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Approved Concepts

Below are concepts approved at the most recent National Advisory Council on Aging (NACA) meetings. We have posted the approved concepts here to give interested researchers maximal lead time to plan projects. Please note that not all concepts will necessarily end up converting to a Funding Opportunity Announcement (FOA), and some of the concepts listed below (particularly from older Council meetings) may have already been converted to FOAs.

February 2019 Councils

Approved concepts in this round:

Aging, Driving and Early Detection of Dementia

Driving is vital to the everyday functioning of many older adults (Dickerson et al., 2011) and whereas the percentage of age-eligible licensed drivers has decreased over the past decade among young adults (16-24 years of age) that percentage has increased for adults over age 60 with the increase being most prominent among elderly women (Sivak & Schoettle, 2012). Thus, older adults constitute an increasingly larger proportion of licensed drivers and this is troubling in the face of age decrements in driving performance as revealed in both naturalistic and simulated driving (e.g., Rizzo, Fisher, Ott and others). Recent research by Catherine Roe and colleagues (Roe et al., 2017) has shown that older adults with high amyloid/tau burden, but who are without measurable cognitive decline, exhibit deficits in driving performance compared with older adults without such burden. This raises a question about whether aspects of driving behavior might be monitored to detect early signs of cognitive decline/dementia.

The challenge of ascertaining ‘fitness to drive’ is complex and families and health professionals who provide services to elderly drivers are often tasked with difficult conversations about driving cessation. The criteria for age-related driving cessation have been extensively debated but a recent report by the Veterans Administration Workgroup on Driving Safety for Veterans with Dementia advocates that persons with moderate to severe dementia should not drive due to safety concerns (December 2017). The policies/procedures for driving cessation remain unspecified and controversial but conversations focused on this topic will benefit from objective data as envisaged in the proposed concept.

If successful, this concept will promote basic research into the use of currently-available automobile technology as a passive-detection system for flagging potential age and/or disease-related aberrant driving that may signal cognitive decline even before standard clinical tests do so. Ultimately, this information could inform decisions about an individual’s fitness to drive, especially when coupled with other relevant information about the driver’s functional status such as mobility, co-morbid conditions and health.

Scientific/Research Contact

Dana Plude, Ph.D.
Division of Behavioral and Social Research
National Institute on Aging
Telephone: 301-435-2309
E-mail Dana Plude, Ph.D.

Basic Biology of Aging in Reproductive Tissues

Substantial evidence shows that male and female reproductive tissues demonstrate age related alterations in function earlier than other systems, and it is well substantiated that aging of these tissues may contribute to many co-morbidities unrelated to reproduction itself, including cardiovascular changes, renal failure, bone loss, sarcopenia and neurological decline. In mice, some of the effects of aging on lifespan and healthspan can be reversed by replacing old gonads with young gonads. It is also known that aging of the reproductive system occurs not only in the germ cells (e.g., in the gonads), but also in the associated stem and non-stem cells supporting these organs.

The interplay between these cell types in tissue homeostasis and maintenance of function is just now beginning to be appreciated. For example, in C. elegans, life span is influenced by counterbalancing signals from proliferating germ cells which reduce longevity, and signals from the somatic gonad that promote longer lifespans. While hormones such as insulin/insulin-like growth factor (IGF) and inhibition of cell cycle progression have been demonstrated to be involved in this regulation, the precise mechanisms of action remain unclear. Moreover, this evidence suggests a significant role for non-autonomous processes that may have an impact on the rate of aging among the different cell types within the reproductive system as well as at distant tissues. Thus, while aging is the major driver in the decline of reproductive tissues that lead to their effects in distal organ systems, it is unclear what mechanisms are involved in the maintenance and function of these tissues as they age, and their role in integrative physiology.

The goal is to expand our limited understanding of mechanistic factors and cellular interactions that regulate aging in reproductive organs and related endocrine system. The focus will be on developing or studying new or unique models to identify novel germ/somatic cells and stem/non-stem cell interactions and their niche that alter healthspan and lifespan.

The increase in the aging population has increased interest in the field of reproductive aging and is capturing the attention of reproductive biologists interested in studying the mechanisms of aging in these tissues. This interest has led to the recent development of new models for reproductive aging. An initiative at this time is timely, as the field is technically and intellectually poised to make significant progress if additional funds become available.

Scientific/Research Contacts

Rebecca Fuldner, Ph.D.
Division of Aging Biology
National Institute on Aging
Telephone: 301-496-6402
E-mail Rebecca Fuldner, Ph.D.

Candace Kerr, Ph.D.
Division of Aging Biology
National Institute on Aging
Telephone: 301-827-4474
E-mail Candace Kerr, Ph.D.

Cognitive Systems Analysis of Alzheimer’s Disease Genetic and Clinical Data

The goal of this initiative is to apply cognitive systems approaches to the analysis of AD genetic and related data. Technological advancements in conjunction with the formation of large, highly collaborative consortia have augmented the capabilities to successfully identify Alzheimer’s Disease (AD) genes. Since 2009, more than 30 new AD genes have been confirmed. The emergence of high throughput technologies to perform genome wide association studies (GWAS), whole exome (WES), and whole genome sequencing (WGS) in a cost-effective manner has triggered an explosion in the amount of genetic data available for analysis.

In 2019 the Alzheimer’s Disease Sequencing Project (ADSP) will have five petabytes of data for analysis, where one petabyte is one quadrillion bytes of data. Some examples of these “big data” are:

  • The number of subjects with GWAS = 94,437 for AD/Alzheimer’s Disease and Related Dementia (ADRD) data.
  • The ADSP expects 27,742 whole genomes to be ready for analysis in 2020.
  • By 2023 the total expected ADSP subjects with whole genomes may be as many as ~50,000 when India, China, Japan, Australia, Taiwan, and Korean sample sets are included.
  • Most of the NIA funded epidemiologic cohorts have genetic data; some have “omic” data.
  • There already is a massive amount of data on ethnically diverse cohorts that the ADSP on its own cannot hope to analyze without the support of alternative approaches to data analysis.

We have an urgent need to develop fast and efficient approaches to identify changes in AD genetic architecture. “Cognitive systems” is a global term that includes artificial intelligence (AI), machine learning (ML), and deep learning/neural networks (DL) approaches. To be successful, cognitive systems analysis needs large datasets to provide informative features for classification, prediction, and pattern discovery. A Division of Neuroscience Focus Group, held in the spring of 2018, was comprised of experts from diverse AI/ML/DL fields, academicians with expertise in bioinformatics, AD geneticists, and NIA staff. A subset of well phenotyped data sets that included genetic, genomic, imaging, epidemiologic and biomarker data was made available to the Focus Group for assessment. Using these data as criteria, it was agreed that there are sufficient high quality genetic and related data available in existing data bases to enable NIA to embark on cognitive systems approaches to genetic data analysis to help drive the field to discovery of novel therapeutic approaches.

The Focus Group stressed that the caveat to assuring successful cognitive sciences approaches in the case of AD genetics is that access to the data should be centralized, and the data should be harmonized. The computational infrastructure that supports processing on a large number of features is available: the NIA Genetics of Alzheimer’s Disease Data Storage Site (NIAGADS) has FISMA clearance and is Amazon and Google cloud enabled.

Focus Group experts stressed that data silos reduce efficiency and increase costs. Retention of harmonized data in a single repository/federated repository for ready access by investigators will be a significant step to the feasibility of advanced data analysis approaches. NIH is already moving in this direction with its Data Commons effort.

It is anticipated that up to ten studies will be funded under this FOA. Data that have already been harmonized by geneticists and epidemiologists can be made available for this FOA. Large amounts of harmonized data are available in other repositories, such as the clinical data from subjects who have been whole genome sequenced at the National Alzheimer’s Coordinating Center (NACC); the Alzheimer’s Disease Neuroimaging Initiative (ADNI) imaging and clinical data stored at LONI; and AMP-AD stored at SAGE. To avoid redundancy in existing infrastructure, access to these harmonized data will be provided through NIAGADS, which will act as a central hub for the effort. Investigators will coordinate efforts through NIAGADS to generate data that are consistent in presentation to the research community, and to integrate at NIAGADs other epidemiological data files necessary for their research.

Scientific/Research Contact

Marilyn Miller, Ph.D.
Division of Neuroscience
National Institute on Aging
Telephone: 301-496-9350
E-mail Marilyn Miller, Ph.D.

Dementia Care: Home and Community-Based Services (HCBS)

Targeted research is needed on services and supports that can improve outcomes for Persons with Dementia (PWD) within the realm of dementia care. Most individuals with dementia live at home and are cared for by a family member or friend—typically a spouse or adult child. In addition to arranging health care visits, participating in medical decision-making, and coordinating supportive services, persons with dementia and their families attend to issues of safety, behavioral and psychological symptoms, and challenges finding home and community-based health services that match the needs of persons with dementia.

Even when long-term services and supports (LTSS), such as home and community-based health services, are available within one’s community, barriers may include a lack of funds to pay for services, difficulty getting to service locations (e.g., transportation), and rules restricting coverage (e.g., Medicaid). Research is needed to identify barriers and the degree they affect use of non-residential services, that is, services obtained in the community versus nursing homes or other residential long-term care facilities. We also seek to better understand what services are being utilized in the community as well as outcomes associated with varied use of services accounting for needs of diverse populations, including those who live alone. Research addressing PWD, caregivers, families, and communities across the socioeconomic spectrum is encouraged.

Given the anticipated demand for and shortage of paid caregivers over the next decade, specifically home health and personal care aides1, this topic is a timely opportunity to understand the health impact of these settings. The initiative will add to the body of evidence focusing on the availability and accessibility of LTSS as well as optimizing health-related outcomes for PWD, including less reliance on anti-psychotic drugs, reduced wandering, greater social engagement, decreased delirium, and improved quality of life. Services of great importance, but that are under-studied include home health care and adult day services. Research should address availability of these non-residential home and community-based health services that impact both the immediate quality of life for persons living in the community with dementia as well as the likelihood of nursing home admission for persons with dementia. The initiative will encourage addressing disparities in access to services such as adult day and home health care.

1Bureau of Labor Statistics. “Occupational Outlook Handbook: Fastest Growing Occupations.” U.S. Department of Labor. (accessed December 13, 2018).

Scientific/Research Contact

Elena Fazio, Ph.D.
Division of Behavioral and Social Research
National Institute on Aging
Telephone: 301-496-3131
E-mail Elena Fazio, Ph.D.

Early Career VA Physician-Scientist Award for Mentored Research in Alzheimer’s Disease (AD) and AD Related Dementias (ADRD)

The number of new physician-scientists with a medical degree entering the workforce is declining, as reflected by the reduced numbers of physician applicants for early career (K and LRP) awards over the past several years. This proposed initiative will provide a chance to attract early stage physician-scientists, primarily with a U.S. Department of Veterans Affairs (VA) appointment, into an AD/ADRD research career that can focus on any aspect of the field (e.g., disease mechanisms, biomarker discovery, diagnosis/clinical assessment, therapeutics, patient care).

The initiative will also promote developing and implementing a collaborative framework to facilitate co-funding and support of shared AD/ADRD research priorities between NIA and the VA. It will provide an opportunity to develop a sustainable process for collaboration and address key barriers or challenges that often hinder communication, sharing of resources and increased coordination between the two organizations. The focus on VA physician-scientists is particularly appropriate as these scientists are not allowed to count any of their effort at the VA as part of the 75% effort that is required on NIH career development awards.

Scientific/Research Contact

Lisa Opanashuk, Ph.D.
Division of Neuroscience
National Institute on Aging
Telephone: 301-827-5422
Email Lisa Opanashuk, Ph.D.

Enabling Storage, Processing and Sharing of Standardized Alzheimer’s and Related Dementia Neuroimaging Biomarkers

One of the most important scientific advances of the past decade has been development of methods to diagnose Alzheimer’s disease (AD) in living humans. High resolution brain MRI, combined with new methods for detecting signatures of ante mortem neuropathology (CSF measures of amyloid, tau, and pTau, or PET radioligands to visualize amyloid plaques or pTau tangles) have transformed clinical AD research. Biomarker characterization is integral to the new NIA/Alzheimer’s Association (AA), β amyloid deposition, pathologic tau, and neurodegeneration (A-T-N) research framework.

However, while we now have the tools to identify neurodegeneration and AD neuropathology in vivo, only a few investigators have the expertise necessary to apply these methods, and there is inconsistent harmonization of methodology and data across research groups. Neuroimaging, particularly positron emission tomography (PET), is expensive, making pilot and proof of concept studies difficult to implement. More investigators must gain access to biomarkers in clinical AD research. Broader dissemination and standardization of neuroimaging and other biomarker tools for diagnosing AD are a priority for NIA.

The 30 Alzheimer’s Disease Research Centers (ADRCs) supported by NIA form the backbone of clinical AD and related dementia research in the United States. Considerable efforts have been made over the years to harmonize clinical and neuropathological methods across Centers, and the National Alzheimer’s Coordinating Center (NACC) was created to store and share standardized ADRC clinical and neuropathologic data. However, neuroimaging data collected by different ADRCs has not been systematically gathered or shared. A voluntary program for transferring and (potentially) sharing ADRC MRI data at NACC, was started and resulted in more than 7,000 scans from over 5,000 participants now available through NACC and connected with all the other data there. Expanding this program to harmonize, aggregate and share neuroimaging biomarker data across all the ADRCs would be beneficial to the field by enabling more detailed and precise analyses across a larger number of participants than could be accomplished without such standardization.

Different ADRCs focus on different aspects of dementia, and the participants studied by ADRCs are both more numerous and more varied than the Alzheimer’s Disease Neuroimaging Initiative (ADNI) or any other existing cohort. Given the range of phenotypes along with the standardized clinical and neuropathological data, the systematic sharing of harmonized ADRC neuroimaging data would have great scientific value. There is a wide range of neuroimaging expertise at different ADRCs, but almost all of the institutions with ADRCs, also participate in ADNI, which collects and shares harmonized MRI and PET data from 57 different clinical sites. While there is usually collaboration and some personnel overlap between ADRCs and ADNI sites, the two are administratively distinct and function independently. Most of the neuroimaging data collected at each ADRC is not funded through the Center, but by investigator-initiated research projects, which may or may not include Center research participants. Greater sharing of data is feasible, but not all neuroimaging data are sufficiently standardized to warrant sharing across Centers.

This initiative will leverage neuroimaging data collection and harmonization methods that are already well developed and widely accepted by the neuroimaging community. It is important to emphasize that the aim is not to inhibit innovation and development of new methods. In fact, one important aspect of the initiative will be continued refinement and improvement of neuroimaging data as technologies and methods advance.

Scientific/Research Contacts

Nina Silverberg, Ph.D.
Division of Neuroscience
National Institute on Aging
Telephone: 301-496-9350
E-mail Nina Silverberg, Ph.D.

Cerise Elliott, Ph.D.
Division of Neuroscience
National Institute on Aging
Telephone: 301-496-9350
E-mail Cerise Elliott, Ph.D.

John K. Hsiao, M.D.
Division of Neuroscience
National Institute on Aging
Telephone: 301-496-9350
E-mail John K. Hsiao, M.D.

Expansion of the Claude D. Pepper Older Americans Independence Centers (OAICs)

The Claude D. Pepper Older Americans Independence Centers (OAICs) are NIA’s centers of excellence in geriatrics research and research training. The OAICs’ overarching purpose is to promote research leading to maintenance or restoration of independence in older persons. Successful OAICs develop programs that focus and sustain progress in a key area of aging research for substantial populations of older persons.

Examples of individual OAIC themes include:

  • Multiple pathways of functional decline
  • Vascular role in age-related functional loss
  • Frailty
  • Pain and symptom management
  • Translating biological mechanisms of aging into interventions
  • Sarcopenia and rehabilitation of disability
  • Promoting independence among vulnerable older populations

The OAICs have a long history of productivity and collaboration. Examples include large-scale multi-site clinical trials, such as Strategies to Reduce Injuries and Develop confidence in Elders (STRIDE), Lifestyle Interventions and Independence for Elders (LIFE), and ENabling Reduction of low-Grade Inflammation in SEniors (ENRGISE). OAICs have also developed large-scale collaborations outside the OAIC network, such as Advancing Geriatric Infrastructure and Network Growth (AGING)—a collaboration between the OAICs and Health Care Systems Research Network—and a collaboration between the OAICs and Centers for AIDS Research (CFARs). In addition, a workshop in 2016 brought together leaders from the Alzheimer’s Disease Centers and the OAICs to identify research priorities at the intersection of both Centers’ areas of interest. The white paper that emerged from that workshop (Brinkley et al. J Gerontol A Biol Sci Med Sci 2018;73:1229-1237) has served as a template for subsequent OAIC pilot studies and career development projects including multiple Alzheimer’s Disease-related administrative supplements. Also, several OAICs have played a prominent role in translating geroscience-related findings from the Shock Centers and other investigators into clinical research studies.

Each OAIC has an organizational structure involving the following cores:

  • Leadership and Administration Core
  • Research Education Component, which supports research training and mentorship for early career investigators
  • Resource Cores, usually numbering 3-5, that provide services and functions essential to the OAIC, such as functional assessments, biostatistical support, subject recruitment, and bioanalytical resources. Resources Cores support Developmental Projects, for methods or technology development, and External Projects, which are non-OAIC-funded institutional projects that can leverage Core resources.
  • Pilot/Exploratory Studies Core, which support multiple pilot/exploratory studies lasting 1 to 3 years.
  • An optional Information Dissemination Core

The OAIC National Coordinating Center website contains additional information about current OAIC awards and activities.

Scientific/Research Contact

Basil Eldadah, M.D., Ph.D.
Division of Geriatrics and Clinical Gerontology
National Institute on Aging
Telephone: 301-496-6761
Email Basil Eldadah, M.D., Ph.D.

Genome Center for Alzheimer’s Disease (GCAD)

The Alzheimer’s Disease Sequencing Project (ADSP) was initiated in 2012 in response to the National Alzheimer’s Project Act. The overarching goals of the ADSP are to:

  1. Identify new genes involved in AD
  2. Identify gene alleles contributing to increased risk for, or protection against, the disease
  3. Provide insight as to why individuals with known risk factor genes escape from developing AD, and
  4. Identify potential avenues for therapeutic approaches and prevention of the disease.

This study of human genetic variation and its relationship to health and disease involves a large number of study participants and will capture not only common single nucleotide variations but also rare copy number and structural variants that are increasingly thought to play an important role in complex disease.

The Genome Center for Alzheimer’s Disease (GCAD) at the University of Pennsylvania was funded to assemble, quality control check, harmonize, and jointly analyze all of the genetic and phenotypic data associated with the ADSP. The Genome Center provides data to the NIA Genetics of Alzheimer’s Disease Data Storage Site for immediate sharing with the research community.

GCAD is the key piece of NIA funded infrastructure that provides cohesion to the activities of the ADSP and individually funded AD geneticists. The team, with international recognition for their role in Alzheimer’s disease gene discovery, has been highly collaborative and extremely productive since the initial award was made in 2016. They work cohesively with the Alzheimer’s Disease Centers, the National Cell Repository for Alzheimer’s Disease, the NIA Genetics of Alzheimer’s Disease Data Storage Site, the National Alzheimer’s Coordinating Center, The American Genome Center at Uniformed Services University for the Health Sciences and with NHGRI funded large scale sequencing centers. They have established pipelines for data analysis that parallel those of other large-scale sequencing projects funded by NIH.

