Ординатура / Офтальмология / Английские материалы / Ocular Therapeutics Eye on New Discoveries_Yorio, Clark, Wax_2007

blindness may be tantamount to a death sentence.

Cataracts are often considered to be a “natural” consequence of the aging process. However, as described in this chapter, there are many ways to reduce the risk of cataracts. We are firmly convinced that thoroughly understanding the factors that contribute to cataract formation will lead to treatments to delay or prevent them. It is not our intent to thoroughly review all aspects of lens biology and aging. Instead, we evaluate the evidence for several different potential causes of cataracts and highlight promising approaches for future cataract therapies.

The lens is an unusual tissue. It is made entirely of epithelial cells that exist in two primary states of differentiation (Beebe,

2003). The bulk of the lens is comprised of greatly elongated, terminally differentiated fiber cells (Figure 8.1). Mature fiber cells contain a high concentration of a limited number of proteins, called crystallins. The high crystallin concentration and the regular organization of fiber cells are responsible for the high refractive index and transparency of the tissue. The surface of the lens nearest the cornea is covered by a sheet of epithelial cells. At the lens equator, the epithelial cells differentiate into fiber cells, which elongate and accumulate crystallins. Soon after they have fully elongated, fiber cells complete the process of terminal differentiation by degrading their nuclei and all other membrane-bound organelles. The lens epithelium and fiber mass are surrounded

by a thick, collagenous capsule, which is synthesized by the epithelial and superficial fiber cells. Around its equator, the capsule is anchored to the ciliary body by thin filaments, called the zonules. The zonules suspend the lens in the anterior of the eye and transmit the forces that change the shape of the lens during accommodation.

The lens grows throughout life by the continual addition of new fiber cells at the equator. The oldest fibers, those made during embryonic and fetal life, are in the center of the lens, a region referred to as the nucleus. Mature fiber cells in the outer half of the lens comprise the cortex. Roughly speaking, the fiber cells in the adult lens nucleus were formed before birth, while those in the cortex differentiated after birth. The youngest fiber cells, those that still contain organelles, are in a 0.1 mm thick shell, just beneath the capsule (Bassnett, 1992; McNulty et al., 2004).

As newly formed fiber cells elongate, they extend along the posterior capsule and underneath the epithelial layer until their growing tips meet fiber cells from the other side of the lens. Instead of coming to a point at the anterior and posterior poles of the lens, the cells meet along planes, called sutures. When the tips of elongating fiber cells reach the sutures, they stop elongating (Bassnett and Winzenburger, 2003) and are overlain by successive layers of differentiating fiber cells, a process that gradually buries them farther from the surface of the lens. Before birth, the suture planes formed by the anterior tips of the fiber cells form an upright “Y” configuration, with the posterior suture planes forming an inverted “Y”. The presence of suture planes belies what appears to be radial symmetry around the anterior–posterior axis of the lens. The suture pattern becomes more complex after birth as each suture successively bifurcates to form a total of six, then 12 or more suture planes. Suture branching begins in the inferior nasal quadrant of the lens, again revealing asymmetry in its radial axis (Kuszak et al., 2004).

Age-related cataracts are typically treated by surgery. Modern cataract surgery

involves removal of most or all of the lens fibers and the insertion of a plastic lens, held in place by the lens capsule. Cataract surgery has been continually refined, such that it is now considered to be a safe, rapid and effective procedure. Whether cataract surgery is eventually able to overcome the growing backlog of patients with visually significant lens opacities is likely to depend on economic and political factors, not the effectiveness of the surgery.

The success of cataract surgery has impeded the search for alternative means to prevent or slow the progression of cataracts. Whether non-surgical means can be found to delay or prevent age-related cataracts is far from certain. However, recent advances promise to define the causal chain of events leading to age-related cataract formation. Once the causal chain of events is understood, new therapies are likely to result.

