Research Goal A: Improve our understanding of healthy aging and disease and disability among older adults.

Aging comprises a set of dynamic biological, physiological, and psychosocial processes and systems—interactive and independent—that result in wide variations among individuals. Adult aging often involves common changes that may not be harmful such as graying hair. For many, however, aging also means a progressive and inexorable loss of function leading to increased vulnerability to disease, frailty, and disability. Many hypotheses and theories to explain this decline have been offered through the years, but none by itself can explain the array of physical, biological, and psychological changes that take place as people age.

NIA-supported researchers are beginning to define the link between genes and lifespan. For example, numerous genes have been implicated in normal aging processes, in age-related pathologies and diseases, and in the longevity of several species including humans. Researchers are also identifying the interactions among genes; the environment; and lifestyle, behavioral, and social factors and their influence on the initiation and progression of some diseases. Further research is needed to determine the roles and interaction of these diverse factors in aging.

One of our challenges in this research is to develop a clearer understanding of the normal changes that accompany aging and distinguish them from the diseases and disabilities that are prevalent among older adults. A common thread, for example, is the process of inflammation, which leads over time to changes in cell, tissue, and organ structure and function. Inflammation may increase the susceptibility to and rate of progression of age-related pathologies and may contribute to frailty, independent of overt disease. This and other risk or protective processes that may occur at various stages, from early life on, may influence health and survival outcomes in old age. Many older people also suffer from anemia, thrombosis, involuntary weight loss, dizziness, sensory deficits such as hearing or vision loss, dementia, frailty, or incontinence. Research into the underlying causes of these and other geriatric syndromes is needed in order to develop new prevention strategies and treatment approaches.

NIA-supported research is also helping to identify lifestyle factors and health behaviors that directly influence physical, cognitive, and emotional fitness and risk of disease. Scientists are developing and refining recommendations for people of all ages regarding optimal diet, use of dietary supplements, mental stimulation, physical exercise, quality sleep, and other healthy practices to increase their likelihood of enjoying healthy old age. Still other researchers are looking for better ways to enhance the physical, mental, and interpersonal abilities of older people and to expand opportunities for them to achieve personal goals and contribute to society in meaningful ways. As we identify more precisely these behaviors and lifestyles that influence health and quality of life, we will be able to reinforce prevention efforts, enhance symptom management, conserve function, and improve caregiving.

To more fully understand aging processes and their relationship to disease and disability among older people, NIA will:

A-1 Support studies on healthy aging, well-being, and longevity.
A-2 Accelerate the discovery of the causes and risk factors associated with disease and disability among older adults.
A-3 Encourage translational research to bridge basic discovery and intervention development.

A-1 Support studies on healthy aging, well-being, and longevity.

Research on the biology of aging has revolutionized our understanding of healthy aging. New findings about genetic, molecular, and cellular factors and processes that affect the course of aging are providing valuable insights about aging, longevity, and the genesis of disease. Similarly, population studies are uncovering potential risk factors such as environmental exposures, health-related behaviors, and social factors, as well as the influence of co-existing conditions across the lifespan and their relationship to the progression of disease. NIA will continue research to:

• Identify cellular and molecular factors that determine the pace of aging processes. Researchers have identified key factors affecting the pace of aging, including the body’s response to a variety of stresses, the function of the immune system, and the role of cellular senescence (deterioration of the cell) as a tumor suppression mechanism. NIA will work to identify additional factors and to elucidate the role of each of these processes in the aging human.
  
  
• Determine how the cellular and molecular bases of changes associated with aging contribute to decreased function and increased incidence of disease. Although increasing age is most often accompanied by a significant and progressive decline in almost all physiological functions, resulting in increased susceptibility to age-related chronic diseases, some functions are remarkably well maintained in a large number of people. NIA will encourage research in both the loss and maintenance of functions during the aging process. Many researchers suspect that this increase in susceptibility to diseases may be due to the changes occurring as a result of the aging process itself. Therefore, manipulation of the basic processes of aging might provide an effective way to prevent or treat age-related diseases. We will foster comprehensive studies both in humans and in animal models to investigate the health- and disease-related effects of manipulating the process of aging at the molecular level.
  
  
• Identify developmental, prenatal, early life, and environmental processes that affect aging, age changes, and disease. Harmful substances can exert profound physical effects on a developing fetus, while childhood exposure to environmental agents such as infections or drugs can greatly limit adult physical and cognitive health and longevity. NIA will continue to support epidemiological studies to identify such factors and participate in translational studies to find ways to minimize their effects in adults.
  
