Research on the biology of aging has led to a revolution in aging research. New findings about the factors that affect aging have begun to provide valuable insights about longevity and the genesis of disease.
No single theory can account for all the changes that take place as people age. Aging today is viewed as many processes—interactive and independent—that determine lifespan and health. These dynamics result in wide variations in aging both among individuals and among different biological processes and systems within the body. Understanding these variations and their causes promises to translate into interventions that extend the proportion of our lives spent in good health.
Chronic diseases and disabilities were once thought to be inseparable from aging. This view is changing rapidly as the means are developed to prevent, treat, or control diseases. If chronic disease is not intrinsic to aging, then what is "normal" aging? Normal or usual changes with aging, similar to diseases, are influenced by genetics, environment, and lifestyle. The link between genes and lifespan is no longer questioned. For example, selective breeding in fruit flies has resulted in flies that live nearly twice as long as average. In addition, recent studies of human centenarians have found that extreme longevity runs in families, suggesting a strong genetic influence on aging. Complementing the genetic influences on aging are the strong effects of environmental factors, such as toxins, radiation, and oxygen radicals—highly reactive molecules produced as cells turn food and oxygen into energy. Progress is being made in understanding and counteracting these environmental effects. Lifestyle choices, including diets, physical activity, and other health habits and behavioral and social factors also have a potent effect on aging processes.
NIA's Goals in Understanding the Normal or Usual Changes With Age
Identify Factors That Pace the Aging Process and "Slow the Clock"
Caloric restriction is the only intervention known to reliably extend the healthy lifespan of rodents and nearly all other nonprimate laboratory animals studied. Fed 30 to 40 percent fewer calories than in usual feeding schedules, but given all the necessary nutrients, the animals studied have lived far beyond their normal lifespans. Animals on restricted diets also have reduced rates of several diseases, especially cancers. Laboratories are now studying caloric restriction in nonhuman primates. Thus far, researchers have identified changes in physiologic function in calorically restricted rhesus monkeys that are associated with delays in aging-related decline in animals. Additional studies of caloric restriction will help identify the fundamental reasons for the increase in longevity and reduction in disease and uncover the mechanisms responsible for disease in old age.
To understand the biologic mechanisms involved in this phenomenon, researchers recently examined 6,500 mouse genes and identified 58 genes that actively produced (or expressed) more than twice as much gene product at older ages. These genes were involved in stress responses and growth of neurons. The major effect of caloric restriction seems to heighten animals' stress response to damage to proteins and other large molecules.
Most cells have a finite lifespan; after a certain number of divisions specific to the cell type, they enter a state of cell senescence no longer dividing their ability to synthesize DNA blocked. This built-in limit on cell division may help explain the aging process. Several genes have been identified that regulate senescence, some of which trigger cell proliferation and others that counter cell division. Research into what causes cells to mature, to lose the capacity to reproduce, and eventually to die promises to provide valuable insights about the genesis of disease.
Telomeres have been regarded as the cell's "molecular clock." These protective segments of DNA on the ends of chromosomes shorten each time most types of cells divide until, at a critical length, cell division ceases. Major advances recently have been made in understanding the role of telomeres. The enzyme telomerase compensates for telomere shortening by adding DNA segments to the ends of chromosomes, enabling cells such as sperm to divide indefinitely. How telomerase activity in cells contributes to cancerous growth is not known, but many scientists view telomerase inhibition as a potential new approach to cancer therapy.
In a recent experiment that inserted the gene for telomerase in normal, telomerase-negative cells, shortened telomeres grew longer, and the cells replicated far beyond the limits observed for normal cells while retaining the function of young, normal cells. This advance not only suggests that telomeres are the central timing mechanism for cellular aging, but also demonstrates that such a mechanism can be reset. Controlled activation of telomerase may provide an avenue for healthy cell division by resetting or extending the timing of the molecular clock.
Oxygen radicals are known to attack proteins, cell membranes, and DNA. The body has a multilayer defense system of antioxidants that react with and disarm these molecules. Vitamins C, E, and beta-carotene can function as antioxidants, along with enzymes such as superoxide dismutase and catalase. They can prevent most, but not all, oxidative damage, and one theory contends that this accumulation of damage results in malfunctioning of genes and other aging-related changes in tissues and organs.
Researchers are actively pursuing research on the effects of oxygen radicals, the body's antioxidant defenses, and the use of antioxidants as dietary supplements. DNA also is assaulted by ultraviolet light and other toxic agents. The ability of an organism to detect and repair certain types of DNA damage is believed to be directly related to the lifespan of the organism. Scientists have found DNA repair defects in people with a genetic susceptibility to cancer and hope to discover the role of DNA repair in the increased risk of cancer in older people. Researchers also are studying other processes that contribute to the rapid and efficient response to stress crucial for a healthy, long life.
