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Cataract: Window for systemic disorders
Medical Hypotheses (2007) 69, 669–677
http://intl.elsevierhealth.com/journals/mehy
Cataract: Window for systemic disorders Toshimichi Shinohara Harry Maisel c
a,*
, Harold White b, Michael L. Mulhern a,
a
Department of Ophthalmology, University of Nebraska Medical Center, 985840 Nebraska Medical Center, Omaha, NE 68198-5840, United States b Bass Rocks Road, Gloucester, MA 01930, United States c Wayne State University Medical School, Detroit, MI, United States Received 6 November 2006; accepted 9 November 2006
Summary Cataract is the leading cause of visual handicap throughout the world, and almost all elderly individuals develop lens opacities. Epidemiological studies have shown that nuclear cataracts in young adults are associated with higher mortality. Many cataractogenic stressors induce endoplasmic reticulum (ER) stress, which in turn induces the unfolded protein response (UPR). The UPR can damage or kill a wide range of cell types and may be involved in many human diseases. We hypothesize that a cataract can be considered a window that can indicate the presence of systemic disorders. This is important because cataract is easily detected during a routine ocular examination. The slightest opacity in any region of the lenses, especially in younger patients, may be a sign of systemic disorders. Earlier detection of systemic disorders can save the lives of patients. If our hypothesis is correct, then elimination of known ER/cataractogenic stressors from individuals with cataracts should be the one of the first steps for treatments of the systemic disorders. We discuss the potential risk factors and beneficial effects of removal of such risk factors in patients with early cataracts. All patients with cataract should be referred for comprehensive medical examination. c 2007 Published by Elsevier Ltd.
Introduction A cataract is an opacity of the lens which interferes with vision, and is the most frequent cause of visual Abbreviations: ASK1, apoptosis signal-regulating kinase 1; BMI, body mass index; Cata, cataractogenic/ER stressors; JNK, C-Jun and N-terminal protein kinase; DTT, dithiothreitol; DTE, dithioerythritol; ER, endoplasmic reticulum; GSH, glutathione; FAD, flavin enzyme adenine dinucleotide; Hcy, homocysteine; LECs, lens epithelial cells; MAPK, MAP kinase; NO, nitric oxide; PSC, posterior sub-capsular cataract; UPR, unfolded protein response; ROS, reactive oxygen species. * Corresponding author. Tel.: +1 402 559 4205; fax: +1 402 559 3869. E-mail address: [email protected] (T. Shinohara).
0306-9877/$ - see front matter c 2007 Published by Elsevier Ltd. doi:10.1016/j.mehy.2006.11.051
impairment worldwide, especially for the elderly because the incidence of cataracts increases with increasing age. From a public health perspective, it is important to identify the risk factors that affect the development and progression of cataract. Cataract is a multifactorial disease process and is induced by various toxic factors, environmental stressors, and gene mutations. Cataract can be classified into four types; nuclear, cortical, posterior subcapsular (PSC), and mixed. Although the etiology of each cataract type remains elusive, cataracts are known from studies on many animal models and humans to be associated with damage or death of lens epithelial cells (LECs) [1].
670 The results of earlier epidemiological studies have suggested that senile cataract is a marker of generalized tissue aging, and in patients between ages 24 and 65 years, the presence of cataracts is associated with a statistically significant higher risk of mortality [2–11]. However, another author did not find the same association [12], and in addition, cataracts in patients older than 75 are not associated with a higher risk of mortality [2,3]. Recent multinational epidemiological studies showed that diabetes was an important risk factor for cortical and PSCs but not for the nuclear cataracts [3,13,14] and only the nuclear cataract is associated with higher mortality [13]. We have reported that the many seemingly complex cataractogenic stressors (Cata-stressors) were surprisingly also endoplasmic reticulum stressors (ER-stressors) [15]. The Cata/ER stressors induce the unfolded protein response (UPR), which up-regulates caspases and produces reactive oxygen species (ROS) in LECs. These caspases and the ROS can then lead to serious cellular damage, cell death, and cataract [16,17]. Many recent studies have shown that the UPR can be up-regulated in patients with Alzheimer’s disease, Parkinson’s disease, diabetes, and many other degenerative disorders [18]. Most Cata/ER stressors induce the UPR systemically [16]. We hypothesized that the presence of a cataract is a warning sign of systemic disorders, and we propose that cataract can be a marker of systemic diseases. If this hypothesis is correct, then the slightest lens opacity, particularly in younger patients, should be an indication that a careful search be made for systemic disorders.
