The NIH Almanac

Mission

Since 1974, the mission of the National Institute on Aging (NIA) has been to improve the health and well-being of older Americans through biomedical, social, and behavioral research.

NIA research focuses on aging processes, age-related diseases, and special problems and needs of the aged. Towards this mission, NIA conducts and supports research on aging through extramural and intramural programs. The extramural program funds research and training at universities, hospitals, medical centers, and other public and private organizations nationwide. The intramural program conducts basic and clinical research in Baltimore and on the NIH campus in Bethesda, Maryland.

The Institute also supports research training across its programs to maintain and build a strong cadre of highly skilled research scientists from all population groups.

Further, NIA communicates with a variety of audiences about research on aging and about healthy aging and age-related diseases and conditions. A major focus of these efforts is to provide evidence-based information to a broad range of older people, families, health professionals, and policymakers.

Important Events in NIA History

December 2, 1971—The White House Conference on Aging recommends the creation of a separate National Institute on Aging.

May 31, 1974—Public Law 93-296 authorizes the establishment of a National Institute on Aging and mandates the Institute develop a national comprehensive plan to coordinate the U.S. Department of Health, Education, and Welfare (succeeded by the Department of Health and Human Services) involvement in aging research.

October 7, 1974—The National Institute on Aging is established.

April 23, 1975—First meeting of the National Advisory Council on Aging is held.

July 1, 1975—The Adult Development and Aging Branch and Gerontology Research Center become the core of NIA.

December 8, 1976—Research plan required by P.L. 93-296 is transmitted to the Congress.

September 20, 1982—NIA Laboratory of Neurosciences Clinical Program admits first inpatient to a new unit at the NIH Clinical Center.

September 9-11, 1983—The Institute marks the 25th anniversary of the Baltimore Longitudinal Study of Aging. The first volunteers joined this unique study in 1958.

1984—NIA funds Alzheimer's Disease Centers, where researchers at medical institutions nationwide focus on prevention and treatment while improving care and diagnosis.

1986—Per congressional direction, NIA funds the Federal Forum on Aging-Related Statistics, a coordinating organization made up of more than 35 Federal agencies, charged with providing an integrating focus identifying national data needs and developing and disseminating these data.

November 14, 1986—P.L. 99-660, section 501-503, authorizes NIA's Alzheimer's Disease Education and Referral (ADEAR) Center as part of a broad program to conduct research and distribute information about Alzheimer's disease to health professionals, patients and their families, and the general public. Under sections 301-302, Congress authorizes NIA to make Leadership and Excellence awards in Alzheimer's Disease (LEAD) to researchers making significant contributions to Alzheimer's disease and related dementias research.

November 4, 1988—P.L. 100-607 establishes the Geriatric Research and Training Centers, renamed the Claude D. Pepper Older American Independence Centers in 1990 and charged with conducting research on diseases that threaten independent living.

1991—NIA sets up the Alzheimer's Disease Cooperative Study, an ongoing consortium of academic medical centers and others to facilitate clinical trials research.

1992—NIA and the University of Michigan begin the Health and Retirement Study, which follows more than 20,000 people at 2-year intervals, providing data from pre-retirement to advanced age to allow multidisciplinary study of the causes and course of retirement.

1993—The first Edward Roybal Centers for Research on Applied Gerontology are authorized focusing on translational research to convert basic and clinical findings into programs that improve the lives of older people and their families.

NIA launches the Longevity Assurance Genes initiative, an interactive network of funded researchers looking for genetic clues to longevity, using a variety of lower organisms such as C. elegans, Drosophila, and yeast.

1994—The first Demography of Aging Centers are funded to provide research on health, economics, and aging and to make more effective use of data from several national surveys of health, retirement, and long-term care.

The Study of Women's Health Across the Nation (SWAN) is launched to characterize in diverse populations the biological and psychosocial influences related to the transition to menopause.

1995—Nathan Shock Centers of Excellence in Basic Biology of Aging are established to further the study of the basic processes of aging.

1996—NIA introduces its Exercise: A Guide from the National Institute on Aging, providing encouragement and evidence-based guidance for older adults to engage in exercise.

1997—The Resource Centers for Minority Aging Research (RCMAR) is funded to investigate the variability of health differences experienced across racial and ethnic groups, as well as the mentoring of new scholars in health disparities research.

1999—As part of NIA's 25th anniversary celebration, a strategic plan is formulated and made available for public comment. The plan addressees scientific topics holding the greatest promise for advancing knowledge in areas such as the basic biology of aging, geriatrics, and social and behavioral functioning.

2000—The Institute distributes established mouse cDNA microarray/clone set containing more than 15,000 unique genes to 10 designated academic centers worldwide. Link to Story.

2001—In a unique private-public partnership, NIA joins the Osteoarthritis Initiative to bring together resources and commitment to the search for biological markers of osteoarthritis. Link to Story.

NIA and the Icelandic Heart Association announce collaboration on a vast study on the interactions of age, genes, and the environment. The collaboration extends 34 years of data on the health of 23,000 Icelandic residents into the new millennium. Link to Story.

NIA funds the ProgeNIA project, an international research initiative to study the underlying genetic processes involved in age-related traits and diseases. Link to Story.

2003—NIA and the National Library of Medicine (NLM) launch NIHSeniorhealth.gov, a web site designed to encourage older people to use the Internet. Link to Story.

The NIA, joined by the Alzheimer's Association, expands the Alzheimer's Disease Genetics Initiative to create a large bank of genetic materials and cell lines for study to speed up the discovery of risk-factor genes for late-onset Alzheimer's disease.

NIA and the American Federation for Aging Research—in collaboration with the John A. Hartford Foundation, the Atlantic Philanthropies, and the Staff Foundation—establish a public-private partnership to support clinically trained junior faculty to pursue careers in aging research.

2004—NIA launches the Longevity Consortium, a network of investigators from several large-scale human cohort studies working in collaboration with individual basic biological aging researchers to facilitate the discovery, confirmation, and understanding of genetic determinants of healthy human longevity.

NIA begins the Long Life Family Study, an international multicenter research project to examine families with high numbers of long-lived individuals to better understand the genetic and environmental contributions to exceptional long life in families.

NIA, in conjunction with other Federal agencies and private companies and organizations through the Foundation for the National Institutes of Health, leads the Alzheimer's Disease Neuroimaging Initiative. Link to Story.

NIA launches Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS), a multidisciplinary community-based, longitudinal, epidemiologic study examining the influences and interaction of race and socioeconomic status on the development of age-associated health disparities among socioeconomically diverse African Americans and whites in Baltimore.

2006—NIA leads the NIH conference “AD: Setting the Research Agenda a Century after Auguste D,” a conclave assessing the state of current Alzheimer's disease research and the most promising routes to progress.

2007—U.S. Secretary of State Condoleezza Rice sponsors the Summit on Global Aging in collaboration with NIA to call attention to challenges and opportunities worldwide from population aging.

Biographical Sketch of NIA Director Richard J. Hodes, M.D.

Richard J. Hodes, M.D., directs the research program of the National Institute on Aging (NIA) at the National Institutes of Health. A leading immunologist, Dr. Hodes was named Director of the NIA in 1993 to oversee studies of the basic, clinical, epidemiological, and social aspects of aging.

Under Dr. Hodes's stewardship, the NIA budget has surpassed $1 billion, reflecting increased public interest in aging as America and the world grow older. Dr. Hodes has devoted his tenure to the development of a strong, diverse, and balanced research program, focusing on the genetics and biology of aging; basic and clinical studies aimed at reducing disease and disability, including Alzheimer's disease and age-related cognitive change; and investigation of the behavioral and social aspects of aging. Ultimately, these efforts have one goal—improving the health and quality of life for older people and their families.

