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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.

September 2019 Council

Approved concepts in this round:

Aging Research Dissertation Awards to Increase Diversity

We are seeking to renew the Aging Research Dissertation Awards to Increase Diversity program. Research shows that diverse teams working together and capitalizing on innovative ideas and distinct perspectives outperform homogenous teams. Scientists and trainees from diverse backgrounds and life experiences bring different perspectives, creativity, and individual enterprise to address complex scientific problems.

This concept supports Ph.D. students whose advancement in research will help ensure that a diverse pool of highly trained scientists is available in the scientific disciplines supporting the NIA mission. That mission includes research on: the basic biology of aging; chronic, disabling, and degenerative diseases of aging, with a particular focus on Alzheimer’s disease; multiple morbidities; individual behavioral and social changes with aging; caregiving; longevity; and the consequences for society of an aging population.

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.

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The Alzheimer’s Disease Sequencing Project (ADSP) Functional Genomics Program (FGP)

The Alzheimer’s Disease Sequencing Project (ADSP) has identified more than 50 unique genetic variants including single-nucleotide variations, rare copy-number, and structural variations. Most of these genetic variations reside in the inter- and intra- genic regions that may affect gene expression rather than protein sequence. These non-protein-coding regions are increasingly believed to play critical roles in AD, but the exact functional consequences of the observed alterations in disease pathogenesis are not understood.

Functional studies aiming at delineating the causal genetic variants and biological mechanisms that underlie the observed statistical associations with disease risk have lagged far behind the discovery of association signals in the genetics of complex neurological diseases in general. The functions of most of the genetic associations identified by the ADSP between 2016 and 2019 are unknown, thereby hindering the discovery of genetics-based targets for therapeutics and diagnostics. Determining the functions of ADSP-identified coding and non-coding genomic elements, transcription factors, and non-coding RNAs will increase the understanding of AD/ADRD endophenotypes and facilitate the transition of genetics from gene discovery to a deeper mechanistic understanding of the genetic etiology of AD/ADRD. The goal of this initiative is to generate comprehensive maps of genome and epigenome annotations with AD/ADRD-associated functional genomic elements.

Driven by ADSP gene discovery, studies funded under the FGP would take a multidisciplinary approach involving integrated teams of scientists with expertise in genetics, bioinformatics, molecular biology, biochemistry, cell physiology, and high throughput experimental methodologies. Investigators funded under the ADSP FGP will apply integrative strategies to systematically determine the biochemical and physiological functions of genes and variants, and the regulatory roles of non-coding DNAs, non-coding RNAs, and transcription factors through genome-wide examination of human brain regions and cell types and use a variety of experimental approaches.

Projects in the ADSP FGP would apply unbiased genome-wide approaches, computational methods, and high throughput screening assays to identify, depict, define relevant functional regions of the genome, regulatory DNA elements, and ncRNAs. Investigators would conduct in-depth validation studies on selected functional elements identified by the ADSP or others in the AD genetics field using in vitro, ex vivo, or in vivo models.

Obtaining a more comprehensive understanding of uncharacterized coding and non-coding genomic elements and ncRNAs in AD/ADRD will establish a fundamental research resource to be made quickly available to the community enabling genetically driven investigation of disease heterogeneity and mechanisms leading to improved understanding of the genetic architecture of AD. It will also serve as a bridge to facilitate the transition of genetic discoveries for the development of potential new targets for medical diagnostics and therapeutics. As with all facets of the ADSP, data sharing will be rapid and broad.

Scientific/Research Contacts:

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

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

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Artificial Intelligence and Technology Centers for Aging Research

The number of Americans aged 65 or older will grow to 95 million by 2060 and comprise nearly a quarter of the population; most will have multiple chronic conditions and many will experience cognitive impairment and/or dementia. The combination of the projected growth of this population and the desire of many older Americans to live independently in their homes and communities makes it critical that the federal government proactively develop strategies, tools, and recommendations to enable them to live healthy, independent lives. Furthermore, recognizing these trends and business opportunities, many companies, large and small, have invested heavily in relevant technology making it more imperative that there is a way to assess the safety, efficacy and utility of these novel tools to support older adults’ independence.

Recognizing the needs of this looming population and the potential role for federal research and development, the President’s Council of Advisors on Science and Technology developed a thoughtful and comprehensive report (PDF, 992K) on “Independence, Technology, and Connection in Older Age.” One of the report’s main recommendations called for NIH and other agencies to “support interdisciplinary and translational research including robotics, advanced mobility technologies, communications technology with special emphasis on emergency situations, cognitive training, and home monitoring.” The report also called for a Task Force, which was subsequently convened by the White House Office of Science and Technology Policy.

The report highlights six areas for technology development which will require coordination across a wide range of disciplines and sectors of the economy: support with key activities of daily living, cognitive skills, communication and social connectivity, personal mobility, access to transportation, and access to healthcare. Research and development of tech solutions in these areas for use in homes and communities will require coordination across a wide range of disciplines.

The evaluation of NIA’s investments in technology to assist older adults indicates a need for an overarching, organizational infrastructure to support and scale up existing research efforts, as well as enable collaboration among various stakeholders from industry, academia, and advocacy organizations to achieve Task Force objectives and recommendations from workshops and publications (see below) aimed at improving the lives of vulnerable elders.

In order to address multiple recommendations, we are proposing a cross-Division Center program. Each Center will consist of in-house scientific and technological expertise and the clinical partnerships necessary to facilitate the identification and integration of enabling technologies into devices that address aging research priorities.

Each center will facilitate the development of a pipeline of technologies for older Americans with scalability potential on a theme the investigators will choose. The Center structure will be designed to include incorporation of clinical input and user needs in the development process. Further, the provision of resources to researchers and end users will address early barriers to scaling and integration of technology specifically for older Americans. Additionally, the Coordinating Center will serve as a communications hub for the Technology Center grant program and will coordinate and provide overarching support to all the centers in the following areas: (1) ethics; and (2) legal. Our review across NIA divisions suggested that no such infrastructure exists.

