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Selected Future Research Directions

Preventing Alzheimer’s Disease: The AD Prevention Initiative. NIA is accelerating efforts to develop novel compounds for treating the cognitive impairment and behavioral symptoms associated with AD. Leads for promising strategies are being identified through a focused effort to understand and predict the initial stages and events in the brain that lead over several decades to AD development. Research has brought science closer to the threshold of discovering effective agents that retard deposition of brain plaques in animal models. As leads are identified and developed in the test tube and in experimental animals, the new findings will be will be translated into clinical interventions. The translation process will involve testing of drugs that target crucial pathways as well as incorporation of efficient processes for channeling drugs of interest into appropriately designed clinical trials. Plans for clinical trials will increasingly emphasize AD prevention, including trials in persons with normal cognition. The first NIH prevention trial for AD, comparing the effects of vitamin E and Aricept, was recently begun at more than 70 sites in persons diagnosed with mild cognitive impairment. The goal of this trial is to prevent the development of AD symptoms in these individuals, who are at high risk for developing AD. Upcoming trials will examine the effectiveness of ibuprofen (an anti-inflammatory drug) in reducing the risk of AD, the effect of estrogen replacement therapy in preventing AD in women with a family history of the disease, and whether treatment with a variety of agents, such as aspirin, vitamin E, antioxidants, or combined folate/B6/B12 supplementation can prevent older women from developing AD. Several approaches will be initiated to increase the efficiency and cost-effectiveness of developing new and novel approaches to AD drug discovery, development, and testing. Future initiatives will also develop more effective methods to treat and manage behavioral symptoms in persons who have AD and to significantly reduce caregiver burdens. Studies will be launched to develop and test new ways of managing the daily activities and stresses of caring for people with AD as well as to help prevent hospitalizations, delay nursing home admission, and prevent caregiver burden.

Combating Health Disparities in AD and Other Neurodegenerative Diseases. It is estimated that the percentage of racial minorities and Hispanics in the population of Americans over the age of 85 will increase from 13% in the year 2000 to more than 30% in 2050.8 It is thus increasingly urgent to identify genetic and nongenetic risk and protective factors for AD and other neurodegenerative diseases of aging in racially and ethnically diverse populations. These risk factors could vary with race, ethnicity, gender and socioeconomic status. Studies of the relative risk of AD for African Americans and Hispanics compared to other ethnic groups have yielded inconsistent findings, indicating the need for further research in this area. Differences in AD risk may exist among ethnic groups in prevalence and incidence rates and in the relative importance of particular genetic and nongenetic risk factors. For example, the increased risk for developing AD conferred by carrying one ApoE4 allele is greatest for Japanese, intermediate in Caucasians, but is not evident in African Americans. The NIA is stimulating research to assess and compare prevalence and incidence rates among different ethnic subgroups, using culturally appropriate instruments; to determine the importance of particular genetic risk and protective factors as well as potential nongenetic risk factors, including comorbid conditions such as cardiovascular and cerebrovascular disease; to determine the risk of developing AD after an initial diagnosis of mild cognitive impairment; and to identify lifestyle differences conferring risk or protection, factors such as early development, diet and education.

Maintaining a Healthy Brain. Neurons atrophy and degenerate throughout life in response to many influences during "normal" development as well as from emotional stress and other pathological processes. Disturbances of cognition and emotion afflict millions of people at every stage of the lifespan. Yet we should not accept nervous system decline, any more than we would now accept deteriorating cardiovascular health, as the inevitable consequence of disease or of normal aging. We must learn how to prevent or reverse the loss of brain function through early detection and intervention. The Healthy Brain Initiative will develop plans for intervention to improve cognitive and emotional health of the American public. The NIA, National Institute of Mental Health, and National Institute of Neurological Disorder and Stroke will organize the initial phase of the study, with other interested NIH institutes or centers invited to participate.