In the past decade, the NIA has worked in new and innovative ways to conduct research and to translate research findings into practical interventions and public information. In Alzheimer's disease, new initiatives to find associated genes and to identify biomarkers are expected to considerably reduce the length and cost of clinical trials, thereby speeding up the testing of new therapies for Alzheimer's disease. In biology, research conducted and supported by NIA examines the genetic and other factors influencing lifespan and age-related diseases and conditions. Research in geriatrics is uncovering new ways to combat frailty with age, and social and demographic research is deepening understanding of the individual behaviors and societal decisions that affect wellbeing.

Dr. Hodes is a Diplomate of the American Board of Internal Medicine. In 1995, he was elected a member of The Dana Alliance for Brain Initiatives; in 1997, he was elected a Fellow of the American Association for the Advancement of Science; and in 1999, he was elected to membership in the Institute of Medicine of the National Academy of Sciences.

Dr. Hodes is actively involved in research on the NIH campus through his direction of the Immune Regulation Section, a laboratory at the National Cancer Institute focused on cellular and molecular events that activate the immune response. This involvement in campus research also serves to strengthen ties with other NIH scientists studying age-related diseases. As author of more than 200 research papers, Dr. Hodes is an influential scientist in the field of immunology.

Dr. Hodes received his undergraduate degree from Yale University (summa cum laude) in 1965 and was a research fellow at the Karolinska Institute in Stockholm, Sweden, prior to attending Harvard Medical School, from which he graduated (magna cum laude) in 1971. Dr. Hodes completed training in Internal Medicine at Massachusetts General Hospital and in Oncology at the National Cancer Institute.

NIA Directors

Name	In Office from	To
Norman Kretchmer (Acting)	October 1974	July 1975
Richard C. Greulich (Acting)	July 1975	April 1976
Robert N. Butler	May 1, 1976	July 1982
Robert L. Ringler (Acting)	July 16, 1982	June 30, 1983
T. Franklin Williams	July 1, 1983	July 31, 1991
Gene D. Cohen (Acting)	July 1, 1991	May 31, 1993
Richard J. Hodes	June 1, 1993	Present

Research Programs

Intramural Research

The goals of NIA's Intramural Research Program (IRP) are 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 general biology of aging have focused 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 has included 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 the 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 IRP comprises 11 scientific laboratories, a clinical branch, a research resources support branch, and 2 sections. The research program includes the scientific disciplines of biochemistry, cell and molecular biology, structural biology, genetics, immunology, neurogenetics, behavioral sciences (psychology, cognition, and psychophysiology), epidemiology, statistics, and clinical research and the medical disciplines of neurobiology, immunology, endocrinology, cardiology, rheumatology, hematology, oncology, and gerontology.

Most IRP research is conducted at the Gerontology Research Center in Baltimore. Some laboratory space is also located at the TRIAD Building and the Holabird Research Facility in Baltimore. 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.

IRP Laboratories

Laboratory of Cardiovascular Science (LCS)

LCS is organized into 4 sections and 5 units, each headed by a senior scientist:

• Cardiac Function Section
• Cardiovascular Biology Unit
• Human Cardiovascular Studies Unit
• Hypertension Unit
• Molecular Cardiology Unit
• Cardioprotection Unit
• Cellular Biophysics Section
• Receptor Signaling Section
• Translational Cardiovascular Studies Section

The overall goals of LCS are: 1) to identify age-associated changes 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 cardiovascular diseases in older persons; 3) to study basic mechanisms in excitation-contraction coupling in cardiac cells and how these are modulated by surface receptor signaling pathways; 4) to elucidate factors that maintain stem cell pluripotentiality, that promote the commitment of stem cells to the cardiac lineage, and that regulate their development as cardiac cells; 5) to elucidate mechanisms that govern cardiac and vascular cell survival; 6) to determine mechanisms that govern neuro-hormonal behavioral aspects of hypertension; and 7) to establish the potentials and limitations of new therapeutic approaches such as changes in lifestyle, novel pharmacologic agents, and gene or stem cell transfer techniques in aging or cardiovascular disease states. In meeting these objectives, studies are performed in human volunteers, intact animals, isolated heart and vascular tissues, isolated cardiac and vascular cells, and subcellular organelles.

Laboratory of Cellular and Molecular Biology (LCMB)

The LCMB comprises 6 independent research programs headed by either a tenure-track scientist or a senior investigator. These programs include:

• Gene Regulation Section
• RNA Regulation Section
• Cancer Genomics Signaling Section
• DNA Repair Unit
• Chromatin Structure and Function Unit
• Molecular Immunology Unit

The individual research programs share several areas of emphasis, including: 1) the elucidation 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 being 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 ultimate goal of these programs is 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.

Combined, the programs within the LCMB provide extensive and broad expertise in the areas of biochemistry, cellular and molecular biology, immunology, and genetics. The LCMB programs also offer specialized expertise in a variety of approaches used to analyze or manipulate gene expression. Important ongoing projects are examining the genetics of ovarian cancer, the regulation of gene expression through transcriptional and post-transcriptional mechanisms, the control of stress- and mitogen-induced signaling cascades, the regulation of T-cell activation, the role of chromatin re-modeling complex in cytokine gene expression, and the mechanism of somatic hypermutation of immunoglobulin genes.

Laboratory of Clinical Investigation (LCI)

The LCI is organized into 4 sections:

• Bioanalytical and Drug Discovery Section
• Diabetes Section
• In Vivo Nuclear Magnetic Resonance Section
• Molecular and Clinical Pharmacology Section

The overall goals of the LCI are: 1) to 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) to 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) to identify therapeutic targets in each of these areas and in other laboratories across the NIA IRP; and 4) to 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.

To support the objectives as well as the more usual biological sciences, the physical sciences (in vivo nuclear magnetic resonance (NMR), bioanalytical separation, and analytic techniques) are brought to bear. This permits asking questions “at the cutting edge” to achieve the above goals. For example, NMR is one of the better (but rarely used) methods of characterizing genetically altered (transgenic) mice. NMR is used by all the LCI sections, and is a resource to the whole NIA IRP, to understand the role of specific genetic changes in whole-animal physiology. In the same manner, to understand post-genetic alterations in cellular constituents, the emerging science of proteomics is assuming greater importance.

The Bioanalytical/Drug Discovery Section uses the best tools for protein analysis, such as matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) and capillary electrophoresis/laser induced fluorescence (CE-LIF). Access to these tools helps all LCI sections and the NIA IRP to be at the leading edge of research to understand the contribution of post-genetic protein alterations as well as genomic variability, which will lead to better understanding of diversity in cellular function in health and disease.

Current ongoing projects include studies of: the genetic polymorphisms associated with variability in vascular response; the use of neural networks and wavelet analysis in pharmacokinetic/pharmacodynamic studies; insulinotropic agents in the differentiation of the pancreatic islet beta cell and their use in the treatment of type 2 diabetes mellitus; the mechanism of insulin receptor signal transduction; human calcium channel function in aging, atherosclerosis, and neurodegenerative disease; the role of skeletal muscle atrophy and inflammation in osteoarthritis; the use of in vivo NMR to characterize the evolution of arthritis and potential therapies; and applications of receptor and enzyme immobilized column technology for identification of candidate molecules as new drugs.

