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Aging in Today's Environment (1987)

Chapter: ENVIRONMENTAL EFFECTS ON AGE-ASSOCIATED DISEASES AND CHANGES IN ORGAN FUNCTION

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Suggested Citation:"ENVIRONMENTAL EFFECTS ON AGE-ASSOCIATED DISEASES AND CHANGES IN ORGAN FUNCTION." National Research Council. 1987. Aging in Today's Environment. Washington, DC: The National Academies Press. doi: 10.17226/1293.
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Suggested Citation:"ENVIRONMENTAL EFFECTS ON AGE-ASSOCIATED DISEASES AND CHANGES IN ORGAN FUNCTION." National Research Council. 1987. Aging in Today's Environment. Washington, DC: The National Academies Press. doi: 10.17226/1293.
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Suggested Citation:"ENVIRONMENTAL EFFECTS ON AGE-ASSOCIATED DISEASES AND CHANGES IN ORGAN FUNCTION." National Research Council. 1987. Aging in Today's Environment. Washington, DC: The National Academies Press. doi: 10.17226/1293.
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Suggested Citation:"ENVIRONMENTAL EFFECTS ON AGE-ASSOCIATED DISEASES AND CHANGES IN ORGAN FUNCTION." National Research Council. 1987. Aging in Today's Environment. Washington, DC: The National Academies Press. doi: 10.17226/1293.
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Suggested Citation:"ENVIRONMENTAL EFFECTS ON AGE-ASSOCIATED DISEASES AND CHANGES IN ORGAN FUNCTION." National Research Council. 1987. Aging in Today's Environment. Washington, DC: The National Academies Press. doi: 10.17226/1293.
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Suggested Citation:"ENVIRONMENTAL EFFECTS ON AGE-ASSOCIATED DISEASES AND CHANGES IN ORGAN FUNCTION." National Research Council. 1987. Aging in Today's Environment. Washington, DC: The National Academies Press. doi: 10.17226/1293.
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Suggested Citation:"ENVIRONMENTAL EFFECTS ON AGE-ASSOCIATED DISEASES AND CHANGES IN ORGAN FUNCTION." National Research Council. 1987. Aging in Today's Environment. Washington, DC: The National Academies Press. doi: 10.17226/1293.
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Suggested Citation:"ENVIRONMENTAL EFFECTS ON AGE-ASSOCIATED DISEASES AND CHANGES IN ORGAN FUNCTION." National Research Council. 1987. Aging in Today's Environment. Washington, DC: The National Academies Press. doi: 10.17226/1293.
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Suggested Citation:"ENVIRONMENTAL EFFECTS ON AGE-ASSOCIATED DISEASES AND CHANGES IN ORGAN FUNCTION." National Research Council. 1987. Aging in Today's Environment. Washington, DC: The National Academies Press. doi: 10.17226/1293.
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Suggested Citation:"ENVIRONMENTAL EFFECTS ON AGE-ASSOCIATED DISEASES AND CHANGES IN ORGAN FUNCTION." National Research Council. 1987. Aging in Today's Environment. Washington, DC: The National Academies Press. doi: 10.17226/1293.
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Suggested Citation:"ENVIRONMENTAL EFFECTS ON AGE-ASSOCIATED DISEASES AND CHANGES IN ORGAN FUNCTION." National Research Council. 1987. Aging in Today's Environment. Washington, DC: The National Academies Press. doi: 10.17226/1293.
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Suggested Citation:"ENVIRONMENTAL EFFECTS ON AGE-ASSOCIATED DISEASES AND CHANGES IN ORGAN FUNCTION." National Research Council. 1987. Aging in Today's Environment. Washington, DC: The National Academies Press. doi: 10.17226/1293.
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Suggested Citation:"ENVIRONMENTAL EFFECTS ON AGE-ASSOCIATED DISEASES AND CHANGES IN ORGAN FUNCTION." National Research Council. 1987. Aging in Today's Environment. Washington, DC: The National Academies Press. doi: 10.17226/1293.
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Suggested Citation:"ENVIRONMENTAL EFFECTS ON AGE-ASSOCIATED DISEASES AND CHANGES IN ORGAN FUNCTION." National Research Council. 1987. Aging in Today's Environment. Washington, DC: The National Academies Press. doi: 10.17226/1293.
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Suggested Citation:"ENVIRONMENTAL EFFECTS ON AGE-ASSOCIATED DISEASES AND CHANGES IN ORGAN FUNCTION." National Research Council. 1987. Aging in Today's Environment. Washington, DC: The National Academies Press. doi: 10.17226/1293.
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Suggested Citation:"ENVIRONMENTAL EFFECTS ON AGE-ASSOCIATED DISEASES AND CHANGES IN ORGAN FUNCTION." National Research Council. 1987. Aging in Today's Environment. Washington, DC: The National Academies Press. doi: 10.17226/1293.
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Suggested Citation:"ENVIRONMENTAL EFFECTS ON AGE-ASSOCIATED DISEASES AND CHANGES IN ORGAN FUNCTION." National Research Council. 1987. Aging in Today's Environment. Washington, DC: The National Academies Press. doi: 10.17226/1293.
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Suggested Citation:"ENVIRONMENTAL EFFECTS ON AGE-ASSOCIATED DISEASES AND CHANGES IN ORGAN FUNCTION." National Research Council. 1987. Aging in Today's Environment. Washington, DC: The National Academies Press. doi: 10.17226/1293.
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Suggested Citation:"ENVIRONMENTAL EFFECTS ON AGE-ASSOCIATED DISEASES AND CHANGES IN ORGAN FUNCTION." National Research Council. 1987. Aging in Today's Environment. Washington, DC: The National Academies Press. doi: 10.17226/1293.
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Suggested Citation:"ENVIRONMENTAL EFFECTS ON AGE-ASSOCIATED DISEASES AND CHANGES IN ORGAN FUNCTION." National Research Council. 1987. Aging in Today's Environment. Washington, DC: The National Academies Press. doi: 10.17226/1293.
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Suggested Citation:"ENVIRONMENTAL EFFECTS ON AGE-ASSOCIATED DISEASES AND CHANGES IN ORGAN FUNCTION." National Research Council. 1987. Aging in Today's Environment. Washington, DC: The National Academies Press. doi: 10.17226/1293.
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Suggested Citation:"ENVIRONMENTAL EFFECTS ON AGE-ASSOCIATED DISEASES AND CHANGES IN ORGAN FUNCTION." National Research Council. 1987. Aging in Today's Environment. Washington, DC: The National Academies Press. doi: 10.17226/1293.
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Suggested Citation:"ENVIRONMENTAL EFFECTS ON AGE-ASSOCIATED DISEASES AND CHANGES IN ORGAN FUNCTION." National Research Council. 1987. Aging in Today's Environment. Washington, DC: The National Academies Press. doi: 10.17226/1293.
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Suggested Citation:"ENVIRONMENTAL EFFECTS ON AGE-ASSOCIATED DISEASES AND CHANGES IN ORGAN FUNCTION." National Research Council. 1987. Aging in Today's Environment. Washington, DC: The National Academies Press. doi: 10.17226/1293.
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Suggested Citation:"ENVIRONMENTAL EFFECTS ON AGE-ASSOCIATED DISEASES AND CHANGES IN ORGAN FUNCTION." National Research Council. 1987. Aging in Today's Environment. Washington, DC: The National Academies Press. doi: 10.17226/1293.
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Page 133
Suggested Citation:"ENVIRONMENTAL EFFECTS ON AGE-ASSOCIATED DISEASES AND CHANGES IN ORGAN FUNCTION." National Research Council. 1987. Aging in Today's Environment. Washington, DC: The National Academies Press. doi: 10.17226/1293.
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Page 134
Suggested Citation:"ENVIRONMENTAL EFFECTS ON AGE-ASSOCIATED DISEASES AND CHANGES IN ORGAN FUNCTION." National Research Council. 1987. Aging in Today's Environment. Washington, DC: The National Academies Press. doi: 10.17226/1293.
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Page 135
Suggested Citation:"ENVIRONMENTAL EFFECTS ON AGE-ASSOCIATED DISEASES AND CHANGES IN ORGAN FUNCTION." National Research Council. 1987. Aging in Today's Environment. Washington, DC: The National Academies Press. doi: 10.17226/1293.
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Page 136
Suggested Citation:"ENVIRONMENTAL EFFECTS ON AGE-ASSOCIATED DISEASES AND CHANGES IN ORGAN FUNCTION." National Research Council. 1987. Aging in Today's Environment. Washington, DC: The National Academies Press. doi: 10.17226/1293.
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Page 137
Suggested Citation:"ENVIRONMENTAL EFFECTS ON AGE-ASSOCIATED DISEASES AND CHANGES IN ORGAN FUNCTION." National Research Council. 1987. Aging in Today's Environment. Washington, DC: The National Academies Press. doi: 10.17226/1293.
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Page 138
Suggested Citation:"ENVIRONMENTAL EFFECTS ON AGE-ASSOCIATED DISEASES AND CHANGES IN ORGAN FUNCTION." National Research Council. 1987. Aging in Today's Environment. Washington, DC: The National Academies Press. doi: 10.17226/1293.
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Page 139
Suggested Citation:"ENVIRONMENTAL EFFECTS ON AGE-ASSOCIATED DISEASES AND CHANGES IN ORGAN FUNCTION." National Research Council. 1987. Aging in Today's Environment. Washington, DC: The National Academies Press. doi: 10.17226/1293.
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Page 140
Suggested Citation:"ENVIRONMENTAL EFFECTS ON AGE-ASSOCIATED DISEASES AND CHANGES IN ORGAN FUNCTION." National Research Council. 1987. Aging in Today's Environment. Washington, DC: The National Academies Press. doi: 10.17226/1293.
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Page 141
Suggested Citation:"ENVIRONMENTAL EFFECTS ON AGE-ASSOCIATED DISEASES AND CHANGES IN ORGAN FUNCTION." National Research Council. 1987. Aging in Today's Environment. Washington, DC: The National Academies Press. doi: 10.17226/1293.
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Page 142
Suggested Citation:"ENVIRONMENTAL EFFECTS ON AGE-ASSOCIATED DISEASES AND CHANGES IN ORGAN FUNCTION." National Research Council. 1987. Aging in Today's Environment. Washington, DC: The National Academies Press. doi: 10.17226/1293.
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Page 143
Suggested Citation:"ENVIRONMENTAL EFFECTS ON AGE-ASSOCIATED DISEASES AND CHANGES IN ORGAN FUNCTION." National Research Council. 1987. Aging in Today's Environment. Washington, DC: The National Academies Press. doi: 10.17226/1293.
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6 Environmental Ejects on Age-Associated Diseases and Changes in Organ Function Biologic changes associated with aging can reasonably be ex- pected to be associated with parallel changes in susceptibility to disease. For some diseases, such as those for which early anti- genic stimulation produces lifelong immunity, resistance usually increases and incidence falls with age. For other diseases, such as those reflecting cumulative, chronic exposures, rates might in- crease with age. Susceptibility to disease changes throughout the human life cycle and is believed to be a function of many factors, including changes in the immune system and in the rate of cellular divi- sion. Thus, exposures to carcinogens or neurotoxins in infancy and childhood (or in old age) might produce stronger responses than those occurring in the middle stages of life. Although there are reasonable theoretical grounds for expecting some disease pat- terns to be normal functions of age, additional research needs to be done to clarify possible mechanisms. Controlled studies of an- imal populations are also needed to determine both the natural occurrence of diseases with aging and changes in immune response and in metabolic and kinetic responses to xenobiotics throughout the life cycle. This chapter reviews some of the animal and human stud- ies on the relationships of the environment with age-associated 109