Association between UPR, cataracts, and systemic disorders We shall demonstrate a correlation between cataract and systemic disorders. Age: It has been well-documented that the incidence of cataract is significantly increased with increasing age, and that aging is the biggest risk factor for all types of cataracts [2–5,11,19,7– 10,13,20–25]. A recent study showed that the effect of the UPR is age-dependent: the percentage of cell death is higher in older than in younger hepatocytes following exposure to ER stressors such as calcimycin and tunicamycin [26,27]. ER stressors also enhance the activation of C-Jun and N-terminal protein kinase (JNK) [26,27]. Csermely [28] suggested a chaperone overload hypothesis, which explains that with aging, there is an overburden of accumulated misfolded protein that pre-
Shinohara et al. vents molecular chaperones from repairing phenotypically silent mutations which might cause disease. These findings suggest that certain systemic disorders may be induced by the UPR in an age-dependent manner. Diabetes: Diabetes is associated with cortical, PSC, and other types of cataracts as well as cataract surgery [5,13,21,23,25,29,30], although one study did not find any association [3]. Diabetic complications include cataract, retinopathy, neuropathy, cardomyopathy and kidney damage. Our recent study showed that rats fed galactose had higher levels of the UPR, generated more ROS, and led to apoptosis in LECs. Either abnormally low or high concentrations of the hexoses induced the UPR. These concentrations are closely associated with the diabetic complications [16,31]. Severe diarrhea and dehydration: Case-control studies in India showed that severe diarrhea and dehydration resulting in confinement to bed for at least 3 days carried a 3–4-fold higher risk for developing a cataract in later life [20,32]. These factors and deficiencies of vitamins and amino acids may be modifiable risk factors. Anorexia nervosa [22,33,34] probably results in a deprivation of all types of nutrients including the essential amino acids and vitamins [35], including vitamin E [36– 38], and is associated with cataracts. Amino acid or vitamin deficiency: There is a gradual decrease in the amount of different amino acids associated with cataract formation due to the reduced concentrations of essential amino acids [39]. Among the amino acids, a lack of tryptophan has been most often associated with the formation of cataract [36,40,41] and the induction of the UPR [18]. Deficits of tryptophan, phenylalanine/tyrosine, or methionine/cystine reduce the weight of the progeny to about 50% or less in normal rats but only low tryptophan was cataractogenic [36,41,42]. Also, excess amino acid such as monosodium-L-glutamate induces cataracts [43,44]. Riboflavin: Riboflavin deficiency which induces cataracts in animals [45,46] also induces the UPR and apoptosis [47,48]. A newly-detected conserved flavin enzyme, adenine dinucleotide (FAD) dependent enzyme (Ero1p), interacts directly with FAD to oxidize protein disulfide isomerase (PDI), which then oxidizes the folding protein. Therefore, riboflavin deficiency results in a striking defect in oxidative protein folding and induces the UPR [49]. Deficit of ascorbate causes cataract [50] and scurvy in certain species of animals. Margittai et al. [51] demonstrated that persistent ascorbate deficiency leads to ER stress, the UPR, and apoptosis in liver cells of guinea pigs, suggesting that insufficient
Cataract: Window for systemic disorders protein processing participates in the pathology of scurvy. Selenium: Selenium is a nutritional trace element essential for growth and fertility, and selenium deficiency combined with low vitamin E can lead to different disorders [52]. The daily intake of selenium in humans recommended by the National Academy of Sciences, USA, is currently 55 lg, although studies on the effect of higher selenium supplementation on health have been conducted. A clinical trial with 200 lg selenium/day showed a dramatic decrease in cancer [53]. Selenium binds to cysteine and generates selenocysteine which is incorporated into selenoproteins [52]. The majority of characterized selenoproteins are redox-associated enzymes, such as glutathione (GSH) peroxidase [54] and thioredoxin reductase-1, -2, and -3 [52]. These enzymes are essential for the regeneration of GSH. Selenium deficiency causes a significant increase in intracellular ROS and peroxidation [55] and is associated with cataract formation in rodents [56,57]. But this association has not been established for human cataract [58,59]. In addition, whether selenium deficiency induces the UPR is unknown. In contrast, an overdose of methylselenic acid (CH3Se2H) induces the UPR [60] and cataracts in animals [61–63] including fish [64]. Body mass index: The results of one study have demonstrated that both low body mass index (BMI) and high BMI are risk factors for cataract [65]. Interestingly, the weight of a baby at one year of age is inversely related to the incidence of nuclear cataract 60–70 years later, supporting the hypothesis that early nutrition is important in age-related cataracts [36,41,42]. In animal studies, deficits of tryptophan, phenylalanine/tyrosine, or methionine/cystine lead to a lower progeny weight to about 50% or less, but only low tryptophan was cataractogenic [36,41,42]. Antioxidants: Oxidation of lens proteins is associated with cataract formation. A case-control study on lens-opacities showed that regular intake of multivitamins is protective against all types of cataracts [66]. In fact, prospective data from 50,000 nurses in the USA determined that the risk of cataract extraction was 45% lower in women taking vitamin C supplements for 10 years [67]. The results of a recent study indicated that 30–50 lM of H2O2 induced the UPR in various types of cells and in rat LECs [16], and treatment with high levels of antioxidants, such as vitamins, may have ameliorated these effects. However, the evidence is varied and no clear consensus has emerged [66,67]. Vitamin E was found to have a protective effect in humans and animals [66], but no significant effect of vitamin E was found in the Nurses Health
671 Study. A protective effect was found for higher carotenoid levels but not for b-carotene [67]. The Linxian cataract studies in the Far Eastern Countries demonstrated a 36% reduction in nuclear cataract in those aged 65–74 taking multiple vitamins, and a 44% reduction in this age group for those receiving riboflavin/niacin supplementation [32,66]. These results suggest that the effect of vitamin supplementation may be small in the relatively well-nourished world. However, deficiency of these vitamins will induce the UPR as well as cataracts in animals, suggesting the importance of these vitamins. Smoking and alcohol consumption: There is now fairly consistent evidence that consuming excessive amounts of alcohol and excessive smoking (nicotine) are related to nuclear cataracts and PSC [20,23,25,35,68]. Acetaldehyde, a major metabolite of alcohol, is able to bind to proteins and induce the UPR [69]. Crowley-Weber et al. [70] reported that 0.8 lM nicotine, the very low submicromolar level occurring in the tissues of smokers, induced ER stress. Hypertension: The Beaver Dam Eye Studies concluded that people with hypertension were more likely to have PSC with an odds ratio of 1.39 (95% confidence), but nuclear and cortical cataract appeared to be unrelated [6]. Heart attacks and strokes: Hypertension, heart attack, and strokes are highly associated with cataract [25]. The role of ER stress in heart disease has been extensively studied, and kinase activation of the apoptosis signal-regulating kinase 1 (ASK1)MAPK cascade is increased in animals following myocardial infarction [71]. This is relevant because recent studies have shown that the ASK1-MAPK cascades are involved in ER stress-induced apoptosis. Protein aggregation diseases such as Alzheimer’s disease and cataract: Since Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and cataract are caused by protein aggregations, it is expected that there will be some features in common among these diseases [72]. So far no epidemiological studies have showed any association between cataract and these diseases. Mutant presenilin [73] and b-amyloid protein [73,74] are found in the lens, and b-amyloid can aggregate in the lens [75], further suggesting that cataract can be associated with Down syndrome [76] and Alzheimer’s disease [75]. In addition, in transgenic mice expressing b-amyloid protein, this protein aggregated in the lenses [76,77], and cataract was more often found in these mice, indicating that cataract and Alzheimer’s disease may be associated [77]. Since b-amyloid and presenilin proteins are present in the lens and brain, it is possible that Alzheimer’s
672 disease can be predicted by analyzing the lens. ER stress is associated with these diseases, as well as ischemia/reperfusion injury and neuron-degeneration. Numerous reports indicate that neurodegeneration can be induced by the UPR [78]. Further research in this area is required, as important correlations may be discovered. Cholesterol biosynthesis inhibitors (U18666A and Ketoconazole): Many patients with hypertension take cholesterol inhibitors, and cholesterol biosynthesis inhibitors induce subcapsular cataracts in animals and increase the risk of cataracts in humans [79–84]. The results of several studies have indicated that U18666A activates Ca++ proteolysis, induces protein modification, lipid peroxidation, and loss of intercellular junctions. Apoptosis is induced in LECs shortly after treatment of animals with U18666A [83], and two recent studies showed that the suppression of cholesterol induces the UPR [85–87]. So far, no cataractogenic effect of Lovastatin or Lipitor has been reported in humans [88], but higher dosages of these drugs for extended periods of time induce cataracts in beagle dogs [89]. Further research in this area is required. Homocysteine (Hcy): There is considerable evidence that Hcy is associated with lens dislocation and cataract formation [90], but there is no direct link between higher levels of Hcy and cataract formation. Because higher levels of Hcy induce the UPR in many cell types, Hcy will probably induce cataracts. A moderate elevation of Hcy is most commonly caused by deficiencies of vitamins B6, B12, and folate, [91] and the elevation is also associated with polymorphisms in the methylenetetrahydrofolate reductase gene [91,92]. The level of Hcy in hyperhomocysteinaemia patients can be lowered by dietary intake of vitamins B6, B12, and folate [90]. With aging, the levels of Hcy increases, especially in populations that have a deficiency of vitamins B6, B12, and folate. We have shown that a single exposure of human LECs in culture to 5 mM of Hcy induced the UPR, production of ROS, and massive cell death [16]. These results suggested that Hcy is a risk factor for cataracts and other disorders, and supplementation with higher doses of vitamins B6, and B12, and folate may delay such cataract formation and mortality [93]. Xanthurenic acid: Xanthurenic acid and 3-hydroxykynurenine, endogenous tryptophan metabolites in the kynurenine pathway, are potential toxins for several types of cells, and they induce apoptotic cell death in LECs [93–96] through the UPR [97]. Xanthurenic acid is an endogenous molecule derived from the degradation of tryptophan by indoleamine2,3-dioxygenase. Indoleamine-2,3-dioxygenase is