The continuation of funding for GCAD will permit their well-designed pipelines and their highly collaborative team to quality control check and harmonize the sequence and genotypic data that are inbound for the ADSP Follow-Up Study. These include the wide swath of data on up to 20,000 ethnically diverse subjects that are already being sequenced. It is essential that these data be quality-controlled and harmonized in a timely fashion in order to help move the field closer to the identification of therapeutic targets.

Scientific/Research Contact

Marilyn Miller, Ph.D. Division of Geriatrics and Clinical Gerontology
National Institute on Aging
Telephone: 301-496-9350
E-mail Marilyn Miller, Ph.D.

Increasing Competitiveness of Potential Alzheimer’s Disease Centers (ADRCs)

ADRCs are poised to play a leading role in many aspects of Alzheimer’s disease and related dementias (AD/ADRD) research, including understanding the mechanisms that lead to cognitive and behavioral impairment, and identifying as well as validating novel biomarkers of the disease. In order to meet the goals of the National Alzheimer’s Project Act, the program needs to include new areas of focus and provide research participation opportunities to new and more diverse participants across the country.

It is critical to bring new perspectives, new ideas and new approaches to AD/ADRD research and to bring them into the network of ADRCs so that they can influence others and assure that the program does not stagnate. In most of the past cycles, applicants from institutions that did not already have an AD Center have not been competitive, although much of the proposed work was deemed to be valuable to the field and all the required components were in place. This initiative will provide resources to institutions to improve their application competitiveness to form the necessary building blocks to be successful as an Alzheimer’s Disease Research Center grant and allow infusion of new approaches to the network.

Scientific/Research Contacts

Nina Silverberg, Ph.D.
Division of Neuroscience
National Institute on Aging
Telephone: 301-496-9350
E-mail Nina Silverberg, Ph.D.

Cerise Elliott, Ph.D.
Division of Neuroscience
National Institute on Aging
Telephone: 301-496-9350
E-mail Cerise Elliott, Ph.D.

Increasing Research Capacity in Behavioral and Social Science Research on Alzheimer’s Disease and AD-Related Dementias (AD/ADRD)

NIA’s research agenda related to Alzheimer’s Disease and Alzheimer’s Disease-related Dementias (AD/ADRD) will benefit from the contributions of the behavioral and social sciences, especially in the areas of dementia care, caregiver research, cognitive and dementia epidemiology, disparities, behavioral and social pathways, early psychological changes, prevention, and the development of research resources. Due to significant funding increases by Congress, research on AD/ADRD has grown rapidly, as has the need for a diverse research workforce in the behavioral and social sciences to work on these issues. While the many initiatives that NIA has already implemented to grow research capacity in AD/ADRD are paying off, there is a need to further expand research capacity by diversifying the number of ways that New, Early Stage and Established Investigators can enter the field for whom existing mechanisms are not the right fit; thus, this concept proposes three different research capacity initiatives.

The contribution of behavioral and social scientists will be enhanced by productive collaborations with clinical researchers. For example, a recent workshop between leaders from the NIA Pepper Centers and the NIA Alzheimer Centers identified research priorities around behavioral risk factors for both dementia and functional decline, opportunities to design behavioral interventions that simultaneously affect both domains, and barriers to practice and implementation of research findings. Another workshop focused on incorporating measures of subjective well-being into biomedically-focused aging studies, and the first cross-Center workshop of the NIA Research Centers Collaborative Network concentrated on achieving and sustaining behavioral change in older adults.

This overall program initiative is intended to offer multiple ways to bring behavioral and social researchers to enrich the study of Alzheimer’s Disease and its Related Dementias and to allow clinical researchers to understand the behavioral and social side of AD/ADRD. These are expected to include support for short courses; formal training programs geared towards MD/PhD students with concentration in the behavioral and social sciences; and leadership awards for senior researchers in the behavioral and social sciences.

Scientific/Research Contact

Georgeanne Patmios, M.P.H.
Division of Behavioral and Social Research
National Institute on Aging
Telephone: 301-496-3138
E-mail Georgeanne Patmios, M.P.H.

Infectious Etiology of Alzheimer's Disease

The role of microbes and antimicrobial defenses in the pathogenesis of Alzheimer's disease has been postulated and investigated for at least six decades. Since then, hundreds of reports have associated AD with diverse bacterial, fungal, and viral pathogens, most frequently implicating Herpesviridae, particularly, HSV-1, EBV, HCMV and HHV-6. These efforts have typically focused on searching the antibody repertoire of AD patients for antibodies against pathogen proteins, but the question of whether microbe-related antigens represent a causal component of AD or are opportunistic “passengers” of neurodegeneration has not been resolved.

Nevertheless, when taken in aggregate, the results of these studies are suggestive of a viral contribution to AD, though findings offer little insight into potential mechanisms, and there has been no consistent association with specific viral species. Recent molecular profiling of a large patient cohort, facilitating the integration of diverse biomedical data into a multilevel view that spans multiple disease stages, brain regions, and -omic domains, provided evidence of complex viral “activity” in the aging brain, including changes specific to AD clinical traits. Once again species of Herpesviridae were implicated. Recent efforts, unlike previous studies, point toward multiple biological mechanisms that are novel in the context of AD.

Understanding the functional roles and mechanisms of viruses in AD network biology will contribute significantly to our understanding of human clinical Alzheimer’s disease onset and progression. It will inform aspects of future translational studies in AD, including the development of “endophenotypes” of AD patients, improved molecular diagnostics, risk stratification biomarkers, and the discovery of candidate therapeutics aimed at regulating pathogen-associated networks and molecules in AD.

The initiative will:

  • encourage studies to answer whether microbial pathogens in AD represent a causal component of the disease
  • support studies that can leverage existing cohorts with associated samples from plasma, CSF, and brain tissue as well as imaging data to address possible links between infectious agents and clinical AD
  • invite research across a broad range of topics on mechanisms underpinning neurodegeneration in AD associated with microbial pathogens in the CNS

Specifically, topics may include, but are not limited to:

  • studies involving Koch’s postulates linking infectious agents and AD (i.e., pathogens must be present in every case of the disease, the pathogen must be isolated from the infected host and grown in culture, and the disease must be reproduced when the pathogen is transferred into a healthy susceptible host)
  • identification of host genes and gene networks that are most commonly perturbed by pathogens in the brains of AD patients
  • research on amyloidosis as a protective mechanism against microbial infection
  • mechanisms linking systemic inflammation with peripheral amyloidosis
  • research on mechanisms by which AD pathology may increase the vulnerability of the CNS to microbial infection

Scientific/Research Contacts

Rebecca Fuldner, Ph.D.
Division of Aging Biology
National Institute on Aging
Telephone: 301-496-6402
E-mail Rebecca Fuldner, Ph.D.

Miroslaw (Mack) Mackiewicz, Ph.D.
Division of Neuroscience
National Institute on Aging
Telephone: 301-496-9350
Email Miroslaw (Mack) Mackiewicz, Ph.D.

Dallas Anderson, Ph.D.
Division of Neuroscience
National Institute on Aging
Telephone: 301-496-9350
Email Dallas Anderson, Ph.D.

Innovations to Foster Healthy Longevity in Low-Income Settings

Between 2015 and 2050, the world’s population of persons aged 65 and over is projected to grow by some 950 million. Nearly 90 percent of that new elderly population will live in Asia, Africa, Latin America, and the Caribbean—the vast majority in countries now classified as low- and middle-income countries (LMICs). Hundreds of millions of older persons in LMICs will be living with chronic, disabling conditions that limit their ability to function—among them mobility impairments, vision or hearing impairments, incontinence, cognitive impairments or dementia. Assistive devices or corrective procedures exist for most conditions but are often out of reach (financially or literally out of reach) for the elderly, especially the rural poor. The need for new low-cost and accessible technology to enable older people to fulfill their social roles and live in reasonable comfort will continue to grow. There are many examples of low-cost innovations in the health sector originating in LMICs that have saved or improved millions of lives, especially in maternal and child health. The goal of this initiative is to focus similar scientific and technological creativity specifically on conditions that limit the full participation of the elderly in society.

The National Academy of Medicine (NAM) has recently launched the Grand Challenge for Healthy Longevity to “support the next breakthroughs in healthy longevity.” The NAM plans a three-tiered structure of awards and prizes, beginning with a first phase of Catalyst Awards (“to explore new, innovative ideas”) leading to Challenge Awards (“to advance a pilot or prototype”) and finally to a limited number of Grand Prizes (“to reward the achievement of a bold and transformative innovation”). The Grand Challenge is not fully funded, but academies of science and medicine in several countries have joined, and an advisory committee, including several NIA grantees, has been formed. The Grand Challenge has some momentum and is likely to grow in the next few years and attract attention. Our expectation is that this initiative will constitute NIH’s contribution to the Health Longevity Grand Challenge—we will consider funding support for grantees under this initiative to participate in Grand Challenge meetings and exchanges, and we will coordinate with the NAM to ensure that those funded under this initiative are eligible to compete for the second tier (Challenge Awards) of the Grand Challenge.

Scientific/Research Contact

John Haaga, Ph.D.
Division of Behavioral and Social Research (DBSR)
National Institute on Aging
Telephone: 301-496-3131
E-mail John Haaga, Ph.D.

Interpersonal Processes in AD/ADRD Clinical Settings

It is widely recognized that effective communication between patients and clinicians plays a central role in patient-centered care and shared decision making, and that strong relationships between clinicians and patients may provide important therapeutic benefits to patients. For older adults with Alzheimer’s disease or a related dementia (AD/ADRD), difficulties in processing, remembering, recalling, and conveying information can serve as barriers to high-quality care. And while spouses or family caregivers often accompany AD/ADRD patients to medical consultations, supporting patient engagement in triadic communication between clinicians, patients, and caregivers in AD/ADRD care settings is not without challenges. Hardly invisible or a neutral bystander, the presence and actions of caregivers may influence information exchange in ways which may compromise patient outcomes. Nevertheless, little is known about effective communication between patients, caregivers, and clinicians in AD/ADRD care settings. Moreover, surprisingly few studies have directly examined whether, and how, caregiver participation impacts the quality of AD/ADRD care, or even if their interactions do more harm than good.

On the one hand, caregivers may serve as a valuable asset to patients and healthcare practitioners by clarifying or contradicting patient self-reports, offering additional information about symptoms, health behaviors, and medication adherence, and contributing to shared decision making. On the other hand, caregivers also bring their own values, beliefs and expectations into the clinical encounter, and these may not always coincide with those of the patient. Caregivers may also be a distraction to patients or health care practitioners which can complicate the diagnostic process. Even worse, they may even deliberately omit important details or provide false information, to discredit the patient and intentionally mislead the clinician, to conceal their acts of neglect, negligence, and abuse.

Impaired relationship functioning between caregivers and patients could have serious health consequences for both. Despite their clear relevance to AD/ADRD patient outcomes, relationship processes have been largely ignored in clinical healthcare settings. Nevertheless, identifying interpersonal processes impacted by AD/ADRD symptomology and their links to mental and physical health of both the patient and the caregiver represents an additional clinical challenge. Caregiving relationships do not exist in a vacuum of the clinical setting—they have been influenced by past experiences and expectations of AD/ADRD care partners and the social and cultural contexts within which they occur. They also develop within close relationships that differed in quality and function prior to symptom onset and who face illness with varying success.

If this concept proves successful, it will support research that can maximize clinical encounters and optimize intervention design for adults with AD/ADRD throughout the progression of the disease and across the care continuum. Examples include interventions that can help foster the development of strong and supportive relationships among patients, caregivers and health care practitioners, to promote rapport-building, accurate information exchange, informed shared decision making, goal-setting and attainment, and the completion of advance directives, and individual- and dyadic-based interventions that can improve care partner satisfaction and high-quality care partnerships.

The growing ubiquity of local and long-distance family caregivers across the AD/ADRD care landscape calls for the establishment of principles of effective communication between clinicians, patients, and caregivers and strategies for optimizing patient and caregiver engagement across all stages of AD/ADRD. As the population continues to age, there will be an increased need for the adoption and adaptation of family medicine approaches, and family system models, in ways that can support patient health.

Scientific/Research Contact

Melissa Gerald, Ph.D.
Division of Behavioral and Social Research
National Institute on Aging
Telephone: 301-451-4503
E-mail Melissa Gerald, Ph.D.

Lucidity in Dementia

Fluctuations in mental status occur commonly in dementia. Such fluctuations are most apparent in earlier stages of disease. However, even in late-stage dementia, patients have been reported to exhibit unexpected episodes of mental clarity or lucidity. These episodes are characterized by spontaneous meaningful and relevant communication at a time when the capacity for coherent speech has presumably been lost. Current scientific literature on lucidity in dementia is confined to anecdotal evidence and case reports. This evidence suggests that most episodes of lucidity are relatively transient and occur close to death. Accurate estimates of incidence do not exist at this point, as no systematic study has been conducted to our knowledge. However, the phenomenon is likely under-reported due to its suspected transience, masking by antipsychotics and other medications, limited scientific reporting channels for family and caregiver witnesses, and biases against reporting due to social desirability.

Further understanding of lucidity in individuals with dementia could yield important insights into the pathophysiology of Alzheimer’s disease and related dementias. Occurrence of lucid episodes in late stages of dementia suggests that neural structures or functions assumed to have degenerated may, in fact, remain intact. Speculative neurobiological explanations might include complex adjustments in signaling cascades, synaptic modifications, neuronal network interactions, and temporary reversal of inhibitory pathways. Case reports of unexpected lucidity occurring in other disease states suggests possible shared mechanisms. Understanding how lucidity in late stage dementia is possible could expand our understanding of mechanistic processes underlying cognitive decline and may point to novel preventative or therapeutic targets.

Greater understanding of lucidity in dementia may also affect families’ and caregivers’ attitudes and behaviors toward patients with dementia. Knowing that an individual with dementia could still be “there” even in late stages could have important implications for the formal and informal caregiving workforce and impact on decision-making or lead to decisional conflicts for family members and proxies.

Scientific/Research Contacts

Basil Eldadah, M.D., Ph.D.
Division of Geriatrics and Clinical Gerontology
National Institute on Aging
Telephone: 301-496-6761
Email Basil Eldadah, M.D., Ph.D.

Kristina McLinden, Ph.D.
Division of Behavioral and Social Research
National Institute on Aging
Telephone: 301-496-2563
E-mail Kristina McLinden, Ph.D.

Elena Fazio, Ph.D.
Division of Behavioral and Social Research
National Institute on Aging
Telephone: 301-496-3131
E-mail Elena Fazio, Ph.D.

Non-invasive Neurostimulation in AD/ADRD

With the recent wave of unsuccessful pharmacological clinical trials, it is imperative that we aggressively pursue novel, non-pharmacological approaches to meet our goals of addressing Alzheimer’s Disease and related dementias (AD/ADRD) by 2025. Non-invasive neurostimulation is a new and rapidly growing area of scientific research. Non-invasive neurostimulation is an umbrella term that encompasses many different technologies: some of which use magnetic stimulation of target brain regions to cause excitatory neurons to fire (e.g., transcranial magnetic stimulation; TMS,) and others use electrical stimulation to suppress or enhance extant neural firing (e.g., transcranial direct current stimulation; tDCS). Non-invasive neurostimulation techniques are particularly attractive to patients because they are, as the name implies, non-invasive and have the potential to be low in cost and/or portable. What remains to be seen is whether these modalities could be useful in the treatment of Alzheimer’s Disease and related dementias.

Relatively little work has tested the efficacy of neurostimulation in treating cognitive decline in AD/ADRD. The current literature consists of small handfuls of under-powered and open label studies. A meta-analysis of these studies by Hsu et al. (2015) pooled together 35 neurostimulation studies totaling 200 participants. Although not all studies showed a positive effect of neurostimulation on AD-related cognitive decline, the cumulative results were positive with a pooled effect size of 1.35. These studies provide initial evidence that neurostimulation may be useful in treating cognitive decline, though more work is needed.

TMS is FDA-approved in the treatment of depression and OCD, with many insurance companies providing reimbursement. However, there is no current indication for its use in AD/ADRD. Other neurostimulation modalities, such as tDCS, are not FDA approved. This regulatory gap, combined with the low-cost and relative ease of making these devices using easy to find products has led to at-home use by the general public, including individuals with cognitive concerns. These at-home users are “making it up as they go along” in their attempts to target brain regions they believe to be affected with self-prescribed stimulation durations and frequencies. Thus, non-invasive neurostimulation represents a regulatory gap area.

Non-invasive neurostimulation represents an area of untapped potential in the non-pharmacological interventions space. Because these interventions have not been well-studied in their treatment of AD/ADRD yet are a promising growth area in other fields such as psychiatry, we have the opportunity to incentivize researchers to turn their attentions to dementia. NIA is poised to fund well-powered and methodologically sound studies refining and testing initial efficacy of these interventions to treat or delay AD/ADRD.

Scientific/Research Contact

Kristina McLinden, Ph.D.
Division of Behavioral and Social Research
National Institute on Aging
Telephone: 301-496-2563
E-mail Kristina McLinden, Ph.D.

NRSA Short-Term Institutional Research Training Grant

Compared to research-oriented graduates, physician scientists and individuals with health professional degrees in aging research are vastly outnumbered by their Ph.D. peers. Despite a higher success rate substantially fewer physician-scientists applied for a first research project grant (R01) in 2018 than did PhD scientists. The National Research Service Award (NRSA) Short-Term Institutional Research Training Grant provides support to academic institutions to recruit and train medical students and individuals with health professional degrees to obtain necessary research training and allow them to expand their technical expertise and skills early during their education and encourages them to pursue a career in research.

For this purpose, we propose continuation of NRSA Short-Term Institutional Research Training support which will expire in July 2019, to support participating institutes to recruit and train talented medical and health-professional degree students, usually in form of summer internships, and help them gain research training and experience and to encourage physician scientists to pursue research careers.

Scientific/Research Contact

Shahrooz Vahedi, Ph.D.
Division of Extramural Activities
National Institute on Aging
Telephone: 301-496-9322
E-mail Shahrooz Vahedi, Ph.D.

Oscillatory Pattern of Gene Expression in Aging and Alzheimer’s Disease

Over the past decade there has been considerable progress in research on circadian clocks and their role in many aspects of physiology. Circadian systems organize critical physiological and behavioral functions by coordinating gene expression and metabolic processes. Circadian disturbances and disorders affect millions of Americans and their onset often coincides with the onset of many age-related diseases. For example, a significant proportion of older adults with Alzheimer’s disease (AD) exhibit disturbances in their circadian clock. Although this has been interpreted as a consequence of AD, there is evidence that circadian disturbances may contribute to AD and other age-related diseases.

This initiative aims to enhance existing transcriptome and proteome datasets by revealing rhythmic patterns of expression associated with aging and AD. This initiative builds on the discovery that a significant fraction of gene transcripts, including non-coding RNA, are consistently expressed in a characteristic oscillating pattern. Unfortunately, there are few public transcriptome or proteome datasets with multiple “timed” human samples to study such patterns, and none available for AD. However, it has been shown that compiling a collection of single “untimed” gene expression samples can generate a snapshot of (the oscillations of) individual clock-controlled genes. This can be achieved through direct computational analyses of existing large transcriptome or proteome datasets. The ability to utilize existing transcriptome or proteome data sets is especially advantageous given that sampling the central nervous system at multiple time points is not feasible.