Laboratory of Epidemiology, Demography, and Biometry (LEDB)
The LEDB conducts research on aging and age-associated diseases and conditions using population-based epidemiologic and biometric methods. Laboratory staff works collaboratively both within and among 4 groups:

• Epidemiology and Demography Section, which plans and conducts studies on chronic diseases, functional status, and disability in the older population.
• Neuroepidemiology Section, which conducts interdisciplinary research on the association of genetic, molecular, and behavioral factors in relation to dementia and neurological disease in old age.
• Geriatric Epidemiology Section, which carries out interdisciplinary studies of the association of behavioral, molecular, and genetic risk factors with health outcomes in old age, including discrete diseases, disability, and mortality.
• Biometry Section, which conducts research on statistical issues and epidemiologic and demographic methodologies related to research on aging. This Section also provides statistical consulting, computing, graphics, and data management services to the other units within LEDB.

Collaborators also include other NIA and outside investigators. The mission of LEDB 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. These general principles have guided a research agenda that emphasizes 3 important and interrelated areas: Physical Function and Disability; Cognitive Function and Dementia; and Age-associated Diseases and Conditions, including successful or effective aging. In each area, studies are influenced by results of analytic efforts of current LEDB-sponsored studies and by opportunities created by advances in biology and medicine. Cross-cutting research themes being addressed by more than one LEDB investigator are: functional status, comorbidity, genetic epidemiology, inflammation, socioeconomic status and health, diabetes/metabolism, and energy balance–physical activity/obesity.

Senior LEDB staff consults with other components within the IRP, NIA, other NIH Institutes, other government agencies, and the academic and private sectors. LEDB research interests use data from the Established Populations for Epidemiologic Studies of the Elderly (EPESE); the Women's Health and Aging Study (WHAS); the Honolulu-Asia Aging Study (HAAS); the Health, Aging, and Body Composition (Health ABC) Study; Age, Gene/Environment Susceptibility (AGES) Study Reykjavik, Iceland; and the In Chianti Study. Senior investigators are leading efforts in 2 large clinical trials: ACCORD-MIND (Action to Control Cardiovascular Risk in Diabetes), a study to evaluate whether aggressive control of risk factors for atherosclerosis in diabetics reduces cognitive decline and LIFE (Lifestyle Interventions and Independence for Elders), a trial to evaluate if physical activity prevents the onset of disability.

Laboratory of Experimental Gerontology (LEG)

The LEG conducts basic research in experimental models focused on interventions that retard aging processes. One of the major projects is a longitudinal study of the potential beneficial effects of diet restriction on aging in nonhuman primates. A second major focus for investigation isin vivo rodent, fly, and nematode models andin vitro cellular models to identify protective mechanisms invoked by calorie restriction. A third major project involves a standardized research program to evaluate various aging interventions (pharmaceuticals, hormones, dietary supplements, genes) in mouse models to assess effects on lifespan, pathology, and functional capacity at older ages. Another important activity of LEG is the development of behavioral assays for assessing aging in rodents and nonhuman primates with a focus on motor and memory performance. Related research seeks to identify mechanisms of age-related decline in motor and memory performance. A primary objective of the research is preclinical development of pharmacological, genetic, and nutritional interventions that improve function.

Laboratory of Genetics (LG)

LG efforts are based on the view that aging is an integrated extension of human development, with important genes influencing the course of aging even in embryonic and fetal life. Our long-term goal is to borrow from development to prolong or ameliorate problems of aging tissues. This is done by understanding the coordinated action of genes in normal pathways and genetic disorders that affect development, and in stem cells that can grow indefinitely and may help to regenerate tissues. The LG includes the following components:

• Developmental Genomics and Aging Section, which performs molecular analysis of stem cells and early embryos
• Human Genetics Section, which conducts genetic analysis of age-related tissue-developmental pathways and risk factors
• Genome Instability and Chromatin Remodeling Section, which focuses on chromatin remodeling and DNA repair
• Gene Recovery and Analysis Unit, which studies long-range gene regulation and recombineering
• Image Informatics and Computational Biology Unit, which focuses on quantitative visual assays

Laboratory of Immunology (LI)

The LI research program 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 (e.g., increasing incidence with advancing age). The LI has 7 major areas of concentration and long-term development, including: 1) the molecular examination of telomere length and telomerase activity in lymphocyte populations; 2) the 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 activation; 4) the 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) the 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 Clinical Immunology Section focuses on several important project areas, including the role of inflammation and cytokines in neurodegeneration and Alzheimer's disease, the role of lipid rafts and cholesterol in the maintenance of chemokine signaling and cellular activation in the aged host and the immunoregulatory effects of pituitary and metabolic hormones in inflammation and immunity. In addition, ongoing studies use high-throughput gene expression profiling techniques to unravel pathways involved in cellular migration and metastasis of cancers such as melanoma, a highly immune-modulated cancer. Especially important are pathways associated with chemokine, cytokine, and T-cell receptor signaling and pathways reflective of melanocyte development that go awry in metastasis, involving molecules such as Wnt5a.
  
  
• The Lymphocyte Cell Biology Unit's recent work has focused on understanding the cell biology of lymphomas; tumor-induced immunosuppression; the roles of PTEN and mTOR in lymphocyte activation and function; and defining the role of CD28-mediated costimulatory signal in immune responses, particularly in cancer and autoimmune disease.
  
  
• The Immunotherapeutics Unit works to develop simpler and more potent vaccines for cancer and other clinically relevant diseases utilizing strategies that target antigen presenting cells. Current research seeks to assess a carrier potency and mechanism of antigen presentation of chemokine- and defensin-based vaccines, to search for alternative delivery methods for DNA vaccines (such as chemokine bearing empty protein particles), and to establish models to study therapeutic efficacy of newly found tumor-associated antigens.
  
  
• The Lymphocyte Development Unit focuses on understanding the role of Wnt-beta catenin-TCF signaling pathway in the development and function of T lymphocytes. Interaction of this signaling pathway with Notch 1 mediated signals, as well as pre-TCR and TCR mediated signals will provide insight into the programs utilized by the bone marrow derived precursors as they commit to the T cell lineage, mature and age in mammals.
  
  
• The Lymphocyte Differentiation Section is investigating the influence of age on telomere length and telomerase expression in peripheral blood T lymphocytes in vivo, regulation and function of telomerase in lymphocytes, and the molecular mechanisms involved in the generation and maintenance of memory T lymphocytes and their effector function.

Laboratory of Molecular Gerontology (LMG)

The LMG investigates processes and mechanisms such as genomic instability, DNA repair, DNA replication, and transcription. This laboratory comprises 4 sections and 3 units:

• The DNA Repair Section examines the role of DNA damage accumulation in senescence as the major molecular change with aging. The goal of LMG and the DNA Repair Section is to understand the underlying mechanisms involved in DNA damage formation and its processing, as well as the changes that take place with aging that make aging cells susceptible to cancer. The investigative focus is on the molecular mechanisms involved in DNA repair and determinants of genomic instability in normal, senescent, and cancer cells.
  
  Also in this section, Premature Aging Disease studies examine the molecular functions and protein interactions of the proteins defective in the premature aging disorders Werner and Cockayne syndromes. The cell biological, biochemical, and functional properties of premature aging proteins are investigated with a special focus on the protein partners, thus searching for the pathways in which they participate.
  
  
• The Unit on Oxidative DNA Damage Processing and Mitochondrial Functions 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. Mechanistic studies dissecting base excision repair at the level of mitochondria are the central work of this unit.
  
  
• The Unit on Structure and Function in Base Excision Repair investigates the mechanism involved in base excision repair, the DNA repair pathway responsible for the removal of oxidative DNA lesions. The Unit studies the functions of individual proteins and the nature of their interactions. The approach is a combination of protein structure and function, with a view of how mutations and alterations in these proteins in the population change their function and cause disease.
  