Below we highlight potential areas a center can focus on (based on recommendations from summits, workshops and publications), all of which are geared toward older adults in the community and ambulatory care settings:

  • Development and integration of sensors to collect high quality data for clinical trials and cohort studies
  • Development and validation of clinical decision support tools that help physicians caring for patients with multiple chronic conditions; or tools for patient self-management of multiple chronic conditions.
  • Validation and assessment of various methods for assessing and monitoring financial activity, including evaluating scam awareness and appropriate user interfaces to assisting older American’s making decisions as they face cognitive decline.
  • Development of innovative monitoring technologies, including applications of machine learning and integration of cognitive instruments into EHR for early detection of cognitive decline and monitoring universal outcomes for diverse aging populations at point-of-care.
  • Development of socially assistive robots to provide cognitive therapy, provide in place monitoring, assistance and care coordination for individuals with dementia.
  • Designing and modifying technology accounting for human factors problems associated with aging.
  • Development of technological applications and big data methods to assist care providers or individuals, with a focus on approaches to assess and mitigate health disparities
  • Development and modification of technology platforms to enable delivery of appropriate care for individuals with cognitive impairment and dementia, including management of common comorbid conditions.
  • Develop technological platforms that identify early biomarkers for functional and cognitive changes, assess the impact of intervening health events on quality of life, well-being, and health status.

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.

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Central and Peripheral Control of Balance in Older Adults

Balance is multifactorial and relies on the complex integration of visual, proprioceptive and vestibular information with musculoskeletal function. Thus, age-related functional declines in any of these systems can markedly disrupt one’s sense of balance. In addition, the manner in which the central nervous system organizes these sensory inputs for balance control may also show age-related modifications. Data from the National Health and Nutrition Examination Survey 2000-2004 indicate that the prevalence of balance disorders increases with age with about 69% among those aged 70-79 years and 85% among those aged 80+ years.

Older adults with balance impairments are also at an increased risk of having a fall and this risk further increases among those who report symptoms of dizziness. Other demographic factors such as sex and race have not been well studied but there is some evidence that dizziness and balance disorders are slightly more common in women than men. Women are also more likely than men to suffer a nonfatal fall injury. While there has been considerable work done on the contribution of vision to balance in older adults, there is a paucity of studies on the aging vestibular system.

The vestibular system consists of the peripheral vestibular organs in the inner ear and the associated central nervous system projections – from the cerebellum and brainstem to the thalamic relays to cortical projections. Vestibular dysfunction arising from peripheral or central components of the vestibular system may manifest as illusory self-motion (dizziness/vertigo) and spatial disorientation which are commonly associated with balance impairment and falls in older adults.

Unfortunately, the complexity of the balance system makes diagnosing and treating the underlying cause of imbalance very challenging. As a result, patients presenting with symptoms of dizziness and vertigo are frequently misdiagnosed. There is a huge need for standardized clinical tools and measures for the diagnosis and assessment of vestibular function in older adults. Moreover, having the ability to use technologies such as ‘wearables’ to monitor balance and possibly predict fall risk would be a significant advancement to the field. This would likely inform the design of interventions for balance disorders.

There is also limited knowledge of how the vestibular system interacts with other sensory systems, the motor system and the brain, both in the context of aging and neurodegenerative disease. Patients with Alzheimer’s disease (AD) have an increased risk of imbalance, falls and spatial disorientation and interestingly, in a recent study, the prevalence of vestibular loss was significantly higher in the spatially impaired AD group relative to the spatially normal AD group. Thus, the role of vestibular function in neurodegenerative disease is yet another area that warrants further exploration.

Scientific/Research Contacts:

Coryse St. Hillaire-Clarke, Ph.D.
Division of Neuroscience
National Institute on Aging
Telephone: 301- 496-9350
E-mail Coryse St. Hillaire-Clarke, Ph.D.

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

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Emotional Well-Being: High Priority Research Networks

Emotional well-being has been defined as an overall positive state of one’s emotions, life satisfaction, sense of meaning and purpose, and ability to pursue self-defined goals. Elements of emotional well-being include a sense of balance in emotion, thoughts, social relationships, and pursuits, or lack thereof. The relative importance of each construct will vary across subpopulations and developmental stages. Currently, fundamental consensus concerning the definition and components of emotional well-being as well as what interventions promote emotional well-being, either as a mediator of health outcomes or as an end in itself, is lacking.

At a 2018 NCCIH/OBSSR Roundtable (co-sponsored by NIA), participants presented and discussed 10 models of success that produced better health outcomes through promotion of some aspect of emotional well-being. They included cases in which a component of emotional well-being was identified as the intervention target, i.e., where a change in emotional well-being was examined as a mediator of change in health. They also included interventions in which improvement of some aspect of emotional well-being itself was the desired outcome. In addition to concepts of satisfaction, purpose, and positive emotions, social or interpersonal processes emerged as key factors in many of these interventions and are considered integral to the broad conceptualization of emotional well-being discussed at the meeting.

The roundtable highlighted research gaps and opportunities including a need to: (1) increase the understanding of the fundamental constituents of emotional well-being (and related constructs including subjective and psychological well-being) across the life-span and among various subgroups; (2) examine the malleability of these constituents as potential intervention targets or outcomes; (3) refine and implement scientifically based intervention strategies to enhance aspects of emotional well-being; and (4) develop measurement methodologies to optimize and scale-up well-being interventions to promote positive health across the full life-span and treat or prevent conditions such as burnout, stress, pain and mental health symptoms in at-risk populations of all ages (e.g., young children, adolescents, new parents, dementia caregivers, military personnel, minority groups, individuals with substance abuse).

To advance work in this area, participants recommended further collaborations between basic and applied researchers examining the role of emotional well-being in resilience and health. These activities should focus on further refining and testing key concepts of emotional well-being, including activities that will: (1) identify the core components of emotional well-being at multiple levels of analysis (biological, neurobiological, psychological, behavioral, and social); (2) identify biomarkers and develop predictive models for interventions to promote individual-based emotional well-being; (3) conduct early stage pilot work to support a prevention intervention agenda aimed at enhancing various aspects of emotional well-being; (4) identify and validate objective measures (behavioral and physiological) using technological advancement (e.g., wearables) and their relationship to subjective self-report measures; and (4) develop and validate patient reported outcome measures, measures of social interactions (i.e., social connectedness, bonding), measures focused on the impact of culture and environment, for the purposes of assessing these aspects of emotional well-being.

NCCIH is leading a coalition of partners including OBSSR, NICHD, NIDA and NIMH, to develop and support the research infrastructure required to support advances in this field. NIA’s proposal to participate in this coalition is an extension of our longstanding support for research on the measurement of subjective well-being and our interest in incorporating measures of well-being in both observational and interventional studies of aging.

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.

