Reducing Chronic Disease and Disability

Besides AD, chronic disease and disability can compromise the quality of life for older people. Some 79 percent of people age 70 and older have at least one of seven potentially disabling chronic conditions (arthritis, hypertension, heart disease, diabetes, respiratory diseases, stroke, and cancer).⁷ The burden of such chronic conditions and disability poses a challenge not only to individuals, but to families, employers, and to the health care system as well. Research to improve understanding of the risk and protective factors for chronic disease and disability can offer effective prevention strategies. Described in this section are recent research advances on the benefits of exercise, treatment of various diseases, and the molecular underpinnings of disease. New directions for research are also outlined.

Benefits of Exercise

Regular exercise is essential to maintain health and function at any age. In older adults, it has been shown that exercise in four key areas—endurance, strength, balance, and flexibility—can improve function and reduce disease. Endurance activity is important for function of the heart, lungs, and circulatory system and may help prevent such diseases as diabetes, colon cancer, heart disease, and stroke. Even in very old adults, strength exercises build muscles, increase metabolism, and help to keep weight and blood sugar in check. Strength exercises have been shown to help prevent osteoporosis. Balance and flexibility exercises help prevent falls and other injuries. As research continues to measure such benefits, investigators also are delving deeper into how exercise does what it does. Better understanding in this area, for instance, in how exercise affects metabolic processes within the older body, may lead to new and innovative interventions.

Fitness Affects Mortality Risk Regardless of Body Fat. Both obesity and being unfit increase risk for chronic disease and death. However, the interrelationship between fitness, body fat, and mortality has not been clear. Recent research suggests that it is fitness, not fat, that may count most. In one study, investigators followed men 30–83 years of age for an average of eight years, classifying participants according to body fat as well as relative fitness based on exercise testing. Not surprisingly, the study showed that the higher the level of fat, the lower the level of fitness. But what intrigued researchers most were data showing that, within each category of body fat, "fit" men were at lower risk of death. Most strikingly, among those more fit, obesity was not significantly related to risk of death. In another study, low fitness increased mortality risk in men approximately fivefold for cardiovascular disease, and threefold for all-cause mortality. These findings suggest that, beyond interventions focusing on weight-loss to prevent and treat obesity-associated conditions, there may also be important benefits for the obese from improved fitness.

Stress Testing May Not Be Needed for Starting an Exercise Program. The role of exercise stress testing and safety monitoring for older people who want to start an exercise program is unclear. Current guidelines for routine exercise stress testing may deter older people from beginning an exercise program, either because of the cost of testing or because it may lead people to believe that exercise poses higher risks than it actually does. The latest research suggests that, in the absence of cardiovascular contraindications, the benefits of exercise for the elderly, balanced against a somewhat minor increase in risk, may be sufficient for starting an exercise program without prior exercise stress testing.

Identifying Gene Variants That Influence the Interaction Between Exercise and Cholesterol Levels. The increase in body fat and loss of muscle mass that occur with age raise risk for disease, including diabetes and cardiovascular disease. Proper diet and/or exercise can be effective in helping to prevent or improve these conditions. However, there can be large variation in response to these interventions, in part because of genetic influences. Detection of specific genes affecting obesity, muscle mass, and blood cholesterollevels may provide a way to identify individuals likely to respond favorably to a particular intervention. In overweight, postmenopausal women, one genetic variation of an enzyme, lipoprotein lipase (LPL), was found to be associated with lower levels of both total cholesterol and LDL-cholesterol, risk factors for heart disease. The same LPL gene variant was found in older men with greater exercise-induced increases in HDL-cholesterol, a protective factor against heart disease. In another study, variants of the gene for apolipoprotein E (APOE), previously shown to influence blood cholesterol levels, were related to exercise-induced increases in HDL-cholesterol in middle-aged and older, overweight men. One form (APOE2) was associated with greater exercise-induced increases in HDL, compared with other variants of the APOE gene. Knowledge of how such specific gene variants interact with each other and with exercise and diet will lead to the development of more targeted and individualized prevention and treatment strategies.