  
• The Unit on Telomeric Maintenance and DNA Repair studies the proteins and functions involved in maintenance of the chromosome ends—known as telomeres—which help to stabilize the genome. Loss of telomere protection is frequently observed in elder populations, cellular senescence, and premature aging syndromes. In addition, mutations in genes that are critical in telomere maintenance have been found in human disorders, such as diseases with bone marrow failure and idiopathic pulmonary fibrosis. Furthermore, telomere dysfunction contributes to genomic instability that leads to cell death, cell proliferation defects, and malignant transformation, which may in turn contribute to age related-disorders and a higher incidence of cancer during aging. This research will elucidate the genes or pathways that are important in telomere length regulation and maintenance and genomic stability. Studies also involve analysis of the repair of damage to telomere DNA.
  
  
• The Section on Gene Targeting is developing oligonucleotides that can form a 3-stranded DNA structure called a triple helix. The third strand lies in the major groove of an intact double helix and is stabilized by hydrogen bonds between the bases in the third strand and the purine bases in the duplex. These oligonucleotides can be linked to DNA reactive compounds, and several research groups have demonstrated site-specific modification of DNA with these oligo-reagent conjugates. This approach can now be used to deliver additional DNA reactive compounds to specific genomic locations. Eventually this approach will be used to modulate genomic sequences with targeted gene knockout as a specific application.
  
  
• The Section on Antibody Diversity investigates the mechanism of somatic hypermutation of immunoglobin genes. Somatic hypermutation occurs at a frequency that is a million times greater than mutation in other genes. Evidence points to a process that involves DNA repair events at sites of lesions in the genes. This Section 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 growing number of DNA helicases implicated in human disease suggests that these enzymes have vital specialized roles during replication, DNA repair, recombination, and transcription. RecQ DNA helicases are of particular interest because the human hereditary disorders Werner syndrome, Bloom syndrome, and Rothmund-Thomson syndrome all arise from mutations in genes of the RecQ helicase family. This Section focuses on understanding the cellular and molecular defects of these disorders and of RecQ and related proteins.

Laboratory of Neurogenetics (LNG)

The LNG aims to understand neurodegenerative diseases based on a resolution of their genetic etiology, and to use this understanding to develop cellular and animal models of disease. These genetic-based models can then be used to test theories of disease pathogenesis.

To achieve this goal, LNG is divided into 3 main research groups:

• Molecular Genetics Section, which seeks to find genes for neurodegenerative disease. At present, the focus of the Section's work is movement disorders. Identifying rare mutations that cause Parkinson's disease, dystonia, ataxia, and other conditions will enhance understanding of the pathoetiology of these and related disorders. Of note has been our observation that triplication of the alpha-synuclein gene can result in a rare form of Parkinson's disease. LNG has also recently found the gene LRRK2/Dardarin as a common cause for Parkinson's disease. In addition, NIA is leading a study to find the basis of the predisposition of late-onset dementias including Alzheimer's disease.
  
  
• Cell Biology and Gene Expression Unit, which studies the effects of mutant genes on cell physiology. The goal of the Unit is to develop an understanding of the cell biology and protein chemistry of proteins involved in disease pathogenesis, and in particular, to try to elucidate which biochemical pathways are affected by pathogenic mutations. Currently, the major focus is on the molecular interactions between the proteins encoded by the multiple genes involved in Parkinson's disease. This involves making use of the mutant forms of proteins to clarify the central events in neurodegeneration and tease out the primary pathways leading to neuronal cell loss from secondary occurrences. Part of this work also involves understanding the normal function of proteins, which is especially important for genes with recessive, loss of function mutations. Some smaller projects focus on other movement disorders such as dystonia and amyotrophic lateral sclerosis (ALS), which largely follow the same logic.
  
  
• Transgenic Unit, which studies pathogenesis in whole animals and tests potential treatments for the diseases. The goal of the Transgenic Unit is to employ the genetically engineered mouse model to study the pathogenic mechanisms and therapeutics of neurodegenerative diseases. Currently, 3 major neurodegenerative diseases: Alzheimer's disease, Parkinson's disease, and ALS are being actively studied. For Alzheimer's disease, the BACE1-null and APP/PS1 transgenic mice have been developed to directly examine the “Amyloid Hypothesis,” in which the aggregation of Aβ is critical for the pathogenesis of the disease. For ALS, the ALS2 knockout mouse has been generated and is ready for characterization on both the cellular and the behavioral levels. Meanwhile, a missense mutation of dynactin/P150 has been introduced into the mouse to model this newly defined genetic mutation that also causes motor neuron disease. For Parkinson's disease, the DJ-1 knockout mouse will be made and analyzed to examine the physiological functions of this protein and the underlying pathogenic mechanisms of this disorder.

Underpinning these Sections are 3 Cores:

• Clinical Core, which aims to identify patients with neurological disorders and facilitate collaborations with clinical investigators from around the world. The Clinical Core has protocols approved to collect clinical data and samples from families with movement disorders and dementia, diseases of the autonomic nervous system, and stroke. The aim of this Core is twofold: to collect information on families with familial disease and, as a longer term goal, to characterize fully the phenotype of these familial diseases, especially features that occur in the preclinical period of the disease process. This plan is designed to enable the identification of very early markers of disease so that treatments can be targeted to disease pathogenesis early in the process. A subsidiary aim of the Core is to examine diseases in minority populations, as it is becoming increasingly apparent that clinical features of diseases have different appearances in different racial groups. The current focus of the Clinical Core is to characterize families with Parkinsonism, dystonia, and restless legs syndrome.
  
  
• Computational Biology Core, which facilitates the analysis of laboratory data in the broad context of the wealth of information available through the Human Genome Project and related endeavors. The roles of the Core are twofold: first, to enable the interpretation of data from genetic, genomic, and proteomic studies in the context of the wealth of data and computational tools available from Web-based sources, and second, to improve our high-throughput data pipeline and database management system to allow the integration and easy access of both clinical and laboratory data while maintaining appropriate data security and patient confidentiality.
  
  
• Linkage Analysis Core, which performs genome screens and linkage and association analyses. The primary function of the Linkage Analysis Core is to carry out linkage analysis on families and populations with neurodegenerative disease. Currently, the main projects of the Core focus on doing genome screens on siblings affected with childhood-onset schizophrenia and families affected with holoprosencephaly. Genetic analyses of families affected with Alzheimer's disease are also ongoing to identify new genes involved in the development of the disease.

Laboratory of Neurosciences (LNS)

The major goals of research at the LNS are 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. To address this area of research, LNS comprises 2 sections and 2 units:

• Cellular and Molecular Neurosciences Section
• Drug Design and Development Section
• Invertebrate Molecular Genetics Unit
• Receptor Pharmacology Unit

The ongoing work in this laboratory pursues a variety of projects, including oxidative stress and calcium regulation in neuronal cell models, signal transduction scaffolds and their modification by aging and disease, the role of dietary and behavioral factors in aging and age-related neurodegeneration, genetic abnormalities and the pathogenesis of neurodegenerative diseases, stem cell biology and therapy, mechanisms of neuronal cell apoptosis, and drug discovery.

For example, LNS investigators are examining the biochemical and cellular consequences of genetic mutations that cause inherited forms of Alzheimer's and Parkinson's diseases and amyotrophic lateral sclerosis. They are using cell culture and animal models of these diseases to screen drugs and dietary supplements to determine their effectiveness in preventing or slowing the progression of disease. Ongoing work has shown that when rats and mice are maintained on a dietary energy restriction regimen, neurons are more resistant to dysfunction and degeneration in experimental models of neurodegenerative disorders. Other studies by LNS investigators have documented beneficial effects of exercise, and adverse effects of diabetes, on neurogenesis (the production of new neurons from stem cells) and synaptic plasticity.