Define the Biologic and Environmental Factors That Maximize Cognitive, Sensory, and Physical Functions
Research has contributed insights into the interactions between the brain and the peripheral nervous system, endocrine system, and the immune system. Findings from these studies will have an important impact on preventive and therapeutic approaches to maintain health in cognition, sleep, and sensory processes.
Hormones are the body's chemical messengers that stimulate specific functions within the body. Researchers have long known that some hormones decline with age. Growth hormone levels decline, as do levels of the sex hormones, testosterone, and estrogen. The most familiar example of this phenomenon is the decline of ovarian hormones that accompanies menopause. When some declining hormones are replaced, various signs of aging diminish. Estrogen replacement therapy after menopause not only alleviates unpleasant symptoms unique to menopause, but also lessens the accelerated loss of bone characteristic of osteoporosis and may help prevent cardiovascular disease. There also is evidence that estrogen replacement may have a positive effect on cognition. The changes specific to the menopause, other hormonal changes with age, and hormone supplementation are being investigated to help define the role of hormones in health and disease and the potential benefits for hormone supplementation.
The ability of the immune system to protect people from infection also undergoes a gradual decline with age. Exciting progress is being made in understanding the complex defenses that are mounted against invading bacteria and other foreign cells and the interactions of hormones with the immune system. Prevention of declines in immune function would make a significant contribution to improving the health span and quality of life of older people. New knowledge in this area has broad implications for improving vaccine efficacy, other prophylactic techniques against infection, and reducing infectious diseases, the cause of much hospitalization and death in older people.
Personality factors also have been shown to have a significant impact on health and survival. New findings are helping to understand the links between personality and health. For example, health can be affected by how conscientious a person is in eating well or taking medication. People with personalities prone to high anxiety and other negative emotions can suffer from stress, which induces the manufacture of neurotransmitters—messengers of the nervous system—and hormones designed to aid the body in responding to dangerous or stressful situations. These hormones can damage cells, tissues, and systems in the body. There is evidence from animal studies that elevated stress hormones can lead to cell death in the hippocampus, which is rich in receptors for the stress hormone cortisol.
Age-associated changes in sensory function—including vision, hearing, taste, smell, proprioception, and vestibular function—can lead to significant health and functional problems and significant decrease in quality of life for older persons. Relatively simple lifestyle changes can lower the risk for some sensory declines. Not smoking and living in a smoke-free environment can lower the risk of hearing loss, and wearing plastic lenses or hats with brims can reduce cataract risk by lowering eye exposure to UV-B from sunlight. Understanding the mechanisms involved in decreased sensory function is expected to lead to interventions to maintain optimal function into the later years.
Identify Genes Associated With Aging, Longevity, Age-Related Diseases, and Behavior
Research has begun to reveal the biologic factors associated with extended longevity in humans and animal models. Within the last 10 years, numerous genes have been implicated in:
- Normal aging processes
- Age-related pathologies and diseases
- Determination of longevity in several species, including humans.
Some of these genes are associated with dramatic extension of lifespan in tiny worms called nematodes, in fruit flies, and in mice. Using advanced technology, 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: (1) studies of longevity-associated genes, (2)changes in gene expression patterns, and (3) 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.
Revolutionary advances in the fields of quantitative and molecular genetics hold great promise in the search for the genetic determinants of complex behaviors. Twin 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.
Identify Social, Psychological, and Lifestyle Factors That Promote Health, Well-Being, and Longevity
Just as psychological and lifestyle factors have been associated with preventing disease and disability (as described in Goal A), similar factors are being identified that are associated with "successful aging." We mean not simply avoiding disease, but rather, achieving full potential and vitality in later years. Research into behaviors and health promotion strategies to achieve well-being in later years will include reducing stress and other risk factors for disease and disability, keeping the mind and body well exercised, and maintaining a vigorous involvement in activities of life.
Disassociate Changes of Normal or Usual Aging From Those of Diseases and Disorders
A special effort is needed to disentangle the normal or usual changes with age from those of disease and disability. Individual health providers and family members have to make difficult distinctions, for example, between age-associated changes in memory and early Alzheimer's disease. Clearer information about how a disease presents in older individuals would help avoid missing a diagnosis such as depression. Changes associated with normal aging also affect the rate and experience of disease and disability and may exacerbate symptoms. Many patients experience multiple problems that complicate diagnosis, treatment, and rehabilitative services. New knowledge will be developed to distinguish among and better understand usual aging, disease, and disability, stimulated by advances in imaging technology and genetics, clinical studies, and improvements in information dissemination.