110 AGING IN TODAY'S ENVIRONMENT TABLE 6-1 Examples of Age-Associated Changes in Organ Structure and Function and Possible Related Agents, Medical Conditions, or Life-style$ Organ or System Agent, Medical Condition, or Changes in Organ Structure and Function Often Associated with Old Age Skin Eye Ear Nervous system Coarseness, wrinkling, malignant neoplasms, immune suppression Cataracts Cataracts, retinopathy High-frequency hearing loss Dementia, confusion Peripheral neuropathy Parkinsonism Amyotrophic lateral sclerosis, parkinsonism, senile dementia of Alzheimer's type Renal Increased nephropathy Immune Reduced decline in immune Lung Cardiovascular Life-style Possibly Related to Changes in Organ Structure or Function Sunlight Sunlight Diabetes Noise Anticholinergics, barbiturates, bromide Acrylamide, vincristine, . · · . ~son~az~a MPTP Chamorro life-style (cycad exposure?) competence Exacerbation of autoimmune reactions Emphysema, cancer Atherosclerotic heart disease Reduced dietary protein Reduced caloric intake Procainamide, estrogen Cotton dust, tobacco smoking Dietary lipids diseases in specific organ systems. It also discusses evidence of age-associated changes in normal functions, such as vision, bone metabolism, and the immune system. Table ~1 presents some examples. DEMOGRAPHICS OF AGE-ASSOCIATED DISEASES Age seems to be the most important determinant of incidence of most human diseases. Characteristic age patterns of risk have been described for all diseases, and many of the patterns have provided the basis for important etiologic theories. For example, the peak in incidence of one type of Hodgkin's disease in the third decade of life suggested an infectious origin (MacMahon, 1971),

ENVIRONMENTAL EFFECTS ON DISEASES AND ORGAN FUNCTION 111 350 z o F A 300 o CL 250 a: ~ 200 LL o o O 150 - `~ 1 00 LU of cat A /' ~ / l / /V . · 10 20 30 40 50 60 70 AGE GROUP (Years) 1 / San Francisco Bay Area White (t 969-1 973) San Francisco Bay Area Black (1 969-1 973) Yugoslavla ~e°O.O slovenly (1968-1972) Japan Osaka (t 970-1 971) FIGURE 6-1 Age-specific incidence rates for female breast cancer in four population groups. Source: Petrakis et al. (1982~. and the plateau in incidence of breast cancer around the ages of 45-55 suggested an effect of the cessation of ovarian function on the development of the disease (Petrakis et al., 1982~. The premenopausa] and postmenopausal incidence curves for breast cancer in different countries suggest that environmental factors play more important roles in the etiology of postmenopausal breast cancer, whereas genetic, endocrinologic, and other endogenous factors strongly influence premenopausal disease (Figure 6-1~. The role of age as a factor associated with increasing incidence appears to be direct (or independent) in some diseases. In others, time and age-associated exposure characteristics, such as obesity and duration of exposure, are the direct factors, and not age itself. The association of disease susceptibility with age—which might be related to intrinsic factors, extrinsic factors, or some combination needs to be assessed for each disease. For example,

112 AGING IN TODAY'S ENVIRONMENT the role of specific intrinsic and extrinsic factors in adult-onset diabetes meDitus has been extensively investigated, but further studies are needed for an adequate understanding of the relative importance and interaction of endogenous and exogenous factors in the disease. Both morbidity and mortality data can be used to evaluate the association of disease with age in the elderly population (65 and over). Morbidity data reflect either the incidence (new cases) of a disease over a fixed period or its prevalence (total cases) at a given time, depending on the study design or the method of data collection. These two measures of disease frequency (inci- dence and prevalence) provide different information, and both are important—one for an understanding of the population risk (in- cidence) and one for an understanding of the burden (prevalence) of a particular disease. Mortality data, which are more readily available than morbidity data for the total population, parallel incidence data for conditions that are life-threatening and of short duration, such as some forms of cancer and cardiovascular dis- ease, but are not as useful for other diseases, such as diabetes and chronic obstructive pulmonary disease. Two-thirds of all deaths in the United States occur in people over age 65, and 30~o occur in persons over 80. Three causes of death heart disease, cancer, and stroke accounted for 75% of these deaths in the elderly population in 1979 and in 1950 (NCHS, 1981b). Turo features of the recent cause-specific mortality pat- terns in the elderly are of interest here the decline in mortality rates for cardiovascular and cerebrovascular diseases among the elderly and the maintenance of those rates for cancer (Figure ~2~. From 1950 to 1979, the overall mortality rate for the population 65 and over decreased by Who. When rates are age-adjusted (to allow for the rapic! increase in the population 85 and over), mortality declined more than 27% and the decline for females was twice that for mates (Figure ~3~. Mortality from heart disease accounted for approximately half the overall decline during the period, and that from cerebrovas- cular disease accounted for another 25% of the overall decline. Heart and cerebrovascular diseases account for the largest and third largest mortality rates, respectively, in this age group. Can- cer mortality, the second largest element and the only major one to show an increase, increased by Who. More than half the deaths from cancer among the elderly are due to cancers of the lung,

ENVIRONMENTAL EFFECTS ON DISEASES AND ORGAN FUNCTION 113 3,000 2,000 at o - J ~ 1,000 o CL lo o o 500 o Or `r 300 co 200 LU 100 - Heart Disease —— Cancer Stroke Influenza and pneumonia Diabetes mellltus _~ - _. 195;0 1955 1960 1965 YEAR - 1970 1975 1980 FIGURE 6-2 Age-adjusted death rates for persons 65 years of age and over, according to leading causes of death: United States, 1950-1979. Source: National Center for Health Statistics (1982~. colon, genital organs, and breast (females). Cancer mortality trends among males indicate a slight deceleration in the large an- nual increases in lung cancer mortality and slowly increasing rates for cancers of the colon and prostate. In contrast with the increase in overall cancer mortality in males, the overall cancer mortality rate in women 65 and over decreased slightly from 1950 to 1978 (Figures ~4 and ~5~. The most obvious changes for females are the large increase in Jung cancer mortality and the decreases in mortality from cancers of the stomach and uterine cervix. An exponential increase in mortality with age is evident for cardiovascular disease (Figure ~6), but absent for all cancers com- bined (Figure 6-7~. In fact, cancer mortality rates (all sites com- bined) increase rapidly in middle age and then more slowly with age to 65. Between ages 65 and 69, cancer accounts for approxi- mately 30~o of all deaths; by age 80, it accounts for only Who. In

114 BOOM 90.0 he o g 70.0 o cat lo to to 0 50.0 80.0 60.0 cr: cat I 40-D LL C] AGING IN TODAY'S ENVIRONMENT \/\ _ 30.0 1 1 1 1 1 ! I I 1 940 in. _` Dyne ~ Female - 1945 1950 1955 1960 YEAR 1965 1970 1975 1980 FIGURE 6-3 Age-adjusted death rates for persons 65 years of age and over, according to sex: United States, 1940-1978. Source: National Center for Health Statistics (1981b). contrast, the proportion of deaths caused by cardiovascular disease increases from 50% at ages 65-69 to 65~o by age 80. Brody (1983, 1987) has suggested that the modest increase in age-specific mor- tality rates for cancer after age 65 might constitute evidence that cancer pathogenesis is not closely related to the aging processes and host susceptibility, and that by the year 2000 cancer will ac- count for fewer than 10% of the deaths in those 85 and over the age group that will experience half of all deaths. Before epidemiologic observations associating cancer mortal- ity with aging processes can be fully evaluated, several considera- tions are essential. Smoking is the most likely cause of the increase in respiratory cancer mortality, and cancer mortality in general, among elderly men and women. Although a higher proportion of elderly men than women smoke, the sex gap in smoking behavior has narrowed considerably in recent years. The proportion of men 65 and over reported as current smokers dropped from 28.5~o in 1965 to 17.9~o in 1980; the proportion of women increased from 9.6~o to 16.8~o. The sex differences for former smokers, which could be more important for respiratory cancer, are even greater:

ENVIRONMENTAL EFFECTS ON DISEASES AND ORGAN FUNCTION 115 80 70 60 At o - g 50 o ~ 40 lo lo o lo o try 30 LL LL a: CI: 20 10 ~ _ l . ~ . `. ~ O -- 1 1 1 1 1930 Esophagus Bladder Pancreas Leukemia Liver Prostate Lung Stomach Colon & Rectum · . . / i/ ! / / . · . . · -A ~ 1~. .,, -. ~ 4_. ., / . . 1940 1950 1960 1970 1980 YEAR FIGURE 6-4 Age-adjusted cancer death rates for selected sites, males: United States, 1930-1978. Source: U.S. OTA (1985~. the proportion of men 65 and over reported as former smokers in- creased from 28.1% in 1965 to 47.4% in 1980, and the proportion of women increased from 4.5% to 14.2~o. Differences in smoking among and between elderly men and women no doubt account for some of the observed differences

6 80 70 60 50 40 CC 30 LL llJ 20 10 AGING IN TODAY'S ENVIRONMENT . - uterus Breast Pancreas Leukemia Liver Ovary Lung Stomach Colon & Rectum ~ . _ . ~ __ ~~ ~ ~ -~ ' - at · ~ ~ - e ~ - - - - O— 1930 1940 1950 1960 1970 1980 YEAR FIGURE 6-5 Age-adjusted cancer death rates for selected sites, females: United States, 1930-1978. Source: U.S. OTA (1985~. in cancer mortality, especially respiratory cancer mortality. It is estimated that cigarette smoking alone accounts for 8~85~o of lung cancer mortality and 30~o of all cancer mortality (Doll and Peto, 1981~.

ENVIRONMENTAL EFFECTS ON DISEASES AND ORGAN FUNCTION 117 1 6,000 1 4,000 At o 1 2,000 Cal o to to to to - a: LO Lo At: TV: 1 0,000 8,000 6,000 4,000 2,000 o Cardlovascular Dlseases - All Cause Mortality ,' , ///~ ~ / i' / 20- 25- 30- 35- 40- 45- 50- 55- 60- 65- 70- 75- 80- 85+ 24 29 34 39 44 49 54 59 64 69 74 79 84 AGE GROUP FIGURE 6-6 Major cardiovascular diseases: age-specific mortality rates versus all causes of mortality. Source: National Center for Health Statistics (1985a). It has been suggested that the reason for the rising incidence of cancer with increasing age might be aging of the immune system itself, but the available epidemiologic evidence does not support this view except for some tumors. Because increasing age is "so- ciated with many time-related factors, including longer exposure to carcinogens, it ~ difficult to separate the effects of increasing age from the effects of increased exposure to carcinogens. Two lines of evidence, however, can address the effect of age itself on cancer incidence. Peto et al. (1975) conducted a large, controlled study in mice at various ages whose skin was exposed to benzota~pyrene. The incidence of epithelial cancers was inde- pendent of age at the start of exposure and was related directly to duration of exposure. A recent review of the available experimen- tal evidence from animate (Hornig, in press) found little support for the notion of a general increase in susceptibility to the effects of all carcinogens with increasing age. In addition, the presence

118 1 6,000 ~ z 14,000 a: ° ~ g 12,000 - <t ~ 1 O7OOO O cL 8,000 ~ ° 6,000 ~ 0 ~~ c 4,000 J ~ 2,000 ~5 o Mortality Incidence All Cause Mortality __, 40- 50- 60- 34 44 54 64 AGE GROUP FIGURE 6-7 All sites: age-specific cancer versus all causes of mortality. Adapted from Brock (1985~. 1 , 1 20 - 30~ 24 AGING IN TODAY'S ENVIRONA~NT 8 000 7~000 pi m :~ 8 lo lo o 2,000 ~ 1,000 o at 6,000 `, 5,000 r In 4,000 ~ in 3,000 o 70- 80- 74 84 i incidence and mortality rates Brady (1983) and Brady and of such factors as time-related cumulative damage and the physi- ologic changes associated with aging that can affect susceptibility makes it apparent that there might not be a single answer to the question of the relation between increasing age and cancer suscep- tibility, and that the relation varies with target organ, cell type, toxic exposure, and animal species (Birnbaum, 1987~. Epidemiologic evidence supports the hypothesis that the in- crease in lung cancer risk with age is independent of the smoking- related increase in risk. The effect of exposure duration can be estimated by noting the increase in incidence over time, measured from the start of smoking in smokers and from birth in nonsmok- ers; the incidence rates are similar over time. However, the effect of age can be estimated by noting incidence over time, measured from birth in all subjects; the incidence increases more rapidly in smokers over time (Doll and Peto, 1978; Peto and Doll, 1984~. As noted by Doll (1978), the tumors for which immune factors are important, such as non-HodgLin's Tymphoma and soft-tissue sarcomas in patients treated with immunosuppressive drugs, are tumors of mesenchymal origin whose incidence does not rise steeply with age, as is observed with the common epithelial cancers. The 1- 1 . - . ~ ~ . ~

ENVIRONMENTAL EFFECTS ON DISEASES AND ORGAN FUNCTION 119 TABLE 6-2 Death Rates for the 10 Leading Causes of Death for Ages 65 and Over, by Age, 1976 Deaths per 100,000 65 Years 65-74 75-84 85 Years Cause of Death and Over Years Years and Over All causes 5,428.9 3,127.6 7,333.6 15,486.9 Heart diseases 2,393.5 1,286.9 3,263.7 7,384.3 Malignant neoplasms 979.0 786.3 1,248.6 1,441.5 Cerebrovascular diseases 694.6 280.1 1,014.0 2,586.8 Influenza and pneumonia 211.1 70.1 289.3 959.2 Arteriosclerosis 122.2 25.8 152.5 714.3 Diabetes mellitus 108.1 70.0 155.8 219.2 Accidents 104.5 62.2 134.5 306.7 Motor vehicle 25.2 21.7 32.3 26.0 All other 79.3 40.4 102.2 280.7 Bronchitis, emphysema, and asthma 76.8 60.7 101.4 108.5 Cirrhosis of liver 36.5 42.6 29.3 18.0 Nephritis and nephrosis 25.0 15.2 34.1 64.6 All other causes 677.5 427.8 908.6 1,638.8 SOURCE: National Center for Health Statistics (1978a). very prompt rise in the incidence of Tymphomas in transplant recipients after treatment with immunosuppressive agents is in marked contrast with the long induction times observed for epithelial tumors resulting from exposure to chern~cal carcinogens (Hoover and Fraumeni, 1973~. Those observations suggest a differ- ent, possibly viral, etiologic process for the mesenchymal tumors that are associated with immune factors. The increased incidence of squamous carcinoma of the skin in patients receiving immuno- suppressive agents suggests that this epithelial tumor is also under immunologic control (Kripke, 1974~. Mortality rates by age group for diseases of the heart, in- fluenza and pneumonia, cerebrovascular disease, arteriosclerosis, and accidents show a marked increase in risk with increasing age, whereas rates for other causes such as cancer, diabetes mellitus, bronchitis, emphysema and asthma, and nephritis and nephrosis- indicate a more modest increase (Table 6-2~. Mortality due to cir- rhosis of the liver does not appear to be associated with increasing age in the elderly population.

120 AGING IN TODAY'S ENVIRONMENT TABLE 6-3 Prevalence of Selected Impairments by Age and Sex, United States, 1981 Condition Prevalence, Number of Persons per 1,000 All Ages 65 or Older Visual impairment 40.4 136.6 Hearing impairment 82.9 283.6 Paralysis (complete or partial) 5.9 19.6 Heart conditions 76.4 277.0 Hypertensive disease 113.4 378.6 Cerebro~rascular disease 8.3 45.4 Chronic bronchitis 35 3 46.1 Emphysema 9.3 42.9 Functional or symptomatic 17.4 39.9 upper gastrointestinal tract disorders Diverticula of intestine 6.8 38.4 Diabetes 24.3 84.8 Urinary system disease 25.9 56.6 SOURCE: National Center for Health Statistics (1981b). Based on household interviews of noninstitutionalized civilians. The prevalence of every chronic condition studied in the Na- tional Health Interview Study is higher among those 65 and over, and the estimates no doubt understate the age effects in that they do not include the elderly who are in nursing homes tTable 6-3~. As early as the 1960s, accumulating evidence was showing that cardiovascular risk factors could be modified to change the risk of morbidity and mortality (Hypertension Detection and Follow- up Program Cooperative Group, 1985, 1987; Langford et al., 1986; Multiple Risk Factor Intervention Trial Research Group tMRFIT], 1982, 1986; Paffenberger, 1979; Paffenberger et aI., 1978; U.S. Public Health Service, 1968; Veterans' Administration Cooperative Study Group, 1967, 1970; Wald, 1976~. Research on human aging processes and the impact of envi- ronmental factors has been increasingly constrained by declining autopsy rates. Many reasons have been given for the decline ir1 au- topsy rates (American Medical Association, Council on Scientific Affairs, 1987), including the fact that the Joint Commission on the Accreditation of Hospitals (JCAH) no longer requires a minimal rate of autopsy for accreditation. At present, only 1~15% of all