Recent findings by LNS investigators include: preclinical evidence of a clinical benefit of treatment with the glucagon-like peptide 1 analog exendin-4 in models of neurodegenerative disorders; the establishment of a role for telomerase in regulating neural stem cell fate during brain cell development; genetic data suggesting that the nervous system controls lifespan in the nematode C. elegans; evidence that brain-derived neurotrophic factor mediates beneficial effects of dietary restriction on glucose regulation and longevity in mice; evidence that Notch signaling plays an important role in synaptic plasticity related to learning and memory, and in brain injury responses; the involvement of innate immune responses and toll-like receptors in stroke pathogenesis; evidence that abnormalities in the metabolism of membrane lipids called ceramides are involved in neuronal dysfunction and degeneration in Alzheimer's disease; advances in understanding the molecular profiles of embryonic human stem cells and the mechanisms that control their self-renewal and differentiation.

Laboratory of Personality and Cognition (LPC)

The LPC conducts basic and clinical research on individuals 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; and employs longitudinal, experimental, and epidemiological methods in the analysis of psychological and psychosocial issues of aging, including health and illness, predictors of intellectual competence and decline, models of adult personality, and correlates of disease risk factors.

• The Personality, Stress, and Coping Section conducts basic and applied research on personality as it relates to aging individuals. Recent work has focused on personality development in adulthood and adolescence, cross-cultural studies of the Five-Factor Model (FFM), and determining the relationship of normal personality traits to psychopathology. This innovative work has contributed to the delineation of the development curve of personality traits backward from adulthood and helped to provide information that bridges the gap with childhood temperament studies. The group's transcultural research has provided important insights into the structure and development of personality traits and the unique expression of traits in specific cultures. In addition, work from this section has underscored the usefulness of lower order personality assessments in the evaluation of anxiety and major depressive disorders.
  
  
• The Cognition Section conducts studies that attempt to distinguish pathological from healthy, age-related cognitive changes in a broad range of cognitive tasks, including short- and long-term memory, visuo-spatial rotation, and attention and decision tasks. Ongoing research centers on modulators of age-associated cognitive changes, age-associated changes in cognition and risks for Alzheimer's disease, age-associated changes in neuroanatomy and neurophysiology, and the effects of hormone replacement therapy on memory and cognition.

IRP Branches

Clinical Research Branch (CRB)

The CRB is organized into the following components:

• Office of the Clinical Director
• Longitudinal Studies Section
• Health Disparities Research Section
• Translational Research and Medical Services Section
• Clinical Support Section
• Clinical Information and Data Management Section
• Cytapheresis Unit

The overall goals of the 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; 2) to support and carry out translational research in the major areas of clinical research focus of NIA IRP laboratories, including longitudinal studies and interventional trials with a focus on cardiology, neurology, endocrinology, rheumatology, genetics, 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 and 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.

Ongoing research projects within the Branch include: 2 large longitudinal studies (BLSA and HANDLS); studies of factors predisposing patients to osteoarthritis and evaluation of muscular changes contributing to disability from this disease; and studies of neuromuscular/strength changes with aging.

The NIA IRP Cytapheresis Unit is a part of CRB that conducts cytapheresis on BLSA participants and other normal volunteers, providing important clinical research materials (T cells, B cells, monocytes) to program investigators examining immunosenescence, the role of telomeres in human aging and other age-related research. In addition, the CRB supports all other clinical studies in the areas of cardiology, neurology, endocrinology, genetics, rheumatology and oncology conducted within the NIA IRP through provision of protocol support, pharmacy support, and laboratory support under the Office of the Clinical Director and nursing support under the Clinical Support Section of the Branch.

Research Resources Branch (RRB)

The RRB provides centralized research resources and research support services essential to the productive conduct of biomedical research by the Intramural Research Program. Personnel in the Research Resources Branch represent a wide variety of talents, skills, and expertise for supporting intramural investigators.

The Branch is divided into 6 Sections that focus on particular specialties or types of service:

• Central Laboratory Services, which is subdivided into the Bioinformatics Unit, Confocal Microscopy, Gene Expression and Genomics Unit, Flow Cytometry, and Proteomics and Mass Spectrometry.
• Comparative Medicine, which includes animal husbandry for a variety of species, producing transgenic and knockout rodents, and the breeding, weaning, and mating of rodents consistent with the genetic model from which they derived.
• Instrumentation, Design and Fabrication
• Network, Computing, and Telephony
• Photography and Arts
• Statistical and Experimental Design.

Although the RRB primarily provides research services, Branch scientists also conduct several investigator-initiated projects. These projects include studies on the role of reactive oxygen species in ischemic preconditioning, bioinformatics, developing novel statistical models for survival analyses and predicting disease conditions, array-based technology development, gene expression studies in rodents, humans, and other species, and the identification of novel markers in quiescent murine and nonhuman hematopoietic stem cells.

IRP Independent Sections

Brain Physiology and Metabolism Section (BPMS)

The BPMS seeks to understand brain function and metabolism in aging and disease by studying animal models and human subjects. "Interface" research is conducted with potential clinical applications to provide fundamental information about how the brain works and what happens when it becomes dysfunctional.

Brain Lipid Metabolism and Function In Vivo. Mathematical models and novel methods are developed to examine the dynamics of brain lipid metabolism, to quantify and image in vivo brain signal transduction and other active processes involving fatty acids and phospholipids in unanesthetized experimental animals and human subjects. We have shown that a brain cascade involving the release of arachidonic acid (a second messenger) from phospholipids, and its conversion to prostaglandins by cyclooxygenase-2, is downregulated by different agents that are used to treat clinical bipolar disorder (e.g., lithium, valproic acid, and carbamazepine) and that this downregulation is due to reduced transcription of an arachidonic acid-specific cytosolic phospholipase A2.

We also have shown that the arachidonic acid cascade is upregulated in animal models of neuroinflammation and excitotoxicity, and that it can be modified by dietary regulation of nutritionally essential polyunsaturated fatty acids, including arachidonic and docosahexaenoic acids. Quantitative autoradiography with pharmacological challenge is employed to characterize signal transduction involving these fatty acids in awake rodent models, in response to pharmacological agents acting at receptors coupled to phospholipase A2, or modulating the release of neurotransmitters. Methods include in vivo pharmacokinetics, radiotracer and chemical analytical techniques applied to brain and plasma lipids, and enzyme chemistry and molecular biology. Basic studies lead to collaborative clinical protocols when using [1-11C] arachidonic or docosahexaenoic acid and positron emission tomography (PET) to quantify human brain polyunsaturated fatty acid metabolism in relation to disease and signal transduction. An independent molecular biology program uses drug-treated and genetic rodent models, as well as cell culture systems, to dissect out the molecular regulation by cyclooxygenase and related enzymes of brain metabolism of arachidonic acid and its eicosanoid metabolites, in models of excitotoxicity and neurodegeneration.

Molecular Dynamics Section (MDS)

The MDS research program has been studying free-radical reactions involving red cells. This includes the oxidative reactions involving free radicals as well as interactions with nitric oxide and nitrite, which may play a role in the transport of nitric oxide to the vasculature.

