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The Journals of Gerontology Series A: Biological Sciences and Medical Sciences 62:500-506 (2007)
© 2007 The Gerontological Society of America

Reduced Age-Related Cataracts Among Elderly Persons Who Reach Age 90 With Preserved Cognition: A Biomarker of Successful Aging?

George S. Zubenko, Wendy N. Zubenko, Brion S. Maher and Norman S. Wolf

1 Department of Psychiatry, University of Pittsburgh School of Medicine, Pennsylvania.
2 Department of Biological Sciences, Mellon College of Science, Carnegie-Mellon University, Pittsburgh, Pennsylvania.
3 Center for Craniofacial and Dental Genetics, University of Pittsburgh School of Dental Medicine, Pennsylvania.
4 Department of Pathology, University of Washington, Seattle.

Address correspondence to George S. Zubenko, MD, PhD, WPIC, 15th Floor, 3811 O'Hara St., Pittsburgh, PA 15213. E-mail: zubenkog{at}pitt.edu


   Abstract
Top
 Abstract
Participants and Methods
 Results
 Discussion
 References
 
Tissue damage due to oxidative stress has been implicated in aging, memory loss, and cataract formation. We hypothesized that persons who achieved exceptional longevity with preserved cognition (successful aging [SAG]) would exhibit a lower rate of age-related cataract (ARC) than the general population. The age-specific rates of ARC for a group of 100 (50 male, 50 female) elderly persons who reached at least age 90 years with preserved cognition were compared to the corresponding rates of ARC reported in five population-based studies. The principal finding of this report was that the SAG group manifested a significant reduction in the age-specific rate and lifetime cumulative incidence of ARC compared to the general population. Steroid use, alcohol consumption, gout, and skin lesions resulting from excessive sun exposure emerged as risk factors. Our findings suggest that the progressive development of lens opacities may be reflective of degenerative events occurring more generally throughout the body.

DURING the last several decades, we have witnessed the aging of the American population and that of the Southwestern Pennsylvania region in particular (1). This realization has led to an understandable emphasis on the goal of "successful" aging (SAG) by many segments of our national community. Although SAG is a complex concept that requires consideration of a multitude of variables reflecting quality of life (2), longevity is a cardinal and indispensable prerequisite to SAG. From an experimental perspective, life span also has the virtue of being a readily quantifiable variable with an irrefutable endpoint. In addition to longevity, most would include the preservation of normal cognition among the essentials required for SAG.

We have previously characterized a sample of 50 men and 50 women recruited from the Southwestern Pennsylvania region who reached age 90 with preserved cognition, as reflected by clinical and psychometric assessments (3). These individuals exhibited a "good" average capacity to carry out their activities of daily living, and the majority were living independently despite multiple medical conditions. Although studies of human twins (4,5) and large extended families (6) suggest that the heritability of the typical human life span is <50%, genes appear to play a more important role in achieving exceptional longevity (>85 years) (7,8) as well as the preservation of cognition in late life (9). A genome survey that compared the genomes of this elderly group to those of an equal number of cognitively normal young adults revealed nine candidate SAG loci, some of which exhibited differential effects in men and women (10). The majority of these SAG candidate loci overlapped with regions previously reported to show linkage to susceptibility genes for cardiovascular disorders, psychiatric disorders, and the development of age-related cataracts (ARCs).

ARC is a leading cause of blindness worldwide [for reviews, see (11,12)]. Although cataracts are often characterized according to predominant location within the lens, overlap of lens opacities from one region of the lens to another is common in older individuals. A substantial body of evidence implicates oxidative damage as an important contributor to the development of cataracts as well as age-related changes in other tissues and organ systems [for review, see (13)]. Experimental manipulations that retard the effects of oxidative stress in animals have been reported to reduce the incidence of ARC while extending life span (14–18). Furthermore, the development of ARC in humans has been reported to predict reduced longevity compared to the general population (19–22). These and other findings suggest that the progressive development of lens opacities in ARC may reflect degenerative changes more generally throughout the body and provide a useful "biomarker of aging" from an organismal perspective (23).

Based on these observations, we hypothesized that elderly persons who met our criteria for SAG would exhibit a lower age-specific rate of ARC compared to corresponding rates reported for the general population. In the current report, we compared these age-specific outcomes and explored whether several risk factors for ARC that emerged from published population-based studies predicted the development of ARC in the group of 90 year-old elderly persons with preserved cognition.


   PARTICIPANTS AND METHODS
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 Abstract
 Participants and Methods
Results
 Discussion
 References
 
Recruitment and Characterization
One hundred (50 male, 50 female) Caucasian persons residing in the Southwestern Pennsylvania region who had reached at least 90 years of age without evidence of cognitive impairment were recruited to participate in this study of SAG, as previously described (3).

