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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.

May 2018 Council

Approved concepts in this round:

A Census of Cells and Circuits in the Aging Brain

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

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

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

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

Scientific/Research Contact

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

Alzheimer’s Disease Genetics Consortium

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

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

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

New initiatives may include:

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

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

Scientific/Research Contact

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

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

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

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

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

Scientific/Research Contacts

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

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

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

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

Scientific/Research Contacts

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

Exploring Molecular Links Between Dietary Interventions and Circadian Rhythm

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

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

Scientific/Research Contact

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

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

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

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

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

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

Scientific/Research Contacts

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

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

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

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

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

Scientific/Research Contacts

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

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

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

Low-Cost Detection of Cognitive Decline in Clinical Settings

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

Development Work:

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

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

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

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

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

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

Scientific/Research Contacts

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

Marmosets as a Translational Model for Aging Research

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

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

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

Scientific/Research Contacts

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

Microbiome and Aging: Impact on Health and Disease

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

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

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

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

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

Scientific/Research Contacts

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

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

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

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

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

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

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

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

Scientific/Research Contacts

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

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

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

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

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

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

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

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

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

Scientific/Research Contacts

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

January 2018 Council

Approved concepts from this round:

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

AD/ADRD Health Care Systems Research Collaboratory

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

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

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

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

Scientific/Research Contact

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

Alzheimer's Disease Translational Center for Structural and Chemical Biology

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

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

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

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

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

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

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

Scientific/Research Contacts

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

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

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

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

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

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

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

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

Results of a recent NIA evaluation revealed that:

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

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

Selected research findings arising from Center projects include:

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

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

Scientific/Research Contact

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

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

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

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

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

Scientific/Research Contact

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

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

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

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

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

Scientific/Research Contacts

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

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

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

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

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

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

Scientific/Research Contacts

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

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

Deciphering Glycosylation Code of Alzheimer's Disease*

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

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

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

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

Outcomes of this initiative might include:

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

Scientific/Research Contact

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

De-prescribing Strategies for Older Adults with Multiple Chronic Conditions

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

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

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

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

Scientific/Research Contact

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

Disparities in Quality and Access to Dementia Care*

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

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

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

Scientific/Research Contact

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

Endosomal Traffic Jams*

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

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

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

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

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

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

Scientific/Research Contact

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

Examining Factors Related to Recruitment and Retention in Aging Research

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

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

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

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

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

Scientific/Research Contact

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

Geroscience Approaches to Animal Models of Alzheimer's Disease*

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

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

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

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

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

Scientific/Research Contact

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

High-Priority Behavioral and Social Research Networks

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

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

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

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

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

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

High-Priority Topics – AD/ADRD-related:

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

Scientific/Research Contacts

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

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

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

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

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

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

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

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

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

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

Scientific/Research Contact

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

Integrative Omics to Enhance Therapeutics Development for Healthy Aging

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

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

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

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

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

Scientific/Research Contacts

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

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

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

Interventions Testing Program Renewal

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

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

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

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

Scientific/Research Contact

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

National Health and Aging Trends Study: U01 Renewal

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

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

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

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

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

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

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

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

Scientific/Research Contacts

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

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

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

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

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

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

Scientific/Research Contacts

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

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

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

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

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

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

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

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

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

Scientific/Research Contact

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

Roybal Translational Center Renewal and AD/ADRD Care Expansion

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

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

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

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

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

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

Finally, a Coordinating Center is proposed that will:

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

Scientific/Research Contact

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

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

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

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

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

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

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

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

Scientific/Research Contact

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

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

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

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

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

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

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

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

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

Scientific/Research Contacts

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

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

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

September 2017 Council

Approved concepts from this round:

Samuel Waxman Cancer Research Foundation (SWCRF) Research Collaborations in Aging and Cancer

The incidence of most human cancers increases dramatically with advanced age, so that cancer incidence is 10 times higher in adults 65 or older compared to younger populations. Aging is characterized by the impairment of multiple cellular and systemic functions collectively identified as hallmarks (or pillars) of the process. However, how the biology of aging affects cancer etiology is not clear, and therefore a better understanding of how aging affects the trajectory of cancer is needed.

The goal of the SWCRF Research Collaborations in Aging and Cancer program is to encourage, support, and facilitate collaboration among NCI and NIA intramural investigators (those conducting research within the labs and clinics of the NCI or NIA) and extramural NCI or NIA grantees (those conducting research in labs outside the NIH) through the initiation of novel interdisciplinary research projects, sharing resources and reagents, and developing novel technologies and approaches needed to address the role of aging in cancer.