II. AGE-RELATED CATARACT: AT LEAST THREE DIFFERENT

DISEASES

It is important to recognize that the three types of cataract that are associated with older age occur in different regions of the lens, cause opacification by different mechanisms, and have distinct epidemiologic risk factors. Therefore, age-related cataracts are due to at least three different diseases which happen to share two characteristics; they cause opacification of part of the lens and they occur with increasing frequency in older age. It is unfortunate that age-related cataract is still sometimes treated as a single clinical entity, especially in epidemiological studies. Lumping age-related cataracts into a single category obscures the risk factors for each type of cataract. However, such studies are still being published.

Below, we describe the characteristics of the three major types of age-related cataracts (Figure 8.2). The risk factors associated with each of these diseases are discussed in the section on the causes of cataract.

Nuclear cataracts are typically the most common type of age-related cataracts (although cortical cataracts may predominate in some populations). Nuclear opacities are characterized by an increase in light scattering, often accompanied by yellow or brown coloration. In some nuclear cataracts, intense coloration is the primary cause of opacification. These “brunescent” cataracts are most often seen in rural populations, especially in the developing world. The factors responsible for the relative contribution of light scattering and color in nuclear cataracts are poorly understood. Nuclear cataracts are also associated with increased hardness of the center of the lens, leading to their common description as “nuclear sclerotic cataracts”. Examination of nuclear cataracts by electron microscopy has shown that the cell structure in the cataractous region is, at most, only slightly altered, compared to the nuclear fiber cells of age-matched lenses (al-Ghoul et al., 1996). Increased light scattering in nuclear cataracts is associated with the accumulation of oxidative damage to proteins and lipids, leading to increased protein aggregation (Spector, 1995). It is believed that these protein aggregates are primarily responsible for the increase in

light scattering. The chemistry responsible for the increased coloration of nuclear cataracts is complex Byproducts of ascorbate, glucose and tryptophan metabolites all contribute to varying degrees.

Cortical cataracts occur in mature fiber cells in the outer third of the lens. Unlike nuclear cataracts, these opacities involve extensive damage to fiber cell cytoplasm, leaving membrane whorls and precipitated proteins in place of the cells. Cortical cataracts typically begin as punctate or spokeshaped opacities in the equatorial plane. Because fiber cells pass through the equatorial plane as they extend from the posterior to the anterior sutures, cortical opacities begin in the middle of a few fiber cells, with the anterior and posterior tips of these same cells remaining transparent (Brown et al., 1993). Cortical cataracts increase in severity by extending along the length of the affected fiber cells toward the optic axis. Cortical cataracts are not clinically significant in their early stages, since they do not impinge on the visual axis. Clinical observations and several studies have reported the tendency for more cortical opacities to occur in the inferior half of the lens, particularly the inferior nasal quadrant, although this tendency is

more pronounced in some populations (Merriam, 1996; Rochtchina et al., 2001; Sasaki et al., 2003).

Posterior subcapsular cataracts (PSCs) usually account for less than 10% of agerelated cataracts. They result from fiber cells that fail to properly differentiate (elongate) at the lens equator. These abnormal cells move along the posterior capsule toward the sutures, along with the basal ends of their normal, neighboring fiber cells (Eshagian, 1982). When they reach the sutures, they typically remain attached to the posterior capsule, rather than being buried deeper in the lens. PSCs progress by the gradual accumulation of these abnormal cells, ultimately forming a plaque of swollen cells at one or more of the posterior suture planes. These cellular aggregates scatter light, resulting in the cataract. Because they lie in the visual axis, PSCs often severely degrade vision. For this reason, although PSCs represent the least frequent form of age-related cataract, they may account for a more substantial fraction of cataract surgery.

III. CAUSALITY AND CATARACTS

Fully understanding the causes of cataracts is the key to developing effective preventive measures or treatments. However, assigning definitive causes to diseases that occur late in life and that may be affected by multiple factors has been difficult. To help clarify the status of our knowledge about the factors that cause cataracts, we have adopted a formal set of standards for assessing causality. These standards are based on Koch’s postulates, the principles that were widely adopted in the 19th century to ascertain the organisms responsible for causing infectious diseases. In this system, to be considered a cause or contributor to one of the three types of age-related cataracts, a candidate agent must fulfill three criteria:

1.Detection – The causative agent or its effect must be detected in the lens prior to the onset of the cataract.