Leveraging the existing information available in “untimed” transcriptome and proteome datasets, including those available in the Accelerating Medicines Partnership—Alzheimer's Disease (AMP-AD) project, will accelerate studies to determine the molecular significance of oscillatory patterns in aging and AD. The oscillatory expression of genes and proteins associated with pharmacotherapeutic targets in AD presents novel opportunities for translational research and the development of personal, optimized treatments based on patient circadian phase and amplitude. This research will add a new temporal dimension to our understanding of gene and protein expression data in existing datasets.

New technological advances have created a transformative opportunity to study the role of circadian “omic” function in health and disease using “untimed” snapshots of gene and protein expression in large transcriptomics or proteomics datasets. Temporal relationships encoded in existing gene and protein expression datasets represent an untapped opportunity for scientific discovery in aging and Alzheimer’s disease.

Scientific/Research Contact

Miroslaw (Mack) Mackiewicz, Ph.D.
Division of Neuroscience
National Institute on Aging
Telephone: 301-496-9350
Email Miroslaw (Mack) Mackiewicz, Ph.D.

Proposed NIA Initiative on Early Stage T1 Translational Aging Research (Bench to Bedside)

There continues to be a need for the translation of scientific discoveries into novel, effective interventions for the treatment and prevention of aging conditions, including therapies for multiple chronic conditions. In this regard, it is essential to foster research at the early developmental phases of T1 translational aging research (bench to bedside) so that more promising therapeutic agents (e.g., biologics, nutraceuticals, new drugs, repurposed drugs) could be poised for further preclinical pharm/tox studies and potentially enter the clinical phases of the translational pipeline. In 2009, the NIA issued an initiative with set-aside funds to encourage exploratory, translational studies and to facilitate the generation of proof of concept data on potential, novel interventions for aging conditions. This initiative was reissued but recently expired in 2018.

Over the years that the T1 translational research initiative was active, the NIA was able to generate a growing interest from the scientific community to pursue exploratory, translational studies and it eventually resulted in a consistent number of scientifically meritorious applications each Council Round. The translational research awards focused on the development of interventions (pharmacological and some non-pharmacological) for a wide range of conditions affecting older adults (e.g., age-related changes in cardiovascular function, therapies to modulate inflammation and immune function, and strategies to improve musculoskeletal health and improve wound healing.)

In April 2018, the NIA convened a meeting of the awardees to discuss their research progress and future plans for advancing their ideas down the translational research pipeline. It was clear from the presentations that significant progress had been made in many of these projects. In a few cases, the investigators had successfully licensed their technology to a small business or established a small business themselves to pursue further translational studies. Nearly all the awardees cited NIA’s support for early stage T1 translational aging research as having been crucial in providing funding to test their ideas for intervention development.

Thus, the proposed NIA initiative serves a need in supporting the early stage research efforts to develop novel interventions for aging conditions. In addition, the proposed initiative is timely due to the growing number of compounds which have been identified to target fundamental mechanisms of aging and thus hold promise for the prevention of multiple chronic conditions in old age.

Scientific/Research Contacts

Chhanda Dutta, Ph.D.
Division of Geriatrics and Clinical Gerontology
National Institute on Aging
Telephone: 301-496-4161
Email Chhanda Dutta, Ph.D.

Rebecca Fuldner, Ph.D.
Division of Aging Biology
National Institute on Aging
Telephone: 301-496-6402
E-mail Rebecca Fuldner, Ph.D.

Lorenzo Refolo, Ph.D.
Division of Neuroscience
National Institute on Aging
Telephone: 301-594-7576
E-mail Lorenzo Refolo, Ph.D.

Regulation of Brain Regional and Cell Type Specific Proteome Dynamics in Normal Brain Aging and Alzheimer’s Disease

The etiology of Alzheimer’s disease (AD) is multifactorial and complex; and the vast majority of cases can't be attributed to a single genetic factor. Many large-scale “omics” and genome-wide association studies (GWAS) of late-onset Alzheimer’s disease (LOAD) have identified at least 20 loci that are associated with AD risk. Although some of these genes and variants only have small effects on AD risk, bioinformatics and pathway analyses have allowed researchers to identify many functional groups, such as endocytosis, immunity, cholesterol metabolism and synaptic transmission, that are heavily involved in the genetics of late-onset AD. Currently, our approaches on both basic and clinical biology of AD are largely focusing on disease related changes at the genomic, epigenetic, transcriptomic, and proteomic levels. However, there are many different aspects of biology and cellular biochemistry that can’t be explained by these types of systems approaches because these types of approaches often fail to provide enough spatial or subcellular information.

For the past few years, the NIA and its Division of Neuroscience has invested significantly in various large-scale studies in the areas of systems biology, integrated physiology, epidemiology, biomarker discovery, imaging and genomic sequencing projects on LOAD to identify potential targets for the early diagnostics and treatment of AD. However, understanding the molecular changes of brain aging from genotypes to phenotypes will require the comprehensive understanding of protein components of neurons and their connections together with how their proteome changes in response to aging, environmental changes, and various insults. Therefore, one of the major goals of this initiative is to comprehensively determine the turnover and synthesis of brain proteome with sufficient cell type and regional specificity to monitor the alteration of brain proteostasis and synaptic plasticity during the course of brain aging and AD.

To overcome many of these issues, this initiative will take advantage of several recent advances in the area of chemical biology, such as using biotin identification (BioID) and engineered ascorbate peroxidase (Apex) as well as bio-orthogonal non-canonical amino acid tagging (BONCAT) synthetic protein approaches to study both newly synthesized and cell type specific brain proteomes in intact mammals. For example, several groups have recently demonstrated that it is possible to engineer or tag specific modifying enzymes to synaptic clefts to monitor the proteome dynamics of excitatory and inhibitory neurons individually in mammals in response to various synaptic stimulations. Further, this type of approach also permits one to bypass the physical or biochemical isolation of single cell types, which are often not only heavily contaminated by high abundant glial proteins, but the isolation of single cells also makes it difficult to detect most of extracellular and secretory proteins in vivo.

Another key advance to examine the cell type and brain regional proteome dynamics is to target expression of a mutant form of tRNA synthetase, which is engineered to charge a synthetic amino acid onto tRNA, to neurons or specific brain regions by using recombinant virus or genetically modified animals in a Cre-inducible manner. The synthetic, bio-orthogonal non-canonical amino acid can then be incorporated into newly synthesized proteins in neurons expressing this particular form of tRNA synthase in live animals. In contrast to other global approaches, this type of targeted analysis also will permit one to monitor the proteome dynamics of neurons and glial cells individually in mammals. Most importantly, BONCAT labeled proteins from neurons or glial cells can be simultaneously enriched and monitored in various biological fluids during the course of the experiment. The successful implementation of this type of targeted proteomic approach will most likely have a broad impact on basic and translational AD research, and potentially provide a conceptual framework for the future development of fluid phase AD biomarker discovery program.

Together, the overall goal of this initiative is to invite research projects that will use the next generation of synthetic enzymes, chemical biology, and bio-orthogonal amino acid whole animal labeling technique to obtain the spatial and temporal proteome dynamics information that will also inform brain anatomical and genetic changes in intact mammals.

Scientific/Research Contact

Austin Yang, Ph.D.
Division of Neuroscience
National Institute on Aging
Telephone: 301-496-9350
E-mail Austin Yang, Ph.D.

Renewal of the Grants for Early Medical/Surgical Specialists’ Transition to Aging Research (GEMSSTAR) Program

The 2008 Institute of Medicine report “Retooling for an Aging America: Building the Health Care Workforce”, emphasized the emergent need for additional health care personnel, especially those in specialty fields, to address the medical needs of a growing population of older Americans with complex medical problems. Responding to this call, the NIA initiated the Grants for Early Medical and Surgical Specialists’ Transition to Aging Research (GEMSSTAR) program. This recurring initiative, whose first awards were made in 2011, targets clinician-scientists in medical, surgical, and dental specialties generally during the initial years of their first faculty appointment. GEMSSTAR supports promising early career investigators to generate pilot data and establish a track record in aging/geriatrics-focused science to enhance their competitiveness for subsequent funding in aging research. The GEMSSTAR award involves an NIA-funded R03 grant that supports a small research project at the intersection of aging and the candidate’s clinical specialty. An applicant-designed professional development plan, which runs concurrently with the R03 award and is funded by applicant-identified sources, supports mentorship, training, and skills development in aging/geriatrics research.

A biennial GEMSSTAR Scholars Conference was added in 2014, funded through a U13 conference grant to the American Geriatrics Society. These conferences bring together past and current GEMSSTAR scholars, mentors, leaders in aging research, and NIA and NIH staff for two days of scientific talks, networking, mentoring, and career development guidance. Each conference focuses on a cross-cutting aging research theme, such as frailty, geroscience, and dementia, through an attendee-driven agenda. GEMSSTAR awardees have consistently rated this conference among the most valuable aspects of their award.

From 2011 to present, NIA has funded 127 GEMSSTAR awards across NIA’s 4 extramural funding divisions. Awardees represent 32 different clinical specialties (19 medical and 13 surgical). To date, 48 GEMSSTAR awardees have gone on to receive career development awards, including 14 Beeson awards and 16 VA career development awards. The majority of subsequent awards come from NIA, indicating that most GEMSSTAR scholars remain in aging research. Collectively GEMSSTAR awardees have authored or co-authored over 930 publications since receiving their awards.

NIA recently developed a new broad-ranging initiative to support clinician-scientists in aging research. Called the Clinician-Scientists Transdisciplinary Aging Research (Clin-STAR) Coordinating Center, this research resources cooperative agreement will advance transdisciplinary research leading to improved patient-centered care of older adults across specialties and disciplines. Among this initiative’s many goals is continued support of the GEMSSTAR scholars conference and GEMSSTAR networking activities. It is currently open for competition under RFA-AG-19-024.

Scientific/Research Contact

Susan Zieman, M.D., Ph.D.
Division of Geriatrics and Clinical Gerontology
National Institute on Aging
Telephone: 301-496-6761
E-mail Susan Zieman, M.D., Ph.D.

Renewal of the Nathan Shock Centers of Excellence in the Biology of Aging

The Nathan Shock Centers of Excellence in Basic Biology of Aging (NSC) were created in 1995 and have served an ever-increasing role in the development of aging biology research. There are currently 6 NSC across the country. They provide intellectual leadership and innovation, pertinent cores focused on the needs of the field and opportunities for research career development for future leaders. They also collaborate substantially with other NSCs and other NIA-funded Centers. In the last few years (following the last iteration of this RFA), the Centers have developed a more robust approach to core development, and in addition, they were directed to develop further outreach, by organizing bi-annual major meetings focused on current controversial areas in the field. A related Coordinating Center has developed a web site and has substantially increased visibility of the NSC.

There is no doubt that research into the biology of aging has accelerated enormously during the last decade or so, and the field has progressed so that we now have enough understanding of the major drivers of aging at the cellular and molecular levels. As a result, the field has moved from a focus on lifespan toward healthspan, and this in turn has led to the development of the field of geroscience. Currently, there is a need for the development of a further emphasis on integrated physiology of aging, providing the foundations on which to test the geroscience hypothesis, that slowing the rate of aging reduces the severity and delays the onset of multiple age-related conditions, frailties and diseases. This in turn means that the requirement for infrastructure and resource development has increased and there is a need not just to keep the momentum, but also to expand the effort. Renewal and expansion of the NSC is one of the most straightforward mechanisms to achieve this in the field of aging biology.

This is a renewal of a successful set of activities, so the opportunity is clear from that viewpoint. However, more important is the enormous opportunity to further research at a time when the field is expanding rapidly. In addition, there is an increased interest in collaboration across NIA centers and, given that research on the biology of aging forms the basis for the development of preventive health interventions, a modest expansion of the current Centers is a timely opportunity.

Scientific/Research Contact

Felipe Sierra, Ph.D.
Division of Aging Biology
National Institute on Aging
Telephone: 301-496-6402
E-mail Felipe Sierra, Ph.D.

Science of Behavior Change (SOBC) Resource and Coordinating Center

The trans-NIH Science of Behavior Change (SOBC) Common Fund Program aims to:

  • Unify the science of behavior change through a focus on mechanisms of change and by strengthening links between basic and applied research, and
  • Transform behavioral intervention designs by implementing the experimental medicine approach to behavior change research and developing the tools required to implement such an approach.

The experimental medicine approach to behavior change involves identifying an intervention target, developing assays (measures) to permit verification of target engagement, engaging the target through experimentation or intervention, and testing the degree to which target engagement produces the desired behavior change. Putative intervention targets represent mechanisms or processes that are hypothesized to be malleable and to play a causal role producing behavior change. In the SOBC Program, three broad behavioral domains were identified as being especially relevant because they contain multiple putative intervention targets with a variety of existing assays (measures): self-regulation, stress reactivity and stress resilience, and interpersonal and social processes.

In 2014, SOBC funded a research network of projects designed to identify, develop, and validate assays of targets in these three target domains and a Resource and Coordinating Center (RCC) to provide national leadership for the coordinated efforts of projects and initiatives of SOBC. The RCC serves as the central resource for the organization of meetings and other activities of the SOBC Program, including the support of its Steering Committee and External Scientific Panel. More visibly, it maintains a publicly available repository of assays developed by research network projects that can be used to measure the activity of specific targets within the three selected target domains. Analytics indicate that there is already a high degree of research community engagement with the repository, and the RCC is currently enhancing the repository interface to enable outside researchers to contribute new assays and to link the repository to other resources supported by both NIH and the behavioral science research community.

The RCC also engages in other dissemination activities related to the SOBC approach (e.g., publications, presentations at scientific meetings, and the development of training materials and workshops). It also facilitates collaborations among SOBC investigators and NIH staff, including collaborative work to develop technical guidelines and best practices for the validation of assays of behavior change targets as well as a pilot core that has been able to provide short-term support for the development of assays measuring newly identified putative targets deemed to be either of higher risk/reward or requiring additional work before deployment in clinical settings. Finally, the RCC conducts systematic reviews of the extant behavior change and adherence to medical regimens literatures to identify and classify other putative targets that may inform the development of future research programs, especially in the area of medical regimen adherence. The collection of all these efforts contributed to the success of two additional Common Fund initiatives (competing revisions and new R21s) that sought to introduce the experimental medicine into the design of new behavioral interventions and allow investigators to measure target engagement in ongoing clinical research.

This initiative will support continuation of the SOBC RCC to maximize the productivity, scientific rigor, and dissemination of SOBC Program products and approaches to meaningfully impact health behaviors. Activities include: (1) expansion of the measures repository through input from the broader research community, (2) communication of emerging behavior change science, (3) outreach and dissemination at scientific meetings, and (4) systematic reviews and meta-analyses of existing clinical trials to generate testable hypotheses concerning potential putative intervention targets, differential response of individuals to treatment, and estimates of intervention efficacy and effectiveness, and (5) engagement with national and international behavior change organizations to promote mechanisms-focused behavior change science.

Scientific/Research Contact

Lis Nielsen, Ph.D.
Division of Behavioral and Social Research
National Institute on Aging
Telephone: 301-402-4156
E-mail Lis Nielsen, Ph.D.

Stimulating Multidisciplinary Programs for Alzheimer’s Disease and Alzheimer’s Disease Related Dementias

The AD/ADRD Research Implementation Milestones provides a framework to support the goal of finding a cure for AD by 2025. The overall goal of this initiative will be to develop and implement excellent multidisciplinary curricula and programs through interchange of ideas that enables institutions to strengthen its existing programs and focus program development that is specific to the goals/milestones of the AD and ADRD Summits.

The initiative will:

  • provide protected time to a senior mentor to produce a program of investigation specific to selected AD/ADRD research implementation goals/milestones
  • support studies that will address selected AD/ADRD research implementation goals/milestones
  • develop a workforce that will continue to address selected AD/ADRD research implementation goals/milestones

Scientific/Research Contact

Cerise Elliott, Ph.D.
Division of Neuroscience
National Institute on Aging
Telephone: 301-496-9350
E-mail Cerise Elliott, Ph.D.

Tailoring Interventions to Improve Preventive Health Service Use

In recent years in the US we have seen dramatic increases in adaptation to electronic health records, expanding the amount of clinical data available to inform preventive interventions and to improve the health of the elderly. Simultaneously, rapid progress has been made in clinical analytics—techniques for analyzing these large quantities of data and gleaning new insights from these analyses to inform interventions. For example, a recent study by Kim et. al (2018) found that vaccination rates decline at the primary care practices studied over the course of the day due to “decision fatigue.” They implemented an “active choice” intervention in the electronic health record that prompted medical assistants to ask patients about influenza vaccination during check-in that produced significantly higher vaccine ordering rates compared with those practices without the active choice intervention.

The proposed concept will encourage researchers to use insights from Electronic Health Records (EHR) data to tailor interventions (targeting for both physicians and patients) to improve take up of preventive treatment recommendations for elderly from U.S. Preventive Services Task Force (USPTF) and CDC immunization recommendations.

It will encourage data analytics approaches (e.g., identification of high risk patients based on previous health utilization rendered by health care provider) from EHR and other relevant health records (e.g., Medicare claims records) to tailor interventions intended to address take up of preventive services from USPTF recommendations (Grade A and B) for preventive services (e.g., colorectal cancer screening) and recommendations by CDC Advisory Committee on Immunization Practices for adults (e.g., discussion and planning for all of the CDC Advisory Committee on Immunization Practice (ACIP)-recommended vaccines for older adults during Medicare Annual Wellness Visit).

The initiative will encourage use of behavioral economics approaches to understand decision-making by patients and providers and to develop interventions to encourage use of preventive care in accord with USPTF and CDC recommendations Additionally, the concept will require development of tailored interventions which will target both providers and patients to address health disparities (e.g., colorectal cancer is the second leading cause of cancer death, yet the take-up of screening is low among Hispanics compared to other racial and ethnic groups).

If this concept is successful, it will result in: (1) increased uptake of preventive services among elderly recommended by USPTF (Grade A or B) and CDC and (2) addressing Department of Health and Human Services, NIH and NIA strategic goals of improving preventive health services delivery among the elderly.

Scientific/Research Contact

Partha Bhattacharyya, Ph.D.
Division of Behavioral and Social Research
National Institute on Aging
Telephone: 301-496-3131
Email Partha Bhattacharyya, Ph.D.

Transition to Aging Research Award for Predoctoral Students

Soon after graduation, many predoctoral students must decide on their post-doctoral scientific career path. Lack of clear career plans and many uncertainties and variables force doctoral graduates to seek non-traditional careers opportunities such as (non)research positions at biopharmaceutical/biotechnology industries, consulting and law firms as well as financial and governmental institutions. Indeed, our analysis show that more than half (53%) of NIA F31 predoctoral awardees between 2000-2013, never applied to any funding opportunity at NIH. This number was lower (37%) for postdoctoral F32 awardees within the same time frame. This pattern is a general trend across NIH. These data suggest that early in the pre- to post-doctoral transition, many of our scholars in aging are leaving science. While many reasons can be attributed for this observation, having a clear professional career plan and freedom to choose a future research area which is supported by NIA, can decrease this mass migration and retain aging research fellows.

This predoctoral to postdoctoral transition award was first launched by the National Cancer Institute in 2016. While it is too early to assess the effectiveness of this program in retaining scientists in academic research, the number of applicants and awardees have been growing since program inception. The overall goal of the NIA Transition to Aging Research Award funding mechanism is first to increase and retain the number of NIA-sponsored predoctoral trainees in the field of aging after graduation and second to enhance recruitment of doctoral students from other disciplines to further diversify the scientific workforce in aging research.