There are 3 major areas of investigation within MDS. These include:

• Delineating red cell oxidative stress in vitro and in vivo. This is accomplished by using electron paramagnetic resonance and fluorescence to quantitate heme degradation products including rhombic heme and low molecular weight fluorescent products formed in the cell. These products are being used as markers for oxidative stress experienced in vivo.
  
  
• Investigating the role of the red cell in the transport of amyloids and their oxidative processes, as well as the interaction of amyloids with endothelial cells and how red cells participate in this interaction. These studies suggest that the red cell may play a role in the pathological responses of amyloids.
  
  
• Examining the role of red cell nitric oxide on blood flow through the microcirculation under hypoxic conditions.

Extramural Research

Office of Extramural Activities

The OEA manages NIA's grants and training policies and procedures. The Office has responsibility for oversight of grants and contract administration, scientific review, and committee management functions. The Office serves as primary liaison for NIA with the NIH Office of Extramural Research and with other Institutes that share research interests. It also has primary responsibility for NIA's extramural training programs, career development programs, small business initiatives, and other special programs. The Office handles appeals, as well as scientific integrity and other ethical issues involved in the conduct of research. The OEA organizes meetings of the National Advisory Council on Aging and meetings of related groups. OEA has central responsibility for research training and career development activities at the Institute, including policies related to different mechanisms, eligibility, and initiatives to increase the number of underrepresented students and researchers trained in aging research.

• The Scientific Review Office (SRO) of the OEA is responsible for initial peer review of specific research applications assigned to the NIA. These include applications for grants to Centers, for program project initiatives, for scientific meetings, and for training and career development. Members of NIA's 4 review panels that correspond to the Institute's program areas and members of the Institute's special emphasis panels include non-government scientists who are themselves grantees and who are expert in the scientific areas of the applications they review.
  
  
• While the SRO interacts with applicants prior to the award of grants, the Grants and Contracts Management Office (GCMO) works with scientists and institutional research administrators to issue, manage, and close awards when the research is completed. GCMO staff members provide guidance on administrative and fiscal policies and practices for the investigator and for the institutional research administrators. For example, they address questions about allowable costs and about major changes in staff or content of the research project. The GCMO has legal responsibility for the fiscal management of the Institute's extramural grants and contracts.

External Scientific Review

In support of research, research training, and career development related to aging, the NIA awards grants to universities, hospitals, and research organizations throughout the U.S. and abroad. Approximately 80% of the funds appropriated to the NIA are disbursed through these extramural awards. Competition for this funding is very high. For example, over the past 10 years, NIA was able to fund fewer than 1 in 3 of the research project grant applications it received. To ensure that funded research is of the highest quality and serves the health needs of the nation, peer review committees comprising external scientific experts are brought together to review proposed and ongoing research.

Extramural Grant Review

Extramural research investigators trigger the grant review process by submitting grant applications to the NIH Center for Scientific Review (CSR). Initial review of applications may be assigned to an NIH Center review group or to NIA's initial review committee which handles program project, center, research career, scientific meeting, and institutional training grant applications, as well as applications submitted in response to Requests for Applications (RFAs) issued by NIA.

Applications within NIA's mandate are forwarded to NIA for funding consideration. Whether the applications are reviewed at the Center for Scientific Review or at the NIA, committees of experts, including NIH grantees, assess the significance, approach, and innovation of the proposed research, as well as the qualifications of the investigators and the quality of the institutional resources. Reviewers also assess applications for treatment of animal models, if relevant. For research involving humans, reviewers assess proposed plans for recruiting women and minorities to the studies. The judgment of the group on these parameters is summarized in a report (summary statement) and overall rating (priority score) of the application. These reports are provided to the applicants and to NIA officials. Among the applications assigned to the NIA, approximately the top half, as judged by initial review, are given a second level of review by the National Advisory Council on Aging.

National Advisory Council on Aging (NACA)

Congress created the National Advisory Council on Aging (NACA) to provide advice on programmatic and policy matters; specifically: "to advise, consult with, and make recommendations to the Secretary, HHS, the Assistant Secretary for Health; the Director, NIH; and the Director, NIA; on matters relating to the conduct and support of biomedical, social, and behavioral research, training, health information dissemination, and other programs with respect to the aging process and the diseases and other special problems and needs of the aged."

Grant applications (other than fellowship applications) must receive Council approval to be eligible for funding. In its deliberations, the NACA reviews summary statements to evaluate the fairness and appropriateness of the initial review of grant applications, and considers the scientific and public importance of the proposed work. In cases in which the applicant or NIA staff has concerns about the initial review of the application, NACA members can evaluate these concerns.

Council members also serve as a conduit for insights into the concerns and opinions of the research community, and assist in keeping the scientific community, Congress, and the public knowledgeable about the activities of the NIA. The NACA meets 3 times each year, typically for a period of 2 days, to review applications for grants and cooperative agreements for research and training. The group recommends funding of research applications that show significant promise of improving the quality of life and health care for the aged or making valuable contributions to our scientific knowledge of the aging process.

The NACA consists of 18 members appointed by the HHS Secretary and 5 non-voting ex officio members. Of the 18 appointed members, 12 are leading representatives of the health and scientific disciplines and are leaders in the fields of public health and the behavioral or social sciences relevant to the activities of the NIA, particularly with respect to biological and medical sciences relating to aging and public health. Six of the members are leaders from the general public in the fields of public policy, law, health policy, economics, and management. Members are invited to serve for overlapping 4-year terms.

Once the Council provides its recommendations, the NIA Director may approve payment of applications that have been favorably reviewed and for which sufficient funds are available. Primary weight is given to the scientific quality of the application as judged by initial peer review. Consideration is also given to the proposed research's relevance to NIA priorities and to the timeliness of the research.

Biology of Aging Program (BAP)

The BAP supports biomedical studies through various NIH grant mechanisms and contracts. The program plans, implements, and supports fundamental molecular, cellular, and genetic research on the mechanisms of aging. It also supports resource facilities that provide aged animals and cell cultures for use in aging research. The BAP includes the following Programs:

• Animal Models. The objective of the Animal Models Program is to identify and develop new animal models, both mammalian and lower organism, for use in aging research. This includes research on rats, mice, birds, fish, rabbits, nonhuman primates, insects, nematodes, and yeast. Mutant and genetically engineered rodent models of both normal aging and specific age-related pathologies are of particular interest.
  
  
• Cardiovascular Biology. Aging, by itself, contributes to declines in heart and vascular function, and heart failure is the major cause of death in the elderly. Specific scientific investigations supported by this program cover the identification and regulation of underlying molecular and cellular changes that lead to age-related declines in cardiac and vascular function. In addition, the program supports basic research that may open the door to pharmacological interventions and cell-based therapies to relieve symptoms or treat underlying causes of cardiovascular diseases.
  
  
• Cell Structure and Function.The objectives of this program are to support research on the molecular basis of age-related changes in signal transduction mechanisms; microenvironment—extracellular matrix; replicative senescence/apoptosis/cancer; membranes and membrane receptors; and protein structure and function.
  
  
• Endocrinology. Hormones secreted by the endocrine system play major roles in informing various organs of the status of other organ systems and in coordinating the functioning of several organ systems. As humans and various animal models age, average serum levels of some of these hormones decline while others rise, changing the overall hormonal milieu of the organism. Also, the sensitivity of some intracellular signaling pathways responsive to endocrine factors change with age, altering tissue response to hormonal signals. The purpose of the Endocrinology Program is to support basic molecular and cellular research into the causes and effects of age-related changes in the endocrine system of humans and various animal models. Areas of investigation in this program include age-related changes in hormone production, metabolism, and action; type 2 diabetes; reproductive aging: biology of menopause and animal models of menopause; age-related changes in control of prostate growth; and endocrine aspects of age-dependent tumors.
  