Reducing Health Disparities. Although an array of factors has been associated with health disparities—including race, ethnicity, gender, socioeconomic status, age, education, and occupation—an intense research effort is needed to identify the causes of these differences. Recent research has found that modification of the Mini-Mental State Examination test by controlling for education and gender resulted in the elimination of significant differences in imputed mental impairment between older Hispanics and non-Hispanic whites. In addition, certain chronic diseases, such as diabetes, hypertension, stroke, and cardiovascular disease, tend to be more prevalent in several racial and ethnic groups. New NIA studies will focus on the influence on aging health of early and midlife health, nutrition, education, and health care. Research will also expand understanding of how to prevent or lessen the effects of disease by designing more culturally appropriate interventions and modes of health information dissemination and by discovering means to enhance healthy behaviors in older racial and ethnic populations.

Assessing the Impact of Aging on Cardiovascular Disease. 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. 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 identifying 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 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, and reducing the progression of early atherosclerotic disease.

Treating and Reducing the Risk of 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.9 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 antitumor 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.

Enhancing Musculoskeletal Function. Osteoporosis, osteoarthritis, and age-related loss of muscle mass (or sarcopenia) contribute to frailty and injury in millions of older people. The NIA supports several initiatives to unravel 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. For example, factors are being explored to define the influences that can predispose older people to fractures and to develop effective prevention and intervention strategies for age-related musculoskeletal decline. The NIA is collaborating with the NIAMS to expedite the development and evaluation of novel therapies for osteoarthritis. The initiative is designed to stimulate innovative strategies to evaluate the process of joint destruction and to accelerate findings in bone and cartilage turnover and genetics related to osteoarthritis.

Evaluating Hormone Replacement Therapy and Dietary Supplements. Counteracting the effects of aging by supplementing hormones—such as estrogen, testosterone, human growth hormone, melatonin, and DHEA (dehydroepiandrosterone)—is an area of active study, but there are concerns that individuals may be taking such agents before their safety and efficacy have been fully assessed. Although levels of some of these hormones may decline, on average, as people age, maintaining levels that are normal at younger ages may not be needed, or even desirable, as a person grows older. Even if effective, supplementation may entail risks. More research is needed to determine how the biologic action of these hormones changes in older people and to assess whether replacement of these hormones will improve health. Based on recent results, planning has begun for a trial to test the impact of testosterone replacement in older men with low testosterone on the incidence of fractures and other potentially important outcomes, such as serum lipids, cardiovascular events, and potential adverse effects on the prostate. Also needed are alternative approaches to realize the benefits of estrogen, testosterone, and other hormonal therapies while minimizing risks and undesirable side-effects. Two principal strategies being pursued. One involves synthesizing compounds that produce the beneficial responses of hormones in the body without detrimental side effects. The other would increase or decrease hormone production in specific body tissues to achieve levels favorable to health. When successful, these innovative approaches will, for example, enable men and women to benefit from the properties of estrogen without estrogen’s unwanted side effects. Related research is underway on the ability of antioxidants such as vitamins C and E to prevent cancer, delay aging, or keep cognition intact. Antioxidants are found in common foods and act as scavengers for oxygen radicals, molecules generated when cells produce energy, that can cause long-term harm and degradation to the body. NIA research will address the special dietary and nutrient needs of elderly persons, especially nutrients capable of delaying or mitigating the degenerative diseases that often accompany aging.

Understanding the Disability Decline and Its Implications. Recent findings have revealed dramatic and unexpected reductions in rates of disability among older persons compared to projected levels. Studies have shown that disability levels for people age 65 and older have been falling at an accelerating pace since 1982, and that the benefits of this trend extend both to men and women and to minority groups. This decline contributes to improved functional ability for individuals and could have important economic and social implications. Continuing the current pace of disability decline over the next 50 years could prevent increases in the number of disabled Americans that will otherwise occur in the face of the demographic challenge posed by the baby boom and overall population aging. In order to sustain continued decreases in disability, it will be critical to identify the underlying causes of the disability decline. Studies have identified social, educational, public health, and biomedical variables that affect rates of disability. Further research will define trends likely to extend the disability decline, such as improvements in health-related behaviors, the increasing education levels of older people, improvements in the availability and effectiveness of assistive devices, disease prevention, and improvements in the treatments of conditions that lead to disability. Based on the explanatory factors identified in this study, additional research will consider the specific interventions, behavioral changes, and survival attributes that could most effectively enhance the disability decline. Efforts will also be made to improve projections of disease and disability rates and to clarify the implications of the disability decline for changes in family demography and medical care costs.