  
• Understand the role of stem cells in tissue maintenance and how stem cells and their environments change with age. Stem cells contribute to tissue development and replenishment throughout life. Stem cells are the ultimate precursors to all the cells of the body, and they are important tools for both cell-based therapies and regenerative medicine. It is clear that tissues and organs lose function with advanced age, and such losses may result from declines in stem cell function. This loss of function occurs at different levels, including the stem cells themselves, the micro-environment where they self renew and differentiate (the niche), the receptiveness of the target tissues, or even in the communication among the target tissues, the niches, and the stem cells. NIA will pursue the major challenges in cell-based therapies and regenerative medicine, including improvement of the mobilization of native stem cell pools and definition of the limitations of stem cell expansion ex vivo, so that stem cells can be grown in adequate numbers for tissue repair while preserving their potency. NIA will also foster research to create a detailed molecular and functional understanding of stem cells, their niches, and their target microenvironments as well as strategies to direct stem cell differentiation into specific cell types. This research will inform efforts to understand and alter the aged environments that decrease stem cell function and improve the efficiency with which stem cells reach their target sites, where they can be effective while minimizing potentially harmful side effects.
  
  
• Understand the influence of obesity and metabolic status in healthy aging. We will continue collaborative studies on the relationships among obesity, insulin signaling, hypertension, and diabetes. We will continue studies on the efficacy of various nutritional and other cognitive and behavioral approaches to maintaining a healthy weight and preventing cardiovascular disease, cancer, diabetes, neurodegenerative disease, musculoskeletal conditions, and other conditions in older people. This research will also help determine whether or not general recommendations for healthy eating, physical exercise, and sleep in the young or middle aged are optimal for older people.
  
  
• Understand the sensory and motor changes associated with aging and how they lead to decreased function and increased incidence of disease. Mobility changes in the aging adult can be age related or the precursor to more severe motor disorders. Loss of sensory functions such as vision, hearing, or the ability to taste foods may result from aging-related processes or may be an indication of more severe underlying diseases or conditions. We will promote a better understanding of the underlying mechanisms of these and other age-associated changes. This research will provide the knowledge base necessary to develop interventions that optimize mobility and sensory function and prevent disease in the later years of life.
  
  
• Continue to support basic research in the psychological science of aging. Understanding age-related psychological change remains essential for advancing our understanding of how age impacts behaviors and decisions that, in turn, shape the subjective well-being, social relationships, physical and mental health, physical function, and economic well-being of older adults. Advances in psychological science are needed to improve behavioral interventions, and to understand the pathways and mechanisms through which psychological and social factors impact health. NIA continues to support research on basic psychological and social processes associated with normal aging; their relationship to individual, contextual, and environmental factors that impact these outcomes; and their neurobiological and genetic basis.
  
  
• Continue research on the impact of social interaction on health and well-being. Although research suggests that positive social interaction is health protective, we must improve our understanding of the mechanisms and pathways through which these factors improve both physical and mental health. We must also better identify the characteristics of social relationships and social environments that promote healthy aging. NIA-supported research to deepen our understanding in this area will aid in tailoring interventions to improve the health and quality of life of older adults.
  
  
• Explore the interplay between genetic, biological, clinical, social, economic, psychological, and environmental factors affecting aging and longevity. Evidence suggests that these factors and their interplay are critical to minimizing disease and achieving full potential and vitality in later years. More research is needed to verify the linkages and to better understand their underlying mechanisms.
  
  
  • Identify factors across the lifespan that contribute to exceptional health or its decline. The study of older people is shedding light on the biological, behavioral, and social factors associated with healthy aging. We will continue research that links laboratory and longitudinal population-based studies, providing insights into the factors that define resilient individuals and contribute to well-being in old age.
    
    
  • Expand our knowledge of age- and longevity-associated genes as well as epigenetic alterations that affect longevity and well-being, including modes of action. NIA-supported research has shown that patterns of extreme longevity run in families. Furthermore, scientists have identified approximately 100 different genes that affect longevity in model organisms. We will continue work to identify the biological functions of longevity genes and to better understand the mechanisms of action of known and yet-to-be-identified longevity genes (longevity assurance genes). This research will facilitate the development of biologically-based interventions to promote longevity, delay age-related dysfunction, extend health span, and improve the quality of life of older people.
    
    Epigenetic alterations (modifications other than changes in the DNA sequence that alter gene expression) are also likely to play important roles in rates of aging, age-related dysfunctions, and development of age-related diseases. Like changes to the DNA sequence itself, epigenetic modifications can be inherited. These modifications affect the cellular machinery responsible for turning genes “on” or “off,” allowing or preventing them from functioning optimally. Environmental agents such as chemicals or dietary components can also modify DNA and can be transmitted to offspring.
    
    
  • Refine our understanding of the interplay among the biological, social, emotional, cognitive, and functional changes associated with normal aging. The impact of changes in emotional, cognitive, and physical capacities at different life stages—in combination with life course changes in motivation and goals—on social and economic behaviors at different life stages remains unknown. We know even less about changes in the neurobiological underpinnings of these interactions. NIA will use the approaches of social neuroscience and neuroeconomics to study how the neurobiological changes associated with aging influence or are influenced by social, emotional, cognitive, and motivational factors.
    
    
  • Elucidate the biological mechanisms and pathways through which social, psychological, and environmental stresses contribute to declines in health and well-being among older adults. Individual differences in the subjective experience and physiological and psychological impact of stressors may exacerbate or buffer the impact of stressors on health. We will encourage multi-level and interdisciplinary research in collaboration with relevant NIH Institutes on the interactive effects of genes, behavior, and social environments on health and well-being as people age.

