Subgoal 1: Prevent or Reduce Age-Related Diseases, Disorders, and Disability

Remarkable progress is being made through basic, clinical, and epidemiologic research toward developing innovative, safe, and effective approaches to prevention and therapy for the population over age 65. These studies seek to improve vaccine and drug development, lessen the disabling effects of disease, delay onset or progression of disease, and enhance pain management.

Aging research targets diseases and conditions that contribute significantly to mortality or disability in old age. A major focus of NIA research is Alzheimer's disease, a devastating neurodegenerative disease that robs people of memory and other intellectual abilities, leading to loss of social and occupational function and ultimately to complete dependence on others. Additional important causes of disease and disability include cardiovascular disease and cancer, the two leading causes of death in older people; bone, muscle, and joint disorders such as osteoporosis and osteoarthritis that contribute to pain and loss of mobility; vision, hearing, and other sensory disorders that can isolate older people; and numerous other age-related conditions, such as diabetes and incontinence, that deprive individuals of their independence.

To reduce the burden of illness and disability in older people, researchers in aging are capitalizing on new findings to:

1. Accelerate discovery of causes and risk factors, and improve early detection and diagnosis of disabling illnesses.
   
   Genes associated with aging processes, longevity, and age-related diseases are providing insight into disease pathologies and individuals' vulnerability to disease. Defining the underlying changes in biologic functions controlled by the genes can lead to possible targets for treatment, and may help in early detection and diagnosis of disease. These findings are derived in part from studies of populations or families known to be at high risk for a disease. Population studies also uncover other potential risk factors, such as environmental exposures across the life span, health behaviors, and the influence of coexisting conditions on the progression of a disease. In addition, remarkable progress is being made through advances in imaging technology, a non-invasive means of observing the body's biological activity. For example, these techniques can provide images of nerve cells as they commu-nicate, can accurately measure cerebral blood flow, and can gauge the production of particular gene products. Plans are being developed to improve the resolution of this technology to assist in early detection and diagnosis.
    
2. Discover new treatment and prevention strategies.
   
   New information on the underlying causes of and risk factors for diseases and disabilities are helping researchers develop interventions to delay onset, slow progression, and reduce the severity of disease and disability. Insights have emerged from studies on alterations in genes or gene products, effects of hormones or other factors external to the cell, and changes in how the body coordinates and integrates its complex activities. These studies have produced promising targets to prevent death or inappropriate proliferation of cells and to reduce inflammation and damage to tissues. Researchers are actively translating new knowledge on genetics, biochemistry, and physiology to develop new preventive strategies and medications. Studies are being considered for tissue repair and cell replacement using stem cells, immature cells that can differentiate into specialized cells to replace those lost due to normal cell turnover or injury. Clinical trials are needed to identify more effective strategies for rehabilitation to improve function and quality of life and to overcome barriers to optimum function. Behavioral and social science findings are also being applied to develop strategies that promote health and prevent disease.
    
3. Improve health behaviors and medication use.
   
   Exercise, proper diet, and other healthy behaviors can help prevent and reduce symptoms of disease. These benefits often rely on an individual's willingness to make and sustain changes in lifestyle. Researchers are exploring strategies that can help motivate elders to adopt changes that promote health and adherence to medical recommendations.
   
   Managing medications can be complex for older people, who may take several drugs for multiple health problems. Complications may occur because of interactions between two drugs or between a drug and dietary supplements, or because of physiological and functional changes associated with aging or age-related diseases. Planned research will provide new knowledge about medications to maximize their effectiveness and will develop new technical aids to assist physicians in monitoring drug use. New technologies and information will enable patients to better manage drugs and avoid adverse reactions.
    
4. Launch clinical studies to improve health and reduce burden of disease.
   
   New clinical studies are being developed to improve treatment of Alzheimer's disease, cardiovascular disease, cancer, osteoporosis, and diabetes, and to test the effects of hormone replacement, dietary supplementation, and exercise and fitness. As pathways and processes of disease are defined, basic research findings can be translated expeditiously to clinical applications. These studies will test new drugs and compounds, strategies for improving physical and mental fitness, or approaches for preventing falls and other injuries. Several novel approaches are being applied to make these studies as efficient and cost-effective as possible. Every effort is being made to ensure participation of diverse populations. In addition to efforts to prevent disability among healthy older persons, studies will also focus on reducing disability and/or preventing or slowing additional decline among persons with disability as they continue to age.
    
