Research and Funding

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, and some of the concepts listed below (particular from older Council meetings) may have already been converted to FOAs.

May 2017 Council

Central neural mechanisms of age-related hearing loss

Hearing loss is the most prevalent sensory loss in older adults and the third most common chronic health condition facing them. Approximately one in three people in the United States between the ages of 65 and 74 has hearing loss, and nearly 50 percent of those older than 75 have difficulty hearing. Age-related hearing loss, also known as presbycusis, is the loss of hearing that gradually occurs in most people as they grow older and is usually bilateral. It is associated with elevated hearing thresholds and leads to reduced speech understanding in noisy and echoing environments. Hearing loss not only affects communication but can significantly impact one's quality of life. For example, hearing loss has been linked to increased risk of falls and injuries, depression and social isolation and there is also some evidence to suggest an association with cognitive decline and dementia.

Interestingly, despite the impact of hearing loss on social interactions, physical function, and psychological function, only about 15 percent of people with a hearing impairment in the United States use hearing aids or hearing assistive technologies. While this statistic is largely attributed to the costs of these technologies and the social stigma of hearing loss, there are many individuals for whom these types of treatments are completely ineffective. Age-related hearing loss most commonly arises from age-related changes in the inner ear, such as degeneration of the hair cells of the cochlea. However, it may also result from alterations in central auditory processing or decoding of sound by the brain.

There is a major gap in our understanding of the central pathways and neural networks that are involved in hearing loss. To develop better interventions for treatment, it is critical to understand the neural mechanisms of hearing loss and how these may be altered in the context of the aging brain. Additionally, insight into the plasticity of the auditory nervous system and how it adapts to changes in levels of auditory stimuli in aging will also help inform this goal.

Hearing health care is moving forward rapidly and has gained significant momentum since a National Academies of Sciences, Engineering and Medicine (NASEM) study report: Hearing Health Care for Adults: Priorities for Improving Access and Affordability, was published in June 2016. This report details the study committee's 12 recommendations that would allow consumers to access and fully use the appropriate, affordable, and high-quality services, technologies, and support they need. The President's Council of Advisors on Science and Technology (PCAST) also issued a report in October 2015 which detailed priorities for hearing health care. There has already been some action on the NASEM and PCAST recommendations. As of December 2, 2016, certain types of hearing aids can now be obtained over the counter, and adults 18 years and older are no longer required to obtain a medical evaluation to access an over-the-counter hearing aid. Given the significant emphasis the reports place on improving the accessibility of hearing aids and other assistive technologies to promote usage and adherence, it is timely for NIA to aid in this effort by stimulating research on age-related alterations in neural pathways, neural networks, and auditory system plasticity to inform these priorities.

Scientific/Research Contact

Coryse St. Hillaire-Clarke, Ph.D.
Division of Neuroscience
National Institute on Aging
Telephone: 301-496-9350
Email: sthillaireclacn@mail.nih.gov

Demonstration Projects for Pragmatic Clinical Trials

The increased adoption of health information technology tools is not only changing how care is delivered but is also providing opportunities for expanded participation of health care delivery organizations in research. Equally, the potential to conduct research studies in real-world settings on large numbers of participants allows questions to be addressed that researchers could not feasibly address with paper records. Demonstration projects may provide innovative approaches to address and overcome important barriers to research in the health care delivery setting. Health care systems have interest in participating in studies that may potentially impact the care they deliver, including pragmatic clinical trials.

We define pragmatic trials as trials "primarily designed to determine the effects of an intervention under the usual conditions in which it will be applied," which is in contrast with explanatory trials that "are primarily designed to determine the effects of an intervention under ideal circumstances" (http://www.bmj.com/content/350/bmj.h2147). Pragmatic trials measure both the positive and negative health impacts, as well as resource implications, of treatments delivered in real-world settings. Pragmatic trials are also well suited for testing how readily practice guidelines can be implemented in health care systems, and for assessing outcomes of implementation across a broad range of patient subgroups.

The program will potentially span the clinical interests of the NIA, for example:

  • Evaluation of beneficial and adverse outcomes from differing management strategies for multiple chronic conditions, testing one, or coordinating several, interventions.
  • Incorporation of specific palliative care services into care of older adults within and/or across specific settings.
  • Evaluation of benefits and harms of screening for cognitive impairment in community-dwelling older adults in primary care-relevant settings, and the effects of screening on decision making, patient, family or caregiver, and/or societal outcomes.
  • Effectiveness of simple, scalable incentive-based interventions to improve health-promoting behavior in midlife and/or older adults in one or more of the following settings: workplaces, community, nursing homes, assisted living facilities, and rehabilitation facilities.
  • Assessment of new organizational and delivery models, which include innovations and care coordination in home health care and adult day services for frail older adults.

Several criteria will be included for the pragmatic trials such as high public health importance of the research question, intention to improve clinically meaningful and important health outcomes, well-characterized and reasonably simple intervention to be delivered flexibly by typical health care practitioners, integration within health care delivery systems and their electronic record systems, and lack of regulatory issues.