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Glial Plasticity in the Aging Brain

Glia outnumber neurons in the brain by a ratio of nearly four to one. Over time, the perception of glia as passive support cells has evolved to recognize their critical role in normal brain function. Even so, most studies selectively identifying and targeting brain cell subtypes have focused only on neurons. In recognition of this research gap, the BRAIN Initiative recently issued a FOA soliciting applications aiming to create tools to target, identify and characterize non-neuronal cells in the brain (RFA-DA-18-018) that complements several ongoing initiatives focusing almost exclusively on neuronal cells.

However, the existing FOA does not mention the aging brain; moreover, applications proposing to investigate the biological or physiological function of glial cells in the brain are considered non-responsive areas of research to the existing FOA. Therefore, there is an opportunity to develop an initiative soliciting applications directly investigating the physiology of glial cell subtypes in the aging brain.

The proposed initiative would build on recent studies showing that there are distinct subpopulations of glia—within the same glial cell-type—that are more prevalent in the aged brain. While research to discover more of these subpopulations is ongoing, the proposed initiative would leverage what is already known to better understand the function of glial subtypes enriched in aging, and how these subtypes could contribute to mechanisms of vulnerability and resilience to disease.

Scientific/Research Contact:

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

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Harmonization of Alzheimer’s Disease and Related Dementias (ADRD) Genetic, Epidemiologic, and Clinical Data to Enhance Therapeutic Target Discovery

A significant challenge to cross-study data analysis is the lack of consistency in measurement of phenotypic characteristics among studies, especially for important outcome measures. Consistent measurement is essential for genetic/genomic studies, where very large sample sizes are required to identify rare or very rare risk and protective variants. The Alzheimer’s Disease Sequencing Project (ADSP) has already harmonized genetic/genomic data and will continue to do so as the project progresses. Harmonization of phenotypic data across epidemiology cohorts, the Alzheimer’s Disease Centers (ADCs), and convenience cohort phenotypic data has not been done in a substantive manner; and there has been little harmonization of outcome measures of highest relevance to the epidemiology of AD/ADRD. There are 57 funded cohorts with genetic data, and there is a massive amount of genetic and phenotypic data available in these cohorts.

To ensure the value of the analysis of the genetic/genomic data, harmonization of the phenotypic data must be done. Substantial NIA funds have already been invested in these cohorts; it will be advantageous to the research community to have harmonized outcome data. In addition to the ADSP genetic and phenotypic data, recently NIA and NHLBI achieved an agreement on joint calling of ADSP and TOPMed whole genome sequence data. Genetic data from the two large consortia will be jointly called during 2019 and will be ready for analysis in 2020. It is important that the phenotypic data from these two large studies also be harmonized.

There is a second major effort in the genetics portfolio that further justifies the implementation of a major data harmonization effort. In January 2019 NIA Council approved of an initiative to apply cognitive systems (artificial intelligence, machine learning, deep learning) approaches to the analysis of the (ADSP) genetic and related data. The caveats to assuring successful cognitive sciences approaches in the case of Alzheimer’s Disease and Related Dementias (AD/ADRD) genetics are that access to the data should be centralized, and the data should be harmonized. The computational infrastructure that supports processing on multiple features is available at the NIA Genetics of Alzheimer’s Disease Data Storage Site (NIAGADS).

Harmonization of the phenotypic data is essential for successful application of “cognitive systems” approaches and this proposal is in keeping with January 2019 Council recommendations. Thus, the present effort is essential to leverage the investments made in the cognitive systems FOA. The need for this effort is urgent based on the number of subjects with whole genome sequence data that will be available in two years (at least 30,000 whole genomes) and because successful analysis of the genetic data by “cognitive systems” approaches depends upon data availability.

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.

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Mechanisms of Rejuvenation and Accelerated Aging in Heterochronic Blood Exchange

There is a need to deepen our understanding of the mechanisms underlying rejuvenation and accelerated aging. Rejuvenation and accelerated aging are the most important outcomes in experiments using heterochronic parabiosis or heterochronic blood exchange (heterochronic exchange experiments, HEE). HEE have been critical to make a key demonstration: old cells and tissues retain the ability to respond to “young signals.” This is an essential foundation permitting the search for mechanisms of rejuvenation. Conversely, HEE demonstrate that young tissues are susceptible to “old signals” and this can narrow the search for causes of accelerated aging.

The “transferred phenotypes” between young and old animals yield, for example, improved repair after injury in an old animal after transfer of young blood (rejuvenation), or increased inflammation and decreased cognitive function in a young animal after receiving old blood (accelerated aging). The changes, observed in multiple tissues and organs, require weeks to months, rather than years (given the availability of young and aged mice for these experiments).

NIA anticipates research on mechanisms for rejuvenation or acceleration of aging in these HEE. We expect better understanding of the cells and the cell-cell communications required for rejuvenation or accelerated aging. Furthermore, from multiple “transferred phenotypes of aging” we expect to learn the cell-specific and shared molecular and cellular signatures for rejuvenation and accelerated aging. Technological advances in single-cell RNA sequencing, epigenetic analysis, and improved methods for analyzing extracellular biomolecules can provide “molecular signatures” that would report those changes that are necessary and causal for the transferred phenotype(s) and those that are reporters and may later serve as biomarkers for rejuvenation or accelerated aging in other experimental situations.

Heterochronic exchange experiments are unique. Using heterochronic experiments, the systems studied to date fall mostly within two categories: loss of function and injury/repair. Progress in the former has been notable in the central nervous system (inflammation and cognition and provides the primary examples of accelerated aging) and liver function. The latter category typically includes skeletal muscle injuries that activate muscle stem cells, or bone fracture. Although transfer of aging phenotypes is often bidirectional, recent efforts in brain, liver, muscle and bone is on rejuvenation. There is no need to change those paradigms to accomplish the goals of this FOA.

Despite the fact that these techniques were re-introduced two decades ago to the modern tool-set for research in the biology of aging, technologies to unravel the complexity of aging phenotypes have more recently become available and sufficiently widespread that their application to transferred aging phenotypes suggest strongly that goals of this RFA can be achieved within a typical five-year funding period. These technologies should facilitate the identification of candidate “geronic factors” that are required for the transfer of aging phenotypes and the molecular signatures of aging and rejuvenation, as mentioned above.

Scientific/Research Contacts:

Ronald A. Kohanski, Ph.D.
Division of Aging Biology
Telephone: 301-496-6402
Email Ronald A Kohanski, Ph.D.

Brad Wise, Ph.D.
Division of Neuroscience (DN)
Telephone: 301-496-9350
Email Brad Wise, Ph.D.