  
• Genetics. The objectives of the Genetics Program are to support research on identification and characterization of longevity assurance genes (LAGs) and senescence assurance genes (SAGs); genome stability; telomere biology; genomics; mouse mutagenesis; single nucleotide polymorphisms/genetic epidemiology; and Werner syndrome.
  
  
• Immunology. Changes in the immune system of older people may contribute to the increased incidence of infection and cancer. Research directed towards understanding the age-related regulation of immune function in health and disease includes regulation of lymphocyte proliferation; regulation of immune specificity; response of immune system to biochemical stimuli; autoimmune disease and other immunopathology; endocrine control of immune function; molecular basis of the age-related decline in immune function; and interventions to retard and/or correct age-related decline in immune function.
  
  
• Metabolic Regulation. Areas of investigation in the Metabolic Regulation Program include nutrition and metabolism; age-related changes in mitochondrial function/mitochondrial dysfunction; mechanism of lifespan extension by caloric restriction; and generation of free radicals and oxidative stress.
  
  
• Musculoskeletal Biology. Age-related changes to the function of various physiologic systems often have a negative effect on the health of the elderly. This program supports high-quality basic molecular and cellular research to understand the causes and effects of these changes, thereby encouraging the development of preventative and interventional strategies to extend the health span of the elderly. Areas of investigation in this program include age-related changes in osteoblast and osteoclast function and bone matrix; age-related changes in muscle structure and function; age-related changes in cartilage, connective tissue, and skin; age-related changes in wound healing; molecular mechanisms of the above age-related changes; and molecular basis of osteoporosis and osteoarthritis.
  
  
• Interventions Testing.  NIA supports a multi-institutional study investigating diets and dietary supplements purported to extend lifespan and delay disease and dysfunction. The Intervention Testing Program allows investigators to submit proposals for interventions to be tested for their ability to decelerate aging and extend lifespan in mice. For more information, see: Interventions Testing Program (ITP).

The Biology of Aging Program also includes the Biological Resources and Resource Development Branch. Because most investigators have neither the facilities nor the resources needed to develop and maintain colonies of aged animals in a barrier facility, the NIA provides support for both rat and mouse colonies for use by the scientific community. NIA partially subsidizes the cost of these animals through contracts. Other NIA resources managed by this Branch include colonies of rhesus macaque monkeys, an aged cell bank, an aged rodent tissue bank, a nonhuman primate tissue bank, and a genetic stock center for nematode mutant strains. For information on these and other resources supported by NIA, see: Scientific Resources.

Behavioral and Social Research Program (BSR)

This program supports basic social and behavioral research and research training on the processes of aging at both the individual and societal level. It focuses on how people change over the adult life course, on the interrelationships between older people and social institutions, and on the societal impact of the changing age-composition of the population. Emphasis is placed upon the dynamic interplay between the aging of individuals and their changing biomedical, social, and physical environments and on multi-level interactions among psychological, physiological, genetic, social, and cultural levels.

BSR supports research, training, and the development of research resources and methodologies to produce a scientific knowledge base for maximizing active life and health expectancy. This knowledge base is required for informed and effective public policy, professional practice, and everyday life. BSR also encourages the translation of behavioral and social research into practical applications.

BSR is administratively organized into 2 branches—the Individual Behavioral Processes Branch and the Population and Social Processes Branch—with substantial interactions between them. A section devoted to Research Resources and Development is housed within the Office of the Director of the BSR Program.

Individual Behavioral Processes Branch supports research and training on biopsychological processes linking health and behavior, emotional and cognitive functioning, and human factors, as well as integrative approaches to the study of social, psychological, genetic, and physiological influences on health and wellbeing over the life course. Vertically integrated studies that run from basic to applied are encouraged, as well as translation in some specific areas. Personality, affect, and social/interpersonal relationships are investigated as causal variables, and as mediators or moderators of the relation between social/structural and health outcomes. Studies exploring factors that influence aging at a single level are welcomed. The Cognitive Aging Section and the Psychological Development and Integrative Science Section will have some areas of overlap.

• Behavioral Medicine and Interventions Section focuses on examining the dynamic interrelationships among aging, health and behavior processes. It expands traditional studies in behavioral medicine by adding an aging perspective as well an emphasis on the influence of the socio-cultural environment on the development and maintenance of a wide range of health and illness behaviors (e.g., healthy lifestyle practices, medical self management, and coping with chronic illnesses and disabilities). Major research topics include: disease recognition, coping, and management, including physiological consequences of life stresses and burdens; social, behavioral, and environmental interventions for health promotion, disease prevention, and disability postponement; and understanding the role that genetic differences play in behavioral responses to treatment and intervention.
  
  
• Cognitive Aging Section supports research on changes in cognitive functioning over the life course. Studies are encouraged that: 1) examine the influence of contexts (behavioral, social, cultural, and technological) on the cognitive functioning of aging persons; 2) investigate the effects of age-related changes in cognition on activities of daily living, social relationships, and health status, and 3) develop strategies for improving everyday functioning through cognitive interventions. Major research topics include: higher-order cognitive processes (e.g., problem-solving, decision-making), social cognition, memory strategies, perceptual skills and reading and speech comprehension. Research is also welcomed that explores the role of individual differences in cognitive functioning (e.g., motivation, self-efficacy, beliefs about aging, emotions, sensory limitations, experience and expertise, genetic factors). This unit collaborates with the NIA Neuroscience and Neuropsychology of Aging Program to encourage research at the intersection of behavior and neurocognition.
  
  
• Psychological Development and Integrative Science Section promotes research that applies an integrative approach to the study of health, motivation, social behavior, stress and coping, affect, resilience, and well-being over the life course. Studies are encouraged that combine diverse levels of analysis and examine reciprocal interactions among these levels, as in the areas of social neuroscience, neuroeconomics, behavior genetics, and sociogenomics. Examples include the effects of sociocultural, psychological (socioemotional, motivational), biological and genetic processes on behavioral, social, and functional aging.
  
  
• Population and Social Processes Branch supports research and training on the causes and consequences of changes in social, demographic, economic, and health characteristics of the older population. Research on the effects of public policies, social institutions and health care settings on the health, wellbeing, and functioning of people is supported—over the life course in their later years and across different levels of analysis from cultural to genetic. International and comparative research is encouraged, as are interconnections with individual behavioral processes. Interdisciplinary and multi-level research is especially promoted.
  
  
• Demography and Epidemiology Section embraces formal, social, family, medical, and bio-demography. Topics encouraged include studies on: trends in and forecasts of functioning, disability, morbidity, and mortality; age trajectories of health; life expectancy and active life expectancy; causes and consequences of changes in age-structure of population, including implications for caregiving needs; interactions between health and socioeconomic status over time and across generations; the effect on health of social networks and social context; interrelationships between work, family, and health; the intersection between demographic processes and social outcome, including intergenerational relationships; macroeconomic and demographic perspectives on population aging; and cohort analyses of aging. Biodemographic research focusing on demographic aspects of genetic variants, population prevalence, and patterns of alleles and related research is also supported, along with research on genetic epidemiology, population genetics, and the intersection between biology, demography, and epidemiology.
  
  
• Economics of Aging Section concentrates on the economic analysis of factors that relate to the health and well-being of aging populations. Topics encouraged include: implications of population aging for public and private retirement and health insurance programs and for income security of future retirees; allocation of family resources across generations; determinants of retirement, family labor supply, and saving; consequences of retirement for health and functioning; the relationship among psychological, cognitive and genetic factors affecting economic behaviors; evaluations of the impact of changes in Medicaid, Medicare, and Social Security policies; health insurance and health care expenditures; interrelationships between health and economic status, including issues related to wealth, poverty, productivity, human capital development, and economic development; the economic costs of disability; and cost-effectiveness of interventions to improve the health and well being of the elderly.
  