Treatment and Prevention of Disease

Treatment of disease in older people can be complicated by the presence of other diseases and disorders and by the use of multiple medications to treat various conditions. Potential interactions of multiple medications, including those of prescribed drugs with over-the-counter drugs and dietary supplements, represent additional concerns. Moreover, compliance with treatment regimens can be difficult, as older patients often must maintain a complex schedule for taking several different medications. Research is ongoing to determine the best treatment approaches for older patients, particularly those with multiple comorbidities, and to identify strategies for improving compliance and minimizing potentially harmful effects of multiple medications.

Inadequate Treatment of Hypertension and Atrial Fibrillation (AF) in the Elderly. According to national surveys, 60–70% of older Americans aged 60 years and older have high blood pressure.⁸ Despite the considerable amount of scientific evidence that hypertension is an important risk factor for cardiovascular disease in all age groups, survey data suggest that in hypertensives over age 70, only 25% of African Americans and only 18% of white Americans have achieved the blood pressure goals (140/90 mmHg) recommended by the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure.⁹

Uncontrolled or inadequately controlled high blood pressure can lead to heart attack, stroke, heart failure, kidney disease, dementia or blindness. Another common cardiovascular problem is AF, a heart rhythm abnormality that can lead to circulating blood clots. Warfarin, a drug used to inhibit blood clotting, dramatically reduces the risk of stroke in patients with AF. Two recent studies suggest that older patients may be under-treated for both hypertension and AF. One found that developing new strategies to improve blood pressure control in older hypertensive patients might prevent an estimated 15% of heart attacks in this population. The other found that many patients with AF and at least one additional stroke risk factor, especially high blood pressure, did not receive appropriate warfarin therapy when such treatment may have been appropriate. These findings suggest the need for new strategies to enhance the appropriate use of currently available warfarin and antihypertensive treatmentsin standard clinical care.

Commonly Prescribed Diuretic Protects Against Osteoporosis. The lifetime risk of osteoporotic fracture in the U.S. is 40% in women and 13% in men. Because age-related bone loss increases susceptibility to fracture, strategies aimed at preserving bone mass are important. Large observational studies have consistently shown that the use of thiazide diuretics, usually prescribed to treat high blood pressure, is associated with higher bone density and about a 30% lower risk of hip fracture. Investigators recently completed a clinical trial to directly test the effect of taking thiazides on bone density in older men and women with normal blood pressure. Among healthy older adults, low-dose hydrochlorothiazide did preserve bone density at the hip and spine. The modest effects observed over three years, if accumulated over 10–20 years, may explain the 30% reduction in hip fracture risk associated with thiazides in the earlier observational studies. The results of this trial suggest that low-dose thiazide therapy may have a role in strategies to prevent osteoporosis.

Molecular Understanding of Disease Processes: Diabetes, Atherosclerosis

Diabetes is one of the leading causes of death and disability in the U.S. Type 2 diabetes, the most common form, usually develops in adults over 40 and is most common in adults 55 and older. Diabetes accelerates the narrowing of blood vessels by atherosclerosis and is a major risk factor for peripheral arterial disease. Atherosclerosis, which impairs blood circulation by narrowing arteries, is the most common form of occlusive vascular disease, a factor in both heart attacks and strokes. Most individuals with peripheral arterial disease have atherosclerosis, and symptoms can include painful cramping in leg muscles during physical activity. Studies reported here include: a new molecular approach for treating type 2 diabetes; gene therapy advances in possible treatment for peripheral artery disease; and advances in understanding and preventing the atherosclerotic process and how to reverse it.

Exendin-4 as a Treatment for Type 2 Diabetes. Type 2 diabetes mellitus (DM) is caused by an inability of the beta cells of the pancreas to compensate for increasing insulin demands; consequently, blood glucose levels rise. Scientists are searching for compounds that act on the pancreatic beta cells to prevent this progressive rise in blood glucose. GLP-1, a gut peptide, can stimulate beta cells to produce more insulin even in type 2 DM; however, its biologic half-life is short and its effects quickly wear off. Exendin-4, a newly studied peptide analog of GLP-1, is long-lived and more potent than GLP-1, and has been shown to reduce blood glucose levels in rodents. A recent study with small numbers of diabetic and nondiabetic humans demonstrated Exendin-4's efficacy in inducing insulin and normalizing blood sugar, even in diabetics. In the near future, an exendin-like drug possibly may become an effective treatment for type 2 DM.