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National Longitudinal Study of Adolescent to Adult Health (Add Health) Wave 6

A core task of aging research is to anticipate what an aging society will look like in the future and to identify factors that promote health and well-being. A key activity needed to accomplish this goal is to understand the experiences of more recent birth cohorts that are just now approaching mid-life. The National Longitudinal Study of Adolescent to Adult Health (Add Health), a cohort study of respondents born primarily between 1976 and 1982, addresses this need.

Add Health is a nationally representative, longitudinal study of adolescents (ages 12 to 19) in grades 7-12 during the 1994-1995 academic year. To date, four subsequent waves of data have been collected at ages 13-20 (1996; Wave 2), 18-26 (2001-2002; Wave 3), ages 24-32 (2008; Wave 4), and ages 32 to 40 (2016-2018; Wave 5). Approximately 12,000 individuals participated in Wave 5.

A hallmark of Add Health from its inception has been a focus on the measurement of social contexts (family, peer, neighborhood, school) that individuals inhabit and the impacts of these contexts on health and health behaviors. This interest is facilitated by the original sampling design, which sampled individuals across and within schools (to examine school and classmate effects) and contained siblings (full, half, step-, and both MZ and DZ twins), as well as classmates that lived in the same and different neighborhoods, permitting an examination of the relative importance of various contexts for health from adolescence onward in the life course. More recent waves of data have focused on contexts salient to the transition to adulthood into middle age including college, romantic relationships, family formation, and employment.

Additional key strengths of the data include large samples of racial and ethnic minority groups, as well as individuals differing by immigrant generation status and family structure Add Health has always included measures of health and health behaviors, with more recent waves collecting increasingly detailed and sophisticated genetic and biometric measures that capture metabolic, immune, cardiovascular, and renal function as well as inflammation.

Studies using Add Health data are already documenting important differences for these individuals approaching early middle age. Prior work with Add Health shows that these individuals have worse cardiovascular and metabolic health than older cohorts at the same ages. The Add Health cohort also had higher levels of obesity over a greater period of their young lives than same-age counterparts in earlier cohorts. These poorer health profiles will potentially have important health implications for Add Health cohort members in later life, including in cognitive health.

As already mentioned, the Add Health cohort is also more racially and ethnically diverse than earlier cohorts and has large sub-samples of racial and ethnic minorities including African Americans, as well as Hispanics and Asian Americans. This facet of the study design enables more detailed analyses (e.g. African Americans from highly educated families) than previous studies have allowed. The longitudinal nature of the study and rich measures (biomarker-based, self-reported) of health permit examination of the dynamics of health disparities across the first half of the life span as well as potential (re)mediating factors.

Another potential opportunity provided by Add Health is that this birth cohort could provide the basis for two future Health and Retirement Study refresher cohorts. The Add Health birth years (1976-1982) overlap with the introduction of those born 1972-1977 in the 2028 HRS and those born 1978-1983 in the 2034 HRS.

Scientific/Research Contacts:

Amelia Karraker, Ph.D.
Division of Behavioral and Social Research
National Institute on Aging (NIA)
Telephone: 301-496-3138
E-mail Amelia Karraker, Ph.D.

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

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New/Unconventional Animal Models of Alzheimer’s Disease

Alzheimer Disease (AD) is the most common cause of dementia, affecting more than 40 million people worldwide. Despite considerable investment and effort to develop effective interventions, the prevalence of AD is expected to rise dramatically in the coming decades due to an increase in the aging population. Several pharmacological and genetic approaches utilizing mice, fish, flies and worms have been developed that can partially reproduce AD neuropathologies and cognitive deficits. However, they primarily model early-onset, familial AD which constitutes less than 5% of the disease burden. Importantly, such models have proven to be of poor predictive validity in human clinical trials. The most used current AD animal models are transgenic mice that do not develop robust neurodegeneration and have poor reproducibility of pathological findings. In addition, massive and non-physiological overexpression of genes is required to produce this partial AD-related pathology and symptomatology.

To develop better in vivo platforms that may accelerate the discovery and development of new therapies, the NIA recently established the MODEL-AD consortium with the stated goal of establishing new mouse models that accurately represent the sporadic, late-onset form of AD in mice. This current concept clearance request aims to expand and complement this effort by supporting the development, characterization, and validation of suitable, new/unconventional animal models of AD that may represent better translational potential by better replicating pathological features of the human disease. Such novel models are expected to contribute to the development of new therapeutics for AD.

This initiative envisions two types of animal models that might have better translational potential than the currently used transgenic mouse models: non-human primates (NHP) because of their close relatedness to humans, and species that naturally develop AD-related symptoms and/or pathology. NHP have a very high translational value because of their close relationship to humans in terms of phylogeny, genetics, physiology, cognition, emotion and social behavior. In the brain, the similarities extend to neuroanatomy and neural functions, including age-related structural and biochemical changes that parallel AD-like pathological, neurochemical and functional alterations. NHP pharmacokinetics have also been revealed to be more closely predictive of human pharmacokinetic parameters than dogs, rats and mice, making NHP a superior candidate also from the drug development standpoint. Several NHP species have been recently evaluated for their suitability as AD models. Studies conducted in both rhesus macaques and marmosets have shown that intracranial injection of pathogenic human Aβ or tau protein accelerates the development of AD-like clinical features, including the development of Aβ plaques and hyper-phosphorylated tau tangles as well as cognitive impairment at earlier ages.

An additional source of animal models that better recapitulate AD might be organisms that develop aspects of cognitive decline and memory loss with age as part of their natural history. One such animal is the Degu (Octodon degu), a rodent from South America that shows age-dependent cognitive impairment and neuropathology similar to human AD. Another is the dog which naturally declines in many different cognitive domains, in some cases resembling humans with mild cognitive impairment. The neurobiological basis for cognitive dysfunction may be related to structural changes that reflect degeneration caused by molecular cascades leading to the progressive accumulation of AD plaques in the cerebral vasculature.

Scientific/Research Contact:

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.

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Oligomer Seed Bank Initiative

The accumulation of protease-resistant protein aggregates is one of the most common features of a large class of diseases known as protein conformational disorders, such as Alzheimer's disease (AD). For the past few years, our understanding of the molecular structures of the protein aggregates that are associated with these diseases has advanced considerably. In AD, it has been shown that the number of Aß fibril polymorphs (or conformers) is at least five and maybe on the order of ten or more based on several recent publications. These observations suggest that the accumulation and assembly of various protein aggregates in many age-related disorders is not totally driven by the amino acid sequences of aggregation-prone molecules; instead, they are governed by the precise cellular and pathological conditions of aggregation growing conditions.