ENVIRONMENTAL EFFECTS ON DISEASES AND ORGAN FUNCTION 121 deaths in hospitals are subjected to autopsy, whereas 3() 40 years ago it was approximately 50~o (Guariglia and Abrahams, 1985~. The Institute of Medicine statement on national autopsy policy emphasized the essential role of autopsy (Mortimer, 1985~. Earlier studies showed that autopsy rates were lower for deaths occurring among older persons than among younger persons, and the differ- ence appears to have persisted. Present autopsy rates might be as low as 1% for deaths among persons over 65. This trend results in a loss of important pathologic informa- tion for studies of human aging information for which there is no substitute (Kohn, 1982~. In the absence of postmortem stucI- ies, epidemiologic studies of ag~associated diseases and mortality must rely on predeath diagnoses or cause-o£death statements on death certificates. For some causes of death, the death- certificate information might be inaccurate for as many as 50~o of deaths. In addition, the existence of a system to ensure the collection, study, and storage of relevant tissues, cells, and body fluids would support studies of body burdens of environmental agents and the consideration of potential causal associations of these agents with tissue changes. SKIN Environmental factors are widely suspected of contributing to the effects of the aging processes and to age-associated patho- logic conditions, but there are few examples. Among the best documented is photoag~ng the changes in skin appearance and function that are due to habitual exposure to the sun rather than to the passage of time alone. Photoaging, also called premature aging and dermatoheliosis, is virtually synonymous in the public mind with "truer chronologic aging and has only recently been differentiated, even by derma- tologists (Gilchrest, 1984~. Clinically, photoaging is characterized by coarseness, wrinkling, mottling, laxity, telangiectasia (dilation of blood vessels), atrophy, fibrotic depigmentation (pseudoscars), and ultimately malignant neoplasia on the face, neck, hands, and other habitually exposed body areas. Fair-skinned people living in areas of high insolation (solar intensity) and having extensive vocational or recreational sun exposure are affected earliest and most severely, but most white Americans manifest the changes to

122 AGING IN TODAY'S ENVIRONMENT some degree by the fifth decade and many by the third decade. Clinical changes are generally progressive throughout life. Cigarette smoking is a second environmental factor that has been repeatedly noted to produce premature aging of the skin, most recently in a prospective blinded study controlled for age, social class, exposure to the sun, and recent weight change (Model, 1985~. Among 116 patients aged 3~69, those who had smoked at least 10 cigarettes per day for at least 10 years were far more likely than nonsmokers to have deeply wrinkled, atrophic, leathery skin. Unfortunately, the probable adverse effect of smoking on cutaneous aging has not been examined in animal or celI-culture experiments. Substantial epidemiologic data and experimental animal data have implicated the ultraviolet (UV) portion of sunlight, partic- ularly UVB (29~320 nary), in both photoaging (Kligman, 1969; Kligman et al., 1982; Smith et al., 1962) and photocarcinogenesis (Blum, 1959; Urbach et al., 1974~. Longer UV wavelengths and even infrared (heat) energy might also contribute (Kligman et al., 1985; Strickland, 1986~. No data either support or exclude inter- actions between UV radiation and other (e.g., chemical or dietary) environmental exposures in those processes. Photoaging has been estimated to account for more than 90% of ag~associated cosmetic skin problems (Gilchrest, 1984), which affect people's self-esteem (Graham and Kligman, 1985) and so- ciety's perception of them (Dion et al., 1972~. Extensive epi- demiologic data support a causal role of photoaging in a similar percentage of basal cell and squamous cell carcinomas (Urbach et al., 1974), which together account for more than half of all malignancies in the United States. Exposure to the sun is also implicated in a smaller (but unknown) percentage of cases of ma- lignant melanoma (Lancaster and Nelson, 1957; Magnus, 1977; Movshovitz and Modan, 1973), a major public-health concern be- cause of its rapidly increasing incidence (Jensen and Bolander, 1980) and substantial fat aTity rate. Apart from its universal adverse long-term ejects on appear- ance and its major role in skin carcinogenesis, habitual exposure to the sun has recently been recognized as exacerbating several of the more subtle age-associated functional losses in human skin. One example of probable medical importance is immune respon- siveness. Both establishment and expression of delayed hypersen- sitivity in the skin are impaired in the elderly (Smith et al., 1962; Waldorf et al., 1968~. The impairment is attributable in part to

ENVIRONMENTAL EFFECTS ON DISEASES AND ORGAN FUNCTION 123 the well-known age-associated decreases in T-lymphocyte function (Mackay, 1977~. In adclition, age-associated Secretes in the number of epider- mal Langerhans cells, the bon~marrow-derived cells responsible for immune expression in the skin, have been measured (Gilchrest et al., 1982b; Thiers et al., 1984~. Two studies that used different histologic techniques have documented a further 2~50~o reduction in Langerhans celb in skin habitually exposed to the sun (Gilchrest et al., 1983; Thiers et al., 1984), and a third study has revealed a similar decrease In the ease of allergic sensitization to dini- trochiorobenzene in adjacent sun-exposed versus sun-protected skin sites in elderly volunteers (O'Dell et al., 1980~. According to the imrnune-surveilIance theory of carcinogenesis (one of several controversial theories), this aspect of photoaging could contribute to the strongly age-associated incidence of skin cancer. Environmentally induced acceleration of the apparent aging of skin has been investigated at the cellular level, as well as clinically, with the in vitro mode} first described by Hayflick some 25 years ago (Hayflick, 1965; Hayflick and Moorhead, 1961~. It is now well accepted that human fibroblasts have a finite, reproducible life span in culture (Hayflick, 1979), that culture life span is inversely related to donor age (Martin et al., 1970; Schneider and Mitsui, 1976), and that culture life span is decreased relative to that of cultures from ag~matched control donors for fibroblasts derived from people with some disorders considered to represent premature aging (Martin et al., 1970~. To determine whether habitual exposure to the sun accelerates chronologic aging in skin-derived cells, cultures of dermal fibro- blasts (Schneider and Mitsui, 1976) and epidermal keratinocytes (Gilchrest, 1980) were established from paired biopsy sites on the inner (sun-protected) and outer (sun-exposed) aspects of the upper arms of nine healthy, fear-skinned, male volunteers aged 28- 86. Volunteers had comparable lifelong annual exposure and no substantial exposure within 4 months of the biopsy. The paired cultures were maintained under identical standard conditions and serially passaged until senescence. The cultures derived from sun-protected sites underwent more cumulative population doublings than did paired cultures derived from the sun-exposed sites, and the magnitude of the discrepancy increased with donor age and clinical severity of the photoaging

124 AGING IN TODAY'S ENVIRONMENT changes. Similar results were obtained with fibroblast cultures de- rived from different paired sites sun-exposed and sun-protected skin removed from around the ears of older women during fac - lift procedures (Gilchrest et al., 1983~. The data suggest that habitual exposure to the sun does accelerate cellular aging, as judged by at least one criterion. Photoaging and chronologic or intrinsic aging in the skin have striking similarities, but the processes can be distinguished at the electron microscopic level (Braverman and Fonferko, 1982a,b; Lavker, 1979~. The ability to distinguish between them offers the hope that the effect of environmental factors other than exposure to the sun might also be differentiated from intrinsic aging, even in the absence of control tissue not environmentally exposed (a major advantage in skin), giver sufficient knowledge of normal morphologic and physiologic aging changes. However, it will not be easily accompILshed. In middle-aged or elderly people, even casual comparison of habitually exposed versus protected sites (e.g., face or hand versus buttock or breath immediately suggests different aging rates, with lines of demarcation corresponding to clothing styles, rather than to anatomic compartments. Nevertheless, the major role of environment in skin aging has only recently been accepted. That implies that overwhelming evidence will be required to convince both scientists and the public of other adverse environmental ~rnpacts on the perceives! aging process. VISION A number of changes take place in the tissues of the eye in association with aging. Some account for a good deal of the bl~nd- ness and visual loss in oider people. The impact of environmental factors on these "biologic markers" of aging is only beginning to be understood. Substantial visual impairment occurs in To of people over 65 and in 46~o of those over 85. Aging-related macular degeneration, associated with changes in the retinal epithelium, accounts for some of these cases; nonneuronal change (cataract and glaucoma) accounts for the rest. Cataracts Cataracts opacities of the lenses of the eyes are so directly

ENVIRONMENTAL EFFECTS ON DISEASES AND ORGAN FUNCTION 125 connected with aging processes that it has been suggested that everyone would develop them if people lived long enough. It is es- timated that the vision of about 17 minion people around the world is impaired by cataracts, and in developing countries cataract is the major cause of curable blindness. About a million Americans are affected by cataract; it is a major cause of blindness in the United States. About 60% of Americans between the ages of 65 and 74 have some signs of cataract. Epidemiologic data show striking regional differences in the prevalence of cataracts and suggest that environmental factors play a role in its etiology (to restore sight). For example, cataract incidence Is extraordinarily high in Tibet and Nepal, and a three- fold difference in prevalence of cataract has been reported among different climatic zones in northern India. Population studies have shown a striking difference between the United States and India in the age-specific prevalence of cataracts: for the age groups 52-64, 6~74, and 7~85, rates were Who, 18%, and Who, respectively, in the United States and 29~o, Who, and 82~o in India. Major identified risk factors related to the etiology of ages related cataract include the following: · Sex. Females are at increased risk, which suggests a role for endocrine factors. Further research on this subject is needed. Ultraviolet irradiation. Geographic studies have shown that increased risk of cataracts is associated with living in areas that receive large amounts of sunlight or are at high altitudes. The high prevalences of cataract in Tibet and Nepal have suggested this association since prolonger! exposure to sunlight, and hence UV irradiation (which is greater at high than at low altitudes), is present in these locations. A current hypothesis suggests that the initial reactions involve oxidative mechanisms that can act on proteins of the lens, including membrane Na+-K+ ATPase, a key element in regulation of salt and water distribution in tissues. Excessive lens hydration causes swelling arid disruption of the cel- lular membranes and cellular destruction, and finally blocks light transmussion through the lens. It is known that various forms of ionizing radiation can cause experimental cataracts and thus are recognized as occupational hazards that lead to cataracts. ~ Diabetes. Biochemical changes in the lens and the fluid that bathes it cause changes in the metabolism of glucose in the .