This program is essential to strengthen the relevance of research results to real-world health practice. Successful approaches and best practices established through this initiative for research partnerships with health care systems should have a major impact on clinical research in the United States.

This program encourages sharing of resources with broad availability of policies, practices, materials, and tools to facilitate collaboration, reuse, and replication. In addition, the program requires sharing of study data from demonstration projects in a timely manner with appropriate privacy and confidentiality protections.

Scientific/Research Contact

Marcel Salive, M.D.
Division of Geriatrics and Clinical Gerontology
National Institute on Aging
Telephone: 301-496-6761
Email: marcel.salive@nih.gov

Tailoring Cardiac Rehabilitation to Enhance Participation of Older Adults

Each year, nearly 2 million Americans have an acute coronary event or revascularization procedure, and millions more have a chronic cardiovascular (CV) condition, such as heart failure, for which cardiac rehabilitation (CR) is recommended by clinical care guidelines (Class 1A). Traditional Phase I CR involves a universal, multifaceted program consisting of an individualized physician-supervised, exercise and strengthening regime with cardiac monitoring, coupled with an comprehensive educational component to promote awareness, lifestyle changes and risk reduction in diet, cholesterol and blood pressure management, smoking cessation, and emotional support. The overall goals of traditional hospital-based CR programs (36 sessions over 12 weeks) are to promote a safe and expeditious recovery and return to work for patients after an acute CV event, and to reduce risk of future CV events. A substantial body of evidence exists showing CV and other benefits of CR, including reduced CV morbidity/mortality, improved quality of life (QOL) and functional status, and reduction in hospital readmissions.

Despite these clear clinical and patient-centered benefits, CR remains severely underutilized with fewer than 20 percent of all eligible patients participating in a CR program. Several general barriers to CR referral, enrollment, and completion have been identified including a lack of referral or strong recommendation from a physician, inadequate follow-up or facilitation of enrollment after referral, limited or no health insurance coverage, conflicting work and home responsibilities, distance and transportation problems, lack of gender and racial diversity among CR staff, language and cultural barriers, and lack of program availability and access. In addition to these general barriers to CR, older CV patients and their providers are confronted with more complex challenges which present opportunities to update, modify, and adapt CR programs to serve as a comprehensive venue for vulnerable and frail older CV patients, including adapting CR components and non-healthcare settings (community centers, home, remote monitoring) to improve referral, use, and more patient-centered outcomes.

Enrollment and completion of traditional CR programs by older adults (over 70 years of age) is even lower (12 percent) than in the general population, despite an age-related rise in CV events and disease incidence and prevalence. This alarmingly low rate of CR use exists despite documented beneficial effects of CR in this population and Medicare reimbursement for CR for those 65 year of age and older with an eligible CV event or diagnoses. In addition to some barriers seen with general CR-eligible patients including transportation and reaching underserved areas and underrepresented populations, other challenges specific to the older CR patient present unique opportunities to enhance the suitability and use of existing CR programs for more vulnerable, frail and multimorbid older patients. Novel programs which focus on global outcomes such as decreasing frailty and falls, maintaining independence, managing multiple chronic conditions, improved cognitive and physical functioning. and medication management may prove more amenable and appropriate for older patients with acute and chronic CV conditions to reduce further morbidity, mortality, disability, dependence, and rehospitalization than traditional CR programs. Additionally, CR programs adapted to accommodate more real-world older CV patients by employing modified exercises and equipment, by including use of assistive devices (canes/walkers), and which blend initial hospital-based and later home-based settings using remote technology and/or telemedicine, may prove more feasible and efficacious for seniors.

The overall goal of this funding announcement is to elicit proposals for novel strategies to enhance referral, participation, and adherence in CR of older and more vulnerable patients who are eligible for CR under current Medicare eligibility criteria. Specifically, NIA seeks clinical trials that address one or more specific age-related factors including patient-related issues, CR program goals and components, and CR program setting-related aspects. These three age-related issues represent distinct, but potentially interrelated, areas that are impacted by advancing age and are not currently addressed in traditional CR programs. Determination of the specific aspects of CR programs that may be better suited to medically complex and vulnerable older adults, such as eligibility, patient-centered goals and outcomes, and novel components and delivery systems may ultimately improve referral, enrollment, completion, and overall benefit. Inter-institutional collaboration to leverage existing resources and programs will be highly encouraged. The National Heart Lung and Blood Institute is concurrently seeking approval of a concept to enhance use of CR and pulmonary rehabilitation in the general population which further emphasizes the need to improve the referral, enrollment, and adherence in this beneficial therapy.