5. Strengthen infrastructure and resources required for clinical trials and other clinical studies.
   
   Until recently, elders have been markedly under-represented in clinical trials-even in some of the disorders most prevalent in older men and women. An invigorated program of clinical studies in older people is designed to produce:
    
   • Innovative changes in the design, planning, and implementation of clinical trials. For example, a special effort will be made through the Alzheimer's Disease Prevention Initiative, which will be discussed later in this section.
   • New drug testing facilities and resources, such as an intramural Interventional Trials Unit to translate laboratory research findings to human findings in several age-related diseases and in immunology and endocrinology.
   • An expanded collaboration with the Veterans Administration Cooperative Studies Program to study osteoporosis and hormone replacement therapy in older men, nutritional interventions in vulnerable geriatric populations, multi-factorial interventions to prevent fall-related fractures, and other topics.
   • New efforts with the National Cancer Institute to improve cancer therapy in older people, including the effects of aging and co-existing conditions on responses to and side effects of surgery, chemotherapy, and radiation therapy.

Research on Selected Geriatric Diseases, Disorders, and Conditions

To achieve these objectives, the NIA has developed specific initiatives in several geriatric diseases, disorders, and conditions, including:

• Alzheimer's disease and other degenerative diseases of the nervous system, and age-related changes in memory
• Major geriatric concerns, including weakness and falls, delirium, urinary incontinence, sleep disturbances, depression, and comorbidities
• Cardiovascular disease
• Cancer
• Diabetes
• Bone, muscle, skin, joint and movement disorders
• Vision, hearing, and other sensory disorders
• Benign prostatic hyperplasia
• Infectious diseases

Alzheimer's Disease

The NIA is the lead federal agency for studying Alzheimer's disease (AD). As many as four million Americans suffer from AD, the most common form of dementia. This brain disorder gradually progresses from mild memory loss to disturbing changes in behavior and personality, decline in the ability to think or recognize people, and profound memory loss. Gradually and inexorably, AD consumes and destroys normal brain function. Patients eventually are unable to care for themselves and sometimes are agitated to the point of causing harm to themselves or others. Both patients and the millions of family members and other loved ones who care for them are devastated by AD. These profound losses are related to abnormal changes in the brain that begin many years before memory loss or other clinical symptoms become apparent. Major breakthroughs in genetic, molecular, and epidemiologic research are rapidly expanding our understanding of these pathologic changes. Researchers are precisely characterizing the regions of the brain, such as the hippocampus, that are involved in memory and other cognitive abilities. In AD, brain cells in these regions die in unusual numbers. Efforts are being made to inhibit loss of neurons, for example, by increasing protective growth factors in the brain. Communication among brain cells in AD patients begins to break down as synapses, the communication points between neurons, are lost. Scientists are exploring ways to prevent this loss. Investigators are also tracking the formation and potential interaction between the two major lesions-amyloid plaques and neurofibrillary tangles-that proliferate in the brains of Alzheimer's patients, with the aim of finding ways to stop their formation, reduce their numbers, and minimize deleterious downstream effects.

Remarkable progress has been made toward a more complete understanding of the agents that damage cells and the subtle changes in cellular function that can trigger cell death in the brain. AD can also interact with other diseases, such as cardiovascular disease and stroke, to make symptoms worse. These findings suggest targets for new diagnostic, preventive, and therapeutic strategies for AD. In addition, these advances will certainly lead to insights about other diseases in which nerve cells die, including Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis and non-AD dementias.

Alzheimer's Disease Prevention Initiative

The Alzheimer's Disease Prevention Initiative strives to prevent AD and to slow disease progression once it is diagnosed. This initiative will intensify collaborative efforts to conquer AD between NIA and other NIH institutes, several government agencies, organizations such as the Alzheimer's Association, pharmaceutical companies, and private foundations. Goals are to:

• Accelerate discovery of new risk and protective factors, and identify promising targets for preventing disease through basic research.
  