Shinohara et al. induced in patients with infectious diseases by liposaccharides, interferon-a, and superoxide radicals [98]. Xanthurenic acid is enzymatically formed by transamination of 3-hydroxykynurenine by kynurenine-aminotransferase [99]. Xanthurenic acid accumulates with increasing age in senile cataracts [100,101] and leads to apoptotic-like cell death [96,102]. Its cytoplasmic BH3 domain is responsible for targeting the proteins in mitochondria, resulting in the release of cytochrome C [103,104]. In addition, proteins with a BH3-domain (Bax, Bak, Bcl-xs, Bad) are transformed in the presence of xanthurenic acid to their proapoptotic-inducing state and are translocated to mitochondria. In vitro, xanthurenic acid leads to covalent oligomerization of Bax, and Bcl-xs. It also alters mitochondrial Ca2+ transport and increases oxygen consumption [105]. Thus, removal of these molecules are important to prevent cataracts and supplementation by higher doses of vitamin B6 helps in the excretion of urinary xanthurenic acid in response to a tryptophan load [106,107]. Ca++ imbalance: Although Ca++ has many functional roles, intralumenal Ca++ storage of the ER is important for the generation of Ca++ signals as well as for the correct folding and post-translational processing of proteins entering the ER after synthesis. Influx of Ca++ into LECs treated with calcimycin or thapsigargin induces the UPR [18,108] and cataract formation [109–112]. On the other hand, a hypo- or hyper-Ca++ environment causes LEC death and cataracts [113]. A Ca++ chelating agent, EGTA, is known to induce the UPR in wide variety of cells and it also induces cataracts [114,115]. Thus, either an overload or depletion of Ca++ induces the UPR in a wide range of cell types. Metal ions: Lead, copper, and mercury induce cataracts[116], the UPR, and cell death. Viral infections: Herpes, retrovirus, and rubella induce cataract [117–119], and viral proteins in the ER activate the UPR [78,112]. Chronic hepatitis B virus infection induces oxidative stress and DNA damage and results in UPR induced apoptosis [68,120,121]. Retroviral infections also induce Bip/GRP78 and the UPR [122], and the Alpha virus induces the UPR and cell death [26]. Thus, viral infections are a high risk factor for systemic disorders as well as cataract development. Nitric oxide (NO): Excessive NO is speculated to induce cataracts [123] in diabetic patients [124] and is also reported to induce the UPR [125,126] in macrophages. Toxic drugs: Methionine sulphoximine induces anterior and peripheral cataracts [127] and ER stress [128]. Dinitrophenol induces cataracts in hu-
Cataract: Window for systemic disorders mans and various animals [129] and also induces the UPR [130]. 3-aminotriazole induces posterior cataracts [131] and the UPR [49]. Local phenomena also contributes to cataract development: Mutant crystallins and other lensspecific cytoplasmic proteins induce cataract, but induce neither the UPR nor systemic disorders. In contrast, mutations of general housekeeping membrane proteins or secretory protein genes induce systemic diseases and the UPR. Epidemiological studies have also shown that sunlight is a risk factor for cataracts, but the evidence from the different studies are conflicting [4,7–11,13,19,24,38,132– 140].
Cause of death among cataractous patients
673 ical examination. Because of the relationship between cataract and the UPR, more detailed studies on this relationship will be important for the prevention of cataracts and secondarily for systemic disorders. Damages induced by ER stress can be ameliorated by an application of chemical chaperones [142].
Acknowledgements The authors are grateful to Dr. Duco Hamasaki for critical reading of the manuscript and discussion prior to publication. This work was supported in part by the RPB and a fund from the Department of Ophthalmology and Visual Sciences, UNMC.
References Only a few general categories of the cause of death in individuals with cataracts have been analyzed. Among the diseases, heart disease, vascular lesions, and arteriosclerosis are relatively high [2,4,141]. In contrast, the percentage of patients with cataracts who died of cancer was nearly 50% of the mortality of the general population [3]. Death from cardiovascular diseases [4] was overrepresented among young patients with cataract [21] suggesting that cardiovascular diseases in young patients are associated with increased mortality. This increased mortality among patients with cataracts may indicate a general deterioration of health for these patients.
