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Goal A: Better understand the biology of aging and its impact on the prevention, progression, and prognosis of disease and disability

One of our challenges is to develop a clearer understanding of the basic biology underlying changes that accompany aging, as distinct from the basic biology underlying disease. Aging is not, in and of itself, a disease. However, aging is the major risk factor for developing many major chronic diseases. Furthermore, many diseases (chronic or inherited) appear to accelerate aging—which is manifested as declines in functionality and reduced quality of life.

For example, in response to bacterial infections or wounds, inflammation is an essential part of the recovery and healing process. However, low-level chronic inflammation that appears in the absence of clinically diagnosed infection may increase the susceptibility to and rate of progression of age-related pathologies. Chronic inflammation may also contribute to frailty in ways that are independent of overt disease.

Another challenge is to take advantage of the most promising opportunities presented by work in laboratory animals and to translate those findings to humans. A few seminal discoveries offer possibilities for improved human health in an aging population. For example:

  • Interventions that extend lifespan also extend health span—the proportion of lifespan spent in good health—implying that interventions that extend life can reduce the burden of multiple diseases.
  • Certain circulating proteins (or other factors) have been shown to reverse some negative effects of aging in mice, possibly suggesting treatments for some age-related functional losses or pathologies found in the human population.
  • Starvation causes normal cells to mount stress-response defenses that are not available to cancer cells, a finding that has entered the early phase of clinical testing as a possible intervention to enhance chemotherapy while also reducing some of its side effects.
  • Longevity can be inherited across generations through epigenetic changes—that is, changes that affect gene expression but do not alter the nucleotide sequence of DNA. This suggests that parental lifespan and even parental behavior can influence the lifespans and health spans of the next generation through mechanisms other than genetics.

These and newly emerging findings from the basic biology of aging hold great promise for improving health, and NIA is committed to continuing support of this research and translating these discoveries into interventions that support better health.

Our objectives in this area are to:

A-1: Identify cellular and molecular factors that determine the rate of aging processes.

Researchers have identified key factors affecting the rate of aging, including the body's response to a variety of stresses, the function of the immune system, the role of cellular senescence, and protein quality control (proteostasis), among others. NIA will support research to identify additional factors and to elucidate the role of each of these processes in both animal models of aging and in humans.

A-2: Determine how the cellular and molecular bases of changes associated with aging contribute to decreased function and increased incidence of disease.

Increasing age is often accompanied by a progressive decline in almost all physiological functions, resulting in increased susceptibility to disease. At the same time, many people maintain physical function and enjoy robust health well into older age. Together, these findings suggest that manipulation of the basic processes of aging in order to maintain physiological function might provide an effective way to prevent or treat age-related diseases. NIA will encourage research in both the loss and maintenance of functions during the aging process and will foster studies both in humans and in animal models to investigate the health- and disease-related effects of manipulating aging-related processes at the molecular or cellular level.

A-3: Improve our understanding of the fundamental factors 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 factors that can alter individuals' susceptibility to disease and affect the response to treatment. In addition, we will work with other NIH institutes and centers to study how phenomena such as anxiety and other negative emotions—high levels of which can damage cells, tissues, and organ systems—can alter nervous system function.

A-4: 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 result from changes in gait, balance, and physical strength, and can negatively influence the number and severity of falls, social participation, and independence. Loss of sensory functions such as vision, hearing, or the ability to taste is also common among older individuals. NIA-supported research to better understand the underlying mechanisms of age-associated sensory and motor changes will provide the knowledge base necessary to develop interventions that optimize mobility and sensory function and prevent disease in the later years of life.

A-5: Understand the role of stem cells in tissue maintenance and how stem cells and their environments change with age.

Stem cells are specialized cells in specialized locations that contribute to tissue development and replenishment throughout life and are important tools for both cell-based therapies and regenerative medicine. 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 specialized locations where they self-renew (the niche), and the ability to engraft and differentiate in tissues undergoing turnover or in need of repair.

NIA will pursue the major challenges in stem cell-based therapies and regenerative medicine, including techniques that will help ensure that stem cells can be grown in adequate numbers for tissue repair or replacement while preserving their potency. NIA will also foster research to create a detailed molecular and functional understanding of the effects of aging on stem cells and their niches, as well as strategies to reprogram somatic cells into pluripotent stem cells and direct pluripotent and stem cell differentiation into specific cell types. This research will inform efforts to devise repair and replacement strategies suitable for older humans, while minimizing potentially harmful side effects.

A-6: Identify the genetic and epigenetic bases of aging and 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, both the aging process and susceptibility to common and complex diseases of aging, particularly those subject to environmental influences. We will support research to understand the basic epigenetic 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 healthy aging and disease.

A-7: Identify the molecular and cellular bases of age-related decline in immune responses and improve our understanding of how the inflammatory process is affected by aging and how these changes impact tissue function.

The age-related decrease in the cellular response for manufacturing antibodies and killing pathogens makes older adults more prone to a variety of infections and reduces the efficacy of vaccinations. NIA will conduct and support research to develop more protective vaccine regimens and strategies to improve immune responses in the aging population.

NIA will conduct and support research to examine the role of different cell types, including immune cells, adipose tissue (fat), and brain cells in the age-related increase in levels of pro-inflammatory cytokines and other circulatory factors. Researchers will also investigate how changes in the circulating levels of these cytokines and factors contribute to pathological changes in tissues and organs. NIA will facilitate exploration of the ways in which the response of different tissues to pro-inflammatory cytokines are affected by age and how these changes contribute to the overall balance of the immune system.

A-8: Understand the influence of metabolic status and nutrient sensing in healthy aging.

We will continue collaborative studies on the interactions and cross-talk among obesity, metabolic pathways and regulation, insulin signaling, hypertension, and diabetes. We will conduct and support exploration into the relationships among mitochondrial biogenesis, oxidative stress, musculoskeletal function, and energy to understand how these factors affect healthy aging.

A-9: Understand the interactions between microbiome and tissue integrity and function.

The human microbiome is important for human health and disease. The gut microbiome is especially important for immunity, and both gut physiology and the microbiome change during aging. Because there are 30 times more lymphocytes in the gut (mucosa) than in peripheral blood, study of the interactions between the gut and its microbiome are important areas of study in the immunobiology of aging, as well as nutrient absorption and metabolism.

A-10: Understand the basis for changes in adaptation to macromolecular damage and response to stress that affect—and are affected by—aging.

Research addressing damage to macromolecules has long been supported by NIA, as this damage has been considered a major driver of aging processes. Resistance to this damage (i.e., resilience) and how the cell responds to damage has gained significant attention and NIA will support further research into these areas, including hormesis and how to differentiate between healthy and unhealthy stresses.

A-11: Identify and characterize interventions that hold the promise of increasing healthy lifespanand determine the differential effects on males versus females.

The NIA established and continues to support the Intervention Testing Program (ITP), to test the reproducibility of candidate interventions that will prolong lifespan and increase health span. In this and other research, the NIA promotes studies in both female and male organisms. Similar studies are supported in the Caenorhabditis Interventions Testing Program (CITP) to explore the impact of genetic diversity on the efficacy of interventions. We support studies on the mechanisms of action of these interventions which will facilitate their translation to benefit healthy aging in humans.