  Potential targets for slowing or stopping the course of AD have multiplied as knowledge of the causes and early predictors of the disease increase. Several genes have been discovered that can cause AD and other dementias in certain families that develop these diseases in early to middle age. Progress in understanding the function of these genes has led to a surge in knowledge about the development of AD pathology, including proliferation of senile plaques and neurofibrillary tangles, and has stimulated efforts to block or even reverse the progression of these pathologies.
  
  Investigators are now better able to detect persons at high risk for developing AD. Powerful genetic tools have helped reveal genes, such as APOE e4, that influence susceptibility and disease progression in late-onset AD. These discoveries not only improve ability to identify persons who have a greater chance of developing AD, before the disease causes damage to the brain, but also lead to new avenues of drug development as the basic mechanisms underlying disease progression are revealed.
  
  Developments in brain imaging and in cognitive testing are enabling researchers to identify people at ever earlier stages of the disease and to characterize brain and behavioral changes that precede clinically diagnosed dementia. For example, a brain imaging study of the size of the hippocampus in older individuals with mild cognitive impairment (a memory deficit beyond that expected for age and education) found that the smaller the hippocampus at the beginning of the study the greater the risk of later conversion to AD. These diagnostic advances will open new opportunities for early interventions to prevent brain changes before clinical deterioration occurs. Research is also producing a number of candidates for diagnostic markers; appropriate markers would enable physicians to accurately distinguish AD from other dementing illnesses as well as from age-related loss of function.
  
  Molecular and epidemiologic research has made progress in identifying possible new targets for drug therapy. These targets include inflammation and toxic oxidative agents known as free radicals. Another possible problem that could be corrected is loss of protective factors, such as estrogen or natural growth factors.
   
• Speed drug discovery and movement of promising new treatments and prevention strategies into clinical trials.
  
  To invigorate drug development, novel proposals are being solicited to target crucial pathways involved in the development of AD. Research has led to the threshold of discovery of effective agents targeting AD pathology. For example, researchers have succeeded in developing agents that retard deposition of brain plaques in animal models. Another promising research area is development of estrogen-like compounds that retain estrogen's beneficial effects on the brain while minimizing its negative effects on other organs. Yet another is development of molecular compounds that prevent brain cells from dying or stimulate the generation of new brain cells. Ultimately, as a long-term goal, methods may be developed to introduce cells into the brain that could either protect brain cells from AD damage or even replace dysfunctional cells.
   
• Launch clinical trials to prevent AD.
  
  Unlike trials that focused on reducing symptoms and slowing the progress of AD, many future trials will emphasize prevention of the disease. Advances in basic research and drug development are likely to include more effective anti-inflammatory compounds and anti-oxidants, agents to prevent cell death, and substances designed to stop the deposition of plaques and tangles in the brain. Such progress will enable more effective intervention at earlier stages in pathogenesis. The first NIH prevention trial, comparing the effects of vitamin E and Aricept was recently initiated at more than 70 sites in persons diagnosed with mild cognitive impairment but not clinical AD. Aricept helps prevent the degradation of acetylcholine, a brain cell communication chemical important for attention and memory. Vitamin E is thought to have antioxidant properties that counteract damage from molecules called oxygen free radicals. The goal is to stop the development of AD symptoms in these individuals, who are at high risk of developing AD. Other trials involve estrogen; non-steroidal anti-inflammatory drugs; cerebrovascular interventions; and a folate, vitamin B6, and vitamin B12 combination. Efforts are also being made to develop sensitive tests and techniques that can quickly and accurately track a drug's effectiveness in slowing or arresting brain changes that precede or accompany the progression of AD. Over the next several years, not only will trials be conducted among persons with mild cognitive impairment, but also in persons with completely normal cognition in order to prevent AD prior to emergence of any symptoms.
   
• Expand strategies for improving patient care and alleviating caregiver burdens.
  
  There is a critical need to develop more effective methods to treat and manage behavioral symptoms in persons who have AD and to significantly reduce caregiver burdens. Focused initiatives will develop and test new ways of managing the daily activities and stresses of caring for people with AD, with focus on behavioral symptoms most distressing to AD patients and their families: wandering, aggression, agitation, sleep problems, and incontinence. Clinical studies of behavior management strategies, both pharmaceutical and behavioral, also will be launched. Successful treatment of AD will help prevent hospitalizations, decrease unscheduled visits to care providers, delay nursing home admission, avoid preventable illnesses unrelated to AD, and prevent caregiver burnout.