Conclusions Extraction of the cataract is a routine procedure; however, extensive examinations for systemic disorders are generally not performed on these patients. Advanced knowledge of the cataractogenic mechanism, such as the UPR, prompts us to propose that yearly diagnostic examination for cataracts can be highly beneficial for the detection of systemic disorders. Any lens opacity in patients younger than 60-years-of-age should precipitate an examination for systemic disorders such as diabetes, Alzheimer’s, Parkinson’s, and cardiovascular diseases. In addition, a search should be made for nutritional deficiencies and damages induced by smoking and alcoholism, hypertension, Hcy, xanthurenic acid, and some other genetic disorders. Ophthalmologists are able to detect cataracts relatively quickly and at low cost, which will be of great benefit to younger patients. Such patients should more be referred for a comprehensive med-
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http://intl.elsevierhealth.com/journals/mehy
Cataract: Window for systemic disorders Toshimichi Shinohara Harry Maisel c
a,*
, Harold White b, Michael L. Mulhern a,
a
Department of Ophthalmology, University of Nebraska Medical Center, 985840 Nebraska Medical Center, Omaha, NE 68198-5840, United States b Bass Rocks Road, Gloucester, MA 01930, United States c Wayne State University Medical School, Detroit, MI, United States Received 6 November 2006; accepted 9 November 2006
Summary Cataract is the leading cause of visual handicap throughout the world, and almost all elderly individuals develop lens opacities. Epidemiological studies have shown that nuclear cataracts in young adults are associated with higher mortality. Many cataractogenic stressors induce endoplasmic reticulum (ER) stress, which in turn induces the unfolded protein response (UPR). The UPR can damage or kill a wide range of cell types and may be involved in many human diseases. We hypothesize that a cataract can be considered a window that can indicate the presence of systemic disorders. This is important because cataract is easily detected during a routine ocular examination. The slightest opacity in any region of the lenses, especially in younger patients, may be a sign of systemic disorders. Earlier detection of systemic disorders can save the lives of patients. If our hypothesis is correct, then elimination of known ER/cataractogenic stressors from individuals with cataracts should be the one of the first steps for treatments of the systemic disorders. We discuss the potential risk factors and beneficial effects of removal of such risk factors in patients with early cataracts. All patients with cataract should be referred for comprehensive medical examination. c 2007 Published by Elsevier Ltd.
Introduction A cataract is an opacity of the lens which interferes with vision, and is the most frequent cause of visual Abbreviations: ASK1, apoptosis signal-regulating kinase 1; BMI, body mass index; Cata, cataractogenic/ER stressors; JNK, C-Jun and N-terminal protein kinase; DTT, dithiothreitol; DTE, dithioerythritol; ER, endoplasmic reticulum; GSH, glutathione; FAD, flavin enzyme adenine dinucleotide; Hcy, homocysteine; LECs, lens epithelial cells; MAPK, MAP kinase; NO, nitric oxide; PSC, posterior sub-capsular cataract; UPR, unfolded protein response; ROS, reactive oxygen species. * Corresponding author. Tel.: +1 402 559 4205; fax: +1 402 559 3869. E-mail address: [email protected] (T. Shinohara).
0306-9877/$ - see front matter c 2007 Published by Elsevier Ltd. doi:10.1016/j.mehy.2006.11.051
impairment worldwide, especially for the elderly because the incidence of cataracts increases with increasing age. From a public health perspective, it is important to identify the risk factors that affect the development and progression of cataract. Cataract is a multifactorial disease process and is induced by various toxic factors, environmental stressors, and gene mutations. Cataract can be classified into four types; nuclear, cortical, posterior subcapsular (PSC), and mixed. Although the etiology of each cataract type remains elusive, cataracts are known from studies on many animal models and humans to be associated with damage or death of lens epithelial cells (LECs) [1].
670 The results of earlier epidemiological studies have suggested that senile cataract is a marker of generalized tissue aging, and in patients between ages 24 and 65 years, the presence of cataracts is associated with a statistically significant higher risk of mortality [2–11]. However, another author did not find the same association [12], and in addition, cataracts in patients older than 75 are not associated with a higher risk of mortality [2,3]. Recent multinational epidemiological studies showed that diabetes was an important risk factor for cortical and PSCs but not for the nuclear cataracts [3,13,14] and only the nuclear cataract is associated with higher mortality [13]. We have reported that the many seemingly complex cataractogenic stressors (Cata-stressors) were surprisingly also endoplasmic reticulum stressors (ER-stressors) [15]. The Cata/ER stressors induce the unfolded protein response (UPR), which up-regulates caspases and produces reactive oxygen species (ROS) in LECs. These caspases and the ROS can then lead to serious cellular damage, cell death, and cataract [16,17]. Many recent studies have shown that the UPR can be up-regulated in patients with Alzheimer’s disease, Parkinson’s disease, diabetes, and many other degenerative disorders [18]. Most Cata/ER stressors induce the UPR systemically [16]. We hypothesized that the presence of a cataract is a warning sign of systemic disorders, and we propose that cataract can be a marker of systemic diseases. If this hypothesis is correct, then the slightest lens opacity, particularly in younger patients, should be an indication that a careful search be made for systemic disorders.