Between 2018 and 2019, NIA has experienced an enormous growth in applications seeking to study the assembly properties of various oligomers and their potential pathological consequences in AD. However, currently there is no standard assay and reliable reagents to study these types of oligomers and aggregates. Therefore, the overall goal of this initiative is to establish a centralized resource to standardize and authenticate most commonly used reagents and assays to study misfolded protein oligomers and seeds, such as amyloid Aß, tau and synuclein in AD and its related dementias (AD/ADRD).

This FOA will take advantage of recent advancements in various biophysical and immunological technology to establish one to three centralized resources to systematically characterize various AD/ADRD related oligomers and seeds. The resources will provide standardized analyses and reagents for all known and unknown AD/ADRD related oligomers and seeds for both basic and clinical research.

Outcomes of this initiatives might include:

  1. Develop and analyze the structures of known and unknown oligomers and seeds isolated from both clinical and biological samples.
  2. Detailed characterization of oligomers in terms of their sizes, structural homogeneities, morphology, image probe binding and immuno-reactivities.
  3. Determine the optimal conditions to maintain, propagate, store and distribute these known and unknown oligomers/seeds.
  4. Distribution of imaging, chemical and immunological probes to detect and quantify these oligomers and seeds along with protocols for verification and replication.

Scientific/Research Contact:

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

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Planning Projects for Clinical Trials on Effects of Sustained Reductions in Caloric Intake and Related Dietary Practices in Younger and Older Persons

Caloric restriction (CR) is the only nutritional intervention that has been shown to extend lifespan and delay onset of a variety of age-related conditions in several (albeit not all) model organisms. In humans, CALERIE (Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy), the first trial of sustained (2 years) CR, demonstrated the feasibility, tolerability, and safety of maintaining a moderate level of CR in non-obese individuals ranging in age from 21 to 50 years. CR effects found in CALERIE include decreased risk factors for age-related cardiometabolic conditions, diminished inflammatory and endocrine factors proposed to modulate aging processes, and slowing of the increase over time of an index of biological aging.

It is important to determine whether a CR intervention longer than 2 years (e.g. 5 years) could be sustained with adequate adherence, whether effects found in CALERIE are amplified or attenuated over time, and whether the longer CR duration influences rates of physiologic aging changes and pre-morbid disease progression with age. Particularly, given evidence for potential CR benefits at ages above the CALERIE population’s, there is also a need to assess CR’s effects in older age ranges, including effects on clinical outcomes and the effects of differing chronic diseases on responses to the interventions.

Model organism studies and short-term human interventions that modify timing of food intake (i.e., intermittent fasting and time-restricted feeding) suggest that they may have favorable effects on aging-related outcomes, possibly by influencing some of the same mechanisms affected by CR. Interventions that modify macronutrient proportions (e.g., lower protein/carbohydrate ratio) or source (e.g., whole-food plant-based) have also shown positive effects on aging-related factors in laboratory animal and/or human studies.

Though these studies suggest that CR and/or one or more related dietary practices may have long-term benefits for delaying multiple age-related conditions, there is the need for trials long enough to provide insights into these dietary practices’ potential long-term benefits and risks if maintained by individuals over years, a health issue of great interest to professionals and the public. Trials allowing comparisons between CR and other dietary interventions would be valuable for understanding possible similarities and differences in their effects, underlying mechanisms, and in factors influencing adherence to the different interventions.

Experience with CALERIE and other nutritional intervention trials indicates that extensive preliminary planning is needed to design and implement trials that will adequately test the above nutritional hypotheses. Such planning requires preliminary data analyses, pilot studies, and consideration of options regarding recruitment, inclusion and exclusion criteria, behavioral intervention design and implementation, adherence measurement and maintenance, outcome selection and measurement, and data quality control.

Scientific/Research Contact:

Giovanna Zappalà, Ph.D., M.P.H.
Division of Geriatrics and Clinical Gerontology
National Institute on Aging
Telephone: 301-827-6240
E-mail Giovanna Zappalà, Ph.D., M.P.H.

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Prodromal α-Synucleinopathies Consortium

REM sleep behavior disorder (RBD) is a parasomnia that presents with abnormal dream mentation, abnormal behaviors, and increased electromyographic tone on polysomnography during REM sleep. Older individuals with RBD frequently develop neurodegenerative diseases, particularly α-synucleinopathies: Parkinson’s disease (PD), Lewy Body Dementia (LBD), and Multi-System Atrophy (MSA). Individuals with idiopathic RBD (iRBD) develop an overt synucleinopathy at astonishingly high rates: 40-50% in 5 years, 50-75% in 5-10 years, and 80-92% in long-term follow-up. RBD provides a unique opportunity to understand the clinical development and evolution of the synucleinopathies, as well as a potential opportunity to develop a trial ready cohort to test disease modifying therapies. While we are not yet able to identify whether subjects will go on to PD, LBD, or MSA, iRBD as a whole, is a prodromal synucleinopathy.

The International RBD Study Group (IRBDSG) comprises investigators engaged in iRBD research across North America, Europe, and Asia. It receives no NIH grant support . The IRBDSG recently published a paper demonstrating that it is possible to identify RBD patients with prodromal synucleinopathy symptoms (comparable to mild cognitive impairment in Alzheimer diseases) before full blown onset of PD or LBD (MSA seems to evolve from PD). While the IRBDSG is able to coordinate RBD research worldwide, individual sites study relatively few iRBD patients with site-specific protocols. Differences in assessment protocols, collection methods for cognitive and potential biomarker data, and assays between sites complicate direct comparison of research findings. There is an urgent need to develop and support a consortium of investigators that will establish a central repository of harmonized clinical, cognitive, and biological data and samples obtained from individuals with iRBD, at high risk for imminent development of PD or LBD.

We propose to establish the Prodromal α-Synucleinopathies Consortium, a multi-site study to coordinate the research in the US on idiopathic RBD, including, possibly, development of a trial-ready clinical pre-synucleinopathy cohort.

Scientific/Research Contacts:

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

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Research Education Resources to Foster Development of Geriatrics-Related Translational and Clinical Scientists

The challenges in recruiting and retaining geriatricians are well-recognized. An even greater challenge, however, is addressing the dearth of geriatricians pursuing research careers. There is a critical need for clinician-scientists who are both competent in the care of older adults and the conduct of clinical and translational geriatrics-related research. Current formal training requirements for physicians and many other clinical specialists do not provide for aging-focused research training to develop a critical mass of future leaders in geriatrics-related science. For example, current geriatric training requirements under the American Board of Internal Medicine involve only a one-year fellowship focused on clinical competencies.