Scientific/Research Contact

Shahrooz Vahedi, Ph.D.
Division of Neuroscience
National Institute on Aging
Telephone: 301-496-9322
E-mail shahrooz.vahedi@nih.gov

Understanding Senescence in Brain Aging and Alzheimer’s Disease

Senescent cells accumulate in aging and disease, and they are defined by an arrested cell cycle with a distinct proinflammatory phenotype affecting neighboring cells. Most published studies on cellular senescence were conducted in peripheral tissues, creating a gap in our understanding of how senescence may distinguish healthy brain aging from neurodegenerative disease (including Alzheimer’s disease and its related dementias [AD/ADRD]). Understanding the role of senescence in healthy brain aging would provide a baseline and appropriate context for studying the role of senescent cells in neurodegenerative disease pathogenesis. While no single marker can independently define a senescent cell, recent research has identified multiple cell-type specific hallmarks of senescence.

However, hallmarks of senescence in some brain cell types are entirely unknown in aging (e.g., oligodendrocytes, endothelial cells, neural stem cells), or debated within the field. For example, it is debated whether terminally differentiated cells—namely, neurons—are capable of undergoing senescence. Although growth-cycle arrested by definition, it is unclear whether aged neurons release proinflammatory molecules to negatively influence neighboring cells. Moreover, the pleiotropic effects of systemic senescence further complicate our understanding of senescence in the brain. For instance, while maintaining cell-cycle arrest slows cancer progression, the characteristic proinflammatory senescent phenotype accelerates the aging process. Systematically assessing the functional consequences of senescence by brain cell type during aging could uncover new targets for AD/ADRD treatment and prevention. The availability of senescent cell-targeting mouse models and senolytic therapies make this an opportune time to encourage applications proposing to design studies addressing these open questions in the aging brain and AD/ADRD.

Scientific/Research Contact

Amanda Dibattista, Ph.D.
Division of Neuroscience
National Institute on Aging
Telephone: 301-827-3342
E-mail Amanda Dibattista, Ph.D.

Back to contents

May 2018 Council

Approved concepts in this round:

A Census of Cells and Circuits in the Aging Brain

Despite the many advances in the neuroscience of the aging brain in recent years, the underlying mechanisms of selective central nervous system vulnerability to aging effects, cellular and molecular mechanisms of brain repair, and involvement of glial cells in brain aging remain unclear. Cataloging brain cell types and their connectivity is a prerequisite to understanding how they are organized into circuits and how they change in brain disorders; uncovering age-related changes will open a new dimension in research on the aging brain. The classification of cell types can be facilitated by systematic collection and integrated analysis of three data elements at a cellular level:

  1. molecular signature (e.g., transcriptome, epigenome, proteome, and metabolome),
  2. anatomy (e.g., location, size, orientation, morphology, and connectivity), and
  3. function (e.g., electrophysiology and functional connectivity).

The systematic identification, characterization, and positional mapping of various cell types in the adult mouse brain have been recently undertaken by the Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative. These efforts involve identifying the gene expression patterns and signatures that define specific cell types, an accurate census of each cell type’s representation, and spatial characterization that includes anatomical features of these cell types within their resident tissue. Although research supported by the BRAIN Initiative will reveal fundamental organizational principles of the mammalian nervous system, and provide invaluable resources for neuroscientists in aging research, its focus is not on aging research.

Current single-cell technologies promise a new era in the call for a brain cell census as high-dimensional molecular information is available at an unparalleled scale and resolution. This unprecedented progress opens new research areas to explore in the aging central nervous system that include cell-type classification based on molecular identity, connectivity, and morphology; a taxonomy of cell types based on molecular identity and connectivity; and estimates of the number and percentage of defined cell types in specific region(s) and/or circuit(s), and their changes with aging.

Scientific/Research Contact

Mack Mackiewicz, Ph.D.
Division of Neuroscience
National Institute on Aging
Telephone: 301-496-9350
Email Mack Mackiewicz, Ph.D.

Alzheimer’s Disease Genetics Consortium

NIA established the Alzheimer’s Disease Genetics Initiative in 2002. At that time, a single gene variant, apolipoprotein E-ε4 (APOE-ε4), was confirmed by classical genetic analytical approaches as a significant risk factor for the common form of late onset Alzheimer’s disease. Technological advancements such as genome-wide association studies (GWAS) in conjunction with the formation of large consortia, particularly the Alzheimer’s Disease Genetics Consortium (ADGC), augmented capabilities to successfully identify additional Alzheimer’s disease (AD) genes. Since 2009, more than 20 new AD genes identified have been confirmed, in large part through the efforts of the ADGC. The ADGC, the linchpin of the AD genetics portfolio, has generated a list of 67 likely genes that now need confirmation and as many as 600 genes if regulatory regions surrounding GWAS hits are considered.

The ADGC was funded to assemble and genetically characterize appropriate AD case and control samples for gene discovery and replication to detect susceptibility and protective genes for AD and AD-related dementias (AD/ADRD) phenotypes. The team has been highly collaborative and extremely productive since its inception. The ADGC is the “global gold standard team” in gene discovery for AD. Working cohesively with the Alzheimer’s Disease Centers, the National Cell Repository for Alzheimer’s Disease, the NIA Genetics of Alzheimer’s Disease Data Storage Site, and the National Alzheimer’s Coordinating Center, the ADGC is the key instrument by which well-phenotyped subjects are genetically characterized. Because this group effectively and efficiently recruits the cohorts for AD genetic studies and performs GWAS on all subjects whose DNA is sequenced, they are essential to successful outcomes for the Alzheimer’s Disease Sequencing Project (ADSP) and have provided the vast majority of the sample sets that have been sequenced. The ADGC is particularly important in recruiting and characterizing diversity sample sets and provides these ethnically diverse cohorts to the ADSP for whole genome sequencing. It is anticipated that 24 cohorts with up to 30,000 subjects of ethnic diversity will be recruited, characterized, and GWAS-ed by the ADGC in the next five years. The continuation of the ADGC therefore is crucial to AD research.

A more comprehensive understanding of AD genetics is needed to increase the number of valid targets for AD therapies. To date, genetics studies can only explain a fraction of the heritable risk for AD and we presently know only a fraction of the genes contributing to AD risk. Work is also needed to connect AD-associated genes to pathways, gene clusters, and specific pathologic processes. This should be done using a variety of genetic approaches to find cost-effective ways of using existing data. A major strength of the ADGC is the ability to assemble large datasets for AD genetic studies and make these datasets available to an extensive collaborative network of investigators. The ADGC, a central activity of the Division of Neuroscience, provides the infrastructure for generating genetic data, assembling diverse datasets, performing complex analysis, and providing analysis ready data to an extensive collaborative network of investigators.

New initiatives may include:

  1. Perform GWAS analysis of different ethnic groups with sample sizes sufficient to discover novel loci. Expand projects to include presently under-represented ethnic groups (Asian, Hispanic, Amerindian, Indian, African).
  2. Collaborative interactions with other funded projects that complement ADGC activities.
  3. Perform functional genomics and other -omics approaches that will benefit by direct collaborations.

Definition of novel AD genetic signals can be integrated with other approaches to accelerate functional characterization of genes of interest. To prevent a funding lapse, impediments to the recruitment of diversity sample sets, and slowing of analysis of the vast amounts of AD genetic data that are now becoming available, a request for concept clearance is being put forward at this time.

Scientific/Research Contact

Marilyn Miller, Ph.D.
Division of Geriatrics and Clinical Gerontology
National Institute on Aging
Telephone: 301-496-9350
E-mail Marilyn Miller, Ph.D.

Building an Infrastructure to Synergize Research for Improved Care of Older Adults across Specialties and Disciplines

The Institute of Medicine’s 2008 report, “Retooling for an Aging America: Building the Healthcare Workforce,” recommended greater efforts to recruit, retain, and educate specialists with aging-related expertise to advance multidisciplinary care strategies, communication, and research. In 2011, NIA created the Grants for Early Medical and Surgical Specialists’ Transition to Aging Research (GEMSSTAR) award program to help launch the careers of early physician- or dentist-scientists wishing to focus their research in an aging aspect of their specialty. To date, NIA has funded 111 GEMSSTAR Scholars representing more than 26 medical and surgical specialties including primary care and geriatrics. In 2014, the NIA awarded a U13 conference grant to the American Geriatrics Society to support three biennial GEMSSTAR conferences, which bring together past and present GEMSSTAR awardees, leaders in aging, clinical specialists focusing on aging research, and NIH staff. Each conference is anchored in an aging research topic of broad relevance to GEMSSTAR scholars. The GEMSSTAR conferences provide a venue for GEMSSTAR Scholars to showcase their research, network, and build collaborative relationships with each other and field leaders, receive mentoring, augment their career development skills, and interact with program officers of the NIA and other NIH ICs.

Despite these efforts, more support is needed for the growing number of clinician-scientists from different disciplines focused on aging. Promising investigators with an interest in aging research are spread out at institutions across the U.S., and many of these investigators lack in-person access to established mentors with strong aging research backgrounds or aging research resources. Moreover, as the envelope of aging research has expanded beyond traditional geriatrics and gerontology and into new clinical disciplines, mentors with multidisciplinary backgrounds bridging aging and other clinical disciplines are even rarer. Furthermore, many emerging investigators are based in institutions with access to special populations of older individuals and could make significant contributions in understudied areas, especially in the area of aging health disparities. Thus, there is a need to provide emerging clinicians who recognize the importance of aging within their discipline with the necessary guidance and resources to be competitive in aging research. Such support can facilitate development of specific transdisciplinary research approaches that better reflect the real-world needs of complex care for older adults including patient-centered care, coordination of prevention and treatment strategies among disciplines, and reduction of redundancy, treatment burden, and the risk to patients inherent in fractured care.

The GEMSSTAR Scholars have rated the U13 conferences as one of the most valuable aspects of their GEMSSTAR award. Several new inter- and transdisciplinary research applications have developed from new collaborations facilitated by these conferences. Moreover, connecting clinician-scientists focusing on aging research with like-minded colleagues within their specialty or from other disciplines allows a unique opportunity for early investigators to solve problems related to barriers within their careers and those pertinent to establishing transdisciplinary care. However, continuation of the GEMSSTAR conference series beyond 2019 as an investigator-initiated U13 award is uncertain because a new or renewal application would be subject to NIA’s general pay line. Thus, a more stable funding mechanism is needed to continue these valuable and productive in-person conferences while also expanding their scope to serve a larger community of clinician-scientists. In addition, a funding mechanism to support research infrastructure and resource building could further augment the activities of this expanding community and provide resources to support transdisciplinary research projects.

Scientific/Research Contacts

Basil Eldadah, M.D., Ph.D.
Division of Geriatrics and Clinical Gerontology
National Institute on Aging
Telephone: 301-496-6761
Email Basil Eldadah, M.D., Ph.D.

Susan Zieman, M.D.
Division of Geriatrics and Clinical Gerontology
National Institute on Aging
Telephone: 301-496-6761
E-mail Susan Zieman, M.D., Ph.D.

Development and Maintenance of an Aged Rodent Tissue Bank (Contract Renewal)

The purpose of this contract is to provide a source of fresh-frozen tissue, suitable for multiple experimental protocols, from the NIA colonies of aged rats and mice. While many researchers require live animals for their experiments, the availability of frozen tissue allows investigators to pursue certain types of experiments at a greatly reduced cost. It also makes more efficient use of the aged rodent resources, effectively allowing multiple investigators to use parts of one rodent. This resource benefits investigators using many experimental approaches, including molecular biology, immunocytochemistry, and histology, among others. The rodent tissue bank includes frozen tissue from the NIA aged rodent colonies, as well as tissue arrays from F344BN F1 rats, C57BL/6 mice, and caloric-restricted C57BL/6 mice, providing a unique resource for exploratory studies.

Scientific/Research Contacts

Manuel Moro, D.V.M, M.P.H, Ph.D.
Division of Neuroscience
National Institute on Aging
Telephone: 301-496-6402
Email Manuel Moro, D.V.M, M.P.H, Ph.D.

Exploring Molecular Links Between Dietary Interventions and Circadian Rhythm

Caloric restriction (CR) is the most effective strategy for improving both health span and longevity in animal species ranging from lower organisms to nonhuman primates. While energy-sensing pathways (mTOR, sirtuins, and AMPK) are important for the CR effects, the molecular mechanisms that could be leveraged for translation remain elusive. Recently, circadian regulation has been recognized as a novel mediator for CR effects in mice, demonstrated through several studies that have indicated interactions between the circadian clock and major longevity pathways including sirtuins, insulin/IGF, and mTOR signaling cascades. Interestingly, mice deficient in BMAL1, the core component of the peripheral circadian clock, fail to respond to CR-mediated life span extension and associated changes in plasma IGF-1 and insulin levels. In addition, entraining the peripheral circadian clocks by time-restricted feeding results in improved health span, even in the absence of CR. These findings thus provide an exciting opportunity to investigate circadian regulation of CR and associated physiological consequences.

Despite current data supporting the importance of circadian regulation of CR, molecular components that couple circadian systems with metabolic control, epigenetic modification, and age-associated pathologies are not fully understood. In addition, little is known about the contributions of central clocks versus peripheral clocks for regulating circadian homeostasis in the context of aging and metabolism. Several CR modifications such as amino acid restriction, intermittent fasting, and fasting-mimicking diets have been shown to improve health span in animals and in human trials. Therefore, this initiative is timely in examining how each of these dietary interventions entrains peripheral clocks and how circadian regulation integrates with various dietary strategies to achieve optimal health benefits.

Scientific/Research Contact

Yih-Woei Fridell, Ph.D.
Division of Aging Biology
National Institute on Aging
Telephone: 301-496-7847
E-mail Yih-Woei Fridell, Ph.D.

Francesca Macchiarini, Ph.D.
Division of Aging Biology
National Institute on Aging
Telephone: 301-827-4013
E-mail Francesca Macchiarini, Ph.D.

Integrative Research to Understand the Role of the Gut-Brain Axis and the Microbiome in Brain Aging and Alzheimer’s Disease

Technological and research advances during the past decade have led to a growing appreciation of the role of the microbiome in human health and disease including its contribution to neuropsychiatric and neurologic disorders. Despite the many new insights gained about the role of the gut-brain axis and the microbiome in neurodevelopmental and neurodegenerative disorders, a systematic and rigorous exploration of their role in the etiology of Alzheimer’s disease (AD) is lacking.

AD is a highly heterogeneous disorder with a long prodromal period and multifactorial etiology. Rich epidemiologic, genetic, and biologic evidence point to immune and metabolic dysregulation (in peripheral systems and in the central nervous system) as major drivers of AD pathogenesis. However, the molecular details of the interplay between immune and metabolic factors as they relate to the neurodegeneration that underlies cognitive decline and the neuropsychiatric symptoms of AD are still poorly understood. Many of the physiologic processes and comorbid conditions involved in AD pathogenesis (such as inflammation, insulin resistance, and the stress axis) are directly impacted or modulated by the microbiome. Deeper understanding of how the bidirectional microbiota-gut-brain axis acts through neuroendocrine, neuroimmune, and autonomic nervous mechanisms during brain aging and in AD will lead to new insights about the gene–environment interactions contributing to the initiation and progression of AD and open new avenues for disease prevention, both pharmacologic and non-pharmacologic.

NIH has made robust investment in the development of reference data, knowledge, and analytical tools for exploring the role of the human microbiome in health and disease through the Common Fund Human Microbiome Project. These efforts, together with NIA’s investment in epidemiology, genetics, deep molecular profiling, and systems biology, provide a rich foundation for launching programs focused on understanding how the microbiome interacts with the genome and an array of lifestyle factors to influence divergent trajectories of aging, brain aging, and AD.

Scientific/Research Contacts

Suzana Petanceska, Ph.D.
Division of Neuroscience
National Institute on Aging
Telephone: 301-496-9350
Email Suzana Petanceska, Ph.D.

Involvement of small business concerns in the preclinical development of novel therapeutics which target fundamental mechanisms of aging

Interest is growing in the development of novel therapeutics and the repurposing of Food and Drug Administration-approved drugs which can modulate fundamental mechanisms of aging (e.g., cell senescence, autophagy, mitochondrial dysfunction, and inflammation). Such therapies would not only be applicable to a wide variety of age-related conditions (diastolic dysfunction, sarcopenia, and age-related dementias, including Alzheimer’s disease) but also have the potential to prevent multiple chronic conditions. Ultimately, the goal is to promote health span—maintenance of good health, including cognitive and physical function, as we age.

To date, efforts in aging research toward this goal have generated proof-of-concept data in model organisms and/or in vitro experimental systems for a variety of compounds. Some of these compounds are new while others entail the repurposing of existing therapies which have been found to extend life span, modulate various aging mechanisms, or alleviate specific age-related deficits in physiological functions, such as endothelial cell dysfunction, impaired wound healing, and alterations in cardiomyocyte function. Despite this encouraging research progress, only a limited number of compounds that target aging mechanisms are developed beyond the basic research/discovery phase to enter preclinical drug development pathways. Consequently, the prospects for taking such potentially novel therapies to first-in human studies and clinical trials remain low. This continues to represent a major bottleneck in translational aging research.

One of the barriers to entry into preclinical drug development pathways is the lack of funding sources to support the types of studies required for the identification of viable candidate compounds, lead optimization, and establishment of their pharmacological and toxicological profiles in animal and in vitro experimental models. Such studies are usually resource intensive and time consuming, but crucial to the design and implementation of initial human testing of novel therapeutics. As a result, promising candidate products may also not be developed due to resource constraints. It is therefore important to engage small business concerns in translational aging research that possess the necessary resources and follow standard operating procedures, such as Good Laboratory Practices and Good Manufacturing Practices that will meet regulatory requirements and increase the likelihood of filing an investigational new drug application.

Scientific/Research Contacts

Chhanda Dutta, Ph.D.
Division of Geriatrics and Clinical Gerontology
National Institute on Aging
Telephone: 301-496-4161
Email Chhanda Dutta, Ph.D.

Rebecca Fuldner, Ph.D.
Division of Aging Biology
National Institute on Aging
Telephone: 301-496-6402
E-mail Rebecca Fuldner, Ph.D.

Lorenzo Refolo, Ph.D.
Division of Neuroscience
National Institute on Aging
Telephone: 301-594-7576
E-mail Lorenzo Refolo, Ph.D.

Low-Cost Detection of Cognitive Decline in Clinical Settings

Early detection of cognitive decline may be critical to the efforts of stopping dementia progression, including Alzheimer’s disease and Alzheimer’s disease-related dementias (AD/ADRD). Dementia and mild cognitive impairment (MCI) are under-diagnosed, and analyses using claims data, as well as other methods, indicate that clinical diagnoses occur late in the process of cognitive decline. As noted by the United States Preventive Services Task Force, fewer than 50 percent of persons with dementia are diagnosed, and the rates are even lower for MCI. Furthermore, detection and diagnosis rates are worse in minority populations. The inability to diagnose and treat cognitive impairment results in prolonged and expensive medical care. Early detection could help persons with dementia and their care partners plan for the future. Early detection will become increasingly important both for recruitment of individuals for clinical trials and, ultimately, as effective treatments become available, for ensuring that people receive early treatment. In October 2017, NIA supported a meeting titled “Cost-Effective Early Detection of Cognitive Decline,” (PDF, 393K) which highlighted the need for (1) development, (2) validation, and (3) translation of screening and assessment tools for measuring cognitive decline. Specifically, researchers highlighted the following research needs:

Development Work:

  1. Develop and test technologies that enable new approaches to assessing intraindividual change in cognition, in part by assessing process as well as product to identify subtle signs of early impairment that are overlooked because of compensatory strategies.
  2. Develop and test self-administered assessments with low false-positive rates.
  3. Develop and test longitudinal assessments to understand indicators of possible decline.
  4. Where possible, embed or associate new assessment methods with existing studies to leverage resources.

