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Division of Aging Biology
To understand the aging process at the cell, tissue, and organ levels, the Division of Aging Biology (DAB) supports research to determine the basic biochemical and genetic mechanisms underlying the processes of aging, and the ways these are communicated among cells and tissues of the body. DAB-supported investigators study the changes in molecular and cellular structure and function that characterize normal aging in diverse laboratory organisms, spanning the range from yeast to nonhuman primates, and where the opportunities arise, in humans. The Division also supports research on the mechanisms that increase or decrease the rate of aging, from the pathologic underpinnings of premature aging syndromes to cellular and molecular activities in the "oldest old."
DAB maintains a number of resources for biology of aging research. They include colonies of aging rodents, tissues from rodents and non-human primates of different ages, and repositories of collections of human cells representing normal aging as well as various disease states.
The Division supports the (mouse) Intervention Testing Program (ITP) and the (worm) Caenorhabditis Intervention Testing Program (CITP) to test the effectiveness and reproducibility of interventions – including foods, hormones, and pharmaceuticals – with the potential to extend lifespan and delay disease and dysfunction. Both programs encourage collaborations to identify the mechanisms by which these compounds extend life and improve health, in order to facilitate translation of these findings to health in humans. A number of DAB-supported investigators are seeking to establish companies, some supported by NIA Small Business Innovative Research (SBIR) and Small Business Technology Transfer (STTR) programs, to translate their scientific findings to practical ways of improving health in the human population.
DAB supports the Nathan Shock Centers of Excellence, which provide national leadership and research resources in the basic biology of aging. In collaboration with the NIA Division of Geriatrics and Clinical Gerontology, DAB has established a program to support research to develop biological markers of aging mechanisms that influence the risk and progression of age-related diseases and conditions in humans. These will be useful in translating the results of basic research into diagnostic and therapeutic interventions.
Division of Behavioral and Social Research
The Division of Behavioral and Social Research (DBSR) supports research investigating the social, economic, and behavioral implications of aging at both the individual and societal level. Their portfolio is broad, spanning topics ranging from the genetics of age-related behavior change to sweeping demographic studies with global reach, and including such research areas as age-related changes in cognition, mood, and behavior; the implications of aging on families and family systems; the psychology of aging; financial and public policy issues that affect the health and well-being of older Americans; and studies of aging around the world. In recent years, the DBSR portfolio has expanded to include dementia care research, especially health and long-term care services, research on support for caregivers, and epidemiology and prevention of Alzheimer's disease and related dementias (ADRD).
Notably, DBSR supports the Health and Retirement Study, the nation's leading source of combined data on health and socioeconomic circumstances of Americans over age 50. It also supports other longitudinal studies focusing on trends in late life disability (National Health and Aging Trends Study) and on the influences of behavioral, psychological, and social factors in midlife on age-related variations in health and well-being (Midlife in the United States Study). The program also coordinates the Centers on the Demography and Economics of Aging; the Edward R. Roybal Centers for Translational Research on Aging; and the Resource Centers for Minority Aging Research (RCMARs).
An emerging area of research in DBSR is technology development. For example, recent Funding Opportunity Announcements (FOAs) supported by DBSR have solicited applications for the development of infrastructure that will enable the monitoring of cognitive abilities and age, state, context, or health condition-related changes in cognitive abilities on mobile devices. Other FOAs, issued in collaboration with other divisions within NIA, utilize SBIR/STTR funds to promote development of assistive technologies (including socially-assistive robotics) to develop new devices to aid individuals with ADRD. Such devices, if successful, would provide another layer of care for these individuals, and would provide respite and support for the often-overburdened caregivers of people with ADRD. Some of these FOAs are currently active (FY 2017), and more are being developed.