Scientific/Research Contacts

Lyndon Joseph, Ph.D.
Division of Geriatrics and Clinical Gerontology
National Institute on Aging
Telephone: 301-496-6761
Email: josephlj@mail.nih.gov

Susan Zieman, M.D.
Division of Geriatrics and Clinical Gerontology
National Institute on Aging
Telephone: 301-496-6761
Email: susan.zieman@nih.gov

Pathogenesis of Age-Related HIV Neurodegeneration

There is a global trend in the rise of HIV among older adults. In 2013, the CDC estimated that 42 percent of Americans living with HIV were at least 50 years old, 25 percent were at least 55 years old, and 6 percent were at least 65 years old. With longer life expectancy, individuals living with long-term HIV infection exhibit many clinical characteristics commonly observed in aging: multiple chronic diseases or conditions, the use of multiple medications, and changes in physical and cognitive abilities. HIV and its treatment have profound effects on the brain. Although once relatively common among people with HIV, AIDS-related dementia in the United States is now rare; still, it remains the most prevalent form of dementia in sub-Saharan Africa. However, it is estimated that half of people with HIV have an HIV-Associated Neurocognitive Disorder (HAND). The clinical presentation of HAND may include deficits in attention, language, motor skills, memory, and other aspects of cognitive function that can drastically alter quality of life. Importantly, age is a significant risk modifier for HAND. Surprisingly, little is known about neural mechanisms underpinning HIV-associated neurocognitive disorder and processes that lead to neurodegeneration in people living with HIV.

Current understanding of HIV neuropathogenesis is largely based on clinical outcomes that were predominantly seen in the era preceding the development of antiretroviral therapy. Moreover, the majority of basic neuroHIV research has focused on evaluating neuronal damage in the context of active viral replication and outcomes related to encephalitis. However, it is critical to examine neuronal impairment caused by HIV in the context of viral suppression and antiretroviral therapies. There is an urgent need to bridge the gap between pathogenesis research and observed clinical outcomes. As a result of a major demographic shift in the HIV-infected population in the U.S., there is also an urgent need to better define the underlying pathophysiology of neurodegenerative processes, neurological complications, and neurocognitive decline accompanying HIV during the course of aging

Among the mechanisms that cause and modulate neuroHIV central nervous system (CNS) impairment are those that play a role in the pathophysiology of Alzheimer's disease. There are, however, controversies as to what features of Alzheimer's disease are present in neuroHIV. Brain abnormalities are common in HIV and account for up to 90 percent of cases in post-mortem examinations, even in patients who died in their late forties or early fifties; neuronal loss is a common feature of neuroHIV. Although neuropathological examinations have demonstrated that many patients with HIV exhibit brain pathologies characteristic of Alzheimer's disease—including diffuse extracellular amyloid β (Aβ) plaques, abundant intracellular Aβ immunostaining, and the presence of Aβ along axonal tracts—the validity of these studies has recently been questioned. There are discrepancies in results on tau and α-synuclein pathologies in HIV brains. Similarly, there are controversies regarding cerebrospinal fluid Aβ42 levels and Aβ imaging results in HIV-positive individuals. Despite these controversies, there are multiple lines of evidence suggesting that HIV and antiretroviral therapies may contribute to Alzheimer's disease pathophysiology. For example, it has been established that HIV interferes with multiple stages of Aβ metabolism, exacerbates neuroinflammation, and disrupts the blood brain barrier and its receptors implicated in Aβ transport. There are also strong data indicating that antiretroviral therapies increase brain Aβ levels.

In summary, older adults comprise the largest segment of the U.S. population living with HIV, and cognitive impairment impacts nearly half the HIV patients. For that reason, it is important to understand the mechanisms that cause and modulate the CNS impairment in older adults with HIV.

Scientific/Research Contacts

Mack Mackiewicz, Ph.D.
Division of Neuroscience
National Institute on Aging
Telephone: 301-496-9350
Email: mackiewiczm2@mail.nih.gov

Rebecca Fuldner, Ph.D.
Division of Aging Biology
National Institute on Aging
Telephone: 301-496-6402
Email: fuldnerr@nia.nih.gov

Harmonizing Outcomes in Existing Cohorts to Enhance the Study of Risk and Protective Factors for Alzheimer's Disease and Alzheimer's Disease Related Dementias

Many putative risk and protective factors for Alzheimer's disease and Alzheimer's disease-related dementias (AD/ADRD) have been identified, but, given their high degree of inter-correlation, determining which of these are truly causal has been difficult. Although new statistical techniques can potentially elucidate causal pathways given sufficient data, we are limited by relatively small sample sizes in individual longitudinal cohorts. Because NIH already supports many cohorts with risk factors and outcome variables directly relevant to AD/ADRD, we can potentially improve the situation by leveraging investments across cohorts in combined analyses. Indeed, this concept proposal stems in part from a longer term effort by staff from NIA, NINDS, NHLBI, and NIDDK to identify and catalog cohorts that could be leveraged to answer long-standing questions about vascular and other contributions to AD/ADRD. A significant challenge to this approach, however, is the lack of consistency in measurement between studies, especially in important outcome measures. This latter point is especially important for genomic studies, where very large sample sizes will be required to identify new risk and protective variants, and where data harmonization efforts have already accelerated discovery in, for example the Alzheimer's Disease Sequencing Project.

