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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

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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),

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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 ~eO.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 agewhich might be related to intrinsic factors, extrinsic factors, or some combination needs to be assessed for each disease. For example,

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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 importantone 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,

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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

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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:

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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

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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~.

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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

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118 1 6,000 ~ z 14,000 a: ~ g 12,000 - OCR for page 109
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.

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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

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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

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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

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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,

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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 ~ . . ~ ~ ~ ~

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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,

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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

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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.

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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

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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

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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~.