Division of Geriatrics and Clinical Gerontology
As we age, our risk for many types of disease and/or disability increases dramatically. The Division of Geriatrics and Clinical Gerontology (DGCG) supports clinical and translational research on health and disease in the aging population. DGCG's areas of interest include translational research for the development of new interventions for age-related conditions, prevention and treatment of multiple chronic conditions in the elderly, and studies that help to promote evidenced-based geriatric care and inform policies affecting older adults. DGCG‑funded investigators are researching aging over the human life span and how aging plays a role in disease. DGCG also supports research on multifactorial geriatric syndromes such as falls, frailty, and various types of disability; determinants of rates of progression of age-related changes that affect disease risk; and complications of multiple ailments. Other funded research includes the development of new interventions for age-related conditions, and prevention, and treatment of multiple chronic conditions in the aged. Recent DGCG FOAs have solicited applications on palliative care, aging in older persons with HIV/AIDS, and possible effects of the commonly-prescribed diabetes drug metformin on the aging process. Other FOAs are soliciting research illuminating the ways that physiological changes early in life can influence health and illness in older age. Studies under these FOAs will be active in FY 2019.
DGCG also coordinates the Claude D. Pepper Older Americans Independence Centers Program, which supports research to identify effective methods to maintain or restore independence in older adults. Funding for this important program is scheduled to be renewed in FY 2018.
Division of Neuroscience
The Division of Neuroscience (DN) supports broad-based clinical, basic, and epidemiologic research and training to enhance understanding of both normal and pathological age-related changes to the nervous system and the influence of these changes on cognition and behavior. A primary focus of DN is research on AD and related forms of dementia. Ongoing AD-related research supported by DN includes molecular, cellular, and genetic studies; biomarker discovery and validation; epidemiological studies to identify risk factors and establish prevalence and incidence estimates; and drug discovery, development, and testing. Earlier this year, an international team of scientists, with NIA support, used cryo-electron microscopy (a technique that facilitates visualization of cellular structures and proteins at extremely high resolution without the need for fixatives or dyes) to image tau filaments, a pathological hallmark of AD, and revealed for the first time their delicate and complex underlying structure. This improved knowledge of tau structure is a tremendous step forward in understanding its role in the progression of AD and some related dementias, with enormous potential for the exploration of possible new therapies. NIA-supported investigators also found that moderate exercise can increase metabolism in brain regions important for learning and memory.
NIA supports a national network of 32 AD centers that work to translate research discoveries into AD diagnostics and treatment interventions, as well as executing a wide range of studies to enhance understanding of AD. In addition, NIA's DN manages a wide variety of other initiatives aimed at understanding and addressing AD and related dementias, including the Accelerating Medicines Partnership on Alzheimer's Disease to identify therapeutic targets and biomarkers of disease; the Alzheimer's Disease Sequencing Project, which supports analysis of whole exome and genome sequencing data for the AD research community; the Molecular Mechanisms of the Vascular Etiology of Alzheimer's Disease (M²OVE-AD) Consortium to dissect the complex molecular mechanisms by which vascular risk factors influence Alzheimer's disease and identify new targets for treatment and prevention; and a number of prevention and treatment clinical trials. Current FOAs in AD and related dementias aim to investigate the impact of health disparities in AD, develop new care methods and treatments, and understand the spectrum of symptoms in AD and related dementias as a measure for diagnosis. Projects funded under these FOAs will be active in FY 2019.
In addition to studies of Alzheimer's disease and related dementias, DN supports basic and clinical research aimed at maintaining or improving cognitive health, sleep, and sensory and motor function with age. Ongoing research includes studies of possible associations between disrupted sleep and cognitive decline and AD in older age; studies of sleep disorders in older Americans; and studies exploring alterations in blood flow in the brain as a possible contributor to gait dysfunction and falls. Recognizing that hearing loss is not only a common condition among older adults but that it is also connected to a higher risk of dementia, NIA recently funded the Aging, Cognition, and Hearing Evaluation in Elders (ACHIEVE) clinical trial. The study aims to examine the potential of hearing rehabilitation to reduce rates of cognitive decline.