The need to support data harmonization efforts across cohorts is not new, and substantial progress has been made for a variety of risk factors for AD/ADRD, which historically have been primary outcomes in other studies. Less progress has been made, however, in outcomes of highest relevance to the epidemiology of AD/ADRD, as well as resilience to these disease processes. In particular, we note specific and persistent challenges in harmonization of:

  • Clinical outcomes (including AD/ ADRD diagnoses and the more sensitive assessment of cognitive abilities);
  • Neuroimaging outcomes (including both structural and functional MRI as well as PET);
  • Quantification of neuropathology (including measures of various proteinopathies and vascular infarcts); and
  • Diagnosis of comorbid conditions.

Scientific/Research Contact

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

Enhancing Central Neural Control of Mobility in Aging

Clinically diagnosable gait abnormalities are highly prevalent among older adults, affecting approximately 35 percent of adults over age 70 and the majority of the adults over age 85. Such gait abnormalities may result in mobility limitation, an important functional disability defined in various disability models such as those by Nagi and the International Classification of Functioning, Disability and Health of the World Health Organization. Mobility limitation is highly associated with disability and increased dependency. It also restricts activity and social participation, and can lead to isolation, anxiety, depression, and an overall poorer quality of life. In addition, mobility limitation has been shown to be a strong predictor of subsequent disabilities, the need for assistance, as well as a higher risk of falling and mortality. Despite the significant public health impact of mobility limitations and gait abnormalities in older adults, our understanding of the underlying mechanisms and our choices of prevention or intervention strategies remain very limited.

Conventional research on mobility limitations in older adults primarily centers on social, environmental, and individual factors related to musculoskeletal mechanisms and processes. In contrast, much less is studied about the central neural control of mobility in older adults without overt neurological diseases. Furthermore, the degree of plasticity in the aging brain and how this may be harnessed to maintain or improve mobility is largely unknown. These major knowledge gaps have hampered the development of effective interventions for mobility limitations and the subsequent reduction of a major functional disability for older adults.

Several major barriers exist for research on central neural control of mobility in aging. First, central nervous system (CNS) research on movement disorders has primarily centered on neurological diseases, whereas older adults with subclinical gait abnormalities have been largely ignored. The traditional disease-based models typically assumed that pathology is fairly localized, specific, and rapidly manifested. In contrast, in aging it is assumed that there is an accumulation of non-specific abnormalities that are distributed across the CNS, possibly over a long period of time. Second, disciplines studying mobility limitations often operate in silos and use multiple conceptual frameworks and terminologies that are largely discipline-specific with overlapping meanings but distinct definitions. This lack of coherence and common standards has limited the exchange of scientific findings across disciplines and the translational values from basic to clinical research. To overcome these barriers and to enhance central neural control of mobility in aging research, we need to develop an initiative that would enable collaboration of investigators from diverse disciplines.

Scientific/Research Contacts

Lyndon Joseph, Ph.D.
Division of Geriatrics and Clinical Gerontology
National Institute on Aging
Telephone: 301-496-6761
Email: josephlj@mail.nih.gov

Coryse St. Hillaire-Clarke, Ph.D.
Division of Neuroscience
National Institute on Aging
Telephone: 301-496-9350
Email: sthillaireclacn@mail.nih.gov

Development of Valid Reliable Markers of Aging-Related Biologic Mechanisms for Human Studies

Interest is increasing in the prospect for extending human health span by modulating fundamental biologic mechanisms proposed to influence multiple aging changes. Examples of these mechanisms include cell senescence, proteostasis/autophagy, mitochondrial functions, stem/progenitor cell functions, nutrient sensing, and intercellular communication processes.

Rigorous measurement methods to assess such mechanisms in humans are crucial for the development and assessment of interventions to modulate them. Sufficiently valid, reliable, and accurate markers of their status and activity are needed in observational studies to assess the influence of these mechanisms on a variety of aging outcomes, and in clinical settings, to assess the extent to which interventions against aging-related conditions influence these mechanisms.

Considerable research is needed to develop more satisfactory markers of these mechanisms in humans. In many cases, crucial measurement properties, e.g., inter-assay, intra-assay, inter-individual, and intra-individual variability, have either not been established or are currently unsatisfactory for human studies. In addition, given that each of these mechanisms involves multiple pathways with multiple steps, there is a need for much more extensive information on the relationships of measures of individual components to functional activities of these pathways in humans. There is also a need for greater knowledge of the relationships between marker levels in one tissue (e.g., serum) and levels in other tissues.

The planned initiative will develop well-characterized, validated markers to assess the activity of aging-related mechanisms in humans. Projects will select candidate markers, and assess their characteristics, such as assay specificity, reproducibility and measurement properties, influence of specimen collection methods, and stability under differing storage conditions. They will develop and test refinements in methods to improve these characteristics if needed. They will also assess the degree of correlation of circulating markers with their levels of activity in target tissues. In addition, they will validate measures of individual mechanism components against indices of pathway activity and effects on various targets in differing tissues, and explore development of combined measures for a given mechanism that could have greater validity than any individual measure. The markers generated through this initiative will provide a valuable resource for a wide range of human observational aging and intervention studies, by enhancing the ability to identify potential targets for interventions and assess the effects of engaging these targets.