Semistructured clinical evaluations were performed by qualified research nurses with specialized expertise in the evaluation and treatment of adult and geriatric patients and were supervised by a faculty psychiatrist who was board-certified in both general adult and geriatric psychiatry. Individuals who had clinical evidence or any history of cognitive impairment or decline were not evaluated further and were excluded from participation. A sociodemographic survey included identifying information, date of birth, marital status, race, ethnicity, years of education, household income, and religious affiliation. Efforts were made to confirm the birth dates of elderly participants through auxiliary sources of information, including available historical and medical records, birth certificates, or family Bibles. The ethnicity of each participant was systematically determined from a standardized list of ethnic groups.

Cognition was evaluated using the Mini-Mental State Examination (MMSE) (24) an 11-item test of cognitive performance (0 = worst performance, 30 = best performance), and the Dementia Rating Scale (DRS, 25) that rates decrements in performance of everyday activities, habits, and personality associated with cognitive impairment (0 = no impairment, 28 = greatest impairment). Functional assessments of activities of daily living (1 = excellent capacity, 6 = completely impaired) were performed using the Older Americans' Resources and Services (OARS) Multidimensional Functional Assessment Questionnaire (26). Descriptions of past and current cigarette smoking and alcohol consumption were recorded using a structured survey. Personal and family histories of medical conditions including cataracts were systematically elicited according to the individual codes and categories listed in the International Classification of Diseases, 9th Revision, Clinical Modification (ICD9-CM) (27). The reliability and validity of this index of medical burden in the elderly population has been previously established (28,29). Lifetime histories of psychiatric disorders of participants were determined using the Structured Clinical Interview for DSM-III-R: Non-Patient Edition (SCID-NP) (30). Medication histories served as a check on the medical conditions reported and were recorded using the individual codes and categories provided in Drug Evaluations, 6th Edition (31).

Individuals affected by ARC had been diagnosed with one or more cataracts in at least one eye by a physician of their choice. These individuals were often treated with cataract surgery, although surgical intervention was not required for classification as affected. For participants who developed ARC, the age at onset was determined by the time at which the cataract was first detected. Establishment of age at onset was facilitated by the use of temporal landmarks such as birthdays, anniversaries, and other life or family events (e.g., relocation, military service, vacation, divorce, deaths); noteworthy historical events; and events associated with the cataract (e.g., visual impairment or treatment).

This research project and associated recruitment materials were approved by the Institutional Review Board of the University of Pittsburgh. All individuals provided written informed consent prior to participation.

Statistical Analysis
Statistical analysis of sociodemographic and clinical variables was performed using SPSS version 10 (SPSS, Chicago, IL). Continuous and categorical variables were presented as means ± standard deviation and proportions, respectively. Effects of variables previously reported to affect the risk of ARC in population samples were explored in the SAG group using survival analysis and Cox proportional hazards models. Age-specific rates of ARC in the SAG group were presented as cumulative incidence (1 – proportion surviving without ARC) ± standard error. Effects of putative risk variables in Cox proportional hazards models were expressed as odds ratios accompanied by 95% confidence intervals.

The age-specific rates of ARC in the SAG group were compared to those from five population-based studies that reported data for opacities that developed in the lens regardless of location (32–36). To achieve this, numbers of affected and assessed cases from the same age strata were combined across the population-based studies. Corresponding cumulative incidence rates of ARC for the SAG group were calculated conservatively using the midpoints of each age interval from the population-based estimates as the upper bounds. Comparisons of the corresponding age-specific rates of ARC in the SAG group to the population-based estimates were made using the chi-square statistic with 1 degree of freedom.


   RESULTS
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 Abstract
 Participants and Methods
 Results
Discussion
 References
 
A description of the sociodemographic and clinical features of the SAG group is provided in Table 1. These cognitively intact elderly persons included 94 nonagenarians and 6 centenarians who had a mean age of 93 years. The group included equal numbers of Caucasian men and women of predominantly British, German, and Slavic ancestry. Eighty-three of the participants had been married, although the majority (n = 59) were widowed at the time of recruitment, and their religious affiliations were similar to those of the communities from which they were recruited. Sixty-one were living independently, whereas 39 required assisted living arrangements. As a group, these participants were well educated relative to their birth cohort and, on average, had completed a high school education. The mean number of years of education for the SAG group was similar to that reported for individuals of similar age, sex, and race in the U.S. Census 2000.


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  		Table 1. Sociodemographic and Clinical Features of the SAG Group.