Institutions have attempted to address gaps such as these through NIH- and NIA-funded awards including fellowships, T32 programs, NIA research center training cores (such as OAIC Pepper Center Research Education Component), and GEMSSTAR. However, these grant programs are generally awarded to single institutions and many involve awards to junior investigators individually. There is a need for multi-disciplinary educational resources that can be implemented across multiple institutions to support development of diverse groups of early-career clinicians into geriatrics-related research leaders.

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.

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Stem Cell Aging and Oncogenic Transformation

Age is the biggest single risk factor for cancer such that more than 90% of all cancers occur after 50 years of age. With the increase in the aging population, it is estimated that in 20 years over 73% of the U.S. population over the age of 65 will have experienced cancer. Several age-related factors play key roles in transformation including long-term chronic inflammation, long-term exposure to free radicals, less-effective DNA damage-repair mechanisms, and an impaired immune system.

To date, tissue resident adult stem cells have been identified as the origin of several cancers, transforming from normal, healthy stem cells into oncogenic cancer-initiating stem cells (CICs). While CICs of hematological and solid tissue adult cancers express similar genes, mutations, epigenetic changes and metabolic traits that promote both aging and cancer, the aging mechanisms that lead to oncogenic transformation in adult stem cells remain elusive. Moreover, the aged niche has been identified as a significant contributor to cancer initiation in hematopoietic stem cells (HSCs), yet little is known about the mechanisms involved and how changes in the niche lead to the development of solid tumors. For example, mutations in normal cells were thought to be rare events but with recent discoveries in clonal hematopoiesis (CH), it is clear that potentially oncogenic mutations accumulate in normal stem cells with age.

With the advent of low cost high-throughput sequencing technologies, more data are available that show healthy individuals harbor mutations in leukemic genes that exhibit clonal expansion in their blood; these occur in 20 - 40% of humans over the age of 60. The highest prevalence of mutations occurring in CH are in genes known to also play roles in aging as well as cancer. Importantly, the high prevalence of mutagenic heterogeneity and clonality recently discovered in aging adult stem cells of healthy patients including blood, esophagus and skin challenges previous dogma that mutagenesis occurs more randomly and slowly within aging tissues.

From these observations, many critical questions arise including: what leads to the eventual transformation of one of these clones; what is the genetic repertoire of healthy versus transformed aging stem cells; and how does the niche impact clonal expansion and oncogenesis? Furthermore, it is not known how various anti-cancer treatments (chemotherapy and radiation) promote CIC expansion and secondary tumors, or whether senolytics can target adult stem cells and circumvent carcinogenesis.

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.

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May 2019 Council

Approved concepts in this round:

Creating an Infrastructure to Optimize Emergency Care of Persons with AD/ADRD

Emergency departments (EDs) in the U.S. currently provide care for acute medical problems, illness and injury, and serve as a ‘safety net’ for those lacking a primary care provider. Yet, delivering efficacious, efficient and reliable emergency care for persons with Alzheimer’s Disease and Alzheimer’s Disease-related dementias (AD/ADRD) presents multiple challenges in the currently strained healthcare system.

The crowding and fast pace of EDs leads too often to chaotic visits for those with AD/ADRD and their families.

Moreover, failure to adequately recognize patients with early cognitive impairment or underlying dementia can result in diagnostic inaccuracies, inappropriate treatment of the patients’ acute medical issues and unsafe hospital admissions or discharges. With older adults, especially those over 85 years old having the highest ED visit rate of any age cohort, and AD/ADRD affecting 1 in 10 adults over 65 years old and 50% of those over age 85, the challenges of optimally recognizing and treating those with underlying AD/ADRD presents a very common problem which has not been systematically addressed.

The overarching goal of this funding opportunity is to synergize a transdisciplinary community of clinician investigators/researchers with expertise in geriatric emergency medicine, AD/ADRD, and technology to identify key research gaps, prioritize a research agenda, to establish a research infrastructure and resources, and to fund pilot studies to explore efficient and effective strategies to optimize the emergent care of persons with dementia (PWD) including ED triage, recognition of cognitive impairment, acute management and safe discharge, and alternative models of emergent care.

The timing for research focusing on recognizing people with dementia in the ER is optimal as over the past 3 decades, Society of Academic Emergency Medicine’s Academy of Geriatric EM Task Force has created and implemented evidence-backed geriatric EM protocols, equipment/rooms/supplies, transitions of care, quality improvement and universal policies and procedures that have advanced to Transdisciplinary ED Geriatric Care Guidelines and a national accreditation system for geriatric EDs. Concurrently, a recent and rapid escalation of AD/ADRD clinical research and networks, prompted by the National Alzheimer’s Project Act funding to the NIA, has resulted in improved diagnostic techniques and care of PWD including caregiver resources. As a result, the 30 NIA-funded Alzheimer’s Disease Research Centers (ADRCs) throughout the U.S. have link up with additional AD centers (imaging, biomarkers, genetics, genomics, etc.) as well as other NIA-funded centers (Nathan Shock, Roybal, Older American Independence [Pepper Centers], RCMAR) through the Research Resource Coordinating Network, providing additional resources and opportunities to synergize with the expanding Geriatric EM community and Geriatric EDs.

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.

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Implementation Research on Hypertension Control to Prevent Dementia and Cognitive Decline

Accumulating evidence suggests that treatment with antihypertensive agents has salutary effects on cognitive decline and dementia, including favorable trial data from the Systolic Hypertension in Europe (Syst-EUR) Study and the Perindopril Protection Against Recurrent Stroke Study (PROGRESS), although some other studies do not confirm the results. The most recent large-scale randomized clinical trial of blood pressure management, the NIH-funded Systolic Blood Pressure Intervention Trial (SPRINT), demonstrated reduced cardiovascular outcomes and all-cause mortality in the intensive hypertension management arm compared to standard hypertension management. Notably, there was no difference in pre-specified safety outcomes including hypotension, syncope, and injurious falls. The SPRINT-MIND subset study results suggest that intensive blood pressure control reduces incidence of cognitive impairment and a non-significant trend for reduced incidence of dementia.

Though hypertension control is widely accepted to prevent stroke and cardiovascular disease, its association with cognitive decline and dementia among older adults is not so well known. Yet published trials and observational studies did inform the revision of the American College of Cardiology/American Heart Association guidelines for blood pressure management in 2017, which, among other recommendations, indicated that “in adults with hypertension, blood pressure lowering [which prevents cardiovascular disease and stroke] is reasonable to prevent cognitive decline and dementia.”