Gene Transfer in Animal Model Stimulates Growth of New Vessels for Treatment of Peripheral Muscle Ischemia. Patients with blocked arteries in limbs are at risk of disabling symptoms in the part of the limb to which blood flow has been interrupted (ischemia). Restoring blood flow involves treatment with factors that promote artery regrowth (angiogenic factors). Until now, these angiogenic factors have been successfully tested only in animals whose blood supply is permanently blocked, and clinical trials in humans with similar permanent blockages are underway. Whether angiogenic treatment could also be used to treat people with intermittent ischemia, a condition in which the symptoms associated with blockage can recur periodically, is not known. Research is suggesting that intervention may be possible. In one recent study, scientists delivered an angiogenic factor by gene transfer into normal rat leg muscle several weeks before inducing ischemia by interrupting blood flow to the same leg. In that study, the angiogenic factor markedly increased formation of new blood vessels to the normal muscle, and these new blood vessels played a role in restoring blood flow and normal metabolism more quickly to the limb following ischemia. Successful development of this technique in humans might permit early intervention in patients with intermittent ischemia.

Regulation of TGF-ß Type II Receptor and Atherosclerosis. Atherosclerosis or narrowing of the arteries is the major risk factor for both heart disease and stroke and is a major complication after arteries have been surgically enlarged by balloon angioplasty. Throughout life, artery wall cells successfully repair injuries related to smoking, high blood pressure or cholesterol, making new cells to replace damaged ones. But constant exposure to such stresses eventually causes the artery wall cells to lose control of their replication. The growing mass of cells forms plaque, which eventually clogs the vessels and causes reduced blood flow. New research is helping to identify the complex series of cellular events causing cells to lose control of their division. In normal circumstances, a protein called TGF-ß1 prevents excessive cell division. It acts on the cells through binding to a protein receptor on the cell surface, the TGF-ß1 receptor, causing intracellular changes that stop cells dividing. In atherosclerotic lesions, it has been shown, unrestricted growth in some cells is caused by mutations in this receptor, inactivating it. Another way of preventing normal receptor function is to make too little TGF-ß1 receptor to be effective. One protein that inhibits the production of TGF-ß1 receptor is called Egr-1. This protein is found at very high levels in plaques, perhaps being induced by artery injury. Finding drugs to repress the activity of Egr-1 may be one way of keeping the key TGF-ß1 receptor functioning effectively to stop excessive cell division and prevent atherosclerosis.

Selected Future Research Directions To Reduce Disease and Disability

Cardiovascular Disease: Its Impact on Aging and Role in Dementia. Diseases of the heart and blood vessels are the leading cause of hospitalization and death in older Americans. The NIA is pursuing a broad program of basic and clinical cardiovascular research, often in collaboration with the National Heart, Lung, and Blood Institute (NHLBI). Characterization of age-associated changes in both the structure and function of the heart and blood vessels is vital to the development of newer, more effective prevention and treatment of cardiovascular disease. Research priorities include identifying genetic and environmental risk factors for hypertension, heart disease, and stroke as well as development of subclinical measures to predict development of cardiovascular disease. Studies are ongoing to determine the causes of age-associated increases in vascular stiffness, a potential risk factor for cardiovascular disease. Other research will focus on age-related changes in the structure and function of the heart's conduction system that can increase the risk of cardiac arrhythmias, especially atrial fibrillation that if uncorrected can lead to strokes. Additional priorities include determining the reasons for gender and racial differences in the aging cardiovascular system, delineating the relationship of cardiac enlargement to aging and disease development, reducing the progression of early atherosclerotic disease, and identification and testing of new therapeutic targets for congestive heart failure.

Further, the interrelationships among cardiovascular disease, cerebrovascular disease, and age-related cognitive declines, including dementia, need to be explored. Such research will help to better understand the range of factors that may contribute to mild cognitive deficits in elders and to develop improved methods for early identification of people at risk for dementia. Additional efforts in this area will look at new approaches for treatment and prevention, such as examining combined use of treatments targeted at cardiovascular disease, cerebrovascular disease, hypertension, and AD pathology. New technological developments in cardiac, vascular, and brain imaging and monitoring will be exploited to advance understanding of these disorders and their comorbidities, in animal models, including nonhuman primates, and in humans.

