Biology of Aging Program:
Understanding Aging Processes, Health, and Longevity
Investigators supported by NIA’s Biology of Aging Program seek to improve our understanding of the basic biological mechanisms underlying the process of aging and age-related diseases. Basic biochemical, genetic, and physiological studies are carried out primarily in animal models, including both mammals and non-mammalian organisms (e.g., flies, worms, yeast). The program’s goal is to provide the biological basis for interventions in the process of aging, which is the major risk factor for many chronic diseases affecting the American population. Ongoing initiatives that will remain active during FY 2014 include the Interventions Testing Program to identify compounds that extend median and/or maximal life span in a mouse model, along with a similar program to identify such compounds in the worm model Caenorhabditis elegans; an initiative to explore the basic biology of aging from a systems perspective – i.e., by investigating the complex interactions at the single-cell level among individual gene products, biochemical pathways, and cell biological mechanisms that impact aging, as well as interactions between tissues; and studies to enhance our understanding of the molecular mechanisms that control circadian clocks in aging tissues. The program also coordinates the Nathan Shock Centers of Excellence in the Basic Biology of Aging, as well as the NIH Geroscience Interest Group (GSIG), which was established in 2012 to accelerate and coordinate efforts to promote discoveries on the common risks and mechanisms behind age-related diseases and conditions by developing a collaborative framework that includes multiple NIH Institutes and Centers.
The FY 2014 President’s Budget estimate is $180.575 million, a decrease of $1.320 million, or 0.7 percent below the FY 2012 Actual level.
Program Portrait: Inflammation and Aging
FY 2012 Level: $18.0 million
FY 2014 Level: $18.2 million
Change: + $0.2 million
Acute inflammation, such as that which occurs with an injury, is transient and usually resolves as the injury heals. Chronic inflammation, on the other hand, can be present over many years, and is associated with blood and tissue levels of pro-inflammatory molecules that are lower than those seen with acute inflammation but still higher than in healthy adults. Scientists increasingly view chronic inflammation as a likely common thread linking a number of diseases and conditions for which aging is the primary risk factor, including cardiovascular disease, Alzheimer’s disease, osteoarthritis, and cancer. This hypothesis is bolstered by current research, using mice, demonstrating two linked findings: a) the process of cellular senescence (conversion to a nondividing state) is associated with secretion of pro-inflammatory molecules, and b) removing senescent cells delayed the onset of disease-related changes and slowed progression of known age-related disorders in several tissues.
NIA supports a robust program of research to understand the causes and consequences of inflammation in aging tissues. For example, one study is evaluating the relationships among age-related changes in angiotensin receptors, which are found on the surface and on the inside of virtually all human cells, and determining how these changes might influence chronic inflammation, frailty, and late life vulnerability. In a large program project, investigators are looking in greater detail at the effects on health resulting from the removal of senescent cells. Other studies explore inflammation’s role in immune response and specific diseases, including heart disease, infectious diseases, and cancer.
In September 2012, the trans-NIH Geroscience Interest Group held a workshop on Inflammation and Age-Related Diseases, which brought together experts in aging biology and in age-related pathology to explore the mechanistic relationships between inflammation and age-associated disease. A report is being prepared that should direct our efforts to identify outstanding questions concerning the impact of inflammation on the diseases of aging and what tools, technologies, resources, or community efforts are required to address these questions. The report is expected to inform NIA’s efforts, including the development of funding opportunity announcements, through FY 2014.
Behavioral and Social Research Program:
Understanding and Addressing the Behavioral, Emotional, and Social Dynamics of Aging
NIA’s Behavioral and Social Research Program supports social and behavioral research to increase our understanding of the processes of aging at the individual, institutional, and societal levels. Research areas include the behavioral, psychological, and social changes individuals experience over the adult lifespan; participation of older people in the economy, families, and communities; the development of interventions to improve the health and cognition of older adults; and the societal impact of population aging and of trends in labor force participation, including fiscal effects on the Medicare and Social Security programs. The program also supports research training; development of research resources such as publicly available, cross-nationally comparable studies that support research to understand the sources of international variations in health outcomes; interdisciplinary studies that integrate biological and genetic measures with traditional social, behavioral and economic measures; longitudinal studies; and interventions to maximize active life and health expectancy. The program coordinates the long-running Health and Retirement Study, the nation’s leading source of combined data on health and financial circumstances of Americans over age 50; the Centers on the Demography and Economics of Aging; the Roybal Centers for Translational Research on Aging; and the Resource Centers for Minority Aging Research (RCMARs). Major program activities for FY 2014 will include studies of social neuroscience and the neuroeconomics of aging and identification of practical interventions to improve medication adherence in the primary care setting.