Association between UPR, cataracts, and systemic disorders We shall demonstrate a correlation between cataract and systemic disorders. Age: It has been well-documented that the incidence of cataract is significantly increased with increasing age, and that aging is the biggest risk factor for all types of cataracts [2–5,11,19,7– 10,13,20–25]. A recent study showed that the effect of the UPR is age-dependent: the percentage of cell death is higher in older than in younger hepatocytes following exposure to ER stressors such as calcimycin and tunicamycin [26,27]. ER stressors also enhance the activation of C-Jun and N-terminal protein kinase (JNK) [26,27]. Csermely [28] suggested a chaperone overload hypothesis, which explains that with aging, there is an overburden of accumulated misfolded protein that pre-
Shinohara et al. vents molecular chaperones from repairing phenotypically silent mutations which might cause disease. These findings suggest that certain systemic disorders may be induced by the UPR in an age-dependent manner. Diabetes: Diabetes is associated with cortical, PSC, and other types of cataracts as well as cataract surgery [5,13,21,23,25,29,30], although one study did not find any association [3]. Diabetic complications include cataract, retinopathy, neuropathy, cardomyopathy and kidney damage. Our recent study showed that rats fed galactose had higher levels of the UPR, generated more ROS, and led to apoptosis in LECs. Either abnormally low or high concentrations of the hexoses induced the UPR. These concentrations are closely associated with the diabetic complications [16,31]. Severe diarrhea and dehydration: Case-control studies in India showed that severe diarrhea and dehydration resulting in confinement to bed for at least 3 days carried a 3–4-fold higher risk for developing a cataract in later life [20,32]. These factors and deficiencies of vitamins and amino acids may be modifiable risk factors. Anorexia nervosa [22,33,34] probably results in a deprivation of all types of nutrients including the essential amino acids and vitamins [35], including vitamin E [36– 38], and is associated with cataracts. Amino acid or vitamin deficiency: There is a gradual decrease in the amount of different amino acids associated with cataract formation due to the reduced concentrations of essential amino acids [39]. Among the amino acids, a lack of tryptophan has been most often associated with the formation of cataract [36,40,41] and the induction of the UPR [18]. Deficits of tryptophan, phenylalanine/tyrosine, or methionine/cystine reduce the weight of the progeny to about 50% or less in normal rats but only low tryptophan was cataractogenic [36,41,42]. Also, excess amino acid such as monosodium-L-glutamate induces cataracts [43,44]. Riboflavin: Riboflavin deficiency which induces cataracts in animals [45,46] also induces the UPR and apoptosis [47,48]. A newly-detected conserved flavin enzyme, adenine dinucleotide (FAD) dependent enzyme (Ero1p), interacts directly with FAD to oxidize protein disulfide isomerase (PDI), which then oxidizes the folding protein. Therefore, riboflavin deficiency results in a striking defect in oxidative protein folding and induces the UPR [49]. Deficit of ascorbate causes cataract [50] and scurvy in certain species of animals. Margittai et al. [51] demonstrated that persistent ascorbate deficiency leads to ER stress, the UPR, and apoptosis in liver cells of guinea pigs, suggesting that insufficient
Cataract: Window for systemic disorders protein processing participates in the pathology of scurvy. Selenium: Selenium is a nutritional trace element essential for growth and fertility, and selenium deficiency combined with low vitamin E can lead to different disorders [52]. The daily intake of selenium in humans recommended by the National Academy of Sciences, USA, is currently 55 lg, although studies on the effect of higher selenium supplementation on health have been conducted. A clinical trial with 200 lg selenium/day showed a dramatic decrease in cancer [53]. Selenium binds to cysteine and generates selenocysteine which is incorporated into selenoproteins [52]. The majority of characterized selenoproteins are redox-associated enzymes, such as glutathione (GSH) peroxidase [54] and thioredoxin reductase-1, -2, and -3 [52]. These enzymes are essential for the regeneration of GSH. Selenium deficiency causes a significant increase in intracellular ROS and peroxidation [55] and is associated with cataract formation in rodents [56,57]. But this association has not been established for human cataract [58,59]. In addition, whether selenium deficiency induces the UPR is unknown. In contrast, an overdose of methylselenic acid (CH3Se2H) induces the UPR [60] and cataracts in animals [61–63] including fish [64]. Body mass index: The results of one study have demonstrated that both low body mass index (BMI) and high BMI are risk factors for cataract [65]. Interestingly, the weight of a baby at one year of age is inversely related to the incidence of nuclear cataract 60–70 years later, supporting the hypothesis that early nutrition is important in age-related cataracts [36,41,42]. In animal studies, deficits of tryptophan, phenylalanine/tyrosine, or methionine/cystine lead to a lower progeny weight to about 50% or less, but only low tryptophan was cataractogenic [36,41,42]. Antioxidants: Oxidation of lens proteins is associated with cataract formation. A case-control study on lens-opacities showed that regular intake of multivitamins is protective against all types of cataracts [66]. In fact, prospective data from 50,000 nurses in the USA determined that the risk of cataract extraction was 45% lower in women taking vitamin C supplements for 10 years [67]. The results of a recent study indicated that 30–50 lM of H2O2 induced the UPR in various types of cells and in rat LECs [16], and treatment with high levels of antioxidants, such as vitamins, may have ameliorated these effects. However, the evidence is varied and no clear consensus has emerged [66,67]. Vitamin E was found to have a protective effect in humans and animals [66], but no significant effect of vitamin E was found in the Nurses Health