Treating and Reducing the Risk of Cancer. The second leading cause of death among the elderly is cancer. People age 65 and over account for 70 percent of cancer mortality in the U.S.¹⁰ In collaboration with the National Cancer Institute (NCI), the NIA supports a research initiative to expand participation of older cancer patients in clinical trials and is expanding basic and clinical research on breast, prostate, and colon cancers. This research focuses on age-related changes that contribute to increased cancer incidence and mortality in older people, aggressive tumor behavior in the aged patient, the contributions of environmental versus hereditary factors to the risk of cancer, and the impact of previous or concurrent conditions and disabilities on the cancer experience of older patients. Specific research topics include: dose adjustment for antitumor agents and radiation therapy, diagnostic cancer imaging, the effect of coexisting diseases on cancer treatment and survival outcome, survival advantages or disadvantages of minority or ethnic populations, and underlying biological or environmental basis for cancers, such as prostate cancer, that disproportionately affect particular groups.

Type 2 Diabetes: An Age-Related Pathology. Unlike insulin-dependent diabetes, in which the pancreas makes no insulin, people with noninsulin-dependent diabetes (NIDDM) produce some insulin. However, not enough insulin is produced or the individual's cells are resistant to the insulin's action. NIDDM patients can often control their condition by weight loss through diet and exercise. Complications of diabetes are pervasive, including damage to the eyes, blood vessels, nervous system, and kidneys. A number of research lines within the NIA portfolio address issues relevant to diabetes. Work described earlier on a potential future drug treatment for type 2 diabetes, Exendin-4, is continuing. Increasing levels of physical activity and participation in exercise are often recommended for the prevention and treatment of common metabolic conditions such as obesity and insulin resistance/diabetes. NIA-funded scientists are investigating whether the metabolic benefits of exercise are mediated through body composition changes and/or occur independently of changes in body fat or leanness.

Potential Role of Caloric Restriction (CR) in Prevention of Multiple Diseases. In animal models, chronic CR has been shown to extend lifespan and delay the onset of age-related pathologies. A recent Request for Applications (RFA), has invited proposals for exploratory human studies on the effects of caloric restriction interventions on physiology, body composition, and risk factors for age-related pathologies, and encourages the use of such outcome measures as insulin sensitivity and glucose metabolism. Another current RFA is soliciting research proposals on the molecular and neural mechanisms underlying the beneficial effects of caloric restriction, and includes as a major objective investigation of the role played by reduction of blood glucose levels in the lifespan extension effects.

Enhancing Musculoskeletal Function. Osteoporosis, osteoarthritis, and age-related loss of muscle mass (or sarcopenia) contribute to frailty and injury among older people. The NIA supports several research initiatives to define the underlying mechanisms of aging in bone, muscle, and joints, and to design and evaluate effective prevention and intervention strategies for age-related musculoskeletal decline. In one area, scientists are exploring factors that may act to predispose older people to fractures. The role of exercise continues to be closely scrutinized. The physiological effects of exercise on muscle and bone are being examined, and the development of interventions to encourage older people to begin and maintain an exercise regimen is particularly important. Also, NIA participates in the NIH Federal Working Group on Bone Diseases, convened quarterly to provide opportunities for sharing information, identifying collaborative projects and carrying out specific joint activities such as conferences and research initiatives. In collaboration with the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), NIA will continue to evaluate future opportunities, currently encouraging researchers studying Paget's disease and osteogenesis imperfecta to focus on the effects of aging in patients with these conditions.

7. National Center for Health Statistics. Health, United States, 1999 With Health and Aging Chartbook. Figure 11, pg. 41. Hyattsville, MD: 1999.
8. Burt VL, Whelton P, Roccella EJ, et al. Prevalence of hypertension in the US adult population: results from the Third National Health and Nutrition Examination Survey, 1988-1991. Hypertension 25: 305-313, 1995.
9. Burt VL, Cutler JA, Higgins M, et al. Trends in the prevalence, awareness, treatment, and control of hypertension in the adult US population: data from the health examination surveys, 1960 to 1991. Hypertension 26: 60-69, 1995.
10. National Center for Health Statistics. Health, United States. 1999 With Health and Aging Chartbook. Table 33, pg. 156. Hyattsville, MD: 1999.