Scientific/Research Contacts

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

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

Collaborators:

Chamelli Jhappan, Ph.D.
Cancer Immunology, Hematology & Etiology Branch
National Cancer Institute
Telephone: 240-276-6220
E-mail Chamelli Jhappan, Ph.D.

Thomas A. Mistelli, Ph.D.
Center for Cancer Research
National Cancer Institute
Telephone: 301-496-4345
E-mail Thomas A. Mistelli, Ph.D.

Luigi Ferrucci, M.D., Ph.D.
Office of the Scientific Director
National Institute on Aging
Telephone: 410-558-8110
E-mail Luigi Ferrucci, M.D., Ph.D.

Immunity and the Elderly

Older individuals exhibit an increased susceptibility to infectious diseases, with increased respiratory and/or cardiovascular complications and prolonged hospitalization. Lower respiratory tract infections are the most common cause of infectious disease hospitalizations in older adults and the sixth leading cause of death in the United States, with 90 percent of the deaths occurring in individuals who are over 65 years old. Complications such as bacterial superinfection and meningitis can result from a primary viral infection, resulting in increased hospitalizations and mortality with age. Although vaccination plays an important role in reducing the burden of infectious disease, the efficacy is variable and reduced in the elderly, likely due to declining immune function. Moreover, aging is associated with chronic low-grade inflammation that is thought to contribute to age-related chronic diseases such as metabolic syndrome, Alzheimer's disease, and atherosclerosis. Little is known about how molecular variations in immune responses related to recognition and interaction with microbes increase the risk of inflammatory diseases in the aged population. Mechanisms connecting chronic inflammation with chronic diseases also remain unclear. A better understanding of the mechanisms of the aging immune response and chronic inflammatory conditions that accompany aging is required.

Knowledge gaps still exist in understanding mechanisms behind poor vaccine efficacy and responses to infection in the elderly. There also is a growing interest in determining connections between immune status and healthy aging versus chronic inflammation, known as "inflammaging." More human studies are needed to elucidate these interactions and this FOA will support basic studies related to defining mechanisms of dysfunction in the aged innate and adaptive immune systems in response to infectious pathogens or vaccines. The gaps in our knowledge were addressed at a 2017 symposium sponsored by NIA and NIAID.

Scientific/Research Contact

Rebecca Fuldner, Ph.D.
Division of Aging Biology
National Institute on Aging
Telephone: 301-402-6402
E-mail Rebecca Fuldner, Ph.D.

Evolving Implementations for Training Cognition in Aging

In 2010, the NIA first commissioned a systematic review by the Agency for Healthcare Research and Quality (AHRQ) that generated a state-of-the-science report on the prevention of cognitive decline and dementia. That review concluded that there was insufficient evidence to make recommendations about anyintervention strategy for either outcome. Because there has been substantially more research on the topic of preventing age-related cognitive decline, mild cognitive impairment (MCI), and dementia (specifically clinical Alzheimer's-type dementia; CATD) since 2010, the NIA commissioned a new AHRQ systematic review of the evidence in 2016. The AHRQ review reported that there was only low- or at best medium-strength evidence supporting any approach.

In the summer of 2017, the Committee on Preventing Dementia and Cognitive Impairment convened by the National Academies of Sciences, Engineering, and Medicine (NASEM) concurred with the AHRQ findings. However, the NASEM committee did note that the NIA might reasonably communicate with the public that three classes of interventions were "supported by encouraging although inconclusive evidence," namely cognitive training to delay or slow age-related cognitive decline; blood pressure management for people with hypertension, to prevent, delay, or slow CATD; and increased physical activity to delay or slow age-related cognitive decline. Moreover, the NASEM committee recommended that the NIA and NIH continue to support research that includes high-quality randomized clinical trials (RCTs) in these intervention classes and thereby raise the strength of experimental evidence for them.