2.Induction – Introducing or increasing the causative agent should increase the risk or severity of cataract, preferably in a dose-dependent manner.

3.Prevention – Elimination or reduction of the causative agent should prevent or reduce formation of the specific type of cataract.

In addition to these criteria, it would be useful if the causal chain of events, between exposure to the agent and the formation of a cataract, were understood in detail. This would provide the maximum information about how one might intervene to prevent the formation or progression of an opacity. We use these criteria for causality and etiology throughout this chapter to evaluate our current understanding of the causes of age-related cataracts and to identify areas where more information is needed.

IV. INVESTIGATING CATARACTS

Many approaches have been used to study cataracts, including the examination of normal and cataractous human lenses, animal models of cataracts and cultured lenses and lens cells from humans and animals. Eventually, all approaches to understand the causes and prevention of human cataracts must involve human subjects. Although studies of humans have many limitations, they have the prime advantage of relevance. We, therefore, begin our examination of the strengths and weakness of the methods used to investigate cataracts with those involving humans.

Epidemiologic studies are designed to disclose, in a large group of individuals, correlations between exposure to factors that may influence cataract formation and the occurrence of cataracts. Some epidemiologic studies correlate the change in cataract incidence or severity with environmental variables over an extended period of time (cataract progression). The “gold standard” for epidemiologic studies is the clinical trial, in which the incidence or progression

of cataracts is monitored in participants who are intentionally exposed to a placebo or to a treatment that is expected to reduce the formation of cataracts.

In spite of the challenges involved in performing studies on human populations, and their dependence on statistical correlations, epidemiologic studies have provided critical information about the likely risk factors for the different types of age-related cataracts. Such studies can also identify factors that can be effectively ruled out as causes of cataracts, at least in populations that are similar to those that were studied. The conclusions of epidemiologic studies are such important indicators of the causes of cataracts that we believe they must be taken into account when postulating mechanisms of cataract formation. At the same time, only complex and expensive clinical trials are likely to satisfy the three standards of causality described above, and even these are not likely to reveal the chain of events between exposure to an agent and the formation of an opacity.

In a variation of epidemiologic studies, one can examine the association of genetic factors with the incidence of disease. Studies of identical and non-identical twins, and of the tendency of cataracts to be present in families, have provided estimates of the contribution of heredity to the likelihood of developing cataracts. For example, over 50% of the risk of developing cortical cataracts and nearly 50% of the risk of nuclear cataracts were attributable to heredity in studies of identical and fraternal twins in the UK (Hammond et al., 2000, 2001). Similarly, the distribution of cataracts in close relatives in a US population were best accounted for by two dominant genes, one accounting for a substantial proportion of cortical (58%) and the other of nuclear cataracts (35%) (Heiba et al., 1993, 1995). The genes responsible have not yet been identified.

Future studies of the genetic basis of agerelated cataract will benefit from the exceptional power of whole-genome analysis.

This approach involves the generation of high resolution maps of the genomes of large numbers of individuals. These maps allow the identification of blocks of DNA sequence that are frequently shared between individuals with a particular type of cataract. The genetic variations that predispose an individual to cataract formation will lie within or near these regions and can be identified by classical genetic means. Using this approach, several chromosomal regions have been linked to age-related cortical cataract in a US population (Iyengar et al., 2004). In this study, a 3 cM interval on chromosome 6 showed the strongest linkage. Although there are still more than 250 potential genes within this interval, this study represents that most promising progress to date in clarifying the genetic susceptibility to agerelated cataracts. Importantly, none of the genes in this region has been linked to congenital or juvenile cataracts, suggesting that distinct mechanisms are responsible for pediatric and age-related cataracts.

The most valuable aspect of genetic studies may not be the identification of the genes that cause cataracts, but the recognition of the pathways in which these genes act. When these pathways are altered, whether by a modification of gene function or some other influence, a person is rendered more (or less) susceptible to cataract formation. Thus, even if a genetic “defect” cannot be altered, the deleterious effects of this genetic alteration may be avoided or circumvented by other means. In some cases, it may be relatively simple to compensate for the genetic defect. In other cases, intervention may be much more difficult. It will be exciting to contemplate new treatments to prevent or slow the progression of cataracts, once the genetic contributions to age-related cataracts are better understood.