The FY 2014 President’s Budget estimate is $186.186 million, a decrease of $1.361 million, or 0.7 percent below the FY 2012 Actual level.
Understanding, Preventing, and Treating Cognitive Decline and Disability
NIA’s Neuroscience Program supports a broad spectrum of research and training aimed at better understanding age-related normal and pathological changes in the structure and function of the aging nervous system and how such changes affect behavior. The program’s basic mission is to expand knowledge on the aging nervous system to allow improvement in the quality of life of older people. Ongoing activities include basic and clinical studies of the nervous system, clinical trials of treatments and preventive interventions for neurological disease, and epidemiological research to identify risk factors and to establish prevalence and incidence estimates of pathologic conditions. Additionally, this program supports research relevant to problems arising from psychiatric and neurological disorders associated with aging. NIA is also the lead federal agency for research on Alzheimer’s disease (AD). The Institute supports a national network of Alzheimer’s Disease Centers to translate research advances into improved diagnosis and care of AD patients while pursing development and testing of effective preventive and treatment interventions for AD, as well as a broad array of initiatives aimed at improving our understanding of this disease.
The FY 2014 President’s Budget estimate is $514.270 million, an increase of $76.827 million, or 17.6 percent above the FY 2012 Actual level. This includes an $80.0 million increase for Alzheimer’s Disease (AD) research and a decrease of $3.174 million to other program areas.
Program Portrait: Alzheimer’s Disease Research
FY 2012 Level: $335.2 million
FY 2014 Level: $415.2 million
Change: +$80.0 million
In FY 2014, the NIH anticipates allocating an additional $80 million to research project grants aimed at speeding drug development and testing new therapies for Alzheimer’s disease (AD). Projects will facilitate fulfillment of the recommendations of the May 2012 Alzheimer’s Disease Research Summit, which was held in response to the passage of the National Alzheimer’s Project Act in 2011. The goal of the Summit was to formulate a strategy for a new integrated, multidisciplinary research agenda that will enable the development of effective therapies across the disease continuum and to identify the resources, infrastructure, and public-private partnerships necessary to implement this translational agenda.
This investment will be targeted at preclinical, translational, and clinical development of preventive and treatment interventions for AD. Specific research areas will include:
Identification of novel therapeutic targets. New discoveries have opened a variety of approaches to identifying candidate molecular targets for prevention and treatment of AD. For example, ongoing and extensive whole genome sequencing has the potential for identifying new genetic variants that either increase risk (risk factors) or reduce risk (protective factors) of AD. Our FY 2014 investment will facilitate the analysis of the sequencing data being generated, supporting efforts of experts in genomics, informatics, and Alzheimer's disease biology to identify the most promising leads for further target identification. A key aspect of these efforts will be the emphasis on the creation of new translational teams consisting of researchers across a broad array of disciplines within a framework that will enable cross-talk and collaboration among basic and translational scientists with the goal of identification and preclinical validation of novel therapeutic targets within molecular networks involved in different stages of Alzheimer’s disease pathogenesis.
Preclinical development of new therapies. Translation of basic discoveries will be accelerated by application of new technologies and research paradigms. For example, researchers who have promising small molecule compounds, but lack outside drug development expertise and infrastructure support to advance these compounds to the clinic, will have access to a “virtual pharma” network of contract research organizations, technical and regulatory experts, and project managers, all with extensive biopharma/industry experience.The long-term goal is to advance projects from medicinal chemistry optimization through Phase l clinical trials and facilitate industry partnership for their further development.