The initiative would enhance the contributions of new translational aging research strategies. Biologic understanding of these mechanisms and their significance in aging continues to increase markedly, providing a strong and growing knowledge base for human studies. Human longitudinal studies are increasingly combining observational data on multiple measures to generate composite indices to predict health span and other aging outcomes. Such indices could be used to assess potential effects of new interventions on such outcomes. Their predictive ability could be substantially increased by the addition of mechanistic markers to the mainly clinical or physiologic markers that have been available to date. In addition, initiatives are underway for human intervention studies to test effects on aging outcomes of new drugs or older drugs originally developed for specific diseases. The availability of reliable valid markers of the activity of mechanisms that these interventions may influence will enhance understanding of these mechanisms' effects and of the interventions' effects, and help to guide development of new interventions.

Scientific/Research Contacts

Evan Hadley, M.D.
Division of Geriatrics and Clinical Gerontology
National Institute on Aging
Telephone: 301-435-3044
Email: hadleye@mail.nih.gov

Felipe Sierra, Ph.D.
Division of Aging Biology
National Institute on Aging
Telephone: 301-496-6402
Email: sierraf@mail.nih.gov

January 2017 Council

Characteristics, Causes, Contexts, and Consequences of Elder Mistreatment

Mistreatment of the elderly is a widespread and complex problem. It affects not only the victim of abuse, but also the families of both victims and perpetrators, and society as a whole. An analysis of the National Social Life, Health and Aging Project, a nationally-representative survey, revealed that approximately 13 percent of adults aged 57 to 85 experienced verbal, financial, or physical mistreatment over a one-year period. Even more troubling is that due to measurement issues and underreporting, this high percentage of self-reported cases likely represents only a subset of all victims. Facing the same obstacles as the child abuse and intimate partner violence (IPV) fields, barriers to disclosure, detection, and classification hinder advances in identifying indicators, risk factors, and intervention design. Rapidly deployable approaches are needed to improve screening, and bioinformatic approaches are needed to distinguish different types of mistreatment from accidental injury or illness and to identify sine qua non or pathognomonic symptoms and signs. Development of a conceptual framework with objective measures is needed to identify risk and protective factors for different types of elder mistreatment and to better assess and understand their cumulative risk or impact.

In October 2015, the NIH convened experts in child abuse, IPV, emergency medicine and elder mistreatment for the NIH workshop: "Multiple Approaches to Understanding and Preventing Elder Abuse and Mistreatment,” to identify key knowledge gaps and barriers to progress, to share insights, and to consider the potential for the field of elder mistreatment to build on advances and experiences in these research areas. Discussion led to the recommendation to pursue research with use of tested and successful approaches from the fields of child abuse and IPV. This initiative addresses two overarching recommendations from this meeting.

The proposed RFA will solicit research in two high-priority areas: (1) development of new and innovative instruments, tools, and analytic strategies and approaches for detecting and assessing outcomes of elder mistreatment, and (2) identification of early risk factors and protective factors that represent putative intervention targets. Applicants will be encouraged to pursue research that builds on principles and adapts successful approaches from the fields of child abuse and IPV. As the aging population is rapidly growing, so is the number of individuals at risk for mistreatment. If this initiative is successful, it will help develop the evidence base needed to support the design of individual-, family-, and community-level interventions for prevention and to promote recovery and resilience in victims and their families and those who inflicted harm and to prevent revictimization.

Scientific/Research Contact

Melissa Gerald, Ph.D.
Division of Behavioral and Social Research
National Institute on Aging (NIA)
Telephone: 301-402-4156
Email: melissa.gerald@nih.gov

Competitive Renewal of the AMP-AD Target Discovery and Preclinical Validation Project

The Accelerating Medicines Partnership (AMP) is a bold new venture among the National Institutes of Health (NIH), 10 biopharmaceutical companies, and several nonprofit organizations to transform the current model for developing new diagnostics and treatments by jointly identifying and validating promising biological targets of disease. This precompetitive collaboration harnesses collective capabilities, scale, and resources across multiple sectors to improve therapeutic development efforts for complex, heterogeneous diseases. AMP's goal is to understand such diseases more fully through research to identify and validate novel, clinically relevant therapeutic targets. As a result, it is expected to accelerate the process of bringing new medicines to patients. AMP is an umbrella partnership with initial programs in three disease areas:

This multi-sector partnership is managed by the Foundation for the NIH (FNIH). NIH and industry partners are sharing expertise and resources—more than $230 million of combined funding support and in-kind contributions over 5 years—in an integrated governance structure that enables the best-informed scientific contributions from all participants. A critical component of the partnership is making AMP data publicly accessible for use by the broad research community.