126 AGING IN TODAY'S ENVIRONMENT lens. In experimental "sugar" cataracts, glucose metabolism pros ceeds by an alternative oxidative metabolic pathway rather than a normal anaerobic series of energy-producing reactions that lead to the accumulation of sorbitol, a sugar alcohol, in the lens fibers (McLean et al., 1985~. The increased sorbito} concentration pros duces an osmotic gradient, draws water from the aqueous humor into the lens fibers, causes the lens fibers to swell and eventually become disrupted, and finally produces opacification of the lens. The enzyme aldose reductase produces the sorbitol, and agents that inhibit it have prevented experimental cataracts (Kador et al., 1985~. Glaucoma Glaucoma (primary open-angle glaucoma) is associated with aging. Glaucoma is characterized by loss of visual field, changes in the appearance of the optic nerve, and increased intraocular prep sure (pressure higher than a given eye can tolerate). Intraocular pressure is regulated by a balancing of the rate of aqueous humor formation and the rate at which it leaves the eye, filtering through the trabecular meshwork. In glaucoma, ultrastructural factors in the meshwork slow the filtration and increase the intraocular pressure. Epidemiologic studies have shown a sharp increase in the prevalence of glaucoma with age. A survey of available information suggests prevalence rates for glaucoma of 2-6% in predominantly white populations. Prevalence at age 70 is several times that at age 40 (U.S. National Advisory Eye Council, 1983~. However, those data are derived from studies conducted under various conditions and in populations of different sizes, and they reflect detection of glaucoma in rather small numbers of patients. Clinical observations have suggested that the prevalence of glaucoma is greater in blacks than in whites. Recent findings of a large, well-designed survey in Baltimore indicate that the overall prevalence of glaucoma among blacks is 5.8~o, distributed as follows: in l.9~o of those aged 4~49, 4.7% of those 50L59, 7.4~o of those 60-69, and 12~o of those aged 70 and older. Data from a comparable white population are under analysis (Tielsch et al., 1986~. A morphometric study of trabecular meshwork specimens col- lected from normal eyes demonstrated a progressive decrease in

ENVIRONMENTAL EFFECTS ON DISEASES AND ORGAN FUNCTION 127 cellularity with aging (Alvarado et al., 1981~. Co~nparable mea- surements of tissues from glaucomatous eyes indicated that the process is accelerated in glaucoma (Alvarado et al., 1984a,b), which suggests premature aging of the meshwork in glaucoma. Diabetic :Ret~nopathy Diabetic retinopathy affects the central macular area of the retina—the region of greatest visual acuity more severely than peripheral areas. Major clinical signs of ret~nopathy are closure of blood vessels, vessel leakage, and growth of new vessels that tend to be fragile and leaky. The resulting hemorrhages often lead to scar-tissue formation, tension on the retina, its detachment, and blindness. Some 905to of people with insulin-dependent diabetes that has bated 15 years show some degree of retinopathy; after 30 years, about 50~o have proliferative retinal vascular changes. To the extent that diabetes can be attributed to environmental factors such as diet, diabetic retinopathy might be avoidable. Ag~g-:Etellated Macular Degeneration Ag~ng-related macular degeneration, formerly known as senile rnacula~ degeneration, affects the central high-acuity area of the retina and leads to severe loss of vision. The disease is a ma- jor cause of visual impairment in people over 60. About 90~o of elderly people have some form of retinal degeneration. Most of them have the mild ~dry" or nonexudative type, which generally progresses slowly. In the more severe "wets form of the disease, exudative maculopathy, neovascuiarization occurs abnormal new vessels grow inward from the choroid, through Bruch's membrane, and lie beneath the retinal pigment epithelium. Bleeding from the new vessels initiates processes that break down the retinal pigment epithelium, elevate the retina, and damage vision. In nonexudative maculopathy, the vessels have not broken through Bruch's mem- brane; however, this form can progress to exudative maculopathy. Maculopathy can be recluced by laser photocoagulation. A recent examination of pathogenetic factors of aging-related macular degeneration indicates that risk factors include drusen, choroidal vascular disease, and vitamin C deficiency (Feeney- Burns and Ellerseick, 1985~. Drusen, small yellowish bodies

128 AGING IN TODAY'S ENVIRONMENT observed ophthalmoscopically under the macula in Bruch's mem- brane, normally increase with age. Special changes In their num- ber and appearance are noted in maculopathy. A recent electron micrographic study surveyed changes in Bruch's membrane with age (Tso, 1985~. Morphologic changes in the macular region pros greased from the second decade. lIEA1lING Hearing impairment is a major affliction of the elderly, affect- ing more than one-fourth of those past 65 (Katzman and Terry, 1983~. Most cases are idiopathic (often they are of genetic ori- gin) and result from loss of sensory hair celb in the inner ear and involvement of the auditory nerve; but ototoxicity due to drug ingestion is also well recognized. The possible contribution of lifelong environmental noise pollution is unknown, although shorter-term exposure to very loud nodes is well known to impair hearing permanently (WorId Health Organization, 1980~. No~se-induced hearing loss (NTHL) ~ caused by dally exposure to intense sound over a long period (months or years). Gradually, slight insult ~ added to slight insult until a permanent hearing loss is produced. This type of hearing i058 constitutes the vast majority of hearing Tosses observed in the occupational setting. Presbycusis ~ the deterioration in hearing associated with aging. It remains to be determined whether there ~ interaction between presbycusis and NIHL and whether one's sensitivity to NTHL depends on age. It has been suggested (HeLnkamp et al., 1984; Spoor, 1967) that interaction between presbycusis and NTHL is not purely additive. NERVOUS SYSTEM Changes Associated with Aging Aging Is associated with important changes in the nervous system (Katzmar1 and Terry, 1983), and an age-related decline in neural function might alIc~w previously silent neurotoxic disorders to reach clinical expression (Caine et al., 1986~. Clinical experience with therapeutic drugs has indicated that the elderly, especially those with metabolic abnormalities or with hepatic or renal im- pairment, are more susceptible to the toxic effects of xenobiotic

ENVIRONMENTAL EFFECTS ON DISEASES AND ORGAN FUNCTION 129 substances (Silverstein, 1982~. However, systematic studies of the effects of chemical neurotoxicants on laboratory animals of various ages have not been undertaken. The most intensively studied and best-documented aspects of normal human aging are changes in intellect and memory. Intellec- tual performance as measured by tests of vocabulary, informa- tion retention, and comprehension reaches a peak between the ages of 20 and 30 and, in the absence of disease, is maintained throughout adult life, at least until the m~cI-70~. Perceptual pros cessing and choice reaction are slowed during aging. Learning, storage, and retrieval of information associated with short-term memory are consistently impaired in older subjects. Motor tasks including locomotion, handwriting, and other purposeful movements are performed more slowly, weakly, or in an uncoordinated manner. Muscle wasting is common, strength is reduced, and tendon reflexes become difficult to elicit (Katzman and Terry, 1983~. Vibration sense is progressively compromised with advancing age, touch sensation is diminished, thermal dis- crimination is impaired, and the pain threshold is mildly raised. Defective thermal regulation and decreased lacrimation also occur with age. Sleeping patterns are altered. Neurobehavioral changes that accompany human aging are as- sociated with structural or functional alterations in the central and peripheral nervous systems. Some changes such as alterations in vascular and cardiac reflexes, galvanic skin response, potency, mic- turition, and pupiliary response probably result from changes in the autonomic nervous system (Katzman and Terry, 1983~. Sym- pathetic hyperactivity is commonly present in the aged and might interfere with cognitive functioning, especially under the stress of psychologic testing. People with sympathetic hyperactivity would be expected to be more susceptible to chemical toxicants with sympathomimetic properties. Changes In cerebral blood flow, es- sential for the maintenance of normal brain function, might occur after the age of 80. Cerebral cortical atrophy and ventricular enlargement have been documented in normal aging people. Some regions of the brain are more susceptible to neuronal cell loss: the locus ceruTeus and substantia nigra (McGeer et al., 1977), both of which undergo maximal reduction in the third and fourth decades and decline slowly thereafter; Purkinje's cells; and putamen neurons, which decline linearly in number (Katzman and Terry, 1983~. But several

130 AGING IN TODAY'S ENVIRONMENT cranial nuclei and the olivary nucleus maintain stable populations. The number of cerebral cortical neurons can be reduced by up to half from age 20 to age 80, and supplementary reductions and alterations occur in their dendritic arborizations and synaptic inputs. The volume of lipofuscin, a yellow, insoluble pigment, increases linearly in most neurons with increasing age, but there is no evidence that this material is cytotoxic. Other neuronal abnormalities in aged brains include neurofiW rilIary tangles, neuritic plaques, and granulovacuolar bodies. Neu- ronal changes and cell loss result in substantial local or generalizes} alterations in the concentration of neurotransmitters, including dopamine, norepinephrine, serotonin, gamm~aminobutyric acid, and choline acetyitransferase, the enzyme required for the syn- thesis of the neurotransmitter acety~choline (Katzman and Terry, 1983~. Morphologic age-related changes in the peripheral nervous shy tem include a probable reduction of sensory neurons, an increase in the incidence of demyelination in spinal roots and peripheral nerves, increases in connective tissue, and a mild loss of myeli- nated fibers (Spencer and Ochoa, 1981~. The central processes of dorsal root ganglion cells typically undergo distal dystrophic and degenerative changes. There is a slight reduction in the number of motor neurons with age (Tomlinson and Irving, 1977), and regres- sive changes have been reported in the terminals of motor axons. Changes in sensory and motor nerve conduction with a progressive slowing of nerve action potentials are also characteristic. induced Disorders and Diseases The neurologic effects of aging and of chemical substances overlap considerably. This overlap might indicate only that the nervous system has a lirn~ted repertoire of biologic expression or that the mechanisms involved in neural aging can be traced to toxic effects of circulating metabolites derived from both endogenous and exogenous sources. It is generally believed that the clinical expression of disor- dered neural function resulting from aging becomes evident only after the considerable structural and functional redundancy of the nervous system has been overcome. For example, a maintained parkinsonian state appears only after a considerable loss of neu- rons in the substantia nigra, and it can occur as a consequence

