The goal of NIA’s Intramural Research Program (IRP) is to support a broad-based research program centered on critical issues regarding the general biology of aging and age-associated diseases and disabilities.
The specific areas of study on the biology of aging focus on 1) characterization of normal aging, 2) cell cycle regulation and programmed cell death, 3) stress response, 4) DNA damage and repair, 5) genetics, and 6) immunology. Age-associated disease and disabilities research includes the study of 1) Alzheimer’s disease; 2) cancer; 3) osteoporosis, osteoarthritis, and frailty; 4) cardiovascular disease and hypertension; and 5) diabetes. In addition, researchers at NIA’s IRP continue to develop and/or test different intervention strategies—e.g., pharmacotherapy, gene therapy, and behavioral or lifestyle changes—to treat many age-associated diseases.
The NIA’s IRP comprises 11 scientific laboratories, a clinical branch, a research resources support branch, and 2 sections. Most of NIA’s intramural research is conducted in Baltimore at the NIH Biomedical Research Center and the Gerontology Research Center. Clinical research resources are located at Harbor Hospital in Southeast Baltimore. Two laboratories and one scientific research section are located in Bethesda. IRP laboratories provide a stimulating environment for age-related research. IRP also offers many excellent training opportunities in both laboratory research and clinical medicine for investigators at all stages of their careers. To read more about the NIA’s Intramural Program, go to www.grc.nia.nih.gov.
The overall goals of LCS are: 1) to identify age associated changes that occur within the cardiovascular system and to determine the mechanisms for these changes; 2) to determine how aging of the heart and vasculature interacts with chronic disease states to enhance the risk for CV diseases in older persons; 3) to study basic mechanisms in excitation-contraction coupling and how these are modulated by surface receptor signaling pathways in cardiac cells; 4) to elucidate mechanisms of pacemaker activity in sinoatrial nodal cells; 5) to elucidate mechanisms that govern cardiac and vascular cell survival; and 6) to establish the potentials and limitations of new therapeutic approaches such as changes in lifestyle, novel pharmacologic agents or gene or stem cell transfer techniques in aging or disease states.
LCMB programs work to uncover knowledge that can be applied to prevent or delay the onset of age-related disabilities and diseases, and provide new strategies for their diagnosis or treatment. Programs share several areas of emphasis, including: 1) the study of signal transduction processes and gene regulatory mechanisms involved in mediating cellular responses to environmental signals such as growth factors, cytokines, immune activators, and stress stimuli; 2) the determination of molecular mechanisms contributing to the maintenance of cellular homeostasis and cell cycle control; 3) the contribution of dysregulated gene expression or loss of critical gene functions to the development of cancer; and 4) the examination of oxidative DNA damage and repair mechanisms in cancer. A wide variety of in vitro and in vivo models are employed to approach these issues. These processes have direct relevance to our understanding of critical events associated with various age-related deficits as well as age-related diseases including cancer.
The LCI seeks to: 1) gain fundamental understanding of age- and disease-related changes in calcium ion channel function, islet cell differentiation and insulin secretion, insulin receptor function, molecular and cellular changes in osteoarthritis, and genetic features of tumorigenesis; 2) carry out translational research in each of these areas in order to take hypotheses generated from fundamental studies and apply them to humans in health and disease; 3) identify therapeutic targets in each of these areas and in other laboratories across the NIA IRP; and 4) develop therapeutic agents for the identified targets and carry out preclinical and clinical studies for proof of principle for the targets. To meet these objectives, studies are performed at the molecular, cellular, animal model, and human levels.
The LEDB conducts research on aging and age-associated diseases and conditions using population-based epidemiologic and biometric methods. LEDB collaborators include other NIA researchers and outside investigators. The mission of the laboratory is to elucidate the etiology of diseases and conditions of old age by analyzing epidemiologic data collected in prospective, population-based studies developed by LEDB, combining epidemiologic data with information from other disciplines, evaluating the consistency of epidemiologic data with etiologic hypotheses developed either clinically or experimentally, and providing the basis for developing and evaluating preventive procedures and public health practices. LEDB’s research agenda emphasizes 3 interrelated areas: physical function and disability; cognitive function and dementia; and age-associated diseases and conditions, including successful or effective aging. Cross-cutting research themes are: functional status, comorbidity, genetic epidemiology, inflammation, socioeconomic status and health, diabetes/metabolism, and energy balance–physical activity/obesity.
The LEG conducts basic research aimed at defining the mechanisms of age-related decline, and the development of effective interventions. One line of investigation uses calorie restriction as a key experimental manipulation for identifying the basis of improved healthspan across a wide range of species, from worms and flies to rats and monkeys. Related efforts focus on neurocognitive aging, using molecular, neuroanatomical and electrophysiological approaches to understand the basis of successful and impaired trajectories. A primary objective is the preclinical development of epigenetic, pharmacological, and nutritional interventions that enable optimally healthy outcomes in aging.
The LG views aging as an integrated extension of human development, with important genes influencing the course of aging even in embryonic and fetal life. The long-term goal is to prevent or ameliorate problems of aging tissues by understanding the coordinated action of genes in the normal pathways and genetic disorders that affect development, and in stem cells that may help to regenerate tissues. The programs include extensions to 1) an initiative to look for biomarkers of aging, disease progression, and gene function using novel pattern recognition algorithms and image informatics systems; and 2) investigation of mechanisms of DNA damage response, chromatin remodeling, and their connections with genome instability diseases and cancer.
