18mm (ScL) and being equal in the others parameters: material (HS100) and centre thickness (0.29mm). At baseline, 20min after insertion and at 8h, the tear meniscus area (TMA) and CCT was measured (with optical coherence tomography) as well as tear osmolarity., Results: TMA revealed statistical differences for both lenses at 20min (p<0.001), and also at 8h (p=0.003), being greater for the C-ScL. CCT showed statistical differences for both lenses at 20min (p=0.002), and also at 8h (p=0.001), being lower for the C-ScL. Osmolarity did not reveal statistical differences at 20min (p=0.29), while it was statistically different at 8h (p=0.03), being lower for the C-ScL., Conclusions: C-ScL lead to a lesser reduction in the TMA and a lower induced hypoxic stress than the ScL. Osmolarity levels remained within normal values across the day with no clinical difference between lenses. Both designs can represent a good optical platform for correcting presbyopia as well as protecting the ocular surface by vaulting the cornea., (Copyright © 2017 British Contact Lens Association. Published by Elsevier Ltd. All rights reserved.)

Purpose: The purpose of the experiments described here was to determine the effects of lipoic acid (LA)-dependent disulfide reduction on mouse lens elasticity, to synthesize the choline ester of LA (LACE), and to characterize the effects of topical ocular doses of LACE on mouse lens elasticity., Methods: Eight-month-old mouse lenses (C57BL/6J) were incubated for 12 hours in medium supplemented with selected levels (0-500 μM) of LA. Lens elasticity was measured using the coverslip method. After the elasticity measurements, P-SH and PSSP levels were determined in homogenates by differential alkylation before and after alkylation. Choline ester of LA was synthesized and characterized by mass spectrometry and HPLC. Eight-month-old C57BL/6J mice were treated with 2.5 μL of a formulation of 5% LACE three times per day at 8-hour intervals in the right eye (OD) for 5 weeks. After the final treatment, lenses were removed and placed in a cuvette containing buffer. Elasticity was determined with a computer-controlled instrument that provided Z-stage upward movements in 1-μm increments with concomitant force measurements with a Harvard Apparatus F10 isometric force transducer. The elasticity of lenses from 8-week-old C57BL/6J mice was determined for comparison., Results: Lipoic acid treatment led to a concentration-dependent decrease in lens protein disulfides concurrent with an increase in lens elasticity. The structure and purity of newly synthesized LACE was confirmed. Aqueous humor concentrations of LA were higher in eyes of mice following topical ocular treatment with LACE than in mice following topical ocular treatment with LA. The lenses of the treated eyes of the old mice were more elastic than the lenses of untreated eyes (i.e., the relative force required for similar Z displacements was higher in the lenses of untreated eyes). In most instances, the lenses of the treated eyes were even more elastic than the lenses of the 8-week-old mice., Conclusions: As the elasticity of the human lens decreases with age, humans lose the ability to accommodate. The results, briefly described in this abstract, suggest a topical ocular treatment to increase lens elasticity through reduction of disulfides to restore accommodative amplitude.

Purpose: To evaluate the efficacy and safety of photorefractive keratectomy (PRK) using a 213 nm wavelength solid-state laser to treat regression in eyes that had previous conductive keratoplasty (CK) for presbyopia., Setting: Outpatient refractive surgery center, Manila, Philippines., Design: Prospective consecutive case series., Methods: Consecutive eyes that had previous CK for presbyopia were treated with PRK using a 213 nm wavelength solid-state laser (Pulzar Z1). Uncorrected near (UNVA) and distance (UDVA) visual acuities (monocular and binocular), corrected distance visual acuity (CDVA), refraction, keratometry, and slitlamp evidence of corneal haze and other complications were evaluated for up to 6 months after surgery., Results: The study evaluated 20 eyes (20 patients). Six months after PRK, 47% of eyes had monocular UNVA of Jaeger (J) 3 or better and 27% had a binocular UDVA of 0.10 logMAR (20/25 Snellen equivalent) or better with a concurrent UNVA of J3 or better. Seventy-three percent of eyes were within ±1.00 diopter of the attempted refraction. No eye lost 2 or more lines of CDVA or developed significant corneal haze., Conclusion: Photorefractive keratectomy after CK using a 213 nm wavelength solid-state laser produced functional visual acuity in presbyopic patients in the short term (6 months)., (Copyright © 2011 ASCRS and ESCRS. Published by Elsevier Inc. All rights reserved.)