Understanding the Genetic Basis of Aging, Longevity, Age-Related Diseases, and Behavior. Interactions between genetic and environmental factors are major determinants of aging and longevity in a many species, including humans. NIA studies have begun to reveal the biologic factors associated with extended longevity in humans and animal models, implicating numerous genes in normal aging processes, age-related pathologies and diseases, and longevity. Some of these genes are associated with dramatic extension of lifespan. Using advanced technology, the NIA plans to accelerate its efforts to discover additional age- and longevity-related genes and to characterize their biological function. A new initiative will extend studies of longevity-associated genes, changes in gene expression patterns, and the genetic epidemiology of human longevity. The ultimate goal of this effort is to develop interventions to reduce or delay age-related degenerative processes in humans. In addition, revolutionary advances in the fields of quantitative and molecular genetics hold great promise in the search for the genetic determinants of complex behaviors. Studies in humans can help identify the relative contributions of environment and heritability to dementia, cognitive abilities, physical functioning, well-being, and social aging. New techniques can track the developmental course of genetic contributions to behavior, identify genetic heterogeneity, and explore genetic links between the normal and abnormal.

Understanding the Effect of Caloric Restriction on Aging. Caloric restriction (CR) has long been known to extend lifespan markedly in rodents and other laboratory animals studied and to delay in these species the onset of numerous age-related diseases common in humans. Over the last two decades, CR has also been shown to delay a wide variety of aging-related changes, including specific cellular and molecular alterations. Most recently, researchers have identified changes in physiologic function in calorically restricted rhesus monkeys that suggest delays in aging-related decline in these primates. These results could have important implications for human intervention programs. Animal studies are now planned to determine the effects on aging of interventions that mimic metabolic effects of CR. Also being considered are preliminary human intervention studies designed to determine whether CR and physical activity differ in their long-term effects on obesity, body composition, prevention and susceptibility to age-related diseases.

Exploring the Potential of Stem Cells and Cell Replacement in Aging. Stem cells in human tissues retain the capacity for self-renewal and the potential to become many of the cell types in the human body. This capacity holds enormous potential for cell replacement or tissue repair therapy in many degenerative diseases of aging, including Alzheimer’s disease, Parkinson’s disease, stroke, myocardial infarction, musculoskeletal disorders, immune system dysfunction, and diabetes. Research is needed to explore the role of stem cells in repairing tissue damage and recovering organ function as organisms age. Emerging research findings suggest that it may be possible to harness the multipotential nature of stem cells to maintain tissue structure and function in aging. Much remains to be learned, however, about the basic biology of stem cells before effective cell therapy can be realized. The NIA is developing an initiative on stem cells in aging that will complement as well as encourage collaboration in activities of other NIH components.

Monitoring Health Through Demography. As the world’s older population grows, demographic research enables us to monitor the impact of population aging on the global burden of chronic disease and disability. This knowledge enables us to identify health and economic trends and to recognize opportunities for research on their causes and impact. NIA will collaborate with other NIH institutes in studying the changes in health and functional status over time of disabled and chronically ill older people. Research is being developed to improve data on burdens and costs of diseases. In response to advances suggesting that disability rates of older Americans are declining, researchers are developing studies to identify and quantify the specific underlying causes contributing to the decline, as well as to design interventions. Demographic research is also planned to track the dynamics underlying the increase in old-age life expectancy in the U.S. and to define the implications of changes in health, disability, and life expectancy for national policies on retirement and on programs for the elderly. A special focus is being developed to provide the necessary data for understanding the large variations in health across racial and ethnic populations.