ENVIRONMENTAL EFFECTS ON DISEASES AND ORGAN FUNCTION 131 of aging. Some people might be at special risk for neurotoxic disorders because of genetic characteristics (e.g., slow acetylators prompting isoniazid toxicity), abnormal metabolic states (e.g., un- dernutrition), leaky blood-bra~n regulatory interfaces (e.g., liver compromise), or aging (e.g., poor renal clearance). The elderly are generally more susceptible than the young to the potential neurotoxic side effects of therapeutic drugs and other chemical substances. Specific environmental influences (such as effects of exposure to chemical toxicants and environmental toxins) on aging have been proposed as a general mechanism for the cause of major de- generative diseases of the elclerly that affect intellectual and motor function (Caine et al., 1986~. Presenile dementia of the Alzheimer type, Park~nson's disease, and amyotrophic lateral sclerosis are proposed to derive from environmental subclinical damage to spe- cific regions of the central nervous system that are particularly vulnerable to age-related neuronal attrition. For parkinsonism, the hypothesis is being tested in people with subclinical dam- age to the substantia nigra after exposure to MPTP (Langston, 1985~. Because nigral neurons decline with age, it is likely that characteristic features of the disease will evolve in later life. For amyotrophic lateral sclerosis and presenile dementia, the spotlight is on the indigenous population of Guam, which is pe- culiarly susceptible to these conditions as well as to parkinsonism (Spencer et al., 1987~. Epidemiologists have found that exposure to the environment of Guam for a minimum of the first 20 years of life is sufficient to establish the conditions necessary to develop amyotrophic lateral sclerosis or parkinsonism-dementia decades later (Garruto et al., 1980~. Suspect etiologic agents are the cycad plant (Cycas circinal") (Spencer et al., 1987) and aluminum (Per! et al., 1982~. Neurotoxicants Among the environmental pollutants with neurotoxic poten- tial, lead and mercury each occupy a prominent position, although the number of people in North America with overt neurotoxic dis- orders attributable to these sources is probably small. In addition, numerous plants and animals secrete or contain potent toxins, of which many disturb nerve conduction and one, ciguatoxin, is a major cause of acute neurotoxicity in the Pacific among those

132 AGING IN TODAY'S ENVIRONMENT who eat contarn~nated fish (Kaplan, 1980~. Other neurotoxins (e.g., a-bungarotoxin and cx-latrotoxin) affect synaptic transrru~ sign. Both types can produce acute, life-threatening conditions. Some of the agents find their way into food and water con- sumed by humans. Some chemicals with experimentally proven neurotoxic potential in animals are used as food additives (e.g., monosodium glutamate), flavors and fragrances (e.g., 2,~'dinitro- 3-methoxy-4-tert-buty} toluene), and antiseborrheic agents (e.g., zinc pyridinethione), but no cases of human neurotoxic dmease from these sources have been reported. In developing countries, biologic toxins (e.g.,Clostridium bot- ulinum, C. tetani, and Corynebacterium dipAtheriae), neurotoxic agents naturally present in food (e.g., cassava, cycad, and Lathyrus spp.) or as contaminants (e.g., ergot and aflatoxin), and pesticides probably account for a large proportion of human neurotoxic d~sor- ders. Pesticide intoxication is a worldwide problem. Uncontrolled cholinergic crises, sometimes leading to death, are common In some regions among agricultural and pesticide workers (Bull, 1982), aIld long-lasting changes in the electroencephaiograrns and behavior of surviving persons have been recorded (Duffy et al., 1979~. Other pesticides contain tremor- and seizure-inducing organochiorines or synthetic pyrethroids that perturb neurotransmission (Narahashi, 1984; Taylor et al., 1979~. The worldwide problem of substance abuse particularly of ethanol, hallucinogens, narcotics, central nervous system stimulants, solvents, and nitrous oxide- leads to various types of short- or iong-lasting necrologic dysfunction. Many other substances encountered in the workplace (e.g., solvents, monomers, and catalysts) have been associated with neurologic illnesses ranging from polyneuropathy to organic brain syndrome. This spectrum of disorders was observed in workers exposed for only a few weeks to one particularly potent industrial neurotoxicant, Lucel-7 (2-tert-butylazo-2-hydroxy-5-methy~hex- ane) (Spencer et al., 1985~. Dementia, delirium, and depression can all result Tom expo- sure to pharmaceuticals. Learoyd (1972) found that 16~o of 236 patients over 65 who were hospitalized for behavioral disturbances had disorders directly attributable to the ejects of psychoactive drugs. In a recent study of 107 unselected outpatients referred for evaluation of global mental impairment (memory loss, confu- sion, slow thought, inability to care, and self-neglect), Larson et al. (1984) found that 15 patients had potentially reversible dementias,

ENVIRONMENTAL EFFECTS ON DISEASES AND ORGAN FUNCTION 133 or chronic progressive deterioration of higher intellectual function. The most common cause was medication. Side effects of single drugs that were potential causes of de- mentia included confusion caused by amantidine, insulin-induced hypoglycemia, and haloperidol-induced oversedation and parkin- sonism. Several drug combinations were ~rnplicated: clorazepate and lorazepam; meprobamate, protriptyline, and thioridazine; and reserpine, diazepam, and meprobamate. Dementia can be reversible, particularly when causer! by drugs, heavy metals, or industrial chemicals (Cummings et al., 1980~. Drugs that have been reported to cause dementia can be grouped into four main categories: psychotropic medications, such as phe- nothiazines, butyrophenones, benzodiazepines, tricyclic antide- pressants, and lithium carbonate; anticonvulsants, such as pheny- toin, mephenytoin, and carbamazepine; antihypertensive agents, such as clonidine, methyIdopa, and propranolol; and anticholin- ergic compounds, such ~ atropine and antihistamines. Heavy metals including react, mercury, thallium, and arsenic~an cause intellectual impairments that are reversible by chelation or reduc- tion of exposure. Even though proprietary bromide preparations are much less available than in the past, bromide intoxication should be consid- ered as another insidious cause of dementia (Raskind et al., 1978~. It has been reported that the concentration of aluminum in the brains of patients who died with senile dementia of Alzheimer's type is 1() 30 times the normal concentration (Crapper et al., 1976~. Later studies have localized alurn~num to cells with neu- rofibriliary tangles (Per! and Brody, 1980~' but its role in the pathogenesis of the disease remains controversial (Glenner, 1982~. Long-term exposure to industrial agents including trichIoroethy- lene, toluene, carbon disulfide, organophosphates, and carbon monoxide has resulted in mental status changes that reversed with elimination of the causative agents (Cummings et al., 1980~. The term delirium applies to organic brain syndromes char- acterized by the rapid onset of cognitive dysfunction Involving fluctuating impairments of attention, memory, and orientation. Common symptoms inclucle insomnia or reduction in wakeful- ness, such perceptual disturbances as illusions and hallucinations, and changes in psychomotor activity, particularly agitation. El- derly patients, particularly those already suffering from dementia, are most susceptible to developing drug-induced delirium (Barnes

134 AGING IN TODAY'S ENVIRONMENT and Raskind, 1980~. Levodopa, arnantidine, corticosteroids, and many drugs with anticholinergic properties are often responsible. Barbiturates and other sedative hypnotic agents can also cause paradoxic agitates] delirium in susceptible patients. Depression can be a complication of drug therapy. Antihyper- tensive agents such as reserpine, methyldopa, and clonidine- have been reported to cause depressive symptoms, but a greater incidence seems to be associated with beta-blockers than with those centrally acting agents. There is ample anecdotal evidence of patients with no prior psychiatric illness who experience malaise, dysphoria, or outright clinical depression when starting treatment with beta-adrenergic antagonists, and central nervous system side effects from propranolol range in frequency from loo to over 70~o (Paykel et al., 1982~. Reported symptoms include depression, drowsiness, sleep disorders, and hallucinations. Furthermore, the use of tricyclic antidepressants has been found to be significantly higher in patients taking beta-blockers (23~o over 2 years) than in patients taking hydralazine or hy- poglycemics (both 15~o) or methyldopa or reserpine (both 10%~. However, the magnitude of this association between bet~blockers and treatment for depression was found to decline with advanc- ing age (Avorn, 1986~. Proposed explanations were d~rninution in receptor sensitivity with age and failure of physicians to apprise ciate the dysphoria or other central nervous system side ejects as abnormal in an older patient. The mechanism of the central effect of beta-blockers could be interference with nonadrenergic neurotransmitter function in the brain, a pathway that is thought to play a causal role in some cases of depression. In general, the signs and symptoms of drug-induced neuro- logic disorders are practically indistinguishable from those seen in nondrug-induced disorders, but are usually reversible if diag- nosed early enough (Lane and Routledge, 1983~. Neurotoxicity commonly accompanies prolonged therapeutic treatment with an- ticonvulsants, anticholinergics, neuroleptics, antineopla~tics, and antiparkinsonism drugs. In addition, a recently recognized iatro- genic neurotoxicity is the sensory neuropathy syndrome associated with pyridoxine megavitarnin therapy (Schaumburg et al., 1983), which has been prescribed for the treatment of premenstrual ten- sion. The incidence of subclinical neurologic and behavioral dis- orders associated with chemical substances is unknown, but is

