Brief Overview

The lens is susceptible to damage with aging since its cells cannot be replaced in this encapsulated tissue and its proteins cannot turn over in the nonnucleated fiber cells. Not only does this result in a decrease in function of the normal aged lens, but it also sets the stage for development of senescent cataract in individuals with additional environmental insult or genetic proclivity. As the lens ages, vacuoles and multilamellar bodies appear between fiber cells, and occasionally the fiber plasma membrane is disrupted. Most of the elaborate cytoskeletal structure of the lens cells disappears with aging, and by the fifth decade the ability to accommodate is essentially lost. There is a decrease in transparency of the normal lens with aging so that the intensity of light reaching the retina is reduced by about ten-fold by 80 years of age.

Cataracts which can be defined as any opacity of the crystalline lens, result when the refractive index of the lens varies significantly over distances approximating the wavelength of the transmitted light. Variation in the refractive index over these distances can result from changes in lens cell structure, changes in lens protein constituents, or both (Hejtmancik, Kaiser-Kupfer, and Piatigorsky, 2001). Cataracts are generally associated with breakdown of the lens micro-architecture. Vacuole formation can cause large fluctuations in optical density, resulting in light scattering. Light scattering and opacity also can occur if there are significant high molecular weight protein aggregates roughly 1000 A or more in size. The short-range ordered packing of the crystallins, which make up over 90% of soluble lens proteins, is important in this regard; to achieve and maintain lens transparency crystallins must exist in a homogeneous phase.

A variety of biochemical or physical insults can cause phase separation of crystallins into protein-rich and protein-poor regions within the lens fibers. The proteins either remain in solution or form insoluble aggregates or even crystals, any of which can result in light scattering. When mutations in crystallins are sufficient in and of themselves to cause aggregation, they usually result in congenital cataracts, but if they merely increase susceptibility to environmental insults such as light, hyperglycemic, or oxidative damage, they might contribute to age-related cataracts (Hejtmancik and Smaoui, 2003). Thus, congenital cataracts tend to be inherited in a Mendelian fashion with high penetrance, whereas age-related cataracts tend to be multifactorial, with both multiple genes and environmental factors influencing the phenotype. This makes them significantly less amenable to genetic and biochemical study. Finally, although the young human lens is colorless, a gradual increase in yellow pigmentation occurs with age. As this pigmentation increases, it can result in brunescent or brown cataracts.

Figure 68.2 A. A diagram showing lens structure including the anterior epithelial cells; the cortical fiber cells, which elongate and loosen their nuclei and mitochondria; and the nuclear cells, in which this process has been completed. The ends of the nuclear fiber cells abut each other in a complex pattern to form the lens sutures. B. Slit lamp photograph of a nuclear cataract, the most common type of age-related cataract in European populations. Courtesy of Dr. Manuel Datiles, National Eye Institute, National Institutes of Health.

Figure 68.2 A. A diagram showing lens structure including the anterior epithelial cells; the cortical fiber cells, which elongate and loosen their nuclei and mitochondria; and the nuclear cells, in which this process has been completed. The ends of the nuclear fiber cells abut each other in a complex pattern to form the lens sutures. B. Slit lamp photograph of a nuclear cataract, the most common type of age-related cataract in European populations. Courtesy of Dr. Manuel Datiles, National Eye Institute, National Institutes of Health.

Lens proteins and their age-related modifications Enzymatic activity in the lens tends to decrease with age and to be lower in the central cells of the lens nucleus than in the cortical and anterior epithelial cells. As the lens ages, the Na+ and Ca2+ concentrations rise, reflecting an increase in lens permeability or a decrease in pumping efficiency. With aging, both the N- and C-terminal arms of half of the intrinsic membrane protein (MP26) molecules undergo proteolysis to form MP22. The lens contains neutral proteinase, also called the multicatalytic-proteinase complex, which preferentially degrades oxidized proteins, leucine aminopeptidase, calpains, and the protease cofactor ubiquitin, whose activation increases after oxidative stress. The activity of these proteinases is controlled by inhibitors, which appear to be concentrated at the periphery of the lens.