Other guidelines recommended (key) elements that could be enhanced through dissemination and implementation research including improved blood pressure measurement and home monitoring, the use of a team-based approach and telehealth interventions, quality improvement strategies, financial incentives for providers, and a clear, detailed and current plan of care based on goals and addressing management of comorbid conditions. Hypertension control programs rarely (if ever) have all these elements, and since the resources and context may differ widely, additional dissemination and implementation research is needed to test prevention strategies for cognitive decline associated with hypertension.

Demonstration projects using multiple strategies for system level interventions may provide innovative approaches to address and overcome important barriers. They can address known disparities in hypertension care and outcomes. 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”1. 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 and diverse range of patient subgroups.

1The PRECIS-2 tool: designing trials that are fit for purpose.” BMJ 2015;350:h2147.

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.

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Lipid Signaling in Healthspan and Longevity Regulation

Lipids are small hydrophobic molecules with important roles in nutrition and human health and disease. For example, lipotoxicity, characterized by increased circulating levels of lipids and metabolic alterations in utilization of fatty acids (FAs) is often associated with functional impairments such as the onset of insulin resistance in skeletal muscle and cardiac dysfunction in obese and diabetic individuals.

Numerous lipids are also important intra- and inter-cellular signaling molecules including ligands to G-protein-coupled receptors (GPCRs) and transcription factors, allosteric modulators, and by direct covalent modification of proteins. Moreover, heterogeneity of acyl chains within general classes of lipids can result in distinct cellular signaling properties.

To date, limited evidence suggests that diverse lipid signaling pathways can modulate lifespan. For example, high intracellular levels of the lipid oleoylethanolamide (OEA) derived from lysosomal catabolism can extend lifespan in the worm by interacting with specific transcription factors. Interestingly, human lipidomics studies hint at an association between plasma lipid composition and long life where higher ratios of monounsaturated (MUFA) to polyunsaturated (PUFA) fatty acids appear to favor longevity. Likewise, a similar trend for higher MUFA: PUFA ratios is found in long-lived animals in model systems. Consistently, increased expression of certain desaturases promoting MUFA production contributes to lifespan extension under caloric restriction.

Taken together, emerging evidence points to an important role of lipid metabolism and lipid signaling in influencing the process of aging where specific organelles and pathways coordinating those systemic responses remain to be elucidated.

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.

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Paul B. Beeson Emerging Leaders Career Development Award in Aging

We expect to renew the Paul B. Beeson Emerging Leaders Career Development award in Aging program for FY 2020.

The Beeson program’s combination of generous funding for research and career development and a stimulating annual meeting continue to attract an extraordinarily strong group of applicants. The freedom it offers physician and other health professional researchers to develop their research and advance their leadership skills, remains its main attraction and the force behind its continuing success.

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.

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Research Infrastructure Development for Interdisciplinary Aging Studies Program

Comprehensive and successful aging research frequently depends on collaborations that draw on expertise from a variety of disciplines. In some cases, these collaborations arise naturally. However in other cases, organizational or fiscal obstacles hinder their effective development. Bridging data platforms, crossing inter-departmental silos, and other such challenges may pose substantial barriers to scientific progress despite the availability of personnel and resources. At the same time, innovative scientific findings often lead to novel opportunities that require the development of new collaborations.

To address these issues, the NIA published two FOAs in 2016 to support the needed resources for interdisciplinary collaborative groups to meet the challenge of developing effective research infrastructure in important aging topics.

One FOA used a milestone driven mechanism to develop novel research infrastructure that will advance the science of aging in specific areas requiring interdisciplinary partnerships or collaborations. The other FOA focused on advanced-stage development and utilization of novel research infrastructure to advance the science of aging in specific areas requiring interdisciplinary partnerships or collaborations.

To date, NIA has awarded nine projects that developed infrastructure for multidisciplinary aging network projects on topics including life course studies on healthy aging, emergency care applied research, geriatrics oncology, wearable technology for real time mobility assessment, and translational geroscience.

The recently approved concept now allows renewal of these FOAs.

Scientific/Research Contact:

Winnie Rossi, M.A.
Division of Geriatrics and Clinical Gerontology
National Institute on Aging
Telephone: 301-496-4836
Email Winnie Rossi, M.A.

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Resource Development to Support Basic Biology of Aging in Health Disparities Research

Health disparities are defined as differences in the incidence, prevalence or burdens of disease, comorbidities, life expectancies, mortality rates or causes of death that exist among human population groups in the United States. Epidemiological studies indicate strongly that there are complex interrelationships among factors that contribute to health disparities. Among these are exposure to environmentally disparate stressors, enduring chronic stress, socioeconomic and educational disadvantages, and other forms of adversity. As a result, aging well is less likely to be achieved in disadvantaged populations.

The NIA’s Division of Aging Biology’s emerging health disparities research goals are to (1) better understand the biological factors and related biological mechanisms that diminish health and reduce life expectancy for human populations, (2) develop strategies to increase healthspan among aging adults and improve the health status of older adults from underserved and disadvantaged populations, and (3) use research insights and advances to for translational research that would address and reduce health disparities.

Most research in the basic biology of aging is conducted in the laboratory using cells and laboratory animals to study the molecular processes of aging. However, there is also significant research on the basic biology of aging in human populations in several research fields, including (for example) immunology, muscle biology, bone biology, lung and kidney function, the circulatory system, depression and dementias. The challenge presented in this FOA is to extend these methods of research to build research infrastructure for the basic biology of aging in health disparities.

The outline of the approach envisioned for this RFA is as follows:

  1. Identify alleles in minority populations that might contribute to health disparities.
    1. The subject human populations are selected from minorities on the basis of accelerated aging (most likely using a methylome clock).
    2. The reference populations are from the same minorities without accelerated aging, other minorities also showing accelerated aging, and populations that show accelerated aging from independent risk factors (such as HIV/AIDS, insomnia, PTSD, obesity, etc.)
  2. Identify hallmarks of aging that might interact with those alleles to produce accelerated aging in that population. (Alleles and hallmarks are therefore in the same population.)
  3. Test the interaction on accelerated aging in genetically engineered laboratory mice. (Diagnostics in the laboratory mice could include lifespan, healthspan, geropathology score, mouse aging methylome, etc. Geropathology Research Network, created under R24 AG047115.)