Another way in which human cataracts have been studied has been the description of the natural history of cataract formation and progression in human patients or in lenses obtained from eye bank or cadaver material. While this seems like a simplistic

aspect of cataract investigation, it is the essential foundation on which all other cataract research must be based. In particular, knowledge about the formation and progression of human cataracts is essential for judging the relevance of animal models of cataract.

It is also important to establish methods to image human cataracts and to quantify the extent of cataract formation. Being able to quantify the extent of cataracts and the progression of cataracts is a necessary aspect of any epidemiologic study. Several cataract grading systems are in use throughout the world. These range from subjective grading scales to be used while observing a patient, to advanced imaging systems that permit quantification of the degree of opacification. Subjective systems have the advantage of simplicity and lower cost, but may suffer from variations between observers and the difficulty in confirming the analysis at a later date. Film-based or digital imaging systems are expensive, but are preferred, because several observers can score the degree of opacity using the same images, or the degree of opacity can be determined objectively by using image analysis software.

Cataracts may sometimes be the unintended outcome of an essential medical treatment. While they are undesirable for the patient, iatrogenic cataracts present a valuable opportunity to study cataract formation in living human eyes, since the time and nature of the inciting insult are known and the progression of opacification is often relatively rapid. Common examples of iatrogenic cataracts are the (mainly) nuclear cataracts that occur following vitreoretinal surgery or hyperbaric oxygen therapy, and the posterior subcapsular cataracts that are associated with therapeutic radiation or long-term, high dose steroid treatments. As discussed below, post-vitrectomy cataracts serve as a valuable model for the formation of age-related nuclear cataracts (Holekamp et al., 2005). By contrast, there has been little study of radiation or steroid-induced

cataracts in humans. Steroid-induced cataracts in human patients present a growing opportunity to study the formation and progression of PSCs in vivo. These opacities are being induced in large numbers by the intraocular steroids that are increasingly being used to suppress the abnormal growth of choroidal and retinal blood vessels (Thompson, 2006). Every effort should be made to exploit these unfavorable side effects of treatment to obtain a better understanding of the formation of human PSCs.

Most cataract research is now being done using animal models. Animal studies are essential because they allow investigators to explore the normal functioning of the lens and its constituents in ways that are not possible in humans. Understanding the normal function of the lens provides a foundation on which to reconstruct the sequence of events leading to cataract formation.

There are also numerous advantages of studying animal models of cataract over studying cataracts in humans. Animal models of cataract are generally homogeneous with respect to genetics, age, sex and environment, avoiding the individual variations inherent in studying humans. Animals can be induced to form cataracts by many kinds of treatments, allowing precise timing of cataract development. Many species can be genetically manipulated to study the effects of one or more genes on cataract formation or progression. Drug treatments and other interventions can be tested for their ability to protect an animal against a genetically or experimentally induced cataract.

In spite of these great advantages, animal models of cataract have significant drawbacks. Laboratory animals often differ from humans in their lifespan, natural environment, metabolism, and in the anatomy and biochemistry of their lenses. For practical reasons, animal models of cataracts are often selected to produce cataracts in days to weeks, rather than the months to years that are typically involved in human cataract

formation. Opacification is the most obvious way that the lens signals its ill health. Therefore, the generation of an opacity in an animal is not sufficient evidence of relevance to human cataracts. Often the cataracts produced in animals do not resemble those seen in humans, even when the inciting insult is similar. In a few cases, there has developed the tendency to treat animal cataracts as the norm, rather than acknowledging the ways in which they may be different from human cataracts. This tendency is exacerbated by the increasing difficulty in obtaining human lens material and by the cultural divide that often exists between clinicians and basic scientists. An example of this propensity is described below in the section on diabetic cataracts.