Concerning the recommendations for blood pressure management, there would appear to be substantial ethical concerns with proposing new RCTs, based on the early termination of SPRINT (SPRINT Research Group et al., 2015). In addition, the results of SPRINT-MIND (SPRINT's cognitive ancillary study) are not yet available. Concerning the need for new trials on increased physical activity, NIA is currently supporting two well-powered and very mechanistically focused RCTs (the MEDEX and IGNITE trials) that are now in the field. The strength of evidence for cognitive training was strongly influenced by the Advanced Cognitive Training for Independent and Vital Elderly (ACTIVE) trial, which recently reported continued domain-specific cognitive benefits for speed of processing and reasoning training even 10 years following the initial intervention (Rebok et al., 2014).

Although ACTIVE was the largest (total N=2802) RCT with the longest follow-up (up to 10 years) to date, some design features of the trial were not ideal (e.g., use of a no-contact control group), and the interventions contrasted were designed approximately 20 years ago. Overall, we now have in place a far richer assortment of potential cognitive interventions, much improved designs and analytic techniques, better instruments and measures to monitor cognitive maintenance or improvement, and vastly improved tools to investigate the brain mechanisms underlying intervention effects and the prediction of who might benefit from which intervention strategies. Moreover, secondary analyses of data from ACTIVE (e.g., Unverzagt et al., 2007) indicate that some cognitive interventions (but notably not memory training) are effective in participants who likely met diagnostic criteria for amnestic MCI. It should, however, be noted that ACTIVE was neither designed nor powered to detect effects on incident dementia, although the long duration of effects in two of the intervention arms are suggestive, and (unpublished and post hoc) data claim that there could be a protective effect against algorithmically defined dementia after 10 years, although no effect was seen after five years (Unverzagt et al., 2012).

Given the recommendations for future research and the current situation as outlined above, the proposed initiative consists of an RFA soliciting one or possibly two planning awards to develop and finalize protocols for well-powered cognitive training intervention trials to remediate or prevent age-related cognitive decline, as well as possibly prevent or delay the onset of dementia. Trial designs would need to include state-of-the-art outcome measures, including behavioral and biological markers, and perform pre-, post-, and maintenance structural and functional imaging.

Scientific/Research Contacts

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

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

Collaboratory on Research Definitions for Cognitive Resilience and Reserve

Although chronological age itself remains the strongest predictor of age-related cognitive decline, mild cognitive impairment (MCI), and many forms of dementia including Alzheimer's disease (AD) and Alzheimer's disease-related dementias (ADRD), there appear to be protective factors against some or all of these outcomes whose mechanisms of protection are poorly understood, and which in some cases are replicated only inconsistently. In some cases, our lack of understanding may be the result of vague or conflicting definitions in the literature, whereas in others, the problem may lie in consistency of measurement. Moreover, although most of these factors are labeled as if there were a modifiable, causal mechanism that could suggest important intervention or intervention strategies, it is not unlikely that in some cases the causal arrow is reversed, and the "protective factor" is essentially a signal of favorable genetic endowment. In still other cases, the factor may be modifiable, but the protection is due to early-life experiences or exposures that cannot be recapitulated later in life. As a group, these factors usually have been described as imparting cognitive resilience to age-related changes in brain structure or neuropathology, the building of cognitive reserve opposing such age-related changes or frank pathology, or augmenting other types of cognitive function that would be beneficial. But without greatly enhanced conceptual and definitional clarity concerning the definition of cognitive resilience and cognitive reserve, or how we could conclusively establish whether cognitive resilience or reserve are responsible for relatively favorable outcomes, we cannot make substantial progress in answering questions concerning what intervention strategies we could reasonably propose or how much benefit such interventions would provide.

Given the growth in the worldwide burden of AD and the continued failure of clinical trials, the focus of the possibility for intervention at ever earlier disease stages or for primary prevention in middle age or earlier has sharpened. Past neuropathological research on autopsied brains coupled with more recent advances in neuroradiology have shown us that a significant proportion of older adults have what should by diagnostic criteria be a clinically meaningful amount of AD neuropathology with no detectable cognitive impairment. Furthermore, at least two U.S. groups have identified a small segment of the older population who appear to be cognitive "super agers" —adults 80 years and older with the cognitive performance of individuals 20 to 30 years younger. These discoveries point to the promise of factors some individuals may harbor that confer cognitive resilience and compensation, or exposures that lead to an accumulation of brain/cognitive reserve.

In April 2017, the NIA, with the support of FNIH on behalf of the McKnight Brain Research Foundation, convened the Cognitive Aging Summit III, the specific focus of which was on the concepts of cognitive reserve and resilience. The Summit brought together a multidisciplinary group of investigators with shared interest in research on age