The Target Discovery and Preclinical Validation Project is a component of the Accelerating Medicines Partnership for AD (AMP-AD). Its central goal is to shorten the time between the discovery of potential drug targets and the development of new drugs for Alzheimer’s disease treatment and prevention, by integrating the analyses of large-scale molecular data from human brain samples with network modeling approaches and experimental validation. The project is a consortium of six multi-institutional, multidisciplinary cooperative agreements and research grants. The grant awardees are applying cutting-edge systems and network biology approaches to integrate multidimensional human “omics” data (genomic, proteomic, metabolomic) from more than 2,000 human brain and blood samples from individuals at all stages of the disease with clinical and pathological data to:

i) discover novel therapeutic targets for Alzheimer’s disease;
ii) gain a systems-level understanding of the gene, protein, and metabolic networks within which these novel targets operate; and
iii) evaluate their drugability in multiple model organisms

In the first iteration of the AMP-AD Target Discovery and Preclinical Validation Project, the Consortium achieved several key milestones starting from the development of a centralized repository for housing high-dimensional human and animal model ‘omics’ data and analytical results (the AMP-AD Knowledge Portal) and making the data and analytical results broadly available, to developing the first set of network models for AD largely based on RNAseq data, nominating the first set of novel therapeutic targets and initiating their preclinical validation in an array of cell-based and animal models. In addition, the participating teams produced a series of publications ranging from data descriptor manuscripts to manuscripts describing new methodology and new disease insights.

As the Project embarks on its fourth year, several limitations and opportunities are becoming apparent. On the limitations end we are realizing that the data generated by the research teams are so rich and complex that only a fraction of it can be utilized in the predictive modeling during the course of the five-year awards and with the available funding resources. In addition, given that one of the pioneering efforts in the Consortium is to develop a data-driven approach for prioritization of novel targets, there is limited bandwidth for the number of targets that can be followed up and insufficient time for full preclinical validation. Lastly, the AMP-AD data and analytical results cannot be easily mined and used by biologists and clinicians because the development of web-based data visualization tools and interfaces to enable biologists to query and interact with the data are not supported by the current resources (with the exception of small supplemental funding to pilot the development of a prototype for one web-based tool).

Several opportunities have presented themselves as well. The initial, as well as supplemental, funding has enabled the generation of very rich and varied human omic datasets (including WGS on ~2000 AMP-AD brain samples) that lend themselves to a multitude of modeling approaches for target and biomarker discovery. A variety of cell-based and animal models are being characterized relative to network models generated from human data for their use in preclinical validation; a large number (~80) of novel candidate targets have been discovered, many of which promise to be tractable for drug discovery and drug development; a series of interlinked pilot projects focused on biomarker discovery has been launched in year 4 of the awards. Lastly and most importantly, the Consortium is a successful proof of concept that an open-science, large-scale team approach to basic and translational research is a viable and more productive alternative to the current research model.

Scientific/Research Contact

Suzana Petanceska
Division of Neuroscience
National Institute on Aging (NIA)
Telephone: (301) 496-9350
Email: sp440u@nih.gov

Coordinating Center for the Claude D. Pepper Older Americans Independence Centers (OAICs)

The Claude D. Pepper Older Americans Independence Center (OAIC) program supports centers of research excellence and research training leading to improved or maintained functional independence in older age. The OAIC Coordinating Center facilitates interactions among OAICs and serves as a conduit for translating OAIC objectives and findings. Functions of the OAIC include:

  • Sponsoring an annual OAIC Investigators Meeting
  • Developing and maintaining a website for scientific exchange among OAIC investigators, the aging research community, and the public
  • Sharing research resources such as databases of measurement tools and recruitment techniques with other NIA and NIH programs and the broader scientific community
  • Providing logistical and educational support for OAIC investigators including trainees
  • Fostering communication, cooperative arrangements, and collaborative projects among multiple OAIC sites and between OAICs and other NIH- or non-NIH-supported research programs

The OAIC Coordinating Center was established in 2005 through an administrative supplement mechanism to an existing OAIC site. In 2007, the Coordinating Center was competed through an RFA using the P30 mechanism. The RFA specified that the Coordinating Center could be funded as either a core within an existing OAIC or as a stand-alone center. The subsequent, and most recent, re-competition of the Coordinating Center took place by RFA in 2012 using similar provisions.

The NIH Office of Extramural Programs is now requiring that coordinating centers for P30 and other centers programs must be funded through a specific award using a mechanism appropriate to a coordinating center’s functions. Moreover, the current OAIC Coordinating Center award will end in 2018, so an initiative is needed in the current planning cycle for its continuation. In addition, since the Coordinating Center’s inception, the OAICs have evolved into a more active and inter-connected research network. Development of the Coordinating Center’s activities is vital to keep pace with the needs of such a network.