ENVIRONMENTAL EFFECTS ON DISEASES AND ORGAN FUNCTION 135 believed by some to be large. Examples include the unresolved controversies about childhood cognitive impairment from envi- ronmental lead contamination and the neurobehavioral effects at- tributed to prolonged occupational exposure to a variety of indus- trial solvents. RESPIRATORY SYSTEM Lung growth and development continue into the second decade of life, and then pulmonary function begins to decline. The de- cline is most easily measured with tests of forced expiration. Many prospective epidern~ologic studies indicate that the forced expira- tory volume in 1 second (FEW ~ decreases continuously with age, even in healthy nonsmokers. The rate of loss is greater in older than in younger people (Beaty et al., 1984; Burrows et al., 1986; Fletcher, 1976; Higgins et al., 1982~. Smokers lose pulmonary function much faster than nonsmokers, but if they stop smoking, their rate of decline reverts to the rate observed in nonsmokers (FIetcher, 1976~. Although an understanding of the association between aging and environmental insults to the lungs is lirn~ted, two features are noteworthy because of pathophysiologic correlations. First, when the structure and function of small airways are measured, age and smoking are found to have important ejects. Even in young, presumably healthy smokers, evidence of inflammatory re- sponses in peripheral airways is striking (Niewoehner et al., 1974~. Small-airway dysfunction increases with age and can be observed in smokers of all ages (Enjeti et al., 1978~. Those observations have led to the recognition of the importance of peripheral lung structure and function in the evolution of lung aging or disease and to the focus for the last 15 years on studies of peripheral lung function in the evaluation of environmental exposures (Macklem 1972~. The second important feature of lung function is airway re- activity. Acute reactions of the airways are typically increased in asthmatic subjects, but might be increased in normal subjects who smoke (Gerrard et al., 1980; Mullen et al., 1986), after viral infec- tions, and after exposure to oxidants, such as ozone (Boushey et al., 1980~. Airway reactivity can be measured in the laboratory with controlled administration of bronchoconstricting agents. A num- ber of studies now point to the potential importance of increased

136 AGING IN TODAY'S ENVIRONMENT airway reactivity as a risk factor for accelerated loss of function with age (Barter and Campbell, 1976; Orie, 1960; Volimer, 1985~. The evidence implicating ambient concentrations of air pollutants in the decline of lung function with age is controversial (U.S. EPA, 1986~. However, the potential impact of environmental exposures, either outdoor or indoor, on susceptible people is real. Not only Is there clear epidemiologic evidence that age and environmental factors, such as smoking, are associated with lo" of lung function, equally clear ~ an important correlation between Jung dysfunction and mortality from all causes (puhnonary and nonpulmonary). From epidemiologic studies in Tecurnseh (Hig- gins and Keller, 1970), Eramingham (Ashley et al., 1975), and Baltimore (Beaty et al., 1982; Menkes et al., 1985), a consistent, strong relationship between lung function and mortality has been reported. It cannot be accounted for by smoking habits and re- flects (to a small extent) deaths from chronic lung disease or lung cancer (Skilirud, 1986~. Although the basis of the intriguing association is not known, two explanations are attractive. First, because the lung is normally an interface between the body and the environment, increased ex- posure to environmental toxins or increased susceptibility of the host leads to disturbances of the lungs, as well as of other systems of the body. Second, disturbances of function in organ systems other than the lungs might leac! to abnormalities in otherwise nor- mal lungs. Both explanations are suggest the importance of lung function in estimating environmental exposure and in assessing individual susceptibility to nonpulmonary, as well as pulmonary, aging and disease. CARDIOVASCULAR SYSTEM Some characteristic aggregated changes in the cardiovascular system are stenotic coronary vascular disease due to atheroscle- rosis, stiffening of the large arteries, an increase in systolic blood pressure, and mild cardiac hypertrophy and concomitant reduced cardiac filling rate with unchanged cardiac filling volume and rest- ing cardiac output (Lakatta, 1985a,b, 1986). More subtle manifestations of aging can be detected with the imposition of a stress, such as exercise. Age-related changes in the hemodynam~c response to vigorous exercise include a diminution in the increment in heart rate, increase in heart size (which is

ENVIRONMENTAL EFFECTS ON DISEASES AND ORGAN FUNCTION 137 . normal at rest) both at the end of the filling period and at the end of the contraction period, and reduction in the increment in ejection fraction (the proportion of the filling volume pumped with each contraction of the heart) (Rodeheffer et al., 1984~. These changes can be explained by an age-related diminution in the response of the cardiovascular system to catecholamines produced by the activation of the sympathetic nervous system (which occurs during exercise). Considerable evidence from both experimental animate and humans indicated that the sensitivity of cardiac and vascular tissue to ,9-adrenergic agonists' autonomic modulation declines with age (Bertel et al., 1980; Conway et al., 1971; FIeisch, 1981; Kuramoto et al., 1978; Vestal et al., 1979; Yin et al., 1979, 1981~. Despite a substantial body of information on the effects of aging on cardiovascular physiology, the extent to which the aged might be particularly vulnerable to the toxic effects of drugs, chemicals, and other environmental agents has received scant at- tention. The possibility of a difference in the response of the aged myocardium to cardiac glycosides, such as ouabain and digoxin, has been investigated in animals and humans (AIgeo et al., 1983~. Developed tension and maximal rate of tension development in isometric trabeculae carneae were approximately 4 times greater in young than in aged Wistar rat myocardium (Gerstenblith et al., 1979~. There was no age-dependent difference in ouabain-induced Na+-K+-ATPase inhibition, which is a postulated mechanism of action for ouabain and other digitalis preparations. In contrast, activity of the Na+-K+ ATPase was 50~o less in aged Fischer 344 rats than in younger rats, and the toxicity of ouabain was inversely related to enzyme activity (Baskin et al., 1977~. Ouabain also inhibited enzyme activity more in older than in younger rats. In guinea pigs, however, the median lethal dose of ouabain infused into adult and aged (up to about 5-6.5 years old) guinea pigs did not differ (Wollenberger et al., 1953~. In elderly humans, an age difference in the Monotropic response to digitalis was not demonstrated (Cokkinos et al., 1980~. The in- otropic response, as measured by systolic intervals, to desTanoside (1.2 mg intravenously) was similar in a group of 20 healthy males and females (mean age 34.3 years) and a group of 20 healthy older subjects (mean age 65.3 years). The clinical effects of acetyIdigoxin in congestive heart failure and digoxin in atrial fibrillation do not differ with age (Aravanis, 1969; CharnberIain et al., 1970~. Thus,

138 AGING IN TODAY'S ENVIRONMENT apart from the increase in plasma digoxin due to diminished re- nal excretion in the elderly, there is little evidence to support the widely held notion that intrinsic myocardia] sensitivity to digitalis is increased in old age. Age-related data on antiarrhythmic agents are even less ex- tensive than those available on cardiac glycosides; they generally indicate no significant increase in sensitivity or toxicity in the absence of abnormal conduction. A recent clinical study demon- strated altered sensitivity to verapamiT, a calc~um-channe} antago- nist. Age differences in pharmacokinetics resulted in higher plasma concentrations in elderly than in young patients (Abernathy et al., 1986~. Doxorubicin (adriamycin), an anthracycline cancer chemo- therapeutic agent, appears to have important age-related cardiac toxicity. A major problem with administration of doxorubicin for therapeutic purposes is the development of often irreversible and often fatal congestive heart failure. The effect seeders to be dose- related, and cumulative doses greater than 550 mg/m2 result in a marked increase in the incidence of heart failure (Lefrak et al., 1973~. If more sensitive measures of cardiac function are used such as systolic intervals, cardiac impairment after doxorubicin therapy (greater than 400 mg/m2) is detectable in approximately 15~o of patients (Dresdale et al., 1983~. Degenerative changes in cardiac histology occur almost universally at doses greater than 240 mg/m2 (Bristow et al., 1978~. Apart from cumulative dose, old age was the major risk factor observed in a retrospective survey of 4,000 patients (don Hoff et al., 1979~. Others have also noted that aging is a risk factor for devel- opment of cardiotoxicity (Bristow et al., 1978; Dresdale et al., IUb3), but not because of a higher incidence of coronary heart disease in older patients (don Hod et al., 1979~. The mechanism of cardiotoxicity of doxorubicin is not known, but could be the production of free radicals (Olson et al., 1981; Unverferth et al., 1982~. Pathways of free-radical detoxification are depressed in some tissues of senescent laboratory animals (Stohs et al., 1982), so myocardial free-radical scavenging might be impaired in elderly patients. The clinical observations related to doxorubicin suggest that other chemicals and environmental agents that produce free rad- icals might be associated with myocardial damage and that the effects might increase with age. Surprisingly, data on that point "d I ~ . . ~ ~ ~ · ~

ENVIRONMENTAL EFFECTS ON DISEASES AND ORGAN FUNCTION 139 are not available; indeed, it appears that the impact of age on cardiovascular toxicity has been virtually ignored by toxicologists and epidemiologists. RENAL SYSTEM Chronic nephropathy involving glomerular sclerosis, mesan- gial cell injury, and mesangial matrix overproduction is commonly found in rats at advanced ages (Coleman et al., 1977; Durand et al., 1964~. Similar progressive lesions are observed in young rats after surgical reduction of kidney mass (Chanutin and Ferris, 1932; Purkerson et al., 1976; Shimamura and Morrison, 1975) and in humans, usually at advanced ages, after disease-induced kidney damage when the initial disease process is no longer active (Bren- ner et al., 1982~. Decreasing the protein content of the diet of rats has been found to retard the development of the nephropathy that occurs during normal aging (Maeda et al., 1985) and that follows surgical reduction of kidney mass (Hostetter et al., 1981; Laouari et al., 1983; Moise and Smith, 1927~. Moreover, there is evidence that reducing the protein intake of humans slows the progression of chronic renal failure to end- stage disease (Mitch, 1984~. Brenner et al. (1982) suggested that a decrease in dietary protein acts by preventing giomerular hy- perperfusion and hyperfiltration, which they thought responsible for the progression of the lesions and for the eventual loss of renal function. Iwasaki et al. (1986) recently reported that the development of kidney lesions in male Fischer 344 rats during normal aging can be retarded by using soy protein as the source of dietary protein without reducing protein intake. That finding is important in two respects: for animal models for the study of aging and in treatment of chronic renal failure in humans. The male Fischer 344 rat has been a major animal mode} (National Research Council, 1981b) for the study of aging, because it is genetically homogeneous and because it does not develop the obesity that occurs with advancing age in many rat strains. However, a major problem with the strain, as with most other rat strains, has been renal failure with advancing age, which precludes the study of normal aging processes in some of the rats by the age of 18 months and in many after the age of 24 months. Diets with soy protein as the sole protein source might, to a great extent,