Major Geriatric Concerns

A number of conditions compromise independence and quality of life in older persons. These conditions result in increased suffering, service utilization, and health related costs. Research will be expanded to address the following geriatric concerns:

• Weakness and falls result in approximately 1.5 million fractures each year, including debilitating fractures of the hip and spine. Muscle weakness, bone loss, dizziness, and impaired mobility contribute to falls and other injuries. New strategies are needed to reduce the risk of falls through health promotion and patient education, safety measures, environmental modifications, and improved therapies.
• Delirium, also known as acute confusional state, is a serious and preventable cause of suffering and service use among elderly people. A recent study showed that hospitals may be able to reduce the number and duration of episodes of delirium in at-risk older patients by addressing specific risk factors. Research is aimed at preventing delirium by understanding and reducing these risk factors-which include cognitive impairment, sleep deprivation, medication error, immobility, visual and hearing impairment, and dehydration.
• Urinary incontinence (UI), a significant medical problem with physical and psychosocial ramifications, affects up to one-third of women over age 65. Studies have shown that medications, surgery, and behavioral approaches can be effective in treating some women with UI. The need remains for additional research on the underlying causes of UI, on development of new, safe treatment methods, and on educating elders and health professionals about the condition.
• Studies suggest that sleep disturbances afflict a majority of the older population in the U.S., contributing to personal discomfort and illness and caregiver burden. Contrary to a commonly held belief, however, chronic insomnia, which occurs in about a third of our elderly population, is not a normal consequence of aging. To reduce the burden of sleep disturbances, scientists are studying the mechanisms underlying sleep-wakefulness cycles, normal and abnormal biorhythmicity of the aging nervous system, and the effects of concurrent disease states on sleep. Planned research should contribute to developing new and more effective therapeutic methods that will correct the underlying pathology of sleep disorders to improve quality and duration of sleep in older persons.
• Serious depression is an important public health problem in older people that may occur along with other common medical conditions. Often overlooked or misdiagnosed, clinical depression can affect cognition and exacerbate physical, mental, and emotional problems. In collaboration with the National Institute of Mental Health, research will continue to refine and develop diagnostic screening tests for depression in older adults, and to develop more effective medications with fewer side effects.
• Comorbidities and their influence on function, health and treatment must be better understood. The risk of multiple diagnoses increases with advancing age, leading to concerns regarding interactions among diseases, interactions between a drug given for one disease and a co-existing disease or condition, and drug-drug interactions as diseases are treated. Efforts are also underway to improve strategies for including in clinical trials persons with comorbidities so that the effects are better understood for the types of drugs most likely to be prescribed for the elderly.

Cardiovascular Disease

Diseases of the heart and blood vessels are the leading cause of hospitalization and death in older Americans. Congestive heart failure is the most common diagnosis in hospitalized patients aged 65 and older. The NIA is pursuing a broad program of basic and clinical cardiovascular research, often in collaboration with the National Heart, Lung, and Blood Institute. Recent findings have demonstrated the effectiveness of both pharmacologic and lifestyle approaches in reducing hypertension and preventing heart disease and stroke. 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 treatment and prevention interventions. Research priorities include genetic and environmental risk factors for hypertension, heart disease, and stroke. 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; if uncorrected, this condition 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, and reducing the progression of early atherosclerotic disease.

Cancer

The second leading cause of death among the elderly is cancer, with individuals age 65 and over accounting for 70 percent of cancer mortality in the U.S. In collaboration with the National Cancer Institute (NCI), the NIA is expanding basic and clinical research on breast, prostate, and colon cancers, common in older people, and launching a new initiative to expand participation of older cancer patients in clinical trials. This research focuses on age-related changes that contribute to increased cancer incidence and mortality in older persons, aggressive tumor behavior in the aged patient, and the impact of previous or concurrent conditions and disabilities on the cancer experience of older patients. Specific research topics include: dose adjustment for anti-tumor agents and radiation therapy, diagnostic cancer imaging, how coexisting diseases affect cancer treatment and survival outcome, and survival advantages or disadvantages of minority or ethnic populations.