Program Portrait: Human Cell Reprogramming to Explore Aging and Alzheimer's Disease
Budget: Projects funded under RFA-AG-17-053 and RFA-AG-17-009
Scientists have identified a number of genetic variants that contribute to the risk of late-onset Alzheimer's disease, as well as over 20 genetic loci, which are specific locations on a chromosome that may contain several genes, along with sections of noncoding material between the genes. It is not always clear which genes in a particular locus are directly involved in the development of AD; furthermore, the non-coding regions, which play an important role in genome maintenance and gene replication, may also play an important role. Determining how and why a particular locus affects risk has been a costly and time-consuming process, providing only indirect evidence of a link between the gene and its effects on the cell, until now.
Two innovative techniques are accelerating the pace of discovery in the complex genetics of Alzheimer's disease. One is the use of induced pluripotent stem cells (iPSCs) to study AD. iPSCs are derived from adult cells – typically blood or skin – that have been biochemically "reprogrammed," or induced, to form stem cells. iPSCs can then be stimulated to make different cell types found in human tissues and organs. NIA-supported investigators have converted iPSCs derived from AD tissue, to neurons which display characteristics of Alzheimer's pathology. The other key technology is a unique tool called CRISPR-Cas9, a molecular scalpel that can excise or modify a snippet of a DNA sequence with unparalleled precision, which is enabling researchers to remove minute sections of DNA from loci of interest and observe the effect.
Now, scientists are generating neurons and other neural cell types with specific Alzheimer's-related genotypes and using CRISPR-Cas9 to remove or modify one or more portions of the cells' DNA. They then watch to see what effect this has on the development, maintenance, or activity of AD's characteristic amyloid and tau pathology, as well as novel molecular phenotypes. This research will provide important information about underlying pathways implicated in the development of the disease, and may even suggest new targets and avenues for intervention.
In late FY 2016, NIA issued a FOA soliciting research applications on the impact of aging in human cell models of Alzheimer's disease. Seven applications were funded in FY 2017 and will be active in 2019. The investigators are using a variety of techniques to induce the development of the hallmarks of aging in iPSC-derived neurons and then to use these cells to further define the links between the brain aging process and pathological processes such as Alzheimer's. To follow up on a FOA funded in 2015, in FY 2017 NIA issued a separate funding opportunity announcement soliciting research to assess the function of Alzheimer's genetic variants, particularly those in non-coding regions, in iPSC-derived neuronal and glial cells using comprehensive molecular phenotyping and genetic editing (including CRISPR-Cas9) approaches. Six applications were funded in FY 2017 and will be active in 2019. NIA is re-issuing this FOA; it will be active in FY 2018-2020.
Intramural Research Program
The NIA Intramural Research Program (IRP) supports wide-ranging basic, behavioral, clinical, epidemiologic, and translational research with the goal of understanding the physiological changes and adaptability of the human body in response to age and stress. Knowledge about the biology of aging and chronic disease is necessary to develop new effective interventions that reduce the burden of disease and disability in the older population, and IRP investigators use this understanding to clarify the pathophysiology of age-related diseases and create new therapeutics and interventions for these conditions. While IRP's ten laboratories each work on separate projects, they interact extensively and share the common goal of expanding our knowledge of the aging process and age-related disease.
IRP investigators conduct research in three main focus areas: aging biology, neuroscience, and translational gerontology. Specific areas of interest include 1) epidemiologic research, such as investigations into neurologic and blood biomarkers, population diversity, health disparities, body composition, cognition, frailty, and disabilities; 2) behavioral research including studies on neuropsychology, cognition, and personality; 3) genetics and genomics, including genetic and epigenetic causes of aging; 4) clinical and translational research in drug development, treatment efficacy, and treatment toxicity as well as immunology, cardiology, neurology, and other topics; and 5) neuroscience and neurogenetics, with a focus on declining cognition due to age-related physiologic and molecular changes and genetic determinants. Age-associated diseases that are priority areas of research include Alzheimer's disease, Parkinson's disease, diabetes, cardiovascular diseases, stroke, osteoporosis and osteoarthritis, autoimmune diseases such as multiple sclerosis and lupus, and cancers.