Not only are human lenses different in many ways from those of non-primates, they also undergo dramatic changes with age. These age-dependent alterations lead to perturbations in the properties of older lenses, and ultimately to disturbances in visual function, which typically become apparent at middle age. Recent data suggest that many, if not all, of these age-dependent features can be traced to the lack of macromolecular turnover in the lens and to the inexorable modifications to proteins and membrane components over a period of decades. Exposure of lenses to heat can reproduce many of these alterations, suggesting that long-term incubation at body temperature may be an important factor in aging the human lens. Two conclusions flow from this. Firstly, the human lens may be an ideal tissue for studying macromolecular aging in man. Secondly, it will be extremely challenging to examine the origin of human age-related conditions, such as presbyopia and nuclear cataract, using traditional laboratory animals. Characterising the unfolding and decomposition of long-lived macromolecules appears to provide the key to understanding the two most common human lens disorders: presbyopia and age-related nuclear cataract., (Crown Copyright © 2010. Published by Elsevier Ltd. All rights reserved.)

All people will be presbyopic by age 50, and we now understand something of the basis for this condition. It turns out to be a direct consequence of two features; first the design of the transparent lens and the way it must change shape to enable focussing by the human eye, and second the instability of proteins over a very long time period. The incremental changes that take place in the lens to render the central region inflexible by middle age and, as a consequence the person presbyopic, may also promote the subsequent development of cataract. Based on the most recent data, heat-induced denaturation of proteins in the lens appears to be a worthy topic for future investigation. Understanding such processes may allow us to glimpse the origin both of presbyopia and age-related nuclear cataract.

Presbyopia, the inability to focus up close, affects everyone by age 50 and is the most common eye condition. It is thought to result from changes to the lens over time making it less flexible. We present evidence that presbyopia may be the result of age-related changes to the proteins of the lens fibre cells. Specifically, we show that there is a progressive decrease in the concentration of the chaperone, alpha-crystallin, in human lens nuclei with age, as it becomes incorporated into high molecular weight aggregates and insoluble protein. This is accompanied by a large increase in lens stiffness. Stiffness increases even more dramatically after middle age following the disappearance of free soluble alpha-crystallin from the centre of the lens. These alterations in alpha-crystallin and aggregated protein in human lenses can be reproduced simply by exposing intact pig lenses to elevated temperatures, for example, 50 degrees C. In this model system, the same protein changes are also associated with a progressive increase in lens stiffness. These data suggest a functional role for alpha-crystallin in the human lens acting as a small heat shock protein and helping to maintain lens flexibility. Presbyopia may be the result of a loss of alpha-crystallin coupled with progressive heat-induced denaturation of structural proteins in the lens during the first five decades of life.