Aging also leads to an increase in high-molecular-weight aggregates and water-insoluble protein between l0 and 50 years of age, especially in the a-crystallins, but also in the and y-crystallins. There is also partial degradation of crystallins and covalent modifications of crystallins and other lens proteins, including an increase in disulfide bridges, deamidation of asparagine and glutamine residues, and racemization of aspartic acid residues. aA-Crystallin is cleaved nonenzymatically, particularly between Asn l0l and Glu l02. An aspartate residue in aA-crystallin appears especially susceptible because it easily forms a succinimide intermediate. Phosphorylation of lens proteins also occurs. Non-enzymatic glycosylation (glycation) occurs, especially of the fi-amino groups of lysine. Through the Maillard reaction, the glycation products can result in increased pigmentation, nontryptophan fluorescence, and nondisul-fide covalent crosslinks. Lens proteins can also undergo carbamylation, which can induce cataracts, and may be the mechanism for the association of cataracts with chronic diarrhea and uremia. y-Crystallins, and especially yS-crystallin, are particularly susceptible to degradation and modification in age-dependent and other cataracts, largely being degraded to low-molecular-weight peptides by increased proteolysis in the cataractous lens.

In age-related cataracts the lens presumably develops reasonably normally during infancy and remains clear in childhood. Then, by somewhat arbitrary definition, at some time after 40 years of age, progressive opacities begin to form in the lens. As mentioned earlier, these opacities almost certainly result at least in part from the cumulative damage of environmental insults on lens proteins and cells. Many of the age-related changes seen in crystallins are accelerated in the presence of oxidative, photo-oxidative, osmotic, or other stresses, which are known to be associated with cataracts. Susceptibility to these alterations may be exacerbated by barriers to movement of small molecules between the central lens nucleus and the metabolically more active epithelium. Many of these changes can be induced in vitro or in model systems by the same stresses epidemiologically associated with cataracts (Davies and Truscott, 2001; Spector, 1995). In contrast, some changes do not appear to be implicated in cataractogenesis and may even serve to protect crystallins from harmful modifications.

The lens crystallins form one obvious target for this accumulated damage, although they are certainly not the only one. Thus, as the and y-crystallins slowly accumulate damage over the lifetime of an individual, they lose the ability to participate in appropriate intermolecular interactions, and even to remain in solution. As these crystallins begin to denature and precipitate, they are bound by the a-crystallins, which have a chaperone-like activity. Binding by a-crystallins maintains the solubility of ^y-crystallins and reduces light scattering, but the a-crystallins appear not to renature their target proteins and release them into the cytoplasm, as do true chaperones. Rather, they hold them in complexes that, though soluble, increase in size as additional damaged protein is bound over time until they themselves begin to approach sizes sufficient to scatter light. Eventually, it seems likely that the available a-crystallin is overwhelmed by increasing amounts of modified ^y-crystallin and the complexes precipitate within the lens cell, forming the insoluble protein fraction that is known to increase with age and in cataractous lenses.

Brief epidemiology of age-related cataracts Age-related cataracts are associated with a number of environmental risk factors, including cigarette smoking or chronic exposure to wood smoke, obesity or elevated blood glucose levels, poor infantile growth, exposure to ultraviolet light, and alcohol consumption (The Italian-American Cataract Study Group, 1991). Conversely, antioxidant vitamins seem to have a protective effect, although this has not been borne out by all studies.

There is increasing epidemiological evidence that genetic factors are important in the pathogenesis of age-related cataracts (McCarty and Taylor, 2001). In 1991, the Lens Opacity Case Control Study indicated that a positive family history was a risk factor for mixed nuclear and cortical cataracts, and the Italian-American cataract study group supported a similar role for family history as a risk factor in cortical, mixed nuclear and cortical, and posterior subcapsular cataracts. In 1994, the Framingham Offspring Eye Study showed that individuals with an affected sibling had three times the likelihood of also having a cataract. The Beaver Dam Eye Study examined nuclear sclerotic cataracts using sibling correlations and segregation analysis. Although a random environmental major effect was rejected by this study, Mendelian transmission was not rejected, and the results suggested that a single major gene could account for as much as 35% of nuclear and up to 75% of cortical cataract variability. Most recently, the twin eye study demonstrated significant genetic influence of age-related cortical cataracts, with heritability accounting for 53 to 58% of the liability for age-related cortical cataracts. This hereditary tendency was consistent with a combination of additive and dominant genes, with dominant genes accounting for 38 to 53% of the genetic effect, depending on whether cataracts were scored using the Oxford or Wilmer grading systems. Similarly, genetic factors were found to account for approximately 48% of the risk for nuclear cataracts.

Was this article helpful?

0 0
Blood Pressure Health

Blood Pressure Health

Your heart pumps blood throughout your body using a network of tubing called arteries and capillaries which return the blood back to your heart via your veins. Blood pressure is the force of the blood pushing against the walls of your arteries as your heart beats.Learn more...

Get My Free Ebook


Post a comment