671 Study. A protective effect was found for higher carotenoid levels but not for b-carotene [67]. The Linxian cataract studies in the Far Eastern Countries demonstrated a 36% reduction in nuclear cataract in those aged 65–74 taking multiple vitamins, and a 44% reduction in this age group for those receiving riboflavin/niacin supplementation [32,66]. These results suggest that the effect of vitamin supplementation may be small in the relatively well-nourished world. However, deficiency of these vitamins will induce the UPR as well as cataracts in animals, suggesting the importance of these vitamins. Smoking and alcohol consumption: There is now fairly consistent evidence that consuming excessive amounts of alcohol and excessive smoking (nicotine) are related to nuclear cataracts and PSC [20,23,25,35,68]. Acetaldehyde, a major metabolite of alcohol, is able to bind to proteins and induce the UPR [69]. Crowley-Weber et al. [70] reported that 0.8 lM nicotine, the very low submicromolar level occurring in the tissues of smokers, induced ER stress. Hypertension: The Beaver Dam Eye Studies concluded that people with hypertension were more likely to have PSC with an odds ratio of 1.39 (95% confidence), but nuclear and cortical cataract appeared to be unrelated [6]. Heart attacks and strokes: Hypertension, heart attack, and strokes are highly associated with cataract [25]. The role of ER stress in heart disease has been extensively studied, and kinase activation of the apoptosis signal-regulating kinase 1 (ASK1)MAPK cascade is increased in animals following myocardial infarction [71]. This is relevant because recent studies have shown that the ASK1-MAPK cascades are involved in ER stress-induced apoptosis. Protein aggregation diseases such as Alzheimer’s disease and cataract: Since Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and cataract are caused by protein aggregations, it is expected that there will be some features in common among these diseases [72]. So far no epidemiological studies have showed any association between cataract and these diseases. Mutant presenilin [73] and b-amyloid protein [73,74] are found in the lens, and b-amyloid can aggregate in the lens [75], further suggesting that cataract can be associated with Down syndrome [76] and Alzheimer’s disease [75]. In addition, in transgenic mice expressing b-amyloid protein, this protein aggregated in the lenses [76,77], and cataract was more often found in these mice, indicating that cataract and Alzheimer’s disease may be associated [77]. Since b-amyloid and presenilin proteins are present in the lens and brain, it is possible that Alzheimer’s
672 disease can be predicted by analyzing the lens. ER stress is associated with these diseases, as well as ischemia/reperfusion injury and neuron-degeneration. Numerous reports indicate that neurodegeneration can be induced by the UPR [78]. Further research in this area is required, as important correlations may be discovered. Cholesterol biosynthesis inhibitors (U18666A and Ketoconazole): Many patients with hypertension take cholesterol inhibitors, and cholesterol biosynthesis inhibitors induce subcapsular cataracts in animals and increase the risk of cataracts in humans [79–84]. The results of several studies have indicated that U18666A activates Ca++ proteolysis, induces protein modification, lipid peroxidation, and loss of intercellular junctions. Apoptosis is induced in LECs shortly after treatment of animals with U18666A [83], and two recent studies showed that the suppression of cholesterol induces the UPR [85–87]. So far, no cataractogenic effect of Lovastatin or Lipitor has been reported in humans [88], but higher dosages of these drugs for extended periods of time induce cataracts in beagle dogs [89]. Further research in this area is required. Homocysteine (Hcy): There is considerable evidence that Hcy is associated with lens dislocation and cataract formation [90], but there is no direct link between higher levels of Hcy and cataract formation. Because higher levels of Hcy induce the UPR in many cell types, Hcy will probably induce cataracts. A moderate elevation of Hcy is most commonly caused by deficiencies of vitamins B6, B12, and folate, [91] and the elevation is also associated with polymorphisms in the methylenetetrahydrofolate reductase gene [91,92]. The level of Hcy in hyperhomocysteinaemia patients can be lowered by dietary intake of vitamins B6, B12, and folate [90]. With aging, the levels of Hcy increases, especially in populations that have a deficiency of vitamins B6, B12, and folate. We have shown that a single exposure of human LECs in culture to 5 mM of Hcy induced the UPR, production of ROS, and massive cell death [16]. These results suggested that Hcy is a risk factor for cataracts and other disorders, and supplementation with higher doses of vitamins B6, and B12, and folate may delay such cataract formation and mortality [93]. Xanthurenic acid: Xanthurenic acid and 3-hydroxykynurenine, endogenous tryptophan metabolites in the kynurenine pathway, are potential toxins for several types of cells, and they induce apoptotic cell death in LECs [93–96] through the UPR [97]. Xanthurenic acid is an endogenous molecule derived from the degradation of tryptophan by indoleamine2,3-dioxygenase. Indoleamine-2,3-dioxygenase is