Validation Work: Validation research is needed to assess computerized or digital screening tools, automated electronic health record tools, and risk indices of early cognitive decline against gold-standard measures.

  1. Validate computerized test batteries, digital assessment tools, and risk indices to establish sensitivity and specificity for biomarker evidence of preclinical AD/ADRD and to compare performance against existing measures, where appropriate.
  2. Consider fit-for-purpose, community, and clinical meaningfulness.
  3. Consider whether a multisite platform and coalition for validating and comparing various tools for predicting and measuring change, possibly modeled on the Alzheimer’s Disease Neuroimaging Initiative approach, could be useful to the research community for organizing these efforts.

Translation Work: Assessment and screening tools, administrative data analysis methods, and risk indices to detect early signs of cognitive decline are often developed in research contexts. More research is needed to adapt, test, and implement such tools in clinical settings and to link them to clinically meaningful care.

  1. Adapt existing tools and methods with input from stakeholders to fit the needs of a clinical workflow. Ideally, instruments would have utility at the individual level as both predictors and indicators of change.
  2. Test existing tools and methods in a variety of diverse regions and populations, and with different modalities such as telemedicine.
  3. Identify and provide evidence for the link between screening and assessment tools and clinically meaningful care recommendations. 4. Conduct usability studies in a variety of geographic regions and populations, and with different modalities such as telemedicine, and leverage substantial existing work from the U.S. Department of Veterans Affairs.

We propose an initiative to solicit research to develop, validate, and translate screening and assessment tools for electronic health record systems that can assist physicians with making clinically meaningful care recommendations for patients experiencing cognitive decline. While the use of AD/ADRD biomarkers may be integrated into the diagnostic process in the future, currently, they are only used for research purposes. It is unclear how long it will take to validate them and, even after they are validated, they may remain expensive or difficult to obtain in certain locations or in certain populations. The screening and assessment tools proposed to be developed through this initiative can be used to select individuals who may be most appropriate for biomarker validation or for therapeutic trials aimed at ameliorating cognitive decline. Therefore, we believe this initiative will be valuable to facilitate current clinical care as well as future clinical assessment for both research and care.

Scientific/Research Contacts

Partha Bhattacharyya, Ph.D.
Division of Behavioral and Social Research
National Institute on Aging
Telephone: 301-496-3131
Email Partha Bhattacharyya, Ph.D.

Marmosets as a Translational Model for Aging Research

The primary aim is to further facilitate the characterization of the marmoset as a model of aging and age-related diseases. The relationships among aging, health, and disease in humans are often not well modeled by rodent studies. Among all animal groups, nonhuman primates (NHP) are the closest evolutionary relatives of humans with whom they share anatomical, physiological, gene interactions, and psychological features. Consequently, research with NHP is particularly relevant for the understanding of human health and disease. Rhesus macaques are the most widely used NHP in aging- related research. They have a median lifespan of 26 years and are considered “aged” at 20 years of age. They are considered a relatively good aging model, replicating many age-dependent conditions seen in humans. However, their long lifespan is a significant disadvantage for aging related studies. In contrast, the common marmoset (Callithrix jacchus) provides some unique advantages for the study of aging and aging-related disorders. Their long-standing use as a model for family interactions, hormonal development, reproductive output, and medical research has resulted in a large collection of baseline values for growth, body weight, and hematological measures.

Marmosets are sexually monomorphic, and adults weigh an average of 300–500 grams in captivity. They typically produce litters consisting of fraternal twins, with a gestational length of 143 days. Marmosets reach sexual maturity at approximately 18 months, and the average lifespan in captivity is 4 to 6 years. Marmosets are often considered “aged” at 8 years of age. The maximum lifespan reported for marmosets in captivity is 16 years. While the population of animals aged 13 to 16 years in any captive colony in the United States is very limited, the short lifespan of these NHP—along with their fast reproduction and recent improvements in husbandry—results in the ability to rapidly form large populations of aged adults. Marmosets are also easily handled and do not carry many of the infectious zoonotic agents common to other NHP currently used in biomedical research. Additionally, there is no evidence of density-dependent deaths related to increased aggression or competition for group-housed individuals, as is commonly seen in many other NHP species such as macaques and baboons. Recent studies have demonstrated that marmosets exhibit many age-related changes in physiology similar to those observed in humans, such as changes in lean mass, calf circumference, circulating albumin, hemoglobin, and hematocrit. In addition, marmosets show age-related spontaneous sensory and neurodegenerative changes such as reduced neurogenesis and β-amyloid deposition in the cerebral cortex. Most recently, scientists have utilized the marmoset as models of age-related hearing loss and hormonal modulation of neurocognitive aging. Importantly, transgenic marmosets that show defects in brain function and neurodegenerative diseases have recently been created. All these factors contribute significantly to making the marmoset an ideal model for the study of biological aging, including studies of functional decline and health span.

In order to have this unique animal model of aging reach its full potential in the near future, it is imperative to continue to develop antibodies, assays, and other experimental resources for this species. Although significant advances have been achieved, there is still a lack of standardized procedures for marmoset captive management, especially regarding diet and husbandry. Several chronic conditions of aging marmosets still need to be adequately defined and characterized.

Scientific/Research Contacts

Manuel Moro, D.V.M, M.P.H, Ph.D
Division of Geriatrics and Clinical Gerontology
Division of Aging Biology
Telephone: 301-496-6402
Email Manuel Moro, D.V.M, M.P.H, Ph.D.

Microbiome and Aging: Impact on Health and Disease

The world population is getting older, including the United States, where the segment of people over 65 is expected to reach 90 million by 2050. How well we can overcome the challenge to public health posed by the expected increase in the incidence of age-related morbidities and debilitating conditions will depend on a more complete understanding of what drives physiological aging and the development of targeted intervention strategies.

The microbiome has recently emerged as a likely key player in determining the health status of aging individuals. The microbiome is the community of viruses, bacteria, protists, and fungi which, together with the host cells, create unique ecosystems that are segregated by topography and function. Long-standing evolutionary pressure has shaped these cellular consortia into an interdependent balance that is needed for the optimal physiological function of all its components. For the microbiome associated with the gastrointestinal tract, for instance, that means that, in exchange for the vital support received through the host’s food intake, microbial populations provide functions that allow the host to digest and absorb nutrients through the breakdown of host-indigestible polysaccharides, biotransformation of primary bile acids, and vitamin synthesis.

The scope of the intestinal microbiota reaches beyond digestive functions. It protects against pathogen overgrowth and, by interacting with the gut-associated lymphoid system directly or via its metabolites, it is instrumental in the maturation and modulation of the host immune system. It also influences host-cell proliferation and vascularization, and regulates intestinal endocrine functions, bone density, and neuronal signaling including neurotransmitter biosynthesis. Recent studies in humans and rodent models have shown that the disruption of the host-microbiome functional balance, or dysbiosis, caused by the loss of beneficial microbes, loss of diversity, or expansion of pathogenic populations, can impact a broad range of ailments including inflammatory bowel diseases, atherosclerosis, cancer, metabolic disorders, asthma, allergies, and even autism and neurodegenerative diseases.

Analyses of fecal microbiota across the life span have shown that its composition in people over 65 is considerably different from what is observed in younger adults. Older microbial populations also show greater interpersonal variability in the core repertoire and level of diversity, thereby revealing aging as a major risk factor for dysbiosis. Age-related dysbiosis has been linked to immunosenescence, chronic systemic inflammation, and the development of the frailty phenotype along with an increase in the incidence of various chronic diseases, a likely consequence of a dysfunctional relationship between the imbalanced microbiota and its metabolites with the host’s immune system. Beyond the use of anti-microbial medications such as antibiotics, age-related dysbiosis could also relate to deteriorating dentition, salivary function, digestion and peristalsis, and the consequent reduction in the consumption of fiber-rich food.

Research conducted to date has only scratched the surface of the physiological underpinnings of microbiome changes with aging and more in-depth investigations are necessary to draw a direct line between cause and effect and identify targets of effective intervention.

Scientific/Research Contacts

Francesca Macchiarini, Ph.D.
Division of Aging Biology
National Institute on Aging
Telephone: 301-827-4013
E-mail Francesca Macchiarini, Ph.D.

Network for Identification, Evaluation and Tracking of Older Persons with Superior Cognitive Performance for Their Chronological Age

With a rapidly growing aged US population, maintenance of cognitive function has become increasingly critical for the health, welfare, and well-being of its citizens. According to a recent survey conducted by the AARP, virtually all adults age 40+ believe maintaining or improving brain health is important; three-quarters of adults age 40+ are concerned about their brain health declining in the future.

Although chronological age itself remains the strongest predictor of age-related cognitive decline and many forms of dementia including Alzheimer’s disease and Alzheimer’s disease-related dementias (AD/ADRD), it has become clear that factors which protect against these outcomes are poorly understood. These factors have often been described as imparting resilience to age-related changes in brain structure or neuropathology, building of cognitive and/or brain reserve that would oppose such age-related changes or frank pathology, or augmenting other types of cognitive and brain function that would be beneficial. Some of these protective factors might suggest important intervention strategies.

In recent years, thanks in part to large genetic epidemiological studies of AD and the Dominantly Inherited Alzheimer’s Network, individuals have been identified, albeit very few, who carry an autosomal dominant mutation for AD, who are homozygous for a known genetic risk factor (e.g., the presence of an ApoE4 allele), or who otherwise are at high risk for AD who appear to have escaped the disease. Similarly, at least two groups in the US have identified individuals who despite their advanced age have the cognitive performance of individuals 20 to 30 years younger. Although these so-called cognitive “super-agers” are believed to constitute a very small minority of older individuals, they represent an unparalleled resource in which to study the behavioral, environmental, health, neural, and genetic profiles that lead to sustained cognitive and brain function in advanced age. The opportunity to study these individuals in depth is expected to reveal important information about the factors critical for maintenance of function, as well as the factors that do not figure prominently. Examples of research questions include, but would not be limited to:

  • Are these individuals able to “tolerate” amyloid and/or tau accumulation in the brain without accompanying cognitive decline/impairment?
  • Do autopsy data reveal structural and neurochemical signatures in cognitive super-agers that differ from typical agers?
  • Do cognitive super-agers demonstrate exceptional performance for their age in cognitive domains other than memory?
  • Do cognitive super-agers have social networks and/or personality factors that distinguish them from typical agers?
  • What factors—behavioral, neural, and/or genetic—distinguish cognitive super-agers from typical agers and what factors are shared between cognitive super-agers and those who show decline/impairment?
  • What is the trajectory of age-related performance across multiple domains in the cognitive super-agers? Are these trajectories highly individualized? Are the trajectories associated with stability or change in the neural environment (activation, connectivity, white matter integrity, etc.)?

A multi-site, systematic effort to identify individuals with sustained cognitive function in advanced age would allow sufficient numbers of these individuals for interpretable studies to be performed. Milestones would be incorporated into the early phases of the research to insure operationalization of criteria for cognitive super-agers and to develop the plan for identification of these individuals at multiple sites. Based on estimates from one US site, somewhere between 5 to 10 percent of people age 80+ who self-identify for possible study inclusion meet the eligibility requirements to be enrolled as cognitive super-agers. Current criteria to identify cognitive super-agers are based on memory performance that is comparable to individuals 20 to 30 years younger and appears to represent maintenance of this function into older age. In other words, the super-agers are not individuals of superior intellect from early in life but rather are exhibiting a notable lack of decline or impairment in memory performance with advancing age. Uniformity in identifying and evaluating multiple variables (imaging, blood biomarkers, social and personality assessment, lifestyle factors, cognitive assessment, and genetic/epigenetics evaluation) would escalate data collection and allow comparison across sites, including international sites. Histopathological examination of brain tissue in individuals who come to autopsy would be an important component. Recruiting close family members (siblings and parents, if possible) who do not show the same sustained cognitive performance but perhaps demonstrate more typical age-related cognitive decline would provide for an important comparison group.

In April 2017, the NIA with the support of Foundation for the NIH on behalf of the McKnight Brain Research Foundation conducted the Cognitive Aging Summit III, the specific focus of which was the concepts of cognitive reserve and resilience. The Summit brought together a multidisciplinary group of investigators with shared interest in research on age-related cognitive decline as well as cognitive reserve and resilience, as compared to cognitive impairment or dementia. Recommendations from the Summit included the specific suggestion to establish a network to study cognitive super-agers; this was viewed as a way to escalate the research enterprise for discovery of factors for resilience, reserve, compensation, and/or preservation of cognition. Because the numbers of individuals identified and followed at any one site to date are small, a structure to allow uniform identification of individuals and uniform data collection would allow the field to push forward more quickly in our understanding of factors that promote sustained cognitive health and those that do not.

Scientific/Research Contacts

Molly V. Wagster, Ph.D.
Division of Neuroscience
National Institute on Aging
Telephone: 301-496-9350
Email Molly V. Wagster, Ph.D.

Jonathan W. King, Ph.D.
Division of Behavioral and Social Research
National Institute on Aging
Telephone: 301-402-4156
E-mail Jonathan W. King, Ph.D.

Dana Plude, Ph.D.
Division of Behavioral and Social Research
National Institute on Aging
Telephone: 301-435-2309
E-mail Dana Plude, Ph.D.

Small Business Innovation Research Early-Phase Clinical Trials of Novel Interventions to Prevent, Delay, or Treat Aging-Related Conditions by Targeting Aging-Related Mechanisms (Clinical Trial Required)

There is a growing interest in the identification and commercialization of compounds that could treat multiple chronic conditions by modulating fundamental aging-related mechanisms (e.g., cell senescence, autophagy, and mitochondrial function) as well as in the compounds that could affect the individual diseases and conditions disproportionally affecting older adults. Such conditions include, but are not limited to sarcopenia, frailty, chronic wounds and ulcers, and dementia, among others.

A variety of candidate compounds were tested in model organisms and in early-stage human intervention studies funded by NIA, including those supported by NIA’s T1 translational research FOAs and other investigator-initiated projects across the NIH. Successful examples include, but are not limited to:

  • identification of selective androgen receptor modulators to accelerate wound healing;
  • novel derivatives of gingerol as a possible treatment for diastolic dysfunction;
  • MitoQ (mitochondria targeted antioxidant) as a potential treatment for age-related artery endothelial dysfunction;
  • topical administration of losartan to accelerate healing of pressure ulcers; and
  • curcumin to improve endothelial function.

Unfortunately, only a few compounds moved beyond early exploratory studies and into the commercialization phase because of the lack of funding at this early stage of drug development. In the past, large pharmaceutical, biotechnology companies, and venture capital firms provided the resources needed to conduct the clinical studies required to fully develop and commercialize biomedical products and technologies. At present, investors prefer funding relatively well-advanced compounds rather than those still in early stages of the process. Accordingly, small business concerns (SBCs) must have clinical data to attract sufficient third-party investment.

The proposed initiative will provide a vehicle for SBCs to submit the applications to test new and repurposed molecular entities in Phase 1, 2a, and 2b clinical trials. The studies will focus on the identification and commercialization of new compounds or repurposing of existing drugs and biologics to treat multiple chronic conditions by modulating fundamental aging-related mechanisms (e.g., cell senescence, autophagy, and mitochondrial function) as well as to test compounds that could affect the individual diseases and conditions disproportionally affecting older adults. This initiative will be part of a set of three Small Business Innovation Research initiatives, two of which are proposed by the Translation Working Group; it will ensure the research continuum from pre-clinical development through early clinical trials.

Scientific/Research Contacts

Sergei Romashkan, M.D., Ph.D.
Division of Geriatrics and Clinical Gerontology
National Institute on Aging
Telephone: 301-435-3047
Email Sergei Romashkan, M.D., Ph.D.

Back to contents

January 2018 Council

Approved concepts from this round:

The concepts marked with an asterisk (*) have been published as part of a Funding Opportunity Announcement (FOA). Please see the parent FOA and this Notice for additional information.

AD/ADRD Health Care Systems Research Collaboratory

There is a pressing need to improve care for persons with dementia (PWD) and their caregivers within the context of health and long-term care systems. Lack of continuity of care is associated with higher rates of hospitalization, emergency department visits, testing, and health care spending. Late diagnoses of dementia and lack of coordination among providers and care settings can lead to inappropriate care, premature institutionalization, and burdensome transitions in late-stage dementia. Poor quality and inappropriate care can mean a worse quality of life for PWD and their caregivers. Incremental changes can be studied within care systems and might relieve the burden for PWD, improve care transitions, and enhance care overall. Small studies in particular settings have provided some evidence that improvements are possible. However, there is a need for studies in realistic settings and at scales adequate to provide evidence for system-wide benefit.

This initiative will foster an infrastructure for collaborative research within and among health care systems to encourage pragmatic trials of innovative dementia care. It will engage health care delivery organizations as research partners. This initiative will build on the experience of the NIH Health Care Systems Research Collaboratory Program, funded by the Common Fund, but in this case will focus on dementia care. The goal of the Alzheimer’s Disease and Alzheimer’s Disease-Related Dementias (AD/ADRD) Health Care Systems Research Collaboratory is to bring together health systems, health insurance companies (e.g., managed care plans), home health care providers, and nursing homes systems for research to improve care of PWD. This Collaboratory will:

  • serve as a national resource to promote development of pragmatic trials to improve care and health outcomes for PWD and their caregivers,
  • support pilot trials within the systems that comprise the Collaboratory,
  • develop and disseminate technical and policy guidelines and best practices for effective conduct of AD/ADRD research studies in partnership with health care systems,
  • work collaboratively with researchers to provide technical support for scaling up pilot studies, and
  • disseminate best practices for engaging stakeholders, conducting ethical research in the special circumstances of dementia care, and involving long-term as well as acute-care providers.

This initiative will benefit from the experience of prior NIH-funded pragmatic trial efforts and translate them to dementia-specific research. It will strengthen the relevance of services research to real-world practice in acute and long-term care. It will help meet the challenges of complex care management for PWD and their families as this population continues to grow over the coming decades.

Scientific/Research Contact

Partha Bhattacharyya, Ph.D.
Division of Behavioral and Social Research
National Institute on Aging
Telephone: 301-496-3131
E-mail Partha Bhattacharyya, Ph.D.

Alzheimer's Disease Translational Center for Structural and Chemical Biology

The need to address the failure of Alzheimer's disease (AD) therapies in the clinic.
The development of effective AD therapies has proven to be very difficult. Despite more than two decades of research, no disease-modifying therapy has successfully completed clinical testing process. In fact, over this time span, there has been an extremely high rate of attrition of AD drugs in Phase II (92 percent) and Phase III (98 percent) with more than half failing due to issues of efficacy.

Given the magnitude of this problem the AD research community has begun to ask: Why do so many AD therapies fail in the clinic? While there is no apparent simple answer to this question, some experts in the field have proposed several likely reasons for the lack of progress including the following:

  1. the drugs do not engage with the intended targets in patients;
  2. the drugs are hitting the targets but are doing so at the wrong stage of disease;
  3. we are targeting the wrong pathophysiological mechanisms (and therefore the wrong targets).

The third supposition, which is the focus of this initiative, suggests that AD drug candidates have failed in the clinic because their development has been based on a very narrow understanding of AD, centered on the amyloid hypothesis, and therefore there has been an over emphasis on drug targets associated with the major pathological features of AD, i.e., beta amyloid plaques and neurofibrillary tangles.