Links to NIA research relevant to Objective A-1

A-2 Accelerate the discovery of the causes and risk factors associated with disease and disability among older adults.

To develop new interventions for the prevention, early detection and diagnosis, and treatment of aging-related diseases, disorders, and disabilities, we must first understand their causes and the factors that place people at increased risk for their initiation and progression. NIA will continue research to:

• Identify the genetic and epigenetic bases of age-related diseases and conditions as well as factors that affect disease initiation and progression. Studies of genes associated with aging processes, longevity, and age-related diseases will continue to provide insights into disease pathologies and vulnerability. However, emerging research suggests that epigenetic mechanisms may also underlie, in part, the susceptibility to common and complex diseases of aging, particularly those subject to environmental influences. We will support research to understand the basic mechanisms influencing the aging process as a whole. In addition, we will work to understand the interplay among genes and environmental influences, as this knowledge will be essential to our understanding of the development of both disease and healthy aging.
  
  
• Improve our understanding of the molecular, genetic, cellular, and tissue bases of aging that contribute to increased risk for, alter the course of, and vary the response to the treatment of major age-associated diseases. We will increase efforts to understand the genetic and epigenetic factors that can alter susceptibility of individuals to disease and affect the response to treatment. In addition, we will work in collaboration with other NIH Institutes and Centers to study how phenomena such as anxiety and other negative emotions can alter nervous system function. Although these processes aid the body in responding to dangerous or stressful situations, they can damage cells, tissues, and organ systems when produced in excess.
  
  
• Identify the molecular and cellular bases of age-related decline in immune responses. The age-related decrease in the adaptive immune response (that is, the cellular response for manufacturing antibodies and killing pathogens) makes older people more prone to a variety of infectious agents and reduces the efficacy of vaccinations in older adults. These factors have a significant effect on the health span and quality of life of older people. We will support research to develop more protective vaccine regimens and strategies to improve immune responses in the aging population.
  
  
• Improve our understanding of how the inflammatory process is affected by aging and how these changes impact tissue function. The degree to which primary age-related changes in inflammation contribute to changes in structure and function of various tissues and organs as well as the risk or progression of age-related pathologies and conditions is not clear. Likewise, researchers are continuing to identify the sources of pro-inflammatory cytokines (proteins used by the body for cell-to-cell communication). We will examine the role of different cell types, including immune cells and adipose tissue (fat), in the age-related increase in levels of pro-inflammatory cytokines. We will also investigate how changes in the circulating levels of these cytokines contribute to pathological changes in tissues and organs. We will facilitate exploration of how the response of different tissues to pro-inflammatory cytokines is affected by age and how these changes contribute to the overall balance of the immune system.
  
  
• Identify, analyze, and track changing patterns of disability for older adults and better understand factors contributing to these patterns. The current pattern of increased “active life expectancy,” the average number of years an individual will live without a limiting disease or disability in parallel with increased length of life, is threatened by increases in obesity and disability rates for younger cohorts. NIA-supported research will address disability dynamics at several levels, including longitudinal research to understand the determinants of onset, severity, and recovery from disabling conditions. At the population level, we will foster research to understand the pathways to disability and the causes of change in mobility and function over time as well as subgroup disparities. We will also invest in research on more sensitive measures of functional disability that are needed to better track these changes.

Links to NIA research relevant to Objective A-2

A-3 Encourage translational research to bridge basic discovery and intervention development.

Translational research provides the two-way bridge necessary to link scientific discoveries with applications in medical practice and public health. For research on aging, basic discoveries typically begin with studies at a molecular or cellular level to understand the mechanisms of normal aging and disease or with studies to better understand the basic behavioral and social science related to aging processes. New knowledge gained at “the bench” takes a variety of paths to human intervention studies—the “bedside.” Equally important is providing a clear path back to the bench for insights gained at the bedside. Several NIH initiatives are focusing on the broad issues of culture change required for the biomedical community to more successfully support translational activities. In support of our other objectives in Research Goal A, NIA will continue to:

• Identify and optimize opportunities for moving new knowledge from basic discovery to intervention development and back. We will accelerate our efforts to promote promising preclinical studies and health systems research. We will also work to ensure that new technologies such as advanced imaging and bioinformatics and other resources needed for effective translational research are accessible to NIA-supported scientists and clinicians.
  
  
• Facilitate communication among NIA-supported researchers and encourage interdisciplinary collaboration. The complexity of contemporary science demands a synergistic approach to ensure collaboration among researchers from multiple scientific disciplines along the continuum of research. We will invest in multidisciplinary research programs and provide supplemental funding to support promising interdisciplinary endeavors.
  
  
• Foster communication and partnerships with other NIH Institutes and Centers and with other Federal agencies as well as other national and international research organizations. NIA will continue to collaborate with other NIH Institutes and Centers on projects with a multi-disciplinary focus such as the NIH Roadmap for Medical Research and the NIH Blueprint for Neuroscience Research. We will continue to participate in partnerships with outside organizations to share resources, support collaborative research, eliminate barriers to drug development, and communicate research findings to the public.

Links to NIA research relevant to Objective A-3

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