Shinohara et al. induced in patients with infectious diseases by liposaccharides, interferon-a, and superoxide radicals [98]. Xanthurenic acid is enzymatically formed by transamination of 3-hydroxykynurenine by kynurenine-aminotransferase [99]. Xanthurenic acid accumulates with increasing age in senile cataracts [100,101] and leads to apoptotic-like cell death [96,102]. Its cytoplasmic BH3 domain is responsible for targeting the proteins in mitochondria, resulting in the release of cytochrome C [103,104]. In addition, proteins with a BH3-domain (Bax, Bak, Bcl-xs, Bad) are transformed in the presence of xanthurenic acid to their proapoptotic-inducing state and are translocated to mitochondria. In vitro, xanthurenic acid leads to covalent oligomerization of Bax, and Bcl-xs. It also alters mitochondrial Ca2+ transport and increases oxygen consumption [105]. Thus, removal of these molecules are important to prevent cataracts and supplementation by higher doses of vitamin B6 helps in the excretion of urinary xanthurenic acid in response to a tryptophan load [106,107]. Ca++ imbalance: Although Ca++ has many functional roles, intralumenal Ca++ storage of the ER is important for the generation of Ca++ signals as well as for the correct folding and post-translational processing of proteins entering the ER after synthesis. Influx of Ca++ into LECs treated with calcimycin or thapsigargin induces the UPR [18,108] and cataract formation [109–112]. On the other hand, a hypo- or hyper-Ca++ environment causes LEC death and cataracts [113]. A Ca++ chelating agent, EGTA, is known to induce the UPR in wide variety of cells and it also induces cataracts [114,115]. Thus, either an overload or depletion of Ca++ induces the UPR in a wide range of cell types. Metal ions: Lead, copper, and mercury induce cataracts[116], the UPR, and cell death. Viral infections: Herpes, retrovirus, and rubella induce cataract [117–119], and viral proteins in the ER activate the UPR [78,112]. Chronic hepatitis B virus infection induces oxidative stress and DNA damage and results in UPR induced apoptosis [68,120,121]. Retroviral infections also induce Bip/GRP78 and the UPR [122], and the Alpha virus induces the UPR and cell death [26]. Thus, viral infections are a high risk factor for systemic disorders as well as cataract development. Nitric oxide (NO): Excessive NO is speculated to induce cataracts [123] in diabetic patients [124] and is also reported to induce the UPR [125,126] in macrophages. Toxic drugs: Methionine sulphoximine induces anterior and peripheral cataracts [127] and ER stress [128]. Dinitrophenol induces cataracts in hu-
Cataract: Window for systemic disorders mans and various animals [129] and also induces the UPR [130]. 3-aminotriazole induces posterior cataracts [131] and the UPR [49]. Local phenomena also contributes to cataract development: Mutant crystallins and other lensspecific cytoplasmic proteins induce cataract, but induce neither the UPR nor systemic disorders. In contrast, mutations of general housekeeping membrane proteins or secretory protein genes induce systemic diseases and the UPR. Epidemiological studies have also shown that sunlight is a risk factor for cataracts, but the evidence from the different studies are conflicting [4,7–11,13,19,24,38,132– 140].
Cause of death among cataractous patients
673 ical examination. Because of the relationship between cataract and the UPR, more detailed studies on this relationship will be important for the prevention of cataracts and secondarily for systemic disorders. Damages induced by ER stress can be ameliorated by an application of chemical chaperones [142].
Acknowledgements The authors are grateful to Dr. Duco Hamasaki for critical reading of the manuscript and discussion prior to publication. This work was supported in part by the RPB and a fund from the Department of Ophthalmology and Visual Sciences, UNMC.
References Only a few general categories of the cause of death in individuals with cataracts have been analyzed. Among the diseases, heart disease, vascular lesions, and arteriosclerosis are relatively high [2,4,141]. In contrast, the percentage of patients with cataracts who died of cancer was nearly 50% of the mortality of the general population [3]. Death from cardiovascular diseases [4] was overrepresented among young patients with cataract [21] suggesting that cardiovascular diseases in young patients are associated with increased mortality. This increased mortality among patients with cataracts may indicate a general deterioration of health for these patients.
Conclusions Extraction of the cataract is a routine procedure; however, extensive examinations for systemic disorders are generally not performed on these patients. Advanced knowledge of the cataractogenic mechanism, such as the UPR, prompts us to propose that yearly diagnostic examination for cataracts can be highly beneficial for the detection of systemic disorders. Any lens opacity in patients younger than 60-years-of-age should precipitate an examination for systemic disorders such as diabetes, Alzheimer’s, Parkinson’s, and cardiovascular diseases. In addition, a search should be made for nutritional deficiencies and damages induced by smoking and alcoholism, hypertension, Hcy, xanthurenic acid, and some other genetic disorders. Ophthalmologists are able to detect cataracts relatively quickly and at low cost, which will be of great benefit to younger patients. Such patients should more be referred for a comprehensive med-
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