IRP's longitudinal cohort studies have contributed greatly to aging research. Prominent studies include the trailblazing Baltimore Longitudinal Study of Aging (BLSA), which looks at the determinants and measures of healthy biological aging over time and is the nation's longest running scientific study of human aging; the Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) study, which looks at the impact of racial and socioeconomic diversity on health disparities and healthy aging; and the Genetic and Epigenetic Signatures of Translational Aging Laboratory Testing (GESTALT) study, which is aimed at discovering biomarkers and their connections to aging.
The IRP also supports training programs for students and recent graduates that give young scientists the opportunity to learn skills in basic and clinical aging research in the biomedical and behavioral sciences. This may help combat the nation's unmet need for aging and geriatric researchers and clinician-scientists.
Program Portrait: NIA's Laboratory of Cardiovascular Science
Despite decades of progress, heart disease remains the leading cause of death for Americans ages 65 and older. 1 Since 1985, the NIA's Laboratory of Cardiovascular Science (LCS), a laboratory within the Intramural Research Program, has conducted groundbreaking research on both the normal and diseased heart, with the goal of reducing the reach and scope of heart disease in the United States.
Scientific goals of the LCS include identifying age-associated changes that occur within the cardiovascular system and determining the mechanisms for these changes; determining how aging of the heart and vasculature interacts with chronic disease states to enhance the risk for cardiovascular diseases in older persons; studying the basic mechanisms that govern the heart's activity; and testing therapeutic approaches such as changes in lifestyle, novel pharmacologic agents, or gene or stem cell transfer techniques in aging or cardiovascular disease states. Research conducted in the LCS ranges from basic studies in cells and their various subunits, to preclinical and translational work in animal models, to human clinical trials.
LCS research has led to a paradigm shift in our understanding of how the sinoatrial node (SAN), known as the "heart's pacemaker," functions. The SAN is a small bundle of cells located in the wall of the right atrium of the heart. These cells produce an electrical impulse that travels through the heart, causing it to contract. In a healthy heart, these electrical impulses occur, and as a result, the heart beats regularly. However, when the impulses are disrupted, "sick sinus syndrome" (SSS), an often dangerously irregular heartbeat, results. SSS is a disease of aging and is the most common cause of electronic pacemaker implantation in older adults worldwide – and the incidence of the condition is projected to increase some 120 percent in the United States alone over the next fifty years. 2
LCS scientists have discovered a "coupled-clock system" in which a "calcium clock" (rhythmic, local, spontaneous cycling of calcium ions within a pacemaker cell) ignites a "membrane clock" (ensemble activities of pacemaker cells ion channels) to generate an action potential that initiates the heartbeat. When these "clocks" become "uncoupled," SSS results. However, when they are re-coupled, normal heart activity can be restored. These findings provide a novel and long-awaited platform to enhance understanding of the pathophysiology of SSS, and open the door to the development of novel therapies at the cellular level targeting pacemaker clock uncoupling.
The next step in the LCS research plan is to attempt to solve the puzzle of how coupled clock systems that operate within individual SAN pacemaker cells, each ticking at their own speeds, work together to generate a rhythmic ensemble signal that emanates from the SAN tissue to ensure the robust yet flexible heart rate control needed to meet the body's requirements for blood flow. This work will be ongoing in FY 2019.
Research Management and Support
NIA Research Management Support (RMS) activities provide administrative, budgetary, logistical, and scientific support in the review, award, and monitoring of research grants, training awards and research and development contracts. RMS functions also encompass strategic planning, coordination, and evaluation of the Institute's programs, regulatory compliance, international coordination, and liaison with other Federal agencies, Congress, and the public.
1. National Center for Health Statistics. Health, United States, 2016: With Chartbook on Long-term Trends in Health. Hyattsville, MD, 2017. See Chart 20 .
2. Jensen PN et al. Incidence of and Risk Factors for Sick Sinus Syndrome in the General Population. J Am Coll Cardiol 64: 531-538, 2014.