Cultured lenses or lens cells from humans or animals provide an even more convenient way to explore the disruptions that may lead to cataract formation. Lenses can be exposed in vitro to metabolic imbalances or to toxic agents that would not be readily tolerated or easily delivered in vivo. Lens cells can be cultured in large numbers, permitting analyses that are more difficult using fresh specimens dissected from living lenses. Cell function can be modulated by transfecting or transducing genetic constructs or viruses that would be difficult to target to the lens in vivo.

The power of organ culture and cellbased analyses must be balanced by several caveats. The intraocular environment is not easily replicated in vitro. This is best illustrated by the fact that no culture system has yet been designed in which whole lenses grow and differentiate in their normal manner. Another aspect of in vitro culture that has been largely overlooked in the past is the low oxygen tension in the fluids around the lens (Holekamp et al., 2005; Shui et al., 2006). Placing a lens in culture in room air involves at least a 10-fold increase in its exposure to oxygen. Such treatment may be toxic to a tissue that is normally protected from exposure to oxygen and is subject to oxidative damage.

Epithelial cells from adult lenses rarely divide in vivo. Yet, to culture large numbers of lens cells, one usually employs a serumsupplemented culture medium to force cell replication. Rapid proliferation is not only an abnormal state for lens cells, but serum is a pathological fluid not found in a healthy eye. Therefore, the advantage of generating large numbers of lens cells may be offset by the abnormal environment in which these cells are maintained.

Nuclear and cortical cataracts involve the opacification of mature fiber cells. However, mature fiber cells cannot be maintained outside of the lens for more than a few minutes before they disintegrate from an influx of calcium ions (Srivastava et al., 1997).

These considerations place significant limitations on the value of cultured lenses and lens cells for understanding the events that lead to age-related cataracts. We do not wish to imply that cultured lenses or lens cells cannot reveal important information about cataract formation. However, if employed, it is important that the limitations of in vitro analysis be understood and explicitly addressed.

V. THE INFLUENCE OF THE INTRAOCULAR ENVIRONMENT

ON CATARACT FORMATION

It is often stated that the human lens is exposed to numerous environmental stresses throughout life, especially oxidative stress. In our opinion, the opposite is closer to the truth. The human lens exists in an environment that protects it from many kinds of damage, especially oxidative stress. As mentioned above, fluids that surround the lens have levels of oxygen that would be severely hypoxic for most cells. As a result, oxygen levels within the human lens are extremely low, minimizing the possibility that molecular oxygen will participate in oxidative damage (McNulty et al., 2004). The metabolism of lens cells may also help to protect them from oxidative

stresses. Lens cells use only low levels of oxidative metabolism to maintain their functions (Winkler and Riley, 1991; McNulty et al., 2004), which should result in the generation of lower levels of reactive oxygen species. In addition, human lenses have potent metabolic pathways that help to protect their constituents from oxidants, including high levels of the antioxidants ascorbic acid and glutathione, along with enzymes that use glutathione to detoxify potentially harmful metabolites (Giblin, 2000).

Much has been made of the importance of hydrogen peroxide in the intraocular fluids as a potential source of oxidative damage and cataract formation (Spector and Garner, 1981). Early observations of high levels of hydrogen peroxide in aqueous humor (20 to 300 micromolar) were likely to have been confounded by two sources of error. Ascorbic acid, which is present at millimolar concentrations in aqueous humor, causes artifactually high readings in the dichlorophenol–indophenol assay that was initially used to quantify hydrogen peroxide (Garcia-Castineiras et al., 1992). The ascorbic acid in aqueous humor readily reacts with molecular oxygen to produce hydrogen peroxide when the levels of oxygen are substantially above those found in vivo (Spector et al., 1998). Therefore, aqueous humor specimens exposed to room air, in which oxygen levels are 5 to 8 times higher than in vivo, generate hydrogen peroxide. Measurement of hydrogen peroxide in freshly isolated aqueous humor from humans or animals using procedures that were not subject to interference by ascorbate and collection methods which did not expose the samples to oxygen demonstrated that hydrogen peroxide levels are below the limits of detection in vivo ( 1–2 micromolar) (Sharma et al., 1997; Spector et al., 1998). In addition, when oxygen concentrations are low, ascorbate reacts with and detoxifies hydrogen peroxide (Spector et al., 1998). Whether hydrogen peroxide reaches detectable levels in vivo when oxygen levels in the intraocular fluids increase

beyond normal levels, for example, during hyperbaric oxygen therapy, has not yet been determined.