The LI aims to uncover the fundamental cellular, genetic, and molecular mechanisms that contribute to changes in the immune system during the aging process and also contribute to age-associated diseases that increase incidence with advancing age. The LI has 7 major areas of concentration: 1) role of telomere length and telomerase activity in lymphocyte function and aging; 2) molecular analysis of differentially regulated genes involved in lymphoid cell and organ development, differentiation, trafficking and activation; 3) molecular mechanisms of memory lymphocyte formation, maintenance and function; 4) study and use of biological response modifiers to optimize and control leukocyte trafficking, activation, organ engraftment and vaccine efficacy in normal and aging hosts; 5) induction of antigen-specific tolerance and use in transplantation and autoimmunity; 6) cellular and molecular dynamics involved in thymic involution and regeneration; and 7) understanding the molecular and biological aspects of tumor cell development and metastasis.
The LMG investigates processes and mechanisms such as genomic instability, DNA repair, DNA replication, and transcription with special attention to examining the role of DNA damage accumulation in senescence as the major molecular change with aging. The Oxidative DNA Damage Processing and Mitochondrial Functions Unit investigates the basis for the mitochondrial hypothesis of aging which states that accumulation of DNA damage with aging leads to the phenotypical changes that are observed in senescence and age-associated disease. The Repair of Endogenous DNA Damage Section investigates the mechanism involved in base excision repair and the function of individual DNA repair proteins and their interaction. The Telomere Maintenance and DNA Repair Unit studies the proteins and functions involved in maintenance of the chromosome ends, telomeres, processes of genome stability to reveal the genes or pathways that are important in telomere length regulation and maintenance and genomic stability. The Gene Targeting Unit is developing oligonucleotides that can form a three-stranded DNA structure called a triple helix. Eventually this approach will be used to modulate genomic sequences with targeted gene knockout as a specific application. The Antibody Diversity Section investigates the mechanism of somatic hypermutation of immunoglobin genes and is studying the roles of DNA polymerases and mismatch DNA repair proteins in the mechanism. The Section on DNA Helicases focuses on the roles of DNA helicases in genomic stability.
The LNG studies neurodegenerative diseases based on a resolution of their genetic etiology. The Molecular Genetics Section is focused on finding genes for neurodegenerative disease; the Cell Biology & Gene Expression Section seeks to develop an understanding of the effects of mutant genes on cell physiology; the Transgenic Unit examines the pathogenesis of neurodegenerative disorders in whole animals and to test potential treatments for the diseases; and the Neuromuscular Disease Research Group works toward an understanding of the genetic basis of neuromuscular disorders. Underpinning this structure are 3 groups: a Clinical Core whose role is to identify patients with neurological disorders and facilitate collaborations with clinical investigators from around the world, a Computational Biology Core whose role is to facilitate the analysis of laboratory data in the broad context of the wealth of information available through the Human Genome Project and related endeavors, and a Genomic Technologies Group whose role is to is to leverage and support the most recent genomic approaches.
The LNS seeks to understand the cellular and molecular mechanisms of neural plasticity during aging and to develop novel interventions for the prevention and treatment of neurodegenerative conditions such as Alzheimer's, Parkinson's, and Huntington's diseases, as well as stroke. The LNS has a particular focus on signal transduction pathways that control the development and plasticity of nerve cell circuits, and how these pathways are altered in aging and neurological disorders. Examples include: neurotrophic factor signaling; adaptive stress response pathways, cellular calcium homeostasis; and pathways that modify energy metabolism and oxidative stress. Using animal models, LNS investigators are discovering how factors such as dietary energy intake and exercise affect the brain during aging, and they are developing and testing novel drugs that preserve or enhance brain function using animal models.
The LPC conducts basic and clinical research on individual differences in cognitive and personality processes and traits; investigates the influence of age on these variables and their reciprocal influence on health, well-being, and adaptation; employs longitudinal, experimental, and epidemiological methods in the analysis of psychological and psychosocial issues of aging, including health and illness, predictors of cognitive decline and maintenance of cognitive health, models of adult personality, and correlates of disease risk factors; and applies neuroimaging paradigms, including MRI and PET scanning, to identify early markers of Alzheimer’s disease and cognitive decline and factors that may modify age-related changes in cognition.
The overall goals of the Clinical Research Branch (CRB) are: 1) the conduct of major longitudinal studies of aging including the Baltimore Longitudinal Study on Aging (BLSA) and the Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) studies; and 2) to support and carry out translational research in the major areas of clinical research focus of NIA Intramural Research Program laboratories including longitudinal studies and interventional trials with a focus on cardiology, neurology, endocrinology and oncology disease areas. In the latter, the branch: 1) provides the infrastructure needed to promote high quality clinical research and to ensure patient safety including: protocol review, clinic infrastructure, nursing and physician support, clinical informatics, data and safety management; 2) monitors and maintains quality assurance of the intramural clinical research program; 3) develops and implements clinical program priorities, allocates clinical resources; 4) integrates the established research themes and projects with clinical relevance from various IRP laboratories and branches; 5) evaluates program effectiveness and represents the IRP in management and scientific decision-making meetings within the Institute; 6) coordinates the credentialing of health care providers within the Institute; 7) coordinates and provides clinical research training for NIA staff and fellows; and 8) develops novel approaches for carrying out translational research in an efficient and cost-effective manner.