Scientific/Research Contacts:

Ronald A. Kohanski, Ph.D.
Division of Aging Biology
Telephone: 301-496-6402
Email Ronald A Kohanski, Ph.D.

Carl V. Hill, Ph.D., M.P.H.
Office of Special Populations
Telephone: 301-496-0765
Email Carl V. Hill, Ph.D., M.P.H.

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The Biological Mechanisms of Metformin Effects on Aging and Longevity

The key question to be answered under the proposed FOA is “What are the molecular mechanisms underlying metformin’s effects on aging and longevity?” For the past six decades, metformin has been the world’s most commonly used medication for treating type 2 diabetes. Recent epidemiological studies also suggest that metformin slows cancer growth and protects against multiple cancers.

Metformin has drawn wide attention among aging researchers after a large British epidemiological study suggested that it may slow aging and prevent multiple aging-related diseases. As aging is the major risk factor for most adult chronic diseases, tools that will enable us to favorably manipulate aging processes will reduce a large number of aging-associated diseases. Preclinical data and observational data from humans suggest that metformin has anti-aging and pro-longevity properties and thereby has the potential to promote healthy aging.

Mechanisms of metformin action have been studied primarily in the contexts of diabetes and metabolism. Inferences can be drawn about the significance of those studies for the biology of aging, but there has been little-to-no experimental work on that specific topic. Metformin has been shown to impact multiple pathways. First, metformin indirectly reduces insulin levels through its ability to reduce hepatic glucose output and improve glucose disposal. Further, metformin also reduces insulin-like growth factor 1 (IGF-1) signaling, which may in part drive its anti-aging effects. But it remains unknown whether metformin affects aging and aging related pathologies in humans by modulating insulin/IGF signaling.

Alternatively, others have argued that metformin prolongs lifespan based on its ability to stimulate a caloric restriction-like response. Many of the reported molecular targets of metformin are potential mediators for anti-aging effects. Further work is needed to determine whether these molecular effects are indeed relevant in aging or whether there are any tissue-specific effects and how they relate to potential beneficial as well as adverse effects of metformin. These types of new, mechanistic insight will be valuable for the identification of novel therapeutic targets and interventions which leverage the favorable effects of metformin and without the use of biguanides.

Metformin was first shown to have an impact on aging in animal models. The first demonstrations of this were in C. elegans and mice, where metformin was shown to have favorable effects on frailty and aging-associated pathologies, even when started late in life. These data suggest that even in the absence of an effect on lifespan, there is a favorable effect on healthspan. However, the effect is complex, and in mice metformin may have both sexually dimorphic effects and diverging effects at different doses or when started at different points in the lifespan. Metformin reduced all-cause mortality in a UK study of populations in which it was compared head to head with sulfonylureas for the treatment of diabetes. In human prospective studies, metformin reduces diabetes incidence; in observational studies, metformin reduces the incidence of all types of cancer and reduces cancer morbidity; it also reduces the incidence of Alzheimer’s Disease.

The “MASTERS trial” is currently underway to test the hypothesis that metformin favorably modulates exercise-induced changes in skeletal muscle of elderly individuals with sarcopenia. The preliminary analysis suggests that metformin might have a favorable effect on body composition by lowering fat mass; however, against the prediction from the major hypothesis, a gain in muscle mass with exercise was blunted in the metformin group. These results suggest that metformin may have different effects on different tissues, and its favorable effects on lifespan may not translate to benefit in all tissues.

Although metformin has been one of the most commonly used medications, its underlying biological mechanisms in the context of aging and aging-related diseases are poorly understood and understudied. This is still a relatively new field. Only one active NIA-funded R01 grant currently focuses on studying the biological mechanisms of metformin’s effect on aging.

The lack of mechanistic understanding of metformin in aging is a major obstacle for developing metformin into an effective anti-aging intervention. Thus, there is a need to better understand the biological mechanisms underlying the effects of metformin on aging and aging-related diseases. These new mechanistic insights will aid our efforts in exploiting metformin-based interventions to favorably modulate the aging process and to maximally promote healthy aging. This proposed FOA aims to stimulate research on a better understanding of the biological mechanisms of metformin’s effects on aging and longevity.

Scientific/Research Contact:

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

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Biopsychosocial Research on the Impact of Social Connectedness and Isolation on Health, Wellbeing, Illness, and Recovery

Cleared Concept from the NIH Office of Behavioral and Social Science Research on behalf of the NIH Basic Behavioral and Social Science Opportunity Network (OppNet)

It is well-established that strong social ties are associated with wellbeing, recovery from acute illness, and self-management of chronic conditions and, in contrast, loneliness and social isolation are linked to adverse psychological and physical health. Less well understood are the basic individual, social, and biobehavioral processes by which social connectedness and isolation lead to positive or negative outcomes. A more comprehensive understanding of the causal pathways through which social connectedness and social isolation are associated with health and well-being outcomes may identify novel targets for intervention.

To these ends, this concept, developed by the NIH Basic Behavioral and Social Science Opportunity Network (OppNet), will call for flexible-length research projects that can illuminate the mechanisms and processes involved in links among social connectedness, isolation, and trajectories of health. This concept is directly aligned with NIA’s interest in the different biological and behavioral pathways through which social isolation and loneliness affect health in middle-aged and older adults. And the timeliness of this initiative is underscored by the fact that the National Academies of Sciences, Engineering, and Medicine is currently conducting a two-year consensus study focused on health and medical dimensions of social isolation and loneliness in older adults.

Specifically, this concept will solicit research in three main areas of particular interest to NIA, which are as follows:

  1. Effects of social connectedness and isolation across the lifespan, e.g., affective/cognitive function; contextual factors that increase or mitigate impact of isolation (e.g., recent serious illness diagnosis; caregivers of people with dementia, severe illness).
  2. Mechanisms of connectedness and isolation, e.g., neurobiological factors, such as the impact on neural systems associated with basic affective, cognitive, and social processes; or neurobiological processes that may ameliorate negative effects of isolation.
  3. Behavioral and environmental factors, e.g., consequences of perceived isolation (or loneliness) and/or objective/observed isolation on behavioral and clinical outcomes in older adulthood.

Scientific/Research Contacts:

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

Amelia Karraker, Ph.D.
National Institute on Aging (NIA)
Telephone: 301-496-3138
E-mail Amelia Karraker, Ph.D.

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February 2019 Council

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.

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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.

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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.

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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 aides2, 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.

2Bureau 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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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, Ph.D.

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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.

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