Throughout life, the lens is irradiated with light, which can initiate photochemical reactions that cause oxidative damage. However, the most harmful wavelengths of light do not penetrate the cornea and do not reach the lens (Dillon et al., 1999). Since most light that does reach the lens passes through its center, one would expect that, if light were directly harmful to lens fiber cells, nuclear cataracts would be associated with increased exposure to sunlight. However, increased sunlight exposure throughout life is not associated with an increased risk of nuclear cataracts (Hiller et al., 1986; Taylor et al., 1988; Leske et al., 1991; Cruickshanks et al., 1992; Hirvelae et al., 1995; West et al., 1998; Sasaki et al., 1999; Delcourt et al., 2000a; AREDS, 2001a; Katoh et al., 2001). Therefore, photochemical reactions are not likely to contribute appreciably to cataract formation. The contribution of sunlight to cortical cataracts is discussed below.

Rather than being exposed to a stressful environment, it is probably more accurate to say that the unusual structure of mature lens fiber cells make these cells susceptible to stress, oxidative or otherwise. Whether age-related cataracts occur when the protective mechanisms within and around the lens break down, or whether these protective mechanisms are overwhelmed by age-related changes in the environment around the lens is discussed in the following section.

VI. RISK FACTORS FOR AGE-

RELATED CATARACTS

Our consideration of the risk factors for age-related cataracts is not intended to be exhaustive. Instead, we consider major risk factors that have been identified in a majority of epidemiologic studies. We also do not intend to review here all of the many

changes in the lens that occur with age, but to highlight those that we feel are most relevant to age-related cataract formation.

A. General Risk Factors: Aging

Of course, age is the major risk factor for age-related cataracts. The incidence of all types of cataracts increases exponentially after age 50. By 80, the majority of individuals will have some form of clinically significant opacity (PBA, 2002). Given the importance of age on cataract formation, it is important to understand how the lens changes with age.

An unusual aspect of lens biology is that the human lens grows slowly and approximately linearly from about age 6 throughout the remainder of life (Scammon and Hesdorfer, 1937). By the age of 90, the lens is approximately twice as large as at birth. It is not known whether this increase in size contributes to age-related cataract formation. However, it is reasonable to assume that PS cataracts, which involve defects in lens fiber cell differentiation, might be avoided if no new fiber cells were being formed.

In contrast to the approximately linear growth of the adult lens, the viscoelastic properties of the whole human lens increase exponentially with age, resulting in a more than 1000-fold increase in stiffness (resistance to deformation) between age 10 and 90 (Heys et al., 2004; Weeber et al., 2005). This increase in the resistance of the lens to deformation is considered to be a major contributing factor to presbyopia, the loss of near vision due to the failure of accommodation during the fifth decade of life. Significant increases in the hardness of the lens nucleus are also associated with the formation of nuclear cataracts (Tabandeh et al., 1994, 2000). No increase in hardness of the nucleus, beyond that due to age, is seen in cortical or PS cataracts. Increased hardness of the lens nucleus during aging has been associated with dehydration (Bettelheim et al., 1986; Bours et al., 1987;

Tabandeh et al., 1994), although these observations have been challenged in other studies (Siebinga et al., 1991; Heys et al., 2004).

Remarkably, the mechanisms that are responsible for the huge changes in the mechanical and biophysical properties of the lens during normal aging and nuclear cataract formation are not well understood. Changes in protein composition cannot explain the increase in lens hardness that occurs with age, since the proteins in the lens nucleus are present there from fetal life. Proteolytic modification of the crystallins may contribute to lens stiffness, although this possibility has not been critically tested and many proteolytic modifications are already present early in life (Garland et al., 1996).