AD clinical trials. Recent discovery of genetic causes and risk factors for Alzheimer's disease has allowed identification of individuals who are at high risk for developing disease. Recent studies have also led to the discovery of brain imaging changes and other biomarkers that identify early stages of Alzheimer's well before the appearance of any clinical manifestations. These advances will permit the design of novel clinical trials that: Initiate prevention intervention before symptoms occur or at very early stages of disease; determine the effectiveness of these interventions by monitoring sensitive changes in brain imaging or other biomarkers, allowing more rapid determination of effectiveness than has previously been possible by monitoring Alzheimer's symptoms; test new agents – e.g., monoclonal antibodies and small molecules - as well as the re-purposing of agents currently approved for use against other diseases; and test non-pharmacologic interventions that have shown effects on cognition in initial studies. Clinical trials may range from Phase I studies to evaluate the metabolic and pharmacological actions of a variety of agents in humans to larger-scale interventions of drugs, exercise, or other lifestyle changes to prevent or ameliorate AD symptoms.
Example: Repurposing Drugs for Alzheimer’s Disease
One strategy NIA is pursuing is “repurposing” drugs originally approved for other conditions as therapeutics for AD and mild cognitive impairment (MCI), which is often a precursor to the disease. In addition to the ongoing NIA efforts, the newly launched repurposing program at the National Center for Advancing Translational Sciences (NCATS), while more broad in nature, will open additional avenues for possible repurposing in AD therapy development. An advantage to the repurposing approach is that detailed information is already available on these drugs’ pharmacology, formulation, dosing, and potential toxicity, meaning that they can be moved into clinical testing much more rapidly than a new compound. Findings from repurposing studies can also inform our knowledge of disease mechanisms, suggesting additional paths for therapeutic development. For example, the NIA-supported investigators who recently found that the skin cancer drug bexarotene reversed cognitive defects and improved function in a mouse model of AD also elucidated the mechanism behind a major genetic risk factor for the disease, ApoE4. ApoE4 is hindered in its ability to clear toxic beta-amyloid from the brain. Bexarotene boosts the levels of functional ApoE in the brain, promoting beta-amyloid clearance. These findings suggest that increasing ApoE levels in the brain may be an effective therapeutic strategy.
NIA is currently supporting studies on several established compounds in patients with cognitive decline, MCI, or AD. For example, an 18-month phase II clinical trial in the NIA Intramural Research Program is exploring the use of exenatide, which is widely prescribed as a treatment for type 2 diabetes, in patients with MCI or early AD. Enrollment will continue in 2013, with analysis and follow-up continuing in the following years. NIA is also supporting a major five-year study of insulin delivered via nasal spray in patients with MCI and mild AD. This study will be ongoing in 2014. Other studies in AD patients include a pilot trial of the beta-blocker carvedilol and a pilot trial of a selective serotonin reuptake inhibitor antidepressant citalopram. Additional compounds will be considered for clinical study as scientifically justified.
Geriatrics and Clinical Gerontology Program:
Reducing Disease and Disability among Older People
As people age, the risk for many types of disease and/or disability increases dramatically. NIA’s Geriatrics and Clinical Gerontology Program supports research on health, disease, and disability in the aged (other than neurodegeneration, which is the focus of the NIA’s Neuroscience Program). Areas of focus include age-related physical changes and their relationship to health outcomes, the maintenance of health and the development of disease, and specific age-related risk factors for disease. Program staff work closely with other NIH Institutes to coordinate research on diseases and conditions that are common among older people or represent a growing threat (for example, an ongoing collaboration with NIAID addresses the increasing incidence of HIV/AIDS among older Americans). The program also plans and administers clinical trials for a number of age-related conditions. In addition, the program coordinates the Claude D. Pepper Older Americans Independence Centers Program, the goal of which is to increase scientific knowledge leading to better ways to maintain or restore independence in older persons.
The FY 2014 President’s Budget estimate is $151.365 million, a decrease of $1.106 million, or 0.7 percent below the FY 2012 Actual level.