The need to diversify of our approach to AD drug targets.
More recent research has found that clinical AD exhibits considerably more neuropathological heterogeneity than originally appreciated, suggesting that clinical AD is a multimodal and multicomponent disease. These findings imply that the pathophysiological processes that underlie clinical AD are more complex than originally thought and highlight the need for novel therapeutic approaches that require the identification of alternative drug targets.

The need to leverage investment in AD translational infrastructure and capitalize on the innovation of ADSP, AMP-AD, M2OVE-AD, Resilience-AD, MODEL-AD.
To address the need for alternative AD drug targets NIH/NIA has spearheaded the launching of several initiatives—AMP-AD, M2OVE-AD, and Resilience-AD—aimed at discovering alternative therapeutic targets and gaining a systems-level understanding of the gene, protein, and metabolic networks within which these novel targets operate. After five years, these programs have identified a significant number of potentially novel, alternative drug targets. It is likely that over the next five years, these programs will bring forward new findings that will enhance alternative target selection for AD. In addition, NIA has launched the MODEL-AD Consortium which is designed to create and characterize next-generation late-onset AD rodent models, and to conduct preclinical testing of candidate AD therapeutics in the next-generation models. It is expected that the center proposed here will leverage this investment and capitalize on the innovations and discoveries emanating from these programs and translate them quickly into potential new drugs.

The need to improve, reinvigorate and diversify the AD drug development pipeline through drug discovery/development efforts aimed at newly identified alternative therapeutic targets.

Scientific/Research Contacts

Lorenzo Refolo, Ph.D.
Division of Neuroscience
National Institute on Aging
Telephone: 301-496-9350
E-mail Lorenzo Refolo, Ph.D.

Suzana Petanceska, Ph.D.
Division of Neuroscience
National Institute on Aging
Telephone: 301-496-9350
E-mail Suzana Petanceska, Ph.D.

Centers on the Demography and Economics of Aging: Renewal and AD/ADRD Expansion

This proposal seeks to renew the Centers on the Demography and Economics of Aging (P30) program and expand the program to include new Alzheimer's disease and Alzheimer's disease-related dementias (AD/ADRD) Centers.

The Centers on the Demography and Economics of Aging (P30) program was initiated in 1994 to seed new lines of research in the demography and economics of aging, and grow the number of researchers engaged in the field, through:

  1. funding pilot research projects,
  2. establishing networks of scholars to advance scientific discourse in selected areas,
  3. holding innovative conferences, workshops and meetings to advance new areas of research,
  4. developing and promoting the use of unique data resources, and
  5. disseminating findings and resources to the research and public policy communities.

There are 11 currently-active Centers (one of which also serves as the Coordinating Center) whose work can be classified into the following thematic areas:

  • Consequences of U.S. and Global Aging,
  • Health Trends and Disparities,
  • Disability, Health Care, and Long-Term Care,
  • Economics of Aging,
  • Determinants of Health, Well-Being, and Longevity,
  • Cognitive Aging and Demography of Dementia,
  • Aging, Genetics, and Social Science,
  • Biodemography of Aging,
  • Effects of Interventions on Population Health, and
  • Population, Economic, and Health Forecasting.

Results of a recent NIA evaluation revealed that:

  1. 184 pilot projects were awarded between 2014 and 2017 that resulted in 730 peer reviewed publications by Center Affiliates;
  2. Center pilot projects led directly to 31 NIH grants funded in the current cycle;
  3. over 100 research conferences, workshops, and networks were supported in the current cycle to discuss research findings and foster new collaborations, many with an international reach;
  4. Center affiliates in the current cycle have been engaged in development and dissemination of at least 36 data resources; and
  5. this P30 program supports data enclaves at three Centers to make datasets available to the large research community.

The Centers have also been successful in recruiting junior researchers into aging research by giving them a start with pilot project funding. Finally, the Coordinating Center produces online articles and reports highlighting new aging-related work conducted by the Centers that is written in a manner to increase awareness of research results and their application to major public and private decision making.

Selected research findings arising from Center projects include:

  • Middle-aged Costa Rican men and women have 18 percent and 10 percent lower mortality, respectively, than their counterparts in the United States, despite higher income and health care expenditures in the United States. These findings suggest that U.S. health could be improved without increasing health expenditures by addressing socioeconomic gradients, health insurance access, health behaviors, and chronic disease management.
  • The annual monetary costs of dementia—including out-of-pocket spending, Medicare spending, nursing home care, and informal care—ranges between $159 billion and $215 billion. These costs are estimated to increase by 80 percent by 2040.
  • County-level inequalities in mortality among older adults increased between 1980 and 2014. In 2014, life expectancy at birth (both sexes combined) was 79 overall, but varied by 20 years between the counties with the worst and best life expectancies.

With regards to the AD FOA, the Centers began focusing on AD/ADRD topics during this cycle so we expect to substantially increase attention to these areas, and recruit new researchers into the field, with a separate AD/ADRD RFA. This is especially true because national U.S. dementia prevalence data from the Health and Retirement Study's Harmonized Cognitive Assessment Protocol are expected in the spring of 2018 that will spur much research interest. Also, we expect recommendations from the October 2017 Dementia Care Summit to increase research efforts on the impact of health care organizations and health care financing policies on outcomes for persons with dementia and on inequality in access and quality of care.

Scientific/Research Contact

Georgeanne Patmios, M.P.H.
Division of Behavioral and Social Research
National Institute on Aging
Telephone: 301-496-3138
E-mail Georgeanne Patmios, M.P.H.

Clinical Trial on Effects of Statins in Older Adults without Clinical Cardiovascular Disease

Although statins have been shown to be effective in preventing cardiovascular events in persons with existing cardiovascular disease (CVD) and in persons up to age 75 who are free of CVD, there is significant uncertainty about the risks and benefits of statin treatment in the large CVD-free population over age 75. The 2013 American College of Cardiology/American Heart Association (ACC/AHA) Guidelines on the Treatment of Blood Cholesterol indicate that there are few data to assess the benefits and risks of statins therapy in individuals over age 75 without CVD. In its 2015 report, the U.S. Preventive Services Task Force (USPSTF) agrees with this assessment: "…the current evidence is insufficient to assess the balance of benefits and harms of initiating statin use in adults 76 years and older." Both the ACC/AHA and the USPSTF list randomized trials to assess the overall benefits and risks of statins in adults over 75 years of age without clinical CVD as a high-priority research area.

Results of several meta-analyses of randomized controlled trials show that statin therapy was associated with significant reductions in the risk of major CVD events in persons over 70 years of age. However, these trials did not have large numbers of participants aged over 75, so questions remain about the size of the potential cardiovascular risk reduction at these older ages. Furthermore, none of the statin trials on CVD outcomes were sufficiently powered to assess effects of statins on other important outcomes for older adults such as dementia, functional status, quality of life, or adverse side effects. A variety of studies suggest that statins may have favorable or unfavorable effects on such outcomes in this population, but the studies are not conclusive. Controlled intervention studies with sufficient power in appropriate populations are needed to assess these effects.

The planned clinical trial will address the above evidence gaps by generating definitive data on the overall risks and benefits of statins in a representative population over age 75. This evidence will inform treatment decisions for approximately 8 million U.S. adults over age 75 without CVD who are not currently taking a statin. The initiative is particularly timely because of the increasing use of statins in this age range which, if continued, would render a controlled trial infeasible or more expensive in the future.

Scientific/Research Contact

Sergei Romashkan, M.D., Ph.D.
Division of Geriatrics and Clinical Gerontology
National Institute on Aging
Telephone: 301-435-3047
E-mail Sergei Romashkan, M.D., Ph.D.

Collaborative Studies on Alzheimer's Disease and Alzheimer's Disease-Related Dementias*

NIA convened an expert panel to make recommendations about the future of the Alzheimer's Disease Centers (ADRC) program, focused on how the ADRCs are uniquely poised to address the goals of the National Plan for Alzheimer's disease and Alzheimer's disease-related dementias (AD/ADRD). Several major themes came across in the recommendations, among them, greater opportunities for collaborations across the ADRCs, increasing interactions with other center programs, and making the resources at the ADRCs available to outside investigators.

Building on this notion, the proposed funding opportunity announcement (FOA) will provide an opportunity for wider sharing and leveraging of other existing resources, including MODEL-AD, AMP-AD, M2OVE-AD, NACC, NCRAD and those available at other NIH and NIA funded centers, such as Udall Centers, Pepper Centers, Roybal Centers, Shock Centers and RCMARs. Applications responsive to this FOA may also leverage existing longitudinal cohort studies with data relevant to AD/ADRD, such as the Health and Retirement Study, the National Health and Aging Trends Study, Rochester Epidemiology Project, and studies participating in the Integrative Analysis of Longitudinal Studies of Aging and Dementia (IALSA).

This FOA will help to facilitate collaborative cross-disciplinary and multi-institutional approaches that will contribute new and vital information about the clinical and pathological course of normal aging and AD/ADRD. Scientists within and outside the ADRCs can gain access to unique resources and support the collection and integration of new data and samples. There will be intellectual collaboration among investigators and a wider participation in the design, analysis and interpretation of studies utilizing these unique resources, further leveraging the existing investment. The applications have an opportunity to build on existing resources and data to answer a broad range of scientific questions. Project data may be used for new grants and/or provide standardization or methodologic development of value to AD/ ADRD research goals.

Scientific/Research Contacts

Nina Silverberg, Ph.D.
Division of Neuroscience
National Institute on Aging
Telephone: 301-496-9350
E-mail Nina Silverberg, Ph.D.

Cerise Elliott, Ph.D.
Division of Neuroscience
National Institute on Aging
Telephone: 301-496-9350
E-mail Cerise Elliott, Ph.D.

Data-Driven Approaches to Understand the Molecular Mechanisms of Neuropsychiatric Symptoms in Alzheimer's Disease and Alzheimer's Disease-Related Dementias*

Individuals diagnosed with Alzheimer's disease and Alzheimer's disease-related-dementias (AD/ARD) often suffer from a range of behavioral changes, referred to as neuropsychiatric symptoms (NPS). These symptoms include depression, anxiety, apathy, delusions, hallucinations, sleep disturbance, agitation, and aggression. NPS are common, cluster together and present at all stages of the disease including the prodromal stage. They are often persistent and are associated with excess morbidity, mortality, increased health care use, earlier institutionalization, as well as greater caregiver distress. Despite having a large impact on the burden of disease, safe and effective long-term interventions for NPS are lacking. Nonpharmacological interventions are suggested as first-line treatment, but are labor and time intensive and costly, resulting in pharmacological interventions consisting of off-label use of antipsychotics, sedative/hypnotics, anxiolytics, acetylcholinesterase inhibitors, memantine, and antidepressants; these treatments are often not efficacious and lead to significant adverse effects including death. Lack of progress in the therapeutic arena is largely due to the poor understanding of the dynamic relationship and mechanistic links between NPS and AD/ADRD.

A recent workshop co-organized by the National Institute for Mental Health and NIA, Novel Approaches to Understanding the Mechanisms of NPS in AD and Advancing Therapy Development, brought together a cross-disciplinary group of researchers to discuss the current state of knowledge and emerging science and technologies that could provide an opportunity for advancing this critically important area of research. Additionally, the recent 10th Annual FDA/Alzheimer's Disease Allies Meeting, Exploring Behavioral and Neuropsychiatric Symptoms in Alzheimer's Disease, brought together industry, academics, and government agencies including NIH and FDA.

Recent advances in genetics, epigenetics/epigenomics, system and network-biology provide an opportunity to gain deep mechanistic insights in the dynamic relationship between NPS and AD/ADRD and the molecular mechanisms underlying this comorbid condition.

Scientific/Research Contacts

Suzana Petanceska, Ph.D.
Division of Neuroscience
National Institute on Aging
Telephone: 301-496-9350
E-mail Suzana Petanceska, Ph.D.

Laurie Ryan, Ph.D.
Division of Neuroscience
National Institute on Aging
Telephone: 301-496-9350
E-mail Laurie Ryan, Ph.D.

Deciphering Glycosylation Code of Alzheimer's Disease*

Glycosylation is a post-translational modification in which a sugar (or carbohydrate) is attached to a hydroxyl or other functional groups of macro molecules (such as DNA, lipids, and proteins). Most glycosylated proteins are glycosylated in the rough endoplasmic reticulum (ER) by glycosyltransferases, however proteins can be also glycosylated in the cytoplasm under various pathological conditions. It is known that glycosylation can affect various cellular and physiological functions including regulation of enzymatic activities, cell differentiation and morphogenesis.

Currently, our approaches on both basic and clinical biology of Alzheimer's disease (AD) are largely focusing on disease related changes at the genomic, epigenetic, transcriptomic, and proteomic levels. However, there are many different aspects of biology and cellular biochemistry that can't be explained by these types of systems approaches. Glycosylation and complex carbohydrates have been reported to play many critical roles in the early pathogenesis and progression of AD, but the potential of these molecules to serve as biomarkers and targets of disease intervention remain largely unexplored.

Many recent studies have also suggested that the deficiency of a sulfotransferase for sialic acid-modified glycan could mitigate AD pathology and binding of Aß to various AD risk glycoproteins such as TREM2, are likely regulated by the change of glycans on these molecules as well. In addition, small molecules that are known to block Aß and glycan interaction have been shown to increase survival advantage of neurons in mouse models of AD. Together, these findings indicate the potential of glycomic aberrations as potential biomarkers and targets of disease prevention. Despite the importance of glycosylation and altered glycan structures in AD, the aberrant molecular and biochemical function of these glycosylated molecules to serve as disease modifiers remain largely elusive.

Traditionally, it has been very difficult to study and monitor the alteration of glycosylation and glycans in relation to aging and early initiation of AD. However, several recently developed technologies have allowed one to systematically monitor the change of protein glycosylation and glycans in various biological fluids and large number of individuals. Therefore, the goal of this FOA is to invite research projects using the next generation of protein carbohydrate analyses to understand the potential impact of glycosylation on the etiology of AD and biomarker discovery.

Outcomes of this initiative might include:

  • Precise biochemical and molecular mechanisms of altered glycan structures underlying the propagation of pathological protein assemblies in AD, including the role of glial cells and other non-neuronal cell types.
  • Molecular, cellular, and physiological studies of glycobiology to define the functional sequences of genetic risk factors for AD.
  • Understanding the roles of extracellular matrix and proteoglycans in modulating synaptic degeneration and accumulation of AD-related pathologies.
  • Impact of microenvironment, such as plaque accumulation, on altered glycans and their roles as potential biomarkers and disease modifiers.
  • Consequences of aberrant glycosylation on the unfolded protein response and protein homeostasis.
  • Understanding the roles of chronic inflammation and immune surveillance in response to altered glycans during the course of AD.

Scientific/Research Contact

Austin Yang, Ph.D.
Division of Neuroscience
National Institute on Aging
Telephone: 301-496-9350
E-mail Austin Yang, Ph.D.

De-prescribing Strategies for Older Adults with Multiple Chronic Conditions

Polypharmacy (taking five or more prescription drugs) increased dramatically among the U.S. population age 65 and older from 24 percent in 2000 to 39 percent in 2012. This results from compounding trends from aging, chronic disease onset, co-occurrence, and increasing availability of drugs for treatment and prevention. As a result, most older adults take multiple medications each day despite known and unknown safety and other potential increased risks. Lack of multi-disease guidelines, fragmentation of care, inertia, and prescriber time pressure works against careful consideration of the medications used late in life.

Beyond sheer numbers, the American Geriatrics Society identifies in its Beers criteria numerous potentially inappropriate medications (PIMs) used in older adults, based on evidence linking them to adverse consequences including morbidity, falls, disability, hospitalization, or death. For example, the Beers criteria identify anticholinergic drugs, benzodiazepines, and H2-receptor antagonists as established PIMs for persons with dementia due to their adverse effects on the central nervous system. Estimates of potentially inappropriate prescribing are less precise than for polypharmacy, but range from 20 percent of older adults, to one-third in long-term care facilities and over half of the persons with advanced dementia in nursing homes.

De-prescribing is increasingly recognized as a fundamental technique of geriatric practice and palliative medicine that might be enhanced and more widely adopted in primary care and other settings to address persons with inappropriate medication use or polypharmacy. A patient-centered definition of de-prescribing is, "the systematic process of identifying and discontinuing drugs in instances in which existing or potential harms outweigh existing or potential benefits within the context of an individual patient's care goals, current level of functioning, life expectancy, values, and preferences." Specific reasons for de-prescribing include lack of efficacy, nonadherence, or introduction of an interacting drug. In some cases, an alternative is de-intensification of therapy or dose reduction in response to identified over-treatment or modified goals of care.

A recent systematic review suggests survival benefits for de-prescribing in observational studies, but the available randomized trials do not confirm this finding. The review included many studies that were not randomized and many small trials that were of low quality. Much of this research has been done internationally and domestic research needs to be stimulated.

Scientific/Research Contact

Marcel Salive, M.D., M.P.H.
Division of Geriatrics and Clinical Gerontology
National Institute on Aging
Telephone: 301-496-6761
E-mail Marcel Salive, M.D., M.P.H.

Disparities in Quality and Access to Dementia Care*

Many persons with dementia (PWD) encounter challenges in gaining access to long-term services and supports (LTSS). Disparities in access and utilization may lead to or exacerbate adverse health outcomes. Disparities in acute care have been well documented, but with few exceptions have not been well delineated and explained in LTSS. More research is needed to examine the extent to which individual, provider, or system-level characteristics combine to produce health disparities among people with Alzheimer's disease and Alzheimer's disease-related dementias (AD/ADRD). Research will need to account for differences in quality and appropriateness of care as well as access. For example, African Americans with dementia generally have higher levels of service use and health care expenditures compared to whites with dementia, but this is no guarantee that outcomes are better. Furthermore, disparities in access often take place within home and community contexts but may also be found in more formal dementia care settings, such as nursing homes. Specifically, racial disparities have been documented in terms of nursing home quality, where lower tier facilities—under-resourced facilities that primarily serve Medicaid beneficiaries—are located in the poorest counties and are more likely to serve African American residents than are other facilities.

Previous NIA FOAs have called for research on caregiving and assessing the impact of formal and informal care with attention to disparities. Research investments in this area have primarily been small-scale, qualitative studies, which will be informative for defining and characterizing sources of disparities in formal and informal caregiving. Building on these previous investments, this initiative will encourage research involving large-scale, population-level, longitudinal cohorts to better explain disparities in service utilization and quality across multiple services and settings, and to place emphasis on outcomes for persons with dementia. Multiple dimensions of disparity will be addressed, including income, education, race and ethnicity, regional, gender, and living situations, and their interactions. For example, what explains disparities in adult day care utilization? Is it socioeconomic status, family preferences, family structure, gender, race/ethnicity, access to information about services, or living in a rural or under-resourced area? The emphasis will be on trajectories of care, not on studies tied to particular episodes or events like hospital readmissions. This information will allow policymakers and practitioners to implement methods to reduce disparities in access to high-quality dementia care.

The National Research Summit on Dementia Care took place in October 2017 under the auspices of the Department of Health and Human Services and the National Alzheimer's Project Act. The Summit aimed to identify what we know and what we need to know to accelerate the development, evaluation, translation, implementation, and scaling up of comprehensive care, services, and supports for persons with dementia, families, and other caregivers. Several priority areas for future research emerged from the Summit, including attention to population heterogeneity and the wide array of factors that characterize PWD and their caregivers, which in turn can lead to disparities in care quality and access. NIA has identified reducing health disparities and inequities as an essential area of research. This initiative is timely given that the projected increases the number of persons with AD/ADRD in the U.S. population underscore the urgency of understanding how to best provide care for persons with dementia and their caregivers.

