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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

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 appear to accelerate the aging process — which is manifested as declines in functionality and reduced quality of life.

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. 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 obvious disease.

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

  • Interventions that extend lifespan also extend healthspan — the portion of lifespan spent in good health — suggesting that interventions that extend life can reduce the burden of multiple diseases.

  • A particularly promising avenue of research involves cellular senescence, a process in which cells lose function, including the ability to divide and replicate, but continue to secrete molecules that damage neighboring cells. Investigators found that when treated with senolytics, or compounds that selectively remove senescent cells, mice that had previously been injected with damaging senescent cells regained physical function. Senolytics also extended lifespan and healthspan in naturally aging mice. In addition, investigators have found that clearing senescent cells from the brain preserves cognition in a mouse model of Alzheimer’s disease. Several senolytics have recently moved into early-stage human trials.

  • Reduction of caloric intake causes normal cells to mount stress-response defenses that cancer cells cannot, a finding that has entered 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 behavior but do not alter the underlying sequence of DNA. This suggests that parental lifespan and even parental behavior can influence the lifespans and healthspans of the next generation through mechanisms other than genetics.

These and newly emerging findings on 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.

Goal A objectives:

Approach

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

Researchers continue to identify and explain 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; the body’s response to macromolecular damage (damage to large molecules such as proteins or lipids), such as that caused by oxidative stress; and protein quality control (proteostasis). Studies of genes and epigenetic mechanisms associated with aging processes, longevity, and age-related diseases, as well as the interplay among genes and environmental influences, also continue to provide insights into disease pathologies and vulnerability. NIA will support research to identify additional factors and to clarify their roles both in animal models of aging and in humans.

A-2: Determine how cellular and molecular changes associated with aging contribute to decreased resilience and increased morbidity and influence response to treatment of age-associated physical conditions.

Increasing age is often accompanied by a progressive decline in most 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 inform the emerging field of geroscience, which hypothesizes that manipulating basic processes of aging could help to maintain physiological function and 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: Determine how cellular and molecular bases of changes associated with aging contribute to the development and course of age-related dementia and treatment response.

Aging itself is the primary risk factor for the development of Alzheimer’s disease and most other forms of dementia, in addition to diseases and conditions (e.g., type 2 diabetes, hypertension, and vascular disease) that are associated with increased dementia risk. However, we do not fully understand the mechanisms through which aging-related changes influence the brain and increase vulnerability to pathological change. NIA will conduct and support research on how aging processes influence the development of neurological disease. In addition, we will test interventions in animal models and ultimately in humans that have been shown to increase lifespan and healthspan in animals to determine their effect on cognitive function.

A-4: Identify factors associated with successful aging and resilience against disease and dysfunction.

Some people seem to be resistant to age-related disease and dysfunction. These “super-agers” may even perform cognitively or physically at levels more often seen in people who are decades younger. NIA will work to illuminate the factors that are associated with this resilience, and to determine whether those factors can be harnessed to increase resilience more broadly across the population.

A-5: Understand the sensory and motor changes associated with aging and how they lead to decreased function and increased risk of morbidity.

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 adults. 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 in the later years of life.

A-6: Identify and characterize interventions that hold the promise of increasing healthy lifespan.

The NIA established and continues to support the Intervention Testing Program to test the reproducibility of candidate interventions that will prolong lifespan and increase healthspan. 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, a multi-institutional study that investigates interventions that might extend lifespan or healthspan using diverse species and strains of the worm Caenorhabditis, 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.

A-7: Develop and/or identify biomarkers (including genetic, epigenetic, molecular, cellular, immunological, metabolic, imaging, and microbiome-related) that are applicable to aging and geroscience research.

Aging is associated with changes at multiple physiological levels. Research is needed to enable us to predict, identify, and where necessary address these changes.

A-8: Use comparative biology to understand how adaptations in diverse species ultimately affect aging.

Lifespan is a complex biological trait resulting from multiple genetic interactions. In fact, we have identified roughly 400 genes involved in human lifespan. Comparing processes at the molecular, cellular, structural, and organismal levels across animal species and diverse human populations can provide important information about how these genes interact and illuminate critical molecular pathways that determine both lifespan and healthy function at older ages.