140 AGING IN TODAY'S ENVIRONMENT circumvent the problem and thus facilitate fuR life-span studies with the Fischer 344 rat. Although available data indicate that restricting dietary pros tein in patients with chronic renal failure delays the further loss of renal function and lengthens the tone before they need dialysis or transplantation, such treatment has the risk of protein mainutri- tion, as well as mineral and vitamin depletion (Mitch, 1984~. The proper selection of the dietary protein source might yield a treat- ment for chronic renal failure as effective as protein restriction but without its risks. IMMUN1: SYSTEM One of the most important body defenses is the immune gym tem. Environmental influences on the immune system include the effects of psycholog~c stress (including bereavement), nutrition, environmental temperature, housing, light, noise, and chemicals. Some environmental influences on immune function affect life span and therefore presumably affect susceptibility to disease or the ag- ing processes themselves. Of the environmental factors, nutrition has a most dramatic effect on both immunity and life span in rodents. Reducing caloric intake of mice and rats by approximately 50%0 of their ad libitum intake inhibits the age-associated decline in immune competence, reduces the incidence of many diseases (including cancer), and extends life span. Undernutrition has been shown to increase the life span of a number of short-lived strains of mice (reviewed in Good et al., 1980~. Whether a similar nutritional regimen would influence the life span of higher organisms, including humans, }s unknown. Clear evidence exists that the barrier between an organism and its environment ~ altered with age (for a review see Weksier, 1986~. The immune function of the skm and the mucosal lining of the respiratory and gastrointestinal tracts change with age, although such change does not always parallel the changes in systemic immunity. Far more is known about the changes in systemic immunity that accompany aging in rodents and humans. The most striking anatorn~c change Is the involution of the thymus gland that begins at sexual maturity and is complete by midlife (45-50 years in humans), and that results in the loss of two thymic functions. The

ENVIRONMENTAL EFFECTS ON DISEASES AND ORGAN FUNCTION 141 first thyme function that declines with age is the capacity to effect the maturation of T-cell precursors that migrate to the gland from the bone marrow. The second Is the activity of thymic hormone in the serum, which begins to decline soon after sexual maturity. Thymic hormone activity in serum is undetectable in humans after midlife. The thymus, the source of mature T lymphocytes, plays a cen- tral role in cell-mediated immune responses and the regulation of the immune response. Not surprisingly, therefore, immune Seneca cence ~ characterized by a loss of thymu~dependent functions required for both cellular immunity and the regulation of hu- moral immunity. Inasmuch as the response to many pathogens— including viruses and fungi, as well as neoplastic cells and some environmental agents depends on cell-mediated immunity, the susceptibility of the aged to diseases induced by these agents Is increased. The striking increase in the morbidity and mortality associated with influenza in elderly people is a common clinical consequence of immune senescence. In addition to the 108s of cell-mediated immunity with age, the loss of thymic function leads to the dy~regulation of immune reactions. The striking increases in the frequency of autoantibod- ies and in the production of monoclonal ~rnmunoglobulins with age reflect this fact. Impaired suppressor-cell activity in old age is thought to contribute to the increases in autoantibodies and mon- oclonal proteins with age. Those autoimmune reactions might be exacerbated when elderly people take such drugs as procainarn~de, a-methyIdopa, or estrogens, which themselves stimulate the pros auction of autoantiboclies. When autoantibodies react with au- toantigens, they form immune complexes. Circulating immune complexes can contribute to vascular injury and thereby to the increasing severity of atherosclerosis in the elderly. Progress has been made in understanding the cellular basis of lymphocyte function that Is attributable to a loss of the capacity of T lymphocytes to divide. The evidence suggests that the cellular basis of immune senescence Is similar to what Hayflick suggested 20 years ago (Hayflick, 1965) in cultured fibroblasts- the loss of replicative capacity. Any environmental agent that compromised the capacity of celb to divide would thus be likely to depress immune competence and accelerate immune senescence.

142 AGING IN TODAY'S ENVIRONMENT SEXUALITY The fear of losing sexual ability or physical attractiveness can be a source of great anxiety for many people as they grow older. Men typically are afraid of sexual impotence; women fear the loss of physical attractiveness and desirability. A number of gradual and fairly predictable physiologic changes do occur with aging, but these changes do not preclude active and satisfying sexual functioning into old age. Most of the sexual changes in older women result from the menopausal decline of female hormones, especially estrogen. Envi- ronmental agents, such as ionizing racliation, pharmaceuticals, and cigarette smoking, have been shown to alter the age of menopause (i.e., ovarian failures (Chapman, 1983; Mattison, 1985; Mattison and Ross, 1983~. However, 60~o of all women do not experi- ence remarkable physical or emotional symptoms associated with menopause, and of those who do, most have only minimal to mod- erate physical problems, including headaches and neckaches, hot flashes, fatigue, and feelings of emotional instability. Physically healthy men do not lose their capacity to have erections and ejaculations as they age, although changes do occur. With age, men ordinarily begin to take longer to obtain an erection and to reach orgasm than when they were younger. Drugs, taken by prescription or otherwise, can aggravate these effects and cause other sexual problems. Some interfere with the autonomic nervous system, which is involved in normal sexual re- sponse. Others affect mood and alertness or change the production or action of sex hormones. In a study reported in 1983, 25~o of sexual problems in men were either caused or complicatecl by med- ications (ButIer and Lewis, 19863. Although less ~ known about drugs and female sexuality, drugs affecting men can be assumed to affect women as well (Butler and Lewis, 1986~. Tranquilizers, antidepressants, and some antihypertensive agents have all been unplicated in erectile impairment in men. The effects of these drugs on women is less well understood. The corticosteroids taken for arthritis can produce temporary impm fence. Analgesics can reduce sensitivity and therefore affect male sexual capacity. Aspirin taken over long periods reduces fertility. Cimetidine (for treatment of ulcers), one of the most widely sold medicines in the United States, can cause impotence. Alcohol in more than small amounts reduces potency in mates and orgasmic

ENVIRONMENTAL EFFECTS ON DISEASES AND ORGAN FUNCTION 143 ability in females. Even nicotine can be a factor in impotence. Although a number of gradual and fairly predictable changes in sexual function occur with aging, they are often confounded by the effects of environmental agents. ROLE OF E:NVI:RONMENT IN BONE M1:TABOLISM AND VITAMIN D NUTRITION One of the major problems associated with aging is the loss of bone mass. It is estimated that upwards of 10 million elderly Amer- icans suffer from marked reduction In bone ma" that compromises the architectural integrity of the skeleton and puts them at sum stantial risk of breaking bones. The magnitude of this public- health problem is evident in the estimated 200,000 hip fractures that occur each year. It has been estimated that $6 billion is spent each year for the acute care of people with age-related fractures (Cummings et al., 1985~. Bone loss in the elderly has many causes; among them are inadequate vitamin D and calcium absorption (influenced by es- trogen concentration). Although it is well documented in Great Britain (a country that does not routinely fortify foods with vi- tamin D) that over 40% of males and 30~o of females with hip fractures are deficient in vitamin D (Aaron et al., 1974; Chalmers et al., 1967), it has been assumed that vitamin D deficiency is not an important health problem in the United States because foods are fortified with vitamin D. An epidemiologic survey in the Southwest has revealed that over 60% of the free-living elderly subjects were obtaining less than 25~o of the RDA of vitamin D from their diets (Omdah] et al., 1982~. In two other studies, about 30~o of elderly patients with hip fractures had evidence of vitamin D deficiency (Doppelt et al., 1983; Sokoloff, 1978~. One of the prunary causes of poor vitarn~n D nutrition in the elderly in the United States is a decrease in or complete absti- nence Tom consumption of milk and milk products. The decrease is related to the common misconception among the elderly that they no longer need to drink milk because milk is important only for maintaining a healthy skeleton in growing children, and to gastrointestinal discomfort caused by lack of lactase, which is re- sponsible for hydrolyzing the lactose in milk. Very few foods nat- urally contain vitamin D (these include fish-liver oil, eggs, liver, and milk) or are fortified with vitamin D (milk, some cereals, and

144 AGING IN TODAY'S ~VIRO~NT in some countries, margarine). One quart of milk contains 400 international units (10 g) of vitamin D, which ~ the RDA (Holick, 1986~. If an elclerly person does not consume milk or other foods that contain vitamin D or take a vitamin D supplement, it is essential for that person to sunbathe to generate enough vitamin D3 to maintain a healthy skeleton. However, because of the increased awareness that exposure to sunlight can cause skin cancer and dry and wrinkled skin, the elderly are often advised to corer their skin with clothing or a sunscreen before going outdoors. Those measures prevent not only the damaging effect of solar irradiation, but also the beneficial effect the production of vitamin D3 in the skin (MacLaughlin and Holick, 1985~.

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