 
Consistent with the results of the clinical evaluations, the SAG group achieved a mean MMSE score that approached the maximal possible score of 30. Raw MMSE scores were not adjusted for performance items that could not be completed due to sensorimotor deficits (e.g., visual impairment). As a result, these raw values are likely to have underestimated the cognitive capacity of the participants. It should be noted that the assessment of cognitive impairment used to satisfy the selection criteria for SAG was multidimensional, and potential participants were not excluded from the SAG group on the basis of sensorimotor deficits alone. Evidence of functional impairment attributable to cognitive decline was negligible in the SAG group, as reflected by the DRS. On average, the capacity of the participants to carry out their activities of daily living remained in the "good" range, as detected by the OARS activities of daily living assessment.

The impairment in activities of daily living manifested by the SAG group was a reflection of their burden of medical problems (Table 2). Participants suffered from an average of 8.5 medical conditions distributed over an average of 5.7 ICD-9-CM categories; only one participant had no identified medical conditions. The three most common categories of medical conditions among the participants were diseases of the circulatory system (most frequently heart problems and hypertension), diseases of the nervous system and sense organs (most frequently vision and hearing problems), and various diseases of the digestive system, in descending frequency. A total of 51 (30 male, 21 female) participants in the SAG group developed ARC, with a mean age at onset of 85.2 ± 8.3 (standard deviation) years. Only four participants fulfilled DSM-III-R criteria for mental disorders (three major depressive disorders and one anxiety disorder), and all four first emerged in late life after the age of 81 years. The average numbers and categories of medications for the group reflected their number and spectrum of medical conditions.


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  		Table 2. Medical and/or Psychiatric Conditions and Medications of the SAG Group.

 
Histories of cigarette smoking and alcohol consumption for the study groups are summarized in Table 3. Approximately 40% of elderly individuals in the SAG group had a history of cigarette smoking, although only one remained a current smoker. The group had smoked cigarettes for an average duration of nearly a decade and had an average exposure of more than nine pack-years. Eighty percent of the participants drank alcohol less than once each month, although 12% drank alcohol at least 2–3 times each week, and 7% drank daily. The average alcohol consumption was a little over one drink per episode.


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  		Table 3. Cigarette Smoking and Alcohol Consumption in the SAG Group.

 
A comparison of the average age-specific rates of ARC reported for five population-based samples and the SAG group is presented in Table 4. The numbers of affected and assessed cases from the same age strata were combined across the population studies (32–36), all of which reported data for opacities in the lens regardless of location. As shown in the table, the age-specific rates of ARC were similar among the population-based samples. Corresponding cumulative incidence rates of ARC for the SAG group were calculated using the midpoints of each age interval from the population-based estimates as the upper bounds. The rates of ARC increased monotonically with age in both the population-based and SAG samples. However, the age-specific rates of ARC in the SAG group were significantly lower than the corresponding population rates. The development of comparable rates of ARC in the SAG group was delayed by about 20 years through most of the age at risk. Moreover, the maximum rate of ARC in the SAG group at 90+ years of age, 50.1%, remained significantly lower than the corresponding population rate, 73.2%.


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  		Table 4. Comparison of Age-Specific ARC Rates Reported in Six Population-Based Studies (%, N affected/assessed) to the SAG Group.

 
Previously reported risk factors for ARC in addition to age [for reviews, see (11,12)] were explored in the SAG group using proportional hazards models. A history of gout, steroid use, and both the frequency of alcohol consumption and amount of alcohol consumed per episode were associated with an increased risk of ARC. As shown in Table 5, a history of diabetes mellitus and male sex (Figure 1) also tended to increase the risk of ARC. Years of education, hypertension, arthritis, and smoking history were not associated with an increased risk of ARC in the SAG group. Although exposure to sunlight (particularly ultraviolet-B) is an established risk factor for ARC in the general population, a direct index of sunlight exposure was not available for the SAG group. However, a history of basal cell skin cancer or related skin lesions (no = 0, yes = 1), a likely proxy for excessive exposure to sunlight, was significantly associated with the development of ARC (odds ratio = 2.81, p = 0.004, 95% confidence interval = 1.39 to 5.68).


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  		Table 5. Evaluation of Previously Reported Risk Factors for ARC in the SAG Group.

 

Figure 01
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  		Figure 1. Effect of sex on the age-specific cumulative incidence (± standard error) of age-related cataracts in the successful aging group

 

   DISCUSSION
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 Abstract
 Participants and Methods
 Results
 Discussion
References
 
The participants who comprised the SAG sample were a highly selected group. Data from the 1990 U.S. Census (1) and subsequent population estimates from the Census Bureau for 1999 (37) indicate that individuals at or above age 90 comprise between 0.5% and 0.6% of the American population, with women outnumbering men by a ratio of about 3 to 1. Moreover, cognitive impairment is common in this age group, even among very old people who are community-dwelling. Our experience identifying and recruiting study participants from Southwestern Pennsylvania who had reached age 90 with preserved cognition was consistent with these estimates.