During accommodation, mammalian lenses change shape from a rounder configuration (near focusing) to a flatter one (distance focusing). Thus the lens must have the capacity to change its volume, capsular surface area, or both. Because lens topology is similar to a torus, we developed an approach that allows volume determination from the lens cross-sectional area (CSA). The CSA was obtained from photographs taken perpendicularly to the lenticular anterior-posterior (A-P) axis and computed with software. We calculated the volume of isolated bovine lenses in conditions simulating accommodation by forcing shape changes with a custom-built stretching device in which the ciliary body-zonulae-lens complex (CB-Z-L) was placed. Two measurements were taken (CSA and center of mass) to calculate volume. Mechanically stretching the CB-Z-L increased the equatorial length and decreased the A-P length, CSA, and lens volume. The control parameters were restored when the lenses were stretched and relaxed in an aqueous physiological solution, but not when submerged in oil, a condition with which fluid leaves the lens and does not reenter. This suggests that changes in lens CSA previously observed in humans could have resulted from fluid movement out of the lens. Thus accommodation may involve changes not only in capsular surface but also in volume. Furthermore, we calculated theoretical volume changes during accommodation in models of human lenses using published structural parameters. In conclusion, we suggest that impediments to fluid flow between the aquaporin-rich lens fibers and the lens surface could contribute to the aging-related loss of accommodative power.

Background: A bifocal rigid gas permeable (RGP) contact lens is now available that totally encapsulates an add segment of a different material within its inferior aspect. The purposes of this study were to determine the effects of the major lens and of its encapsulated segment region on the oxygen uptake rates of underlying cornea., Methods: Corneal oxygen uptake rates of 10 human corneas were measured--both centrally and inferiorly--for non-wearing conditions and then immediately after 300-second wearing periods of a polymethylmethacrylate (PMMA) lens and of this RGP-encapsulated segment bifocal contact lens. Corneal responses associated with these three environmental conditions were compared statistically (i.e., without the influence of blink-driven tear flow)., Results: Under the nonblinking conditions maintained (i.e., with oxygen availability restricted to lens transmissibility alone), central corneal hypoxia was found for the RGP bifocal lens to be only 47% of that induced by the PMMA (Dk/L = 0) condition, while the cornea under the encapsulated segment of the bifocal lens averaged 78% of the hypoxic response induced by that same condition. Central site responses were found to be significantly different for the bifocal and the PMMA lens (p < 0.001), as they were for the two inferior sites with these two lenses (p < 0.001). All lens-related responses were found to be significantly different from the no lens condition (p < 0.001)., Conclusions: Using Smith's model (JAOA, 1997) to estimate lens transmissibility, the major lens of this RGP bifocal design appears to meet approximately 80% of the Holden-Mertz daily-wear oxygen requirement--even without post-lens tear exchange, but only about 25% of that requirement appears to be met beneath the encapsulated segment region. Efficient supplementary infusion of oxygen under this lens by blink-driven tear exchange, then, is necessary to maintain optimal corneal health.

Purpose: To characterize changes in the sagittal dimensions of the human crystalline lens and anterior segment as a function of accommodation, to determine the potential age dependence of these changes, and to evaluate these changes in relation to the development of presbyopia., Methods: Scheimpflug slit-lamp photography, as well as a variety of standard ophthalmologic methods, was used to collect information about lens and anterior segment sagital dimensions in a population of 82 adults with refractive error < or = magnitude of 2.0 diopters and at least 0.25 diopter of accommodation for subjects 18 to 70 years of age. Data were analyzed statistically for dependence on accommodation, age, and age dependence of accommodative rate., Results: The rate of change per diopter of accommodation for each measured variable within the lens is independent of age for the entire adult age range. With increasing accommodation, the lens becomes thicker and the anterior chamber shallower along the polar axis. This increase in sagittal lens thickness is entirely because of an increase in the thickness of the lens nucleus. Because the anterior and posterior halves of the nucleus increase in thickness at approximately the same rate with accommodation, the increase in lens thickness results from equal changes in the lengths of the anterior and posterior portions., Conclusions: Because changes along the sagittal axis of the anterior segment with accommodation are independent of age, any explanation of presbyopia that relies on simple changes in the rates of lens thickening and anterior chamber shallowing with age does not hold. In light of other age-related changes in the anterior segment and lens (e.g., increased sharpness of lens curvature, increased lens sagittal thickness, decreased anterior chamber depth), it appears that compensatory mechanisms to preserve far vision with age also preserve the rate of change per diopter of sagittal spacings.