The age-related changes in its mechanical properties may be related to another unusual characteristic of the lens. The protein concentration in the center of the adult lens is significantly higher than in the cortex, a property that contributes to the ability of the lens to correct for spherical aberration (Banh et al., 2006). This protein gradient dictates that the osmotic activity of the proteins in the center of the lens must be lower than in the cortex. Otherwise, water would have to be constantly transported out of the lens nucleus, a process that is not consistent with the relatively low metabolic activity of the adult lens. The biophysical properties that lead to this concentration difference are obscure. Presumably, the ability of lens proteins to be concentrated in the nucleus reflects the properties of the proteins themselves, although this has not been directly tested. Whatever these properties, they are likely to be an important aspect of the hardening of the nucleus that occurs with age.

Recently, a substantial decrease was detected in the rate of diffusion of small molecules between the lens cortex and nucleus in older lenses (Sweeney and Truscott, 1998; Moffat et al. 1999; Moffat and Pope, 2002). With age, this “diffusion barrier” was postulated to increasingly limit the transport of intracellular antioxidants, like glutathione

and ascorbate, to the lens nucleus (Truscott, 2000). Although a causal relationship has not been demonstrated, it seems plausible that decreased diffusion could account for much of the increased susceptibility of older lenses to the oxidative damage that characterizes nuclear cataracts (McGinty and Truscott, 2006). It has been suggested that the reduced rate of diffusion seen in older lenses is linked to the physical changes in the lens that underlie presbyopia (McGinty and Truscott, 2006). If this is correct, understanding the etiology of barrier formation will provide valuable insight into the aging lens. However, the age-related changes in lens stiffness that accompany loss of accommodation occur with remarkable uniformity in all lenses. Therefore, these physical changes cannot, by themselves, fully account for why some develop age-related cataracts and others do not.

B. Differences in the Natural History

of the Three Types of Age-Related

Cataracts

The lenses of all older persons increasingly develop nuclear color and opalescence (light scattering). These changes resemble the early stages of nuclear cataracts. For this reason, it is often difficult to define whether someone has an early nuclear cataract or “normal” age-related changes in the lens nucleus. After age 75, the gradual increase in nuclear opalescence and browning has usually progressed to a stage where they interfere with vision. The similarity between the appearance of aging lenses and the early events in nuclear cataract suggests that nuclear cataracts may involve the acceleration of processes that normally occur in the aging lens. In contrast, some older individuals will have a cortical or posterior subcapsular opacity, while others will have no trace of these opacities. Unlike changes in the lens nucleus, there is no gradual agedependent progression of cortical and PS opacities in all individuals. Cortical and PS cataracts appear to be caused by age-related

defects that are, themselves, not part of the aging process.

C. General Risk Factors: Sex

There is striking agreement among epidemiologic studies that women are more likely than men to develop all kinds of age-related cataract, even when greater female longevity is taken into account. The explanation for this association is obscure. One obvious difference between men and women is exposure to different sex hormones. However, no consistent positive association has emerged between female sex steroids and increased risk of cataract in women. In fact, the opposite seems true. Most studies have found that hormone replacement therapy either has no effect or a modest protective influence on cataract risk (Klein et al., 1994; Cumming and Mitchell, 1997; Younan et al., 2002; Defay et al., 2003; Freeman et al., 2004; Nirmalan et al., 2004; Aina et al., 2005). Early age of menarche or late menopause, which should increase lifetime hormone exposure, is also associated with lower cataract incidence (Klein et al., 1994; Younan et al., 2002; Freeman et al., 2004). Use of the estrogen antagonist tamoxifen increases the risk of cataract development, a finding not consistent with a causal role for estrogen in age-related cataract (Fisher et al., 2005). These studies suggest that long-term exposure to female sex hormones protects against cataracts.

From the studies performed to date, it seems possible that female sex hormones are weakly protective and male hormones are more strongly protective against agerelated cataracts. A higher serum level of the testosterone metabolite, DHEAS (but not testosterone), was associated with a lower risk of cataracts in women (Defay et al., 2003). Another study found lower serum testosterone levels in male and female cataract patients than in controls. However, the number of controls was small, the sex distribution of the controls was not specified and no significant differences in hormone