Preventing Medication Misuse in Aging Populations. Older people are especially vulnerable to medication-related problems, not only because of the large numbers of medications taken for multiple health problems, but also because of both physiological and functional changes with aging. With an increased number of new drugs in development to combat the diseases and chronic conditions associated with aging, there are many more opportunities for medication misuse resulting either from patient noncompliance with medical regimens or physician prescribing errors. The NIA is planning new studies as part of a multifaceted research agenda for understanding and alleviating medication problems in older populations. Reducing these medication problems will help enhance the health and quality of older people and also save unnecessary health care expenditures.

Gathering Data on Elder Abuse and Neglect. The Institute of Medicine (IOM) reported that there was a "paucity of research" on elder abuse and neglect. A recent NIA-supported study showed that, compared to nonabused elders, victims of abuse have three times higher mortality from all causes, and those identified as self-neglected have almost twice the mortality. Supporting the need for systematic study of elder abuse and neglect are the lack of reliable, probability-based national prevalence estimates of elder abuse; the growing numbers of older people; the increasing public awareness of the problem; legal requirements for reporting; recent advances in techniques to elicit both the reporting and estimation of socially stigmatized behaviors; and the availability of interventions that facilitate prevention and treatment programs. The NIA is developing plans to mount a study on elder abuse in collaboration with the National Academy of Science and relevant federal agencies. This initiative will employ racially and ethnically sensitive measurement techniques for elder abuse and neglect that are applicable to people of both genders and of all socioeconomic statuses.

Providing the Science Base for Caregiving Policies and Programs. Caregiving and long-term care are becoming major national policy issues. In 1997, at least one family member in each of more than 22 million households in the U.S. was providing some form of unpaid caregiving. Caregiving often is burdensome and stressful, and can lead to major emotional trauma or illness for the caregiver. While the number of older persons is expected to increase rapidly, demographic changes in families (more childless, one-child, and step-families) and increasing participation of women in the work force suggest a likely decrease in provision of informal care for aging baby boomers. Studies using new data sources are being planned to provide the information we need to carefully examine caregiving needs, patterns of family caregiving, decisionmaking on providing care, and costs of care. For example, the 1999 National Long-term Care Survey caregiver supplement will provide new trend data on caregivers’ health and functional status, the types and amounts of care delivered, the implications of new family roles and relationships, and the links between family and formal care. New community surveys, such as the Washington University Black Rural and Urban Caregiver Study, will promote research on how race, ethnicity, and socioeconomic status affect caregiving needs and related issues. Initiatives will also examine the effectiveness of various interventions aimed at reducing Alzheimer’s disease care burdens, such as skills training and environmental modifications, with special attention to caregiving in minority populations.

Developing and Distributing Research Resources. Physical resources—such as animal models, chemicals, tools, and other technologies--play a critical role in research. The NIA develops and distributes these high quality resources to investigators efficiently and at reduced cost. These resources include:

  • Central aging colonies of animal models, including genetically altered animals, necessary for research on aging processes and specific age-related diseases
  • Cell cultures and tissue, cell, and blood banks for basic and epidemiologic research
  • DNA resources for genetics
  • Imaging technologies for exploring the body, from the interior of the cell to organ systems
  • Bioinformatics technologies to record and analyze findings on basic biological research

The NIA will continue to identify and evaluate opportunities for providing research resources and infrastructure development using the advice of extramural and intramural researchers. The NIA is also evolving information technologies to assure broad access to archived data vital to researchers and policymakers and to ensure protection of anonymity and confidentiality of participants in clinical studies. In conjunction with other NIH institutes, the NIA will support research on new mathematical and informatics methodologies and on improved instrumentation and computational techniques for modeling systems changes in aging.

  1. Day, JC, Population Projections of the United States by Age, Sex, Race, and Hispanic Origin: 1995 - 2050, U.S. Bureau of the Census, Current Population Reports, P25-1130, U.S. Government Printing Office, Washington, DC 1996.
  2. National Center for Health Statistics. Health, United States. 1999 With Health and Aging Chartbook. Table 33, pg. 156. Hyattsville, MD: 1999.