Scientific/Research Contact

Elena Fazio, Ph.D.
Division of Behavioral and Social Research
National Institute on Aging
Telephone: 301-496-3131
E-mail Elena Fazio, Ph.D.

Endosomal Traffic Jams*

Genetic and molecular characterization of Alzheimer's disease (AD) may be the single most important step in identifying new targets for treatment and prevention. Recent advances in the AD field have indicated that several classes of genes are associated with the disease including those related to innate immune response, inflammation, cholesterol metabolism, synaptic function, and endosome trafficking. The list of genes associated with endosomal trafficking is rapidly growing for both early- and late-onset AD. A partial list includes: PICALM, SORL1, CD2AP, BIN1, ABCA7, EPHA1, Rab family, PLD3, and PSD2. That such a large number of the newly identified genes are associated with a single pathway suggests that the endosomal pathway is central to normal brain function and that dysfunction of this common pathway may be an etiological factor in the disease.

The endocytic pathway is comprised of distinct membrane compartments that internalize molecules from the plasma membrane, recycle them back to the surface, or process them for intracellular function. Perturbation of the stream of traffic for cargo sorting can occur by altering the balance of membrane traffic into the early endosomes; by altering traffic out of the early endosome in a degradation pathway; by changes in a recycling pathway to the cell surface; or by alteration of function in a retrograde pathway back to the trans-Golgi network.

There are several classes of genes in the endosomal trafficking pathway:

  1. Mutations in APP and the presenilins lead to accumulation of amyloid β-42 (Aβ-42).
  2. SORL1, BIN1, CD2AP, and PICALM can affect the balance of membrane trafficking into and out of the early endosome.
  3. Cholesterol metabolism genes such as APOE-ε4 can decrease the clearance of Aβ-42 and may reduce endosomal recycling.
  4. Immune response genes such as TREM2 can directly or indirectly contribute to increases in intracellular Aβ-42.

Perturbation of these gene pathways, especially if more than one trafficking pathway is affected, may result in a pathological downward spiral and the accumulation of intracellular toxicity. These genes or gene sets may also affect Aβ and tau-related catabolism and/or toxicity. Alternatively, there may be other indirect or downstream effects on cell membranes or cell function.

In addition, some of the known endosome-related genes participate in more than one physiological function. This suggests that cascades of events that may involve the endosomal pathway and other pathophysiologic processes may be triggered as the result of aberrant gene-related events. Some of these known genes participate in more than one physiological function, suggesting that cellular processes that may involve the endosomal pathway and other pathophysiologic events may be triggered as the result of aberrant genetic activity. Identification of the effects of altered genetic structure on physiologic function in the endosomal processing pathway, will help direct us toward novel therapeutic approaches.

Scientific/Research Contact

Marilyn Miller, Ph.D.
Division of Neuroscience
National Institute on Aging
Telephone: 301-496-9350
E-mail Marilyn Miller, Ph.D.

Examining Factors Related to Recruitment and Retention in Aging Research

Participation of many different types of volunteers for many different types of studies has taken center stage as one of the leading challenges in aging research. Both clinical trials and natural history studies have yet to demonstrate anywhere near adequate representation of diverse cohorts. A complete study of a disease state requires the inclusion of diverse cohorts of research participants in terms of race, ethnicity, gender, age, and status of disease. Diversity among research participants broadens scope and improves the generalizability of scientific investigations. In particular, classifications of race, ethnicity, socioeconomic status, sex/gender are multifactorial and dynamic in their influence on disease state. Studies that incorporate factors at environmental, sociocultural, behavioral, and biological levels of analyses need to be established with robust diversity of the research participants. All divisions of NIA will benefit from an active effort in recruitment and retention of research participants.

The Division of Behavioral and Social Research supports social, behavioral, and economic research and research training on the processes of aging at both the individual and societal level. There is a need to have persons of a wide array of characteristics included in clinical trials and related research: small and large family groups, racial, ethnic, social, economic, linguistic, gender, cultural, and neighborhood.

The Division of Geriatrics and Clinical Gerontology supports clinical and translational research on health and disease in the aged, and research on aging over the human life span, including its relationships to health outcomes. Investigators often exclude children (defined here as individuals under age 18) or older adults (individuals ages 65 and older) either (1) explicitly, by limiting the age range of eligible participants in their exclusion criteria, or (2) implicitly, by excluding those with co-morbid conditions or polypharmacy use, both of which are common in older populations. As a result, many interventions are inadequately tested in the very old and the very young. Recruitment needs to consider the age distribution of the disease, condition, or study topic in the general population. Investigators should seek to better understand the historical and social context of historically vulnerable and consistently underrepresented groups to ensure their improved recruitment and representation in clinical trials and research.

The Division of Neuroscience fosters and supports extramural and collaborative research and training to further the understanding of neural and behavioral processes associated with the aging brain. Increased public and private investment in Alzheimer's disease and Alzheimer's disease-related dementias research has spurred a rise in the number of therapeutic targets, drugs, and other interventions that need to be tested in clinical trials. Further, a new challenge has emerged in recruiting healthy normal volunteers, as prevention trials seek to enroll participants prior to evident symptoms of cognitive decline and dementia. For healthy volunteers, there is little history of best practices or research providing evidence of optimal ways to reach these cohorts, which must also include underrepresented groups to best capture the distribution of the disease across the population and the potential variability in risk factors, and preventive options.

Overall, investigators focused on improving the research tools, research methods, and recruitment practices are needed to bring the practice of recruitment and retention to the next level and to produce a significant number of committed research participants to aging research. This targeted program seeks to focus investigators on the development and evaluation of innovative participant recruitment and retention methods and strategies that seek to enhance diversity of study participants.

Scientific/Research Contact

Cerise Elliott, Ph.D.
Division of Neuroscience
National Institute on Aging
Telephone: 301-496-9350
E-mail Cerise Elliott, Ph.D.

Geroscience Approaches to Animal Models of Alzheimer's Disease*

The basic biology of aging affects functional performance of all organs in the body, including the brain. The field of geroscience aims to understand, at the cellular and molecular levels, the interconnections between aging and disease/disabilities, with a focus on understanding the mechanisms by which aging is the major risk factor for most chronic diseases. The geroscience hypothesis posits that manipulation of aging will simultaneously delay the appearance or severity of multiple chronic diseases because these diseases share the same underlying major risk factor: the aging process.

Recent progress in the field of aging biology has allowed researchers to develop robust behavioral, genetic, and pharmacological approaches to expand lifespan of multiple species. Importantly, interventions that extend lifespan often result in improvements in multiple aspects of healthspan, resulting in significant delays in the appearance of pathology and frailty. Conversely, when lifespan is shortened, diseases and frailty occur earlier. In other words, disease susceptibility scales with the lifespan of the organism.

As for other chronic diseases of the elderly, Alzheimer's disease (AD) is not an exception in that aging is the major risk factor for sporadic AD, and as mentioned, this risk is the centerpiece of the geroscience hypothesis. Importantly, modifying the rate of aging has already been shown to modify resilience to pathological challenges, including in genetic mouse models of AD. Understanding the role of the basic biology of aging thus provides new venues for research and inquiry into the etiology of this disease. A better understanding of the role of aging biology in the advent of AD might also lead to badly needed new therapeutic approaches.

AD is a progressive, multifactorial disease with multiple symptoms, the best-recognized of which is neurodegeneration. In addition to plaques and tangles formed in the brain, AD patients have symptoms in other tissues, potentially linked to the AD genes but of unknown relationship to the dementia itself, suggesting that the disease is systemic, and as such, it might be susceptible to interventions that act systemically. Indeed, there is substantial evidence in the literature indicating that Alzheimer's patients develop multiple diseases and functional decline in peripheral systems, often before the onset of overt neurologic disease.

This proposal is timely as it aims to test the geroscience hypothesis, using AD as a test disease. In short, the RFA aims at testing whether interventions known to systemically affect the rate of aging will be effective as modulators of the incidence, progression, etiology, and treatment of AD.

Scientific/Research Contact

Felipe Sierra, Ph.D.
Division of Aging Biology
National Institute on Aging
Telephone: 301-496-6402
E-mail Felipe Sierra, Ph.D.

High-Priority Behavioral and Social Research Networks

NIA's Division of Behavioral and Social Research (BSR) supports several initiatives to seed integrative and interdisciplinary research and development of infrastructure in emerging areas of behavioral and social science. These networks aim to build resources to advance research in basic and applied BSR fields and focus on program development in high-priority areas, as highlighted in BSR's most recent National Advisory Council on Aging Review. Our experience with network grants from prior FOAs suggests that these networks have not only served their intended purpose of developing new interdisciplinary research areas but also led to the recruitment of outstanding scientists to aging research, ensuring continued growth in these fields. Successful networks have created novel training opportunities, developed research resources, stimulated interdisciplinary information exchange, supported innovative pilot studies, and helped fuel the pipeline of new investigators applying to NIA to conduct research on topics such as decision-making, stress and early-life adversity, and the integration of behavior and biology in the study of health and disease.

Several ongoing networks have made substantial strides in building infrastructure, transdisciplinary alliances, and generating new knowledge to stimulate novel work relevant to aging. Continued support will allow them to realize this potential and to draw more investigators into the aging field. These networks for possible renewal are:

  • Life Course Health Dynamics and Disparities
  • Stress Measurement
  • Early Adversity and Later Life Reversibility
  • Replicability of Scientific Research

Several new networks are proposed to capitalize on opportunities and infrastructure needs articulated at recent BSR-sponsored meetings or to build on existing NIA investments. A goal for all the proposed networks is to seed these areas so they can develop to the point where the network activities can be supported through other grant activities, such as research projects, conference grants, program projects, centers, and/or institutional training grants. The development of research networks is critical to advance the science in the following areas, where integration across studies, disciplines, and institutions is needed:

High-Priority Topics – not related to Alzheimer's disease and Alzheimer's disease-related dementias (AD/ADRD):

  • Genomics and Behavioral and Social Sciences
  • Integrating Animal Models to Inform Social Research on Aging
  • Rural Aging

High-Priority Topics – AD/ADRD-related:

  • ADRD Care and Services Research Network
  • Coordination of International Studies conducting the Harmonized Cognitive Assessment Protocol

Scientific/Research Contacts

Lis Nielsen, Ph.D.
Division of Behavioral and Social Research
National Institute on Aging
Telephone: 301-402-4156
E-mail Lis Nielsen, Ph.D.

Georgeanne Patmios, M.P.H.
Division of Behavioral and Social Research
National Institute on Aging
Telephone: 301-496-3138
E-mail Georgeanne Patmios, M.P.H.

Improving the Lives of Persons with Dementia: Impacts on Individuals, Families, and Communities*

The current state of care for persons with dementia (PWD) leaves room for improvement—there is little continuity of care, and health care and long-term services and supports are expensive but likely variable and ineffective. Projections of future growth in the population of PWD indicate that these problems will only be exacerbated. This proposal is intended to encourage research to better understand the desired outcomes of care of the PWD across disease stages and etiologies.

The National Research Summit on Dementia Care, Services, and Supports for Persons with Dementia and their Caregivers took place on October 16 – 17, 2017 under the auspices of the Department of Health and Human Services and the National Alzheimer's Project Act. From this, several priority areas for future research emerged, including a call for more observational analyses on the impacts of dementia on persons living with dementia, their families and caretakers, and the community.

Preliminary recommendations from the Summit suggest that current research does not focus on person-centered outcomes, the lived experience, and psychosocial processes of the persons living with dementia. There is also a need to conduct research on families, caregivers, relationships, and networks impacted by dementia. The impacts of shifting roles and trajectories of care must be explored; research should be encouraged across the whole care spectrum. Research should begin to examine the supportive components of communities, especially dementia-friendly communities, to better understand the impacts of the disease.

Three specific issues addressed by this initiative include: Burden of disease, including costs of care and other financial implications of disease; health outcomes, including quality of life of the person living with dementia; and community support. The proposed initiative calls for research investigating these outcomes, and an emphasis on developing new measures and measurement approaches in these areas is highly encouraged.

For burden-of-disease factors, research is needed that extends beyond broad societal costs, looking at the entire distribution of individuals affected by the disease rather than population averages. Trends and differences in expenditures and other burdens across regions, household types, socioeconomic status, and racial/ethnic groups are thus encouraged. Workforce dynamics should also be examined; both the shortage of formal caregivers in the community as well as the impacts of informal caregiver responsibilities on labor force participation are areas of concern.

For health outcomes, we have a good amount of research about caregiver health but little research on the impact of dementia on the person living with dementia (e.g., quality of life). It is particularly critical to explore the impacts of dementia on persons living alone, perhaps without a caregiver at all. Research that considers health impacts and how they might shape the relationships between PWD, their families/caregivers, and their communities is highly encouraged.

For community support, insufficient research has been conducted to understand the elements of the existing infrastructure (e.g. transportation services; meals on wheels, etc., that provide necessary support to PWD, caregivers, and their families. Gaps that this proposal could address include determinants of the availability of a range of services for PWD and determinants of service utilization.

Scientific/Research Contact

Elena Fazio, Ph.D.
Division of Behavioral and Social Research
National Institute on Aging
Telephone: 301-496-3131
E-mail Elena Fazio, Ph.D.

Integrative Omics to Enhance Therapeutics Development for Healthy Aging

There is a strong relationship between exceptional longevity and exceptional health span. For example, centenarians show delayed onset of age-related disabilities and morbidities such as cardiovascular disease and Alzheimer's disease. These findings are consistent with the concept that aging mechanisms influence both longevity and the development of multiple age-related conditions. Identifying factors that influence such mechanisms could facilitate the identification of interventions to enhance human health span. To develop such interventions, there is a need to identify therapeutic targets and assess the effects of engaging these targets.

GWAS analyses of exceptional longevity and healthy aging in humans have identified several variants associated with longevity and health span. These can serve as a starting point for efforts to identify therapeutic targets. However, strategies based on genetics alone have substantial limitations. Many gene products have multiple targets that interact with each other and with multiple genes. The relationships of genetic variants to expression profiles of RNA, proteins, and metabolites that influence longevity and health are complex. Thus, there is a need for multi-omics/integrative approaches (i.e., omics profiles) which could yield better predictors of healthy aging phenotypes than can be found based simply on individual gene variants, as well as guide the assessment of drugs targeted at specific molecules. In addition, to distinguish between factors that affect only one aging-related condition or have opposing effects on differing conditions vs. factors with more consistently beneficial effects, there is a need for phenomic approaches to assess the relationship of genetic factors and omics profiles to a wide range of aging-related outcomes. Studies on species with widely varying life spans also suggest that comparative omics approaches could yield insights into crucial factors influencing life span and health span. There is a need to integrate such approaches with human studies to enhance strategies to find potential targets for human interventions.

The proposed initiative will address the above needs. It will identify omics profiles associated with protection against multiple aging conditions and with exceptional health span, and refine strategies for utilizing these profiles in therapeutics development. Specifically, it will support multiple omics measurements (e.g., transcriptomics, proteomics, metabolomics) from the same individual and from multiple tissues from extensively phenotyped cohorts with substantial numbers of long-lived individuals and controls. It will also:

  • harmonize and extend phenotypic data from these studies to apply phenomics to transcriptomic, proteomic, and metabolomic findings;
  • select species or strains with varying life spans for comparative omics studies and identify potential determinants of species differences in longevity and rates of disease development;
  • develop appropriate computational and analytical tools to identify omics profiles associated with exceptional longevity and healthy aging;
  • apply informatics drug screening tools and other databases to identify molecules that could produce profiles associated with exceptionally healthy aging; and
  • exchange and harmonize data with related omics activities such as AMP-AD and other public-private partnerships.

This initiative is timely because of the advent of technologies that enable the collection and integration of large omics data sets including genome, transcriptome, proteome, metabolome and phenome. This type of integrative approach could identify crucial profiles that reveal connections between biological pathways and thereby enhance therapeutic development.

Scientific/Research Contacts

Nalini Raghavachari, Ph.D.
Division of Geriatrics and Clinical Gerontology
National Institute on Aging
Telephone: 301-435-3048
E-mail Nalini Raghavachari, Ph.D.

Max Guo, Ph.D.
Division of Aging Biology
National Institute on Aging
Telephone: 301-402-7747
E-mail Max Guo, Ph.D.

Suzana Petanceska, Ph.D.
Division of Neuroscience
National Institute on Aging
Telephone: 301-496-9350
E-mail Suzana Petanceska, Ph.D.

Interventions Testing Program Renewal

The Interventions Testing Program (ITP) was established by the NIA to investigate the potential of dietary interventions to promote healthy aging (see website listed below). This cooperative agreement program has been funded for 15 years and funding of the current funded program is scheduled to end in 2019. The ITP uses a four-way genetically heterogeneous mouse model (UM-HET3) to reduce the impact of strain-specific characteristics on outcomes. Lifespan tests are done in parallel, using the same protocol at three independent sites to increase robustness of the findings. Cohort sizes are large enough that the protocol will detect a 10 percent change in mean life span, in either sex, with 80 percent power, pooling data from as few as two sites. Standard operating procedures have been developed to maintain as much consistency in animal husbandry as possible among the three sites. Interventions for testing are proposed by the research community through an annual call for proposals. Proposed compounds tested to date range from drugs and dietary supplements to micronutrients and metabolic intermediates.

The list of all compounds tested by the ITP and in progress is on the ITP website. To date, six compounds have shown significant extension of lifespan:

  • Aspirin – males only
  • Rapamycin – males and females
  • 17αEstradiol – males only
  • Acarbose – males and females
  • Nordihydroguaiaretic acid (NDGA) – males only
  • Protandim® – males only

The interventions that have been shown to affect life span appear to involve different mechanisms, demonstrating that different cellular pathways may be modulated to influence the aging process. Moreover, sex-specific differences in the effects of the interventions have been discovered and four of the six positive interventions have been demonstrated to have a response in only one sex. This finding was unexpected and has led to many additional research projects to uncover the basis of these differences.

Scientific/Research Contact

Manuel Moro, Ph.D.
Division of Aging Biology
National Institute on Aging
Telephone: 301-496-6401
E-mail Manuel Moro, Ph.D.

National Health and Aging Trends Study: U01 Renewal

The National Health and Aging Trends Study (NHATS) collects detailed information annually about the disability and care needs of a nationally representative panel of over 8,000 Medicare beneficiaries ages 65+. NHATS also includes an oversample of persons at older ages (75+) and black individuals. Unique aspects of NHATS are: annual periodicity on a nationally representative sample that captures the dynamics of disability onset, progression and recovery; measures of unmet need for long-term care and support services; direct links to caregiver outcomes; information on participation in respondent-defined valued activities; a disability protocol that distinguishes between "capacity" of individuals to carry out activities and complex tasks and "accommodations" that individuals make to enhance their capacity; and rich data on the environment and available services in a variety of residential settings. In addition, NHATS is in the field on average 6 months prior to and after death of a respondent, providing valuable data for end-of-life research.

The NHATS agreement is currently in its ninth year; the study has conducted seven annual rounds of data collection to date. Round Eight will be conducted in 2018, the final year of the current award. The sample was replenished in Round Five (2015) to keep the sample representative of the entire age range and to achieve comparability for study of long-term trends in disability.

NHATS has been very productive, with more than 2,000 registered users of the publicly available data as of March 2017. As of March, approximately 90 publications in peer-reviewed journals used NHATS data, 41 of which have been published since January 2016, which speaks to the fast-increasing interest in the data as more annual rounds of data accumulate. NHATS is used in several separately funded NIA grants.