Diabetes

Type 2 diabetes, which results from insulin resistance and abnormal insulin action, is most prevalent in the older population. Diabetes complications, such as heart disease and loss of sight, increase dramatically when blood sugar is poorly controlled and often develop before diabetes is diagnosed. Working with the National Institute of Diabetes and Digestive and Kidney Diseases, the NIA is exploring strategies to prevent type 2 diabetes and to expand knowledge on usual age-related increases in insulin resistance and glucose tolerance. Studies are also focusing on how changes caused by type 2 diabetes affect responses to treatment and prevention strategies in older persons. Other studies will develop critical resources to study genetic susceptibility and gene/environment interaction in type 2 diabetes.

Bone, Muscle, Skin, Joint and Movement Disorders

Osteoporosis (loss of mass and quality of bones), osteoarthritis (inflammation and deterioration of joints), and sarcopenia (age-related loss of skeletal muscle mass and strength) contribute to frailty and injury in millions of older people. Several initiatives, some in collaboration with the National Institute of Arthritis and Musculoskeletal and Skin Diseases, are unraveling the underlying mechanisms of aging in bone, muscle, skin, and joints with the goal of conserving or enhancing their function and preventing pathologies. For example, factors are being explored to define the influences that can predispose older people to fractures and develop effective prevention and intervention strategies for age-related musculoskeletal decline. Also contributing to loss of mobility and independence are changes in the central nervous system that control movement. Cells may die or become dysfunctional with age, as in Parkinson's disease. Older people therefore may have difficulty with gross motor behavior, such as moving around in the environment, or with fine motor skills, such as writing. Research is being conducted to understand the underlying age-related changes that occur in the motor control areas of the brain with the aim of developing therapeutic interventions. One such approach, deep brain stimulation, is being pursued as a collaborative effort with the National Institute of Neurological Disorders and Stroke.

Vision, Hearing, and Other Sensory Disorders

Age-associated changes in sensory function, including vision, hearing, taste, smell, proprioception, and vestibular function, can lead to significant loss in function, as well as decrease the quality of life for many older persons. In collaboration with the National Institute of Deafness and Other Communication Disorders, and the National Eye Institute, progress is being made in discovering risk factors for age-related hearing loss and vision decline. Increased emphasis is being given to research on multiple sensory deficits in older people, which increases their risk for mortality and loss of independence. Ongoing research is redesigning products and developing new technologies for older people to make reading easier and more understandable, enhance hearing and other sensory abilities, and otherwise contribute to functional independence. Age-related declines in taste and smell may have an impact on both the enjoyment and nutritional choices of the elderly. Studies on flavor enhancement are aimed at maintaining healthful eating habits, especially in sick and otherwise debilitated elderly. Understanding the mechanisms involved in decreased sensory function is also expected to lead to interventions to maintain optimal function into the later years.

Benign Prostatic Hyperplasia

It is common for the prostate gland, part of the male reproductive system, to enlarge with age. More than half of men in their 60s and as many as 90 percent in their 70s and 80s have some symptoms of this condition, known as benign prostatic hyperplasia or BPH. Symptoms stem from obstruction of the urethra (the canal through which urine passes out of the body) by the adjacent prostate gland. Severe BPH can lead to urinary tract infections, bladder or kidney damage, bladder stones, and incontinence. Although some researchers believe that factors related to aging may spur development of BPH, the cause is not well understood. The NIA stimulates research on the causes of the high incidence of prostate growth in older men and on issues related to treatment and potential regimens to minimize prostate growth.

Infectious Diseases

The mechanisms that underlie the decline of immune function often accompany advancing age, leaving older people more vulnerable to conditions such as influenza and pneumonia. Success in understanding changes with age in immune competence and the underlying mechanisms of these changes have broad implications for vaccine development and reduction in infectious illness, which often leads to hospitalization and death in older people. An emerging research focus involves prevention of HIV/AIDS in older people, a growing health problem. NIA research on these issues is coordinated with the National Institute of Allergy and Infectious Diseases and the NIH Office of AIDS Research.