  
• Health Services and Systems Section encourages research on the impact of formal health care and long-term care systems and settings on the health and well-being of older persons. The emphasis is on how older people and their families deal with multiple services, often for multiple conditions, not on the efficacy or effectiveness of treatments for particular conditions. This Section supports research on the long-term care system; health services and health care financing for older people with multiple chronic conditions; hospital-level and regional differences in health expenditures, services, and outcomes for older persons; and U.S. and comparative cross-national studies of the efficiency and effectiveness of health-care systems.
  
  
• Office of Research Resources and Development (ORRD) coordinates and implements initiatives related to research data and resources. It manages the Health and Retirement Study (HRS), the National Archive of Computerized Data on Aging (NACDA), and all Interagency Agreements. ORRD also serves as the administrative site for the Federal Interagency Forum on Aging-Related Statistics that was established in 1986 to encourage cooperation among federal agencies responsible for the collection, analysis, development, and dissemination of data on the aging population.

Geriatrics and Clinical Gerontology Program (GCG)

The GCG supports research on health and disease in the aged and research on aging over the human lifespan, including its relationships to health outcomes. GCG comprises three major research areas: Geriatrics, Clinical Gerontology, and Clinical Trials. Program-wide emphases include research training and career development to attract new investigators to the field of aging and to further the development of active investigators in clinical medicine and biomedical research, and the application of new technologies to expand opportunities for clinical aging research.

The Geriatrics Branch focuses on health issues regarding the aged.  Research emphases include multifactorial geriatric syndromes such as falls, frailty, and various types of disability; effects of comorbidity and polypharmacy; effects of age-related changes on clinical or functional disease outcomes or treatment responses; effects of physical activity on disease and disability in older persons; and the elucidation, diagnosis, and treatment of previously unappreciated pathologic changes in old age (e.g., sarcopenia, vascular stiffening, diastolic dysfunction). The Geriatrics Branch supports the Claude D. Pepper Older Americans Independence Centers (OAICs). The OAICs conduct basic and clinical research to enhance the ability of older persons to maintain their independence. These centers support research to develop and test interventions to prevent or delay disorders and diseases associated with aging. They also train individuals in research in these areas.

The Clinical Gerontology Branch focuses on clinically related research on aging changes over the lifespan. Research emphases include healthy aging across the lifespan (including exceptional longevity); protective factors against multiple age-related conditions; determinants of rates of progression of age-related changes that affect disease risk, particularly those for multiple age-related conditions; menopause and mid-life aging changes; translational human research to follow up findings from basic research on aging; long-term effects of current or new interventions that may be administered over a large part of the lifespan; and long-term effects of physical activity throughout the lifespan.

The Clinical Trials Branch plans and administers clinical trials on age-related issues. Research emphases include interventions to prevent or treat “geriatric syndromes,” disability, and complications of comorbidity or polypharmacy; trials to detect age- or comorbidity-related differences in responses to interventions against conditions found in middle age and old age; interventions for problems associated with menopause and other mid- and late-life changes; interventions that may affect rates of progression of age-related declines in function in early and mid-life; and interventions with protective effects against multiple age-related conditions.

Neuroscience and Neuropsychology of Aging Program (NNA)

This program fosters and supports extramural and collaborative research and training to further the understanding of neural and behavioral processes associated with the aging brain. Research on dementias of old age—in particular Alzheimer's disease—is one of the program’s highest priorities. The Program supports a number of resources and initiatives:  The Alzheimer’s Disease Centers (http://www.alzheimers.org/adcdir.htm) and the National Alzheimer’s Coordinating Center (www.alz.washington.edu/); the National Cell Repository for Alzheimer’s Disease, and the associated Alzheimer’s Disease Genetics Initiative (http://ncrad.iu.edu/); the Alzheimer’s Disease Neuroimaging Initiative (http://www.loni.ucla.edu/ADNI/); the Translational Initiative (PAR-05-021, PAS-05-022 ); and, along with NINDS and NIMH, the Cognitive and Emotional Health Project (http://trans.nih.gov/CEHP/).

Neurobiology of Aging Branch fosters research on age-related cellular, molecular, and behavioral changes in the structure or function of the nervous system. Studies of neuroimmunology, neurovirology, neuroendocrinology, neuropharmacology, sensory and motor processes, sleep, biorhythmicity, cell death, and neural plasticity are of particular interest.

• Fundamental Neuroscience Section supports research at cellular, molecular, and behavioral levels that explore age-related structural and functional changes in brain, including cell death, energy and metabolic changes, synaptic plasticity, neural stem cells, and neurogenesis.
  
  
• Integrative Neurobiology Section supports research on neural mechanisms underlying age-related changes in endocrine functions; neurodegenerative diseases of aging associated with infectious agents; and central nervous system, neuroendocrine system, and immune system interactions in aging.
  
  
• Sleep and Biological Rhythms Section focuses on studies of epidemiology, etiology, pathogenesis, diagnosis, treatment, and prevention of sleep disorders of older people; age-related mechanisms underlying sleep-wakefulness cycles and behavioral sequelae in the aged; and biorhythmicity in the aging nervous system.
  
  
• Sensory Processes Section focuses on mechanisms of normal aging and disease-related alterations in visual, auditory, somatosensory, vestibular, and chemosensory functions, and pain from the level of the gene to the whole organism as well as epidemiological studies of populations.
  
  
• Motor Function Section supports research on proprioception, postural control, sensory motor integration, vestibular, and movement disorders in aging, including Parkinson's disease.

Dementias of Aging Branch supports studies of etiology, pathophysiology, epidemiology, clinical course/natural history, diagnosis and functional assessment, drug design, drug development and trials, and behavioral management and intervention in the dementias of later life, especially Alzheimer’s disease.

• Population Studies Section supports research in the epidemiology of cognitive decline, mild cognitive impairment, and Alzheimer's disease including prevalence, incidence, and risk and protective factors and on models for large-area registries for Alzheimer's disease.
  
  
• Clinical Studies Section supports research on the diagnosis, treatment, and management of patients with cognitive decline or Alzheimer's disease. Research on diagnosis is aimed at the development and evaluation of reliable and valid multidimensional procedures and instruments for diagnosis, progression, and response to treatment. Research in the treatment and management of Alzheimer's disease seeks to develop the knowledge required to interrupt the course of the disorder, to manage its behavioral manifestations, and to ultimately prevent it. Treatment approaches include clinical trials of pharmacologic and other agents and studies of behavioral and environmental interventions. Preclinical drug discovery, development, and animal testing studies are important aspects.
  
  
• Research Centers Section supports Alzheimer's Disease Research Centers and Alzheimer's Disease Center Core programs, which provide a multifaceted approach to research on Alzheimer's disease, including clinical and other core services, neuropathological evaluation, basic and clinical research, professional and public information, and educational activities. It also supports the National Alzheimer's Coordinating Center and several multi-center collaborative research projects.

Neuropsychology of Aging Branch emphasizes research, including the use of animal models, on the neural and psychological mechanisms underlying age-related changes in basic cognitive processes, including learning, memory, attention, and language. Studies of age-related changes in emotion also are supported. The use of neural modeling and computational neuroscience approaches—and the integration of these approaches—to understanding these structural and dynamic brain changes and adaptations are encouraged.