Scientists have used NHATS data to advance knowledge in a variety of areas, including:

  • behavioral adaptation to activity limitation,
  • end-of-life care;
  • characterizing vulnerable subpopulations;
  • informal care;
  • dementia care;
  • unmet need for assistance;
  • pain;
  • long-term trends in active life expectancy; and
  • participation in valued activities.

An external Data Monitoring Committee (DMC) advises NIA about the study, and in March, 2017, the DMC expressed its enthusiasm for the productivity of the study to date and underlined the need to continue annual in-person interviews to retain high-quality data about disability dynamics (recovery and decline) which would be missed with less frequent interviews. DMC members also reviewed the current sample replenishment design which calls for replenishment at four-year intervals (e.g., 2015, 2019, 2023). At the time of replenishment, new birth cohorts are brought into the sample and older age and race groups are replenished to preserve the age-race targets of the initial design. Continuing this design would mean replenishing twice in the new cycle (in 2019 and 2023) which would substantially increase the U01 budget over the current cycle. Although there would be greater attrition, the DMC recommended—and NIA staff agree—that changing the replenishment design to once every five years (from once every four years, as currently done) is acceptable as a way to reduce costs.

The NHATS cooperative agreement (U01) was originally funded in September 2008 through RFA-AG-09-007. The goal was to fund a new national survey of disability trends and dynamics among the U.S. older population to address two overarching aims: 1) to promote scientific inquiry into late-life disability trends and dynamics, and disparities therein, and 2) to advance study of the social and economic consequences of late-life disability for individuals, families, and society. The first renewal application was submitted to the NIA U01 FOA PAR-13-097 "NIA Limited Competition: Renewals of, and Revisions to, Existing Cooperative Agreement Awards (U01)" that expired in May 2016. Since PAR-13-097 is no longer active, an RFA is necessary to continue supporting the study.

A cross-sectional National Study of Caregiving (NSOC) was conducted in 2011 and repeated in 2015 with supplemental funding from DHHS/ASPE. NSOC interviewed over 2,000 family and unpaid caregivers of NHATS respondents, one-third of whom provided care to someone with AD/ADRD. Under separate NIA funding, a longitudinal NSOC is in the field in 2017, re-interviewing all current caregivers (as in 2011 and 2015) as well as all caregivers from 2015. The 2017 NSOC, combined with NHATS, will permit analyses contrasting caregivers to older adults with and without AD/ADRD.

Scientific/Research Contacts

Georgeanne Patmios, M.P.H.
Division of Behavioral and Social Research
National Institute on Aging
Telephone: 301-496-3138
E-mail Georgeanne Patmios, M.P.H.

Amelia Karraker, Ph.D.
Division of Behavioral and Social Research
National Institute on Aging
Telephone: 301-496-3131
E-mail Amelia Karraker, Ph.D.

NIA Small Research Grant Program for Investigators New to Alzheimer's Disease and Alzheimer's Disease-Related Dementias Research

A major goal in the National Plan to address Alzheimer's disease and Alzheimer's disease-related dementias (AD/ADRD) is to accelerate the development of treatments that would prevent, delay or reverse the course of Alzheimer's and improve early diagnosis. However, there is a workforce shortage to conduct the wide variety of innovative and interdisciplinary research, including clinical, translational, prevention, and treatment research in AD/ADRD. This small grant program concept will address National Alzheimer's Project Act (NAPA) Milestone 4.1: "to establish new training programs as well as fellowship and career development programs to develop a new translational and data science workforce" especially targeting recruitment of junior investigators to NIA's AD/ADRD portfolio. A major barrier for non-AD researchers to obtain an R01 grant to conduct AD research is the lack of critical preliminary data. This FOA would help them to overcome this barrier.

The overall goal of this FOA is to support important and innovative research in areas in which more scientific investigation is needed to improve the prevention, diagnosis, treatment, and care for AD/ADRD. The aim is to encourage the next generation of researchers in the United States to pursue research and academic careers in neurosciences, Alzheimer's disease. and healthy brain aging. Another aim is to stimulate novel research ideas from researchers in other fields.

Numerous reports suggest that there are critical times in new investigators' careers when a boost of funding to begin investigation of a novel idea would offer the opportunity to catalyze both the topic and the investigator's career. With the strong focus on AD/ADRD, the next generation is important to include explicitly in the funding opportunities.

Scientific/Research Contacts

Nina Silverberg, Ph.D.
Division of Neuroscience
National Institute on Aging
Telephone: 301-496-9350
E-mail Nina Silverberg, Ph.D.

Yuan Luo, Ph.D.
Division of Neuroscience
National Institute on Aging
Telephone: 301-496-9350
E-mail Yuan Luo, Ph.D.

Partha Bhattacharyya, Ph.D.
Division of Behavioral and Social Research
National Institute on Aging
Telephone: 301-496-3131
E-mail Partha Bhattacharyya, Ph.D.

Susan Zieman, M.D., Ph.D.
Division of Geriatrics and Clinical Gerontology
National Institute on Aging
Telephone: 301-496-6761
E-mail Susan Zieman, M.D., Ph.D.

Research Network on Telomeres as Sentinels of Environmental Exposures, Psychosocial Stress, and Disease Susceptibility

A growing number of investigators across a range of scientific fields have become intrigued by the role of telomeres in health and aging, with respect to both its functional properties and predictive value. In addition to their direct role in certain diseases, telomeres also appear to be "sentinels" for environmental exposures and psychological stress, potentially representing a readout of the accumulated life history of exposures of an individual. However, inconsistent epidemiological findings, concerns about comparability of telomere assessments across multiple studies, and emerging findings about the more prominent role that early-life exposures play in setting telomere length (TL) suggest that more research is needed to understand exposure effects and the role of telomeres in health.

A recent NIA/National Institute of Environmental Health Sciences workshop brought together experts from basic telomere biology, medicine, biopsychology, epidemiology, and related fields to explore and discuss the potential use and value of TL as a biomarker for environmental exposures, psychosocial stress, and disease susceptibility in population-based research. Experts discussed how insights from basic biological science can advance epidemiological and clinical investigations, and vice versa. Discussions also addressed factors that need to be measured alongside of telomeres, interactions between genes and the environment (including both the physical and the social environment) on health, tissue-specific effects, and the potential to use surrogate tissues in situations where the "true" tissue of interest (e.g., the brain) is inaccessible. Building on this productive dialogue, attendees highlighted an immediate need to enhance the comparability of results obtained using different assays and possibly across different cell types, set standards for sample preparation, DNA extraction, and reporting of assay protocols, and to make recommendations for conducting telomere assessments in different research contexts (e.g., lab-based vs. population-based). Continued dialogue across disciplinary lines will be essential to move this agenda forward. Consensus was reached concerning the need for definitive studies about methods and universal standards for laboratory protocols, involving a wide range of labs working together and bringing in biostatistics expertise. Participants also recommended that distinct sets of recommendations be developed for laboratory, clinical, and population-based studies given that no single approach would simultaneously meet the needs of all types of studies.

Continued transdisciplinary dialogue can support a more coordinated research strategy to address:

  • Whether TL and other markers are early sentinels of premature aging or early disease processes because they encapsulate the life history of the individuals. What studies are necessary to enhance the quality of data that allows us to test this hypothesis? Is the telomere a marker of the exposures or is it a cumulative index of overall health status? If it's a marker of cumulative exposure, what is driving that measure?
  • Given accumulating evidence that initial setting of TL at birth and exposures in early development play important roles in predicting long-term outcomes: What governs the range of shortening early in life and why is there a window of susceptibility? Is there a set-point during early development and is this universal? What are the reasons for race and sex differences, observable already early in life? What are the best times and conditions to measure telomeres?
  • How should we think of TL as an "integrative marker?" Does focusing on telomeres have advantages and disadvantages relative to other biomarkers related to aging or exposures? What is the most important set of assays for determining cell aging in healthy humans? What other markers can be combined? Should we examine TL in addition to other indices of cellular aging such as inflammation, senescence-associated secretory phenotype, genetic index, or epigenetic aging? Mitochondrial function? In what contexts do replicative senescence and TL matter most?
  • Given that longitudinal data in well-characterized cohorts will be necessary to advance this agenda to determine the impact of a range of stress and environmental exposures on health and aging, what are the next steps for this field?

Scientific/Research Contact

Lis Nielsen, Ph.D.
Division of Behavioral and Social Research
National Institute on Aging
Telephone: 301-402-9156
E-mail Lis Nielsen, Ph.D.

Roybal Translational Center Renewal and AD/ADRD Care Expansion

This proposal seeks to renew the Roybal Center program and to expand the program to include new Alzheimer's disease and Alzheimer's disease-related dementias (AD/ADRD) Roybal Centers and to add a coordinating center that will serve as a hub for sharing best practices, dissemination of Roybal findings, and compiling evaluation metrics for the program. The Roybal Centers were authorized by Congress in FY1993. They were renewed in FY1998, FY2002/FY2003, FY2008, and FY2013. The first Roybal RFA (RFA-AG-93-02) stated that they were, "Designed to facilitate the process of translating basic behavioral and social research theories and findings into practical outcomes that will benefit the lives of older people." This purpose has been maintained over the years, and the most recent RFA (RFA-AG-14-004) re-emphasized the need: "…for the development and piloting of new and innovative ideas for early-stage as well as late-stage translation of basic behavioral and social research findings about established or hypothesized mechanisms of action…into programs and practices…" Currently, there are 13 NIA Roybal Centers, which have produced results and findings that have had or could have a significant impact upon practical outcomes. Some specific accomplishments include:

  • The development and testing of interventions, based upon choice architecture theory, to encourage pharmacy home delivery that has enormous cost-reduction benefits without reducing quality and efficacy of care. (NBER Roybal)
  • The development and testing of behavioral economics-based interventions that have more than doubled the rate at which consumers sign up for automatic medication refills, improving adherence for millions of individuals. (Penn Roybal)
  • The development of evidence-based pain self-management programs that continue to be implemented in many New York City senior centers (Cornell Roybal)
  • A finding that earlier cataract surgery would reduce automobile crashes at the societal level. This finding could have a practical impact upon American Academy of Ophthalmology guidelines when new guidelines are considered. (Alabama Roybal)

This initiative will renew the highly productive Roybal program. The timing is important so there can be continuity of support when the Roybal funding is due to end in FY 2018.

In addition, this initiative will expand the Roybal program to address pressing needs related to AD/ADRD. An expert panel at the 2017 NIA Workshop, "Innovating the Next Generation of Dementia and Alzheimer's Disease Care Interventions," highlighted this need. Recommendations included

  • conducting basic mechanistic research to determine the mechanisms underlying efficacious and effective interventions aimed at improving quality of life for persons with AD/ADRD and their caregivers;
  • translating existing care models, services, and technologies to improve the lives of persons with AD/ADRD and their caregivers into real-world settings; and
  • conduct research that considers the scalability and sustainability at the beginning of intervention development and throughout subsequent research.

These recommendations were underscored at the 2017 Summit on Dementia Care and Caregiver Support. Expansion of the Roybal model for translating basic research into outcomes that affect real-world programs and practices holds promise for accelerating progress toward these three AD/ADRD research goals.

Finally, a Coordinating Center is proposed that will:

  • serve as a coordinating hub to strengthen the infrastructure and interconnectedness of the Roybal Centers to potentiate the value of translational intervention/implementation research, and bring Roybals together around relevant topics, such as principle-based intervention development, the SOBC experimental medicine approach, the stages of intervention development, integrating use-inspired basic science into intervention development, SMART & adaptive designs, etc.;
  • coordinate grantee meetings;
  • disseminate translation research to the public and;
  • collect materials to evaluate the Centers (including research outcomes, pilots, publications).

Scientific/Research Contact

Lisa Onken, Ph.D.
Division of Behavioral and Social Research
National Institute on Aging
Telephone: 301-496-3131
E-mail Lisa Onken, Ph.D.

Studying in vivo Synaptic Function in Alzheimer's Disease and Related Dementias*

These FOAs will advance development of methods to study synaptic structure and function in living humans. Recent development of a PET radioligand for a synaptic vessel protein, SV2A, has good evidence to support proof of concept in humans. These FOAs will encourage rapid testing and development of this potentially game-changing biomarker in Alzheimer's disease and Alzheimer's disease-related dementias (AD/ADRD), as well as encourage development of other novel methods to study human synapses in vivo.

The synapse is fundamental to brain function. Phenomena like long-term potentiation; neurotransmitter release; second-messenger activation; formation; and pruning of dendrites during development all involve the synapse. Many tools have been developed to study synaptic morphology and function in living animals using intracranial confocal, 2 photon, and other microscopy methods. Synaptic structure and function have been studied in animal models of neurodegeneration using in vivo microscopy. However, nothing comparable has been possible in humans. Our understanding of synapses in the human brain has been limited to postmortem examinations. We have not been able to study synaptic structure or function in living humans.

Scientists at UCB, a Belgian biopharmaceutical company, along with investigators at Yale University have developed PET radioligands that bind to SV2A, a presynaptic vesicular protein. These radiotracers are based on levetiracetam (Keppra, developed by UCB), an anticonvulsant that acts at SV2A. Since SV2A is found in presynaptic nerve terminals throughout the brain, it could serve as a marker of synaptic integrity. Loss of synapses should be reflected in decreased SV2A binding.

A PET radioligand developed at Yale, 11C-UCB-J, binds with high affinity to SV2A. Data on 11C-UCB-J PET as a measure of synaptic density have been tantalizing, including preliminary data in AD/ADRD, but require replication, validation, and exploration, particularly in longitudinal studies in larger cohorts. 11C-UCB-J PET also provides (potential) proof of principal for human in vivo examinations of synapses. A second, much more speculative goal of this concept, is to encourage development of novel methods to study in vivo synaptic structure or function in humans. These might be based on neuroimaging (PET or MRI) or neurophysiological (EEG, MEG, ERPs) measures. Preclinical or animal studies would be appropriate as part of the developmental process.

The only group using 11C-UCB-J at this point is Yale. However, many other PET centers are interested in the tracer and have been in touch with the Yale investigators. Yale is eager to share their expertise, and there are no IP or commercial barriers. This is an 11C tracer, with limited commercial appeal, that should be analogous to PiB.

This concept is not intended to support studies focused on neurotransmitter receptor function (e.g., raclopride D2 PET, or DASB SERT PET), even though these receptors are part of the synapse, nor is this concept intended to support study of overall markers of synaptic damage (e.g., CSF NfL).

Scientific/Research Contact

John Hsaio, M.D.
Division of Neuroscience
National Institute on Aging
Telephone: 301-496-9350
E-mail John Hsaio, M.D.

Testing Life Span/Health Span Extension Interventions in the Models of Alzheimer's Disease

In the United States, more than 5 million people suffer from Alzheimer's disease and Alzheimer's-disease-related dementias (AD/ADRD). By 2050 this number is forecast to rise to more than 15 million. The care and treatment of patients with AD/ADRD is estimated to cost approximately $200 billion each year. This concept intends to use Small Business Innovation Research Program (SBIR) and the Small Business Technology Transfer Program (STTR) mechanisms as part of the NIA's strategic plan to support the development of innovative strategies and therapies to prevent, diagnose, and treat AD/ADRD. The goal is to encourage research and development of commercially viable pharmaceutical interventions that already have been shown to extend life span and/or health span of animal models of aging, as a means to prevent, treat, and/or slow the progression of symptoms associated with AD/ADRD.

In the past three decades, research on the biology of aging has acquired a broad knowledge of the underlying mechanisms of aging and longevity. These studies have led to a quite comprehensive understanding of the cellular mechanisms of aging, including changes in many genes, pathways, important cellular components, and biomolecules involved in the aging process. The work conducted so far has been done mostly in model organisms (from yeast to nonhuman primates), and has demonstrated that these life span-regulating pathways are shared across species. Along with these mechanistic studies, considerable research efforts have been devoted to test various interventions for their ability to extend lifespan and/or health span in animal models.

To advance the goal of identifying pharmaceutical lead compounds, deal with the variability of life span assays, and establish rigorous testing methodology, in 2003 NIA started the Intervention Testing Program (ITP). Using a genetically heterogeneous mouse model, the ITP tests compounds/diets purported to benefit healthy aging, with life span as the primary read-out and health span measurements as secondary readouts. Some compounds tested in the ITP have shown significant extension of median life span, including aspirin, rapamycin, 17α-estradiol, acarbose, nordihydroguaiaretic acid (NDGA), and protandim. In 2014, NIA also started the Caenorhabditis Intervention Testing Program (CITP), which aims to identify pharmacological interventions that increase lifespan and/or health span in a robust manner using a collection of diverse species and strains of Caenorhabditis. Success in this kind of approach is likely derived from the fact that many life span-extending pathways are conserved. In fact, in the past two decades, many pharmaceutical interventions have been identified that effectively extend life span in most animal models, including rapamycin, resveratrol, some senolytics, and ThioflavinT. ThioflavinT is also known to suppress the aggregation and toxicity associated with the expression of a human neurotoxic peptide (A1-40) and promote protein homeostasis, a process that is dysfunctional in many forms of neurodegeneration linked to various dementias.

Aging is a major risk factor for most chronic diseases and degenerative conditions in adults, including AD/ADRD. By this reasoning, those interventions that can slow aging should be effective in preventing or treating AD/ADRD. Despite a strong rationale and the rapid progress in discovering anti-aging interventions in animal models, most of these life span/healthspan extension interventions have never been tested for their potential benefits in AD/ADRD models. This FOA concept aims to encourage the small business community to test these interventions, mostly pharmaceutical compounds, in AD/ADRD models for their effects on the activities of AD/ADRD genetic alleles, their cellular properties, and cognitive/behavioral phenotypes that are related to the progression and pathogenesis of AD/ADRD.

In conclusion, the FOAs that would emerge from this SBIR/STTR concept are intended to encourage the development and commercialization of pharmaceutical compounds to prevent, treat, or slow the progression of symptoms or phenotypes associated with AD/ADRD, where those interventions have been shown to extend life span and/or health span in animal models. However, the interventions covered by this concept are not limited to those tested in the ITP or the CITP. Testing these interventions could be done using in vitro approaches with human cells or tissues, and/or laboratory animals.

Examples of topics that might be supported by this concept include but are not limited to:

  • Development of assays that can test the effects of life span/health span extension compounds on activities of AD/ADRD genetic alleles or proteins;
  • Testing of the effects of life span/health span extension compounds on properties of cells with AD/ADRD genetic alleles;
  • Testing of the effects of life span/health span extension compounds in AD/ADRD invertebrate models for phenotypes related to AD/ADRD;
  • Testing of the effects of life span/health span extension compounds in AD/ADRD rodents or other vertebrate nonhuman animal models for phenotypes or symptoms related to AD/ADRD; and
  • Testing of the effects of life span/health span extension compounds in AD/ADRD human iPSCs or tissue culture systems (including 3-D culture and organoid) for their properties related to AD/ADRD or AD/ADRD genetic alleles.

Scientific/Research Contacts

Max Guo, Ph.D.
Division of Aging Biology
National Institute on Aging
Telephone: 301-402-7747
E-mail Max Guo, Ph.D.

Lorenzo Refolo, Ph.D.
Division of Neuroscience
National Institute on Aging
Telephone: 301-594-7576
E-mail Lorenzo Refolo, Ph.D.

Yuan Luo, Ph.D.
Division of Neuroscience
National Institute on Aging
Telephone: 301-496-9350
E-mail Yuan Luo, Ph.D.

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