The principal finding of this report was that the SAG group manifested a significant reduction in the age-specific rate and lifetime cumulative incidence of ARC compared to estimates reported for population-based samples. Although the participants who comprised the SAG sample were recruited on the basis of exceptional longevity and preserved cognition, it was not obvious that the application of these selection criteria would result in a group of individuals who were resistant to the formation of ARC. Our findings suggest that the constitutional and environmental factors (and their potential interactions) contributing to the preservation of essential organ systems and brain function in the SAG group also had beneficial effects on organismal health in general.

Tissue damage due to oxidative stress has been implicated in aging and memory loss, as well as cataract formation (13–22). As a result, this shared pathophysiologic process suggests one mechanism that could contribute to our findings. A considerable body of evidence supports an important role for oxidative damage in the formation of cataracts in mice, rats, and humans. Several experimental manipulations that protect against oxidative tissue damage in rodents have been reported to extend life span, while interventions such as caloric restriction that extend life span delay the development of cataracts (14–18). Moreover, human studies suggest that early cataract development is associated with shorter life span (19–22). Oxidative stress has also been implicated in the development of age-related cognitive impairment including Alzheimer's disease, the most common cause of memory impairment in late life [for review, see (38)]. These observations and our current findings suggest that the progressive development of lens opacities may serve as a biomarker of degenerative events occurring throughout the body. This phenotype can be readily and quickly evaluated by noninvasive methods with minimal risk and discomfort to individuals, characteristics that are attractive in both practice and research settings, and lend themselves to longitudinal evaluations. If validated as a biomarker of aging, this phenotype could make a valuable contribution to clinical care and to investigative studies of normal and pathological aging.

The evaluation of potential risk factors for ARC in the SAG group warrants further discussion. As expected from previous population studies [for reviews, see (11,12)], steroid use, alcohol consumption, gout (or its treatments), and skin lesions resulting from excessive sun exposure emerged as risk factors for ARC. However, the selection criteria used to recruit the SAG group are likely to have influenced the ability to detect at least some risk factors that may be more readily detectable in the general population. For example, both diabetes mellitus and cigarette smoking have established negative effects on longevity, cognition, and cataract formation. As a result, the SAG group included only seven participants with diabetes and one current smoker, small numbers that limited the statistical power to evaluate these variables as risk factors for ARC in the SAG group. Similarly, the SAG group was well educated on average, a characteristic that may have contributed to successful aging, but which limited opportunity to evaluate the effect of lower educational attainment as a risk factor for ARC. Finally, cross-sectional population studies have reported no effect of sex or small increases in risk for women. Sex did not emerge as a significant risk factor for ARC in the SAG group, although a trend towards increased risk among men was found. If the development of ARC is associated with reduced life span, as has been reported (19–22), cross-sectional population studies may overestimate the age-specific prevalence of ARC in women because, on average, they live longer than men.

A history of gout emerged as one of the strongest risk factors for ARC in the SAG group (odds ratio = 5.38), a finding that illustrates the complexity in interpreting such observations. Whether the age-specific risk of cataracts associated with gout is conferred by a shared pathophysiology with gout, or the actions of its treatments, cannot be determined from our data. Previous studies have reported that long-term exposure to allopurinol or "gout medications" is associated with an increased risk of lens opacities (39,40). Colchicine may influence the risk of lens opacification by microtubule disruption that leads to DNA fragmentation (41). A complex interaction of gout, its treatments, and alcohol consumption may also influence cataract formation (42).

The current study design was limited by the lack of systematic ophthalmologic examinations and reliance on retrospective assessments of age at onset. The confirmation of several previously reported risk factors for ARC in the SAG group provides a measure of support for the validity of the assessments of ARC and corresponding ages at onset for affected individuals. Moreover, patient responses have been reported to provide reliable and valid indications of changes in visual acuity, visual function, and health status among patients with cataracts (43–48). A longitudinal study design using systematic, prospective, multidimensional assessments, including ophthalmologic examinations, seems most likely to clarify the validity of ARC as a biomarker of aging and global health.


   Acknowledgments
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 Abstract
 Participants and Methods
 Results
 Discussion
 References
 
This research was supported by research project grants MH43261 and MH47346 from the National Institute of Mental Health (GSZ) and EY11733 from the National Eye Institute (NSW). GSZ was the recipient of Independent Scientist Award MH00540 from the National Institute of Mental Health.

The contributions of colleagues, research staff, and research subjects to this work are gratefully acknowledged.


   Footnotes
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 Abstract
 Participants and Methods
 Results
 Discussion
 References
 
Decision Editor: Huber R. Warner, PhD

Received October 7, 2006

Accepted January 8, 2007


   References
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 Participants and Methods
 Results
 Discussion
 References
 

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