Scientific/Research Contact

Basil Eldadah, M.D., Ph.D.
Division of Geriatrics and Clinical Gerontology
National Institute on Aging (NIA)
Telephone: (301) 496-6761
Email: eldadahb@mail.nih.gov

Development and Commercial Availability of Cell-Based Tests for Age-Related Changes in Resiliencies to Physical Stressors

Declines in resilience, defined as a dynamic property which enables an organism or individual to resist or recover from the effects of a physiologic or pathologic stressor (i.e., physical in nature) can contribute to a variety of adverse health and functional outcomes as we age. Examples of specific resiliencies include maintenance of cardiovascular function after major surgery, successful fracture union and recovery of hematopoietic function after cancer chemotherapy. Unfortunately, our current understanding of age-related changes in resiliencies to physical stressors is quite limited and interventions to promote or enhance resiliencies are not available. This important research gap prompted the NIA to issue three FY2017 initiatives on the resilience concept. These initiatives are focused on different aspects of the resilience concept:

  1. RFA-AG-17-014 focuses on characterization of resiliencies in humans and underlying mechanisms;
  2. RFA-AG-17-040 focuses on mechanisms underlying global resilience in mice; and
  3. RFA-AG-17-061 focuses on the molecular characterization of individuals who remain free of dementia despite being at high risk for Alzheimer’s disease.

Regardless of one’s perspective on the concept of resilience, we currently lack standardized research tools to probe resiliencies at the cellular level. Critical features of such in vitro tests involve an element of “challenge” or perturbation, assessment of response in a short time scale/real-time, and over a robust range (graded tests). The development and commercial availability of standardized tests of specific resiliencies (e.g., patient-specific tests, in vitro stimulation tests using primary cell cultures or co-culture systems), especially focusing on cellular processes or pathways associated with aging such as DNA damage and repair, cell senescence or inflammation, could lead to a more in-depth understanding of different degrees of resiliency (phenotypic features) and underlying mechanisms. The commercial availability of such assays could:

  • Reveal aging mechanisms underlying decrements, as well as factors contributing to the maintenance of resilient phenotypes.
  • Complement and inform studies in pre-clinical models and vice versa (e.g., help to identify potential common mechanisms underlying resiliencies).
  • Accelerate research progress on the characterization of cellular mechanisms underlying physiologic responses and the identification of novel therapeutic targets and interventions to enhance resiliencies as we age.
  • Be used as clinical diagnostics (i.e., patient-specific assays) and improve clinical management of patients.

Importantly the availability of such standardized research tools would also facilitate the comparison of findings across different studies of resilience. The proposed set of FY2018 FOAs on the development and commercialization of cell-based assays of resiliencies are timed to work in tandem and in conjunction with the projects supported by the FY2017 initiatives so that important research tools will be available to enhance their research progress.

Scientific/Research Contact

Chhanda Dutta, Ph.D.
Chief, Clinical Gerontology Branch
Division of Geriatrics and Clinical Gerontology
National Institute on Aging (NIA)
Telephone: (301) 435-3048
Email:DuttaC@nia.nih.gov

Effects of Aging on Hematopoiesis

Hematopoiesis is often considered as a lifelong process in which myeloid and lymphoid cells are continually generated throughout life. However, it is now evident that there is a decline in T and B cell development with age, whereas myelopoiesis remains relatively stable. This is thought to contribute to the impairment of immune function observed in the elderly which is associated with an increased susceptibility to various infectious diseases and a reduced efficacy of vaccination regimens. It is thought that age-related changes in the microenvironment of the bone marrow such as an accumulation of adipocytes and plasma cells may contribute to the decreased capacity of the hematopoietic microenvironment to support lymphopoiesis. The identification of various factors regulating the differentiation of hematopoietic stem cells with aging have significant implications for our understanding of age-associated immune dysfunction and may lead to the development of new therapeutic approaches to rejuvenate the aged immune system. There is a need for a greater understanding of the basic biology that regulates hematopoiesis in older individuals. The gaps in our knowledge and technology of the pathogenesis of non-malignant hematologic disease in older adults was addressed at a workshop held in 2016 as part of a continuing program on hematology research at NIDDK: the SHINE program (Stimulating Hematology Investigators New Endeavors: PAS-16-033).

Scientific/Research Contact

Nalini Raghavachari, Ph.D.
Division of Geriatrics and Clinical Gerontology
National Institute on Aging (NIA)
Telephone: (301) 435-3048
Email: nraghavachari@mail.nih.gov

HIV and Aging

The number of older individuals living with HIV is rising. In 2005, 29 percent of Americans infected with HIV were age 50 years or older. By 2012, this proportion had risen to 42 percent. By 2020, it is projected that over half of HIV-infected Americans will be 50 years or older. These trends are mirrored globally. The rise in HIV infection among older individuals is due primarily to the successes of modern antiretroviral therapy, which has allowed individuals infected at a younger age to survive well into older age. A smaller but growing fraction of the rising prevalence of HIV in older adults is attributed to new infections in later life.