Intramural Research at NIA
Investigators with NIA’s Intramural Research Program (IRP) conduct research in the areas of basic, behavioral, clinical, epidemiologic, and translational research. High priority research endeavors and areas of specific focus include: Molecular and Cellular Biology, including caloric restriction, cell cycle control, signal transduction, DNA damage and repair, physiology, and medicinal chemistry; Neuroscience, including neurodegenerative diseases, drug design and development, and neuronal cell apoptosis; Genetics, particularly genetic determinants of aging as an integrated part of human development; Behavioral Research, including personality, cognition, and psychophysiology; Clinical and Translational Research in cardiology, oncology, immunology, neurology, and endocrinology; and Epidemiology, including studies of frailty, cognition, body composition, disability, and molecular biomarkers of aging. The clinical research effort focuses on the translation of basic research findings, prevention and therapeutic clinical trials focused on age-associated diseases, modulation of treatment efficacy and toxicity in older patients, and establishment of and maintenance of diverse longitudinal cohorts for aging research. Many studies focus on common age-related diseases such as Alzheimer’s disease, Parkinson’s disease, stroke, atherosclerosis, and diabetes. Others, such as the groundbreaking Baltimore Longitudinal Study of Aging, explore the determinants of healthy aging. Work is also continuing on the Healthy Aging in Neighborhoods of Diversity Across the Life Span (HANDLS) study, which is examining the influences of race and socioeconomic status on the development of age-related health disparities among socioeconomically diverse African Americans and whites living in Baltimore. In 2012, the IRP underwent a major review and reorganization which included the formation of a Translational Gerontology Branch; the number of laboratory units was reduced from 15 to 10, and plans were made to consolidate a number of operations at the NIA Biomedical Research Center in Baltimore. IRP investigators also identified a protein, PGC-1alpha, in mice that may play an important role in forming and maintaining healthy dendrites and synapses in the hippocampus (a brain region important to learning and memory); PGC-1alpha may be a promising therapeutic target for Alzheimer’s disease and other neurodegenerative disorders. Other IRP investigators began to elucidate the pathways through which the CR1 gene influences Alzheimer’s disease risk, determining that the amount of brain amyloid (one of AD’s hallmark pathologies) is influenced by the interaction of CR1 the APOE gene, but that individuals carrying the AD risk allele of CR1 have significantly lower brain amyloid burden than those without the risk allele. These findings suggest that the risk of AD associated with CR1 may not be mediated by increasing brain amyloid but through some other means.
The FY 2014 President’s Budget estimate is $118.601 million, a decrease of $0.001 million from the FY 2012 Actual level.
Program Portrait: Identifying the Genetic Bases for Neurological Diseases: NIA’s Laboratory of Neurogenetics
FY 2012 Level: $10.0 million 1
FY 2014 Level: $10.3 million
Change: +$0.3 million
1 Estimate, includes personnel and proportion of overhead costs.
Understanding a disease at its most basic levels is an important first step toward developing interventions to prevent, slow, halt, or reverse disease progression. Since 2001, the NIA Laboratory of Neurogenetics (LNG) has had one overarching goal: to find genetic variation and gene mutations that cause or contribute to neurological disease.
The LNG has been a key laboratory in furthering the basic understanding of neurodegenerative diseases, including Alzheimer’s disease and related dementias. In addition, LNG investigators explore the genetic bases of a number of other neurological disorders, including amyotrophic lateral sclerosis, dystonia, ataxia, and Parkinson’s disease. LNG investigators were the first to describe a triplication mutation of the alpha-synuclein gene that causes a severe, early-onset form of Parkinson's disease. The laboratory was at the forefront of the international research team that was the first to identify mutations in the LRRK2 gene as a cause of familial Parkinson's disease, as well as the more common sporadic Parkinson's disease. More recently, the LNG identified the most common genetic cause of both amyotrophic lateral sclerosis and frontotemporal dementia, and was a leading contributor on the international team that identified variations in the TREM2 gene as risk factors for Alzheimer’s. The LNG has also focused on the complex genetics of Parkinson's disease, describing more than 15 common genetic risk factors for this disease. Integrated with this basic genetic approach are groups within LNG that focus on understanding the biology of these varied diseases using genetic modeling in cell and animal systems. This work has shed significant light on the processes underlying Parkinson’s disease and Alzheimer’s disease. In addition, the LNG has active research programs investigating genetic diversity and the consequences of genetic alterations, particularly in the context of the brain and aging, using systems biology-based approaches. One of the laboratory’s strengths is its broad network of collaborators, including laboratories within NIA and NIH, across the nation, and internationally.
In FY 2014, the LNG anticipates continuing its groundbreaking work in the genetics of neurological disease, taking the well-established approach of studying rare familial forms of disease and then extrapolating the function of genes involved to related conditions.