The Lens

In the process of image formation, the crystalline lens of the eye performs two important functions, refraction and accommodation. For refraction, the lens requires an appropriate crystalline structure and transparency; while for accommodation, it needs to be elastic, amenable to changes in its curvature. The increase in the opacity (optical density) and the hardness (loss of elasticity) of the lens with aging are two of the best-known changes in the eye's optical properties that interfere with refraction and accommodation, respectively (6,24).

Knowledge of the structure and development of the lens is essential for understanding its aging. The biconvex lens is basically a fibrous and relatively acellular structure, consisting of a core surrounded by a capsule (Fig. 2A). Anteriorly, the capsular epithelial cells form the fibers and other lens proteins. The collagen fibers of the lens capsule facilitate changes in lens shape during accommodation. The lens core is packed with transparent protein fibers and consists of an inner nuclear zone surrounded by a cortex (Fig. 2A).

Structural Aspects of Lens Growth and Aging

The lens is formed during the embryonic period and is fairly spherical in the fetus and newborn. During postnatal development and throughout maturity, the lens continues to grow by addition of new layers of protein fibers laid down by the capsular epithelial cells. As new fibers form, older fibers are pushed into the lens core. This mode of growth results in increased horizontal thickness of the lens together with increased compaction of the fibers in the nuclear zone (8,24). The lens thickness increases from about 3.5 mm in infancy to 4.5 mm in middle age and to 5.5 mm in old age, growing at a steady, linear rate of 25 m per year (8,12,24). Underlying this process of growth are the capsular epithelial cells, which divide and differentiate, losing their nucleus and organelles, and eventually transforming into an inert skeleton of fibrous proteins (24).

Recent Volumetric and Morphological Studies on Aging Lens

According to Koretz et al. (25), although total lens volume increases with age, the volume of lens nucleus and the shape of nuclear boundaries do not show any significant changes with aging. The lens center of mass and central clear region move anteriorly with aging (25). In addition to an increase in lens mass and volume with age, changes occur in point of insertion of the lens zonules (24). Also, the radius of the lens' anterior surface curvature decreases with aging. The increase in sagittal lens thickness with age is caused, in part, by the anterior movement of lens mass and shallowing of the anterior chamber (8,24).

Aging Changes in Lens Dimension

In a recent in vivo study, Dubbelman et al. (26) used densitometry and compared thickness of the lens cortex versus nucleus with age and found cortex thickness increases with age seven times more than the nucleus; also the anterior cortex was thicker than the posterior one. These increases were limited to zone C2 and did not involve zones C1 and C3. In vitro aging changes in human lens between the ages of 20 and 99 years were investigated: the lens dimensions and the anterior radius of curvature increased linearly with age while the posterior curvature remained constant (27). The ratio of anterior thickness to posterior thickness was constant at 0.70. It is suggested that in vivo forces alter the apparent location of the lens equator (27).

Increased Opacity of the Lens

Although many cytoskeletal proteins such as actin, tubulin, and vimentin are found in the lens core, the transparency of the lens is, in principle, due to a particular supramolecular arrangement of the specific lens proteins, a-, b-, and g-crystallins, within an ion- and water-free environment (8,24). During aging, the lens opacity increases, leading to decreased transparency and increased refraction. Because the crystallin fibers in the lens interior are not regenerated during growth and aging, they undergo many posttranslational changes, including glycation, carboamination, and deamidation. These changes increase crossover and interdigitation among crystallins, making them less elastic, more dense, opaque, and yellowish (8,12,24,28,29).

Some of these aging changes in the lens proteins occur as a consequence of oxidative damage (Chapters 4 and 5) to the protein antioxidants, such as glutathione (GSH) and ascorbate, which diminish in concentrations in the aged lens, while yellow chromophores, particularly metabolites of tryptophan (b-OH-kynurenine, anthranilic acid, bityrosine), increase in frequency of occurrence and concentration. The net results of this increased oxidative damage are:

n a threefold increase in lens optical density (at 460 nm, blue)

between 20 and 60 years (13), n a resulting decreased transmission and increased light scattering, particularly in the blue and yellow range but much less so in the red range, and n a decreased percentage of transmission of light by the eye from about 75% at 10 years to 20% at 80 years.

In addition to impairing transparency and refraction of light, these aging changes may also affect color perception. Excess lens opacity as a consequence of extensive accumulation of pigments may result in a pathological condition known as cataract, characterized by a cloudy lens (7-10,24). This condition may cause reduced vision or blindness (see also below). In normal aging, the accumulation of yellow chromophores and the increased refraction of blue light may protect the retina from the damaging effect of blue light, "blue-light-hazard" (8,24).

Recent Studies on Biochemical and Biophysical Changes in Lens with Aging

Biochemical changes in the human lens with aging include increased insolubility of nuclear-region crystallins, accompanied by formation of high-molecular weight aggregates that may underlie the deformity of the lens nucleus. Increased light scattering, spectral absorption, and lens fluorescence are likely causes of the decrease in light transmission with age. Accumulation of glutathione-b-hydroxykynurenine (GSH-bOHKyn) glycoside causes increased yellowing and fluorescence of the lens, and these may be responsible for accumulation of high-molecular weight aggregates (24). Aging changes were observed in some but not all crystallins, including increased truncation of N-termini, degradation of C-termini, and partial phosphorylation (29). Other studies show increased b-crystal-lin, but decreased g-crystallin proportions during the postnatal period. A major portion of water-soluble proteins in adult lenses is truncated between b-B1 and b-A3/A1 crystallins, and all crystallins are susceptible to deamination with aging (24,30). According to a recent study by Wilmarth et al., deamidation in lens crystallins significantly increased with age, especially in the water-insoluble fractions, and methylated cysteines with other products of posttranslational modification were present at lower levels (31).

Phospholipid and Lipid Changes in the Lens Membranes Phosphatidylcholine decreases with age in epithelial and fiber membranes, but the rate of decrease is higher in the epithelial membranes; both membranes show a steady increase with age in the percentage of sphingomyelin (32). Epithelial membranes contained about five times more phosphatidylcholine than age-matched fiber fractions (32). The distribution of 3-b-OH-cholesterol shows a decrease in the anterior region of the lens relative to the posterior region with aging (24). Lipid oxidation increases linearly with age (Chapter 16) (33). Ganglioside composition changes with age; ganglioseries gangliosides increase, with no significant accumulation of sialyl-Lewis X gangliosides; however Lewis X-containing neolacto-series glycolipids increase with age and cataract progression (34). Lens aging is accompanied by decreased transport of water and water-soluble low-molecular weight metabolites and antioxidants entering the lens nucleus via the epithelium and cortex; this may lead to progressive increase in oxidative damage (35).

Decline in Accommodation and Development of Presbyopia With aging, the increased crossover and interdigitation and compaction of collagen fibers in the capsule and crystallins in the lens nucleus result in gradual hardening and reduced elasticity of the capsule and lens interior (6-8). These changes make the lens gradually less resilient to accommodate for near vision. Indeed, the point of near vision, that is, the minimum distance between the object and the eye for formation of a clear image, increases tenfold during human life, from 9 cm at the age of 10 years to 10 cm at 20 years, 20 cm at 45 years, and 84 cm at 60 years.

The loss of accommodation with aging can also be determined by studying the changes in the eye's refractive power, measured in diopters (reciprocal of the principal focal distance of the lens in meters). Thus, the newborn's lens, being more spherical, shows the highest refractive power (about 60 diopters). As shown in Figure 3, the accommodation power of the human lens decreases to about 14 diopters at the age of 10, and 5 diopters at 40 years, reaching a minimum of 1 diopter by the sixth decade. At this age, the lens becomes hard and nonresilient, and is essentially unable to accommodate for near-vision tasks. This condition is known as presbyopia (Fig. 3) and is of major clinical significance, as practically everyone over 55 years needs corrective convex lenses or eyeglasses for reading and other near-vision tasks.

Environmental effects such as those of heat and temperature can increase the rate of aging changes in the lens fibers, accelerating presbyopia. People from warmer climates show earlier presbyopia (9,14). The aging changes in the suspensory ligaments, the ciliary muscles, and their parasympathetic nerve supply and the associated synapses may contribute to the decline in accommodation with aging. Latency of accommodation reflex decreases during aging.

Recent Studies on Aging of Accommodation Response and Its Causes

The accommodation response shows a decrease in magnitude of fluctuation as well as in amplitude and speed of accommodation with age, indicating a decrease in accommodation dynamics. In older subjects, lens shape contributes little to power, while lens position in the eye significantly influences the power spectrum (37). The time constant for far-to-near accommodation increases with age at a rate of 7msec/yr, while that for near-to-far accommodation increases at 6 msec/yr, supporting a lenticular cause of presbyopia (37). The damping coefficient of the lens increases 20-fold between 15 and 55 years of age (37).

The static accommodation response with aging reveals a slow decline from youth to the age of 40, after which the curve slope shows a rapid decline (38). Also observed is a decrease in tonic accommodation and its amplitude, presumably caused by biomechanical factors (38). However, subjective depth of focus increases due to increased tolerance to defocus, which is related to onset of presbyopia (38). Based on analysis of aging changes in focal length, surface curvature, and resistance to physical deformation, carried out in isolated human lens, lens hardening appears to be the major cause of presbyopia, and the loss of accommodation cannot entirely explain presbyopia (39). A

magnetic resonance imaging study shows that ciliary muscle contraction remains active during aging, but the accommodated ciliary muscle diameter decreases with increasing lens thickness, indicating that presbyopia may depend on the loss of the ability of the lens to disaccommodate due to increased lens thickness or inward movement of the ciliary ring, or both (40).

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