In contrast to the pre-modern era of HIV treatment, where AIDS-related opportunistic infections and cancers were common, the most frequent morbidities and causes of death currently in treated HIV infection are similar to those seen in older non-infected adults. These so-called HIV-Associated Non-AIDS (HANA) conditions include cardiovascular disease, lung disease, infection-related and non-infection-related cancers, HIV-associated neurocognitive disorders (HAND), neuropsychiatric disorders, osteopenia/osteoporosis, liver cirrhosis, and renal disease. In addition, individuals living with HIV infection may exhibit many of the clinical and socio-behavioral characteristics commonly observed in aging, such as multiple comorbidities, polypharmacy, declining physical and cognitive function, alterations in body composition, social isolation, and increasing caregiver burden. People living with HIV also exhibit molecular changes associated with aging such as epigenetic alterations, mitochondrial impairment, and telomere shortening. Thus, accumulating evidence suggests that HIV and/or its treatment may lead, at least in part, to an accelerated aging phenotype.

In 2015, the NIH Office of AIDS Research (OAR) released NOT-OD-15-137 outlining scientific priorities that would be the basis for HIV-related research funding. These priorities are:

  1. research to reduce the incidence of HIV/AIDS, including the development of safe and effective HIV/AIDS vaccines;
  2. development of the next generation of HIV therapies with improved safety and ease of use;
  3. research towards a cure for HIV/AIDS; and
  4. HIV-associated comorbidities and co-infections.”

The Notice also identified support for “[b]asic research, health disparities, and training that cross-cut these priorities.” These priorities suggest numerous opportunities for studying HIV and aging-related research questions.

This initiative will focus on the intersection of HIV and aging by addressing two overarching objectives:

  1. to improve understanding biological, clinical, and socio-behavioral aspects of aging through the lens of HIV infection and its treatment; and conversely,
  2. to improve approaches for testing, prevention, and treatment of HIV/AIDS, and management of HIV-related related comorbidities, co-infections, and complications in different populations and cultural settings by applying our current understanding of aging science.

Scientific/Research Contact

Basil Eldadah, M.D., Ph.D.
Division of Geriatrics and Clinical Gerontology
National Institute on Aging (NIA)
Telephone: (301) 496-6761
Email: eldadahb@mail.nih.gov

Novel Mechanisms of Non-autonomous Signaling in Aging and Longevity

The key question to be answered under this RFA is “How is cell-autonomous aging communicated to other cells?” In the past few decades, most of the studies on the molecular mechanisms of aging have focused on the events within cells (cell-autonomous aging). These studies have led to a quite comprehensive understanding of the cell-autonomous mechanisms of aging, including changes in many genes, pathways, biomolecules, and organelles involved in the aging process. A dominant hypothesis, supported by observations obtained in the past several decades, has been that the underlying cause of aging is the cell-autonomous, time-dependent accumulation of stochastic damage to biomolecules, organelles, and cells. However, it has become apparent in recent years that cell-autonomous mechanisms alone are inadequate to explain aging at a tissue or organismal level. In multicellular organisms, it would be hard to imagine that cell-autonomous changes would limit their impact only within the border of a cell without causing cell non-autonomous consequences that affect aging at a tissue or organismal level. In fact, some compelling evidence in recent years, such as parabiosis, serum transfer, cell ablation, and molecular mechanistic studies, suggests that cell non-autonomous mechanisms also play important roles in driving degenerative changes of aging that arise as the consequence of cell-autonomous aging. Although the damages and changes initially occur in specific cells and tissues, it seems that these initial changes need to be communicated to other cells, tissues, or organs and thereby impact lifespan and healthspan of the organism. For most of the non-autonomous players, we don’t know what they are, how they are released from cells, how they are transported and communicated to other cells, and how they elicit aging-processes upon reaching their target cells. This proposed RFA aims to stimulate research on a better understanding of the cell non-autonomous signaling in aging.

Scientific/Research Contacts

Max Guo, Ph.D.
Division of Aging Biology
National Institute on Aging (NIA)
Telephone: (301) 402-7747
Email: max.guo@nih.gov

Jose Velazquez, Ph.D.
Division of Aging Biology
National Institute on Aging (NIA)
Telephone: (301) 496-6402
Email: jvelazqu@mail.nih.gov

Socioeconomic Disparities in Health at Older Ages

It has long been established that better-educated and higher-income people live longer, on average, than less educated and lower income people. But in recent decades, there have emerged new, surprising and largely unexplained trends: the gaps in life expectancy at older ages by income, education, and geographic region have been widening in the United States. In June 2016, BSR sponsored an expert meeting of the National Academy of Sciences Committee on Population entitled “Health Disparities Across the Life Cycle.” Workshop participants discussed the recent research findings pointing to widening health disparities in the US and what the implications might be for NIA’s research agenda. (See workshop summary) Given the momentum generated by this workshop, and by the recent availability of datasets with life history information and with linkages to geographic contextual data, the time is ripe for an NIA initiative that will contribute to the literature on this topic, moving beyond description to the identification of mechanisms and modifiable risk factors.

Scientific/Research Contact

Georgeanne Patmios, MPH
Division of Behavioral and Social Research
National Institute on Aging (NIA)
Telephone: (301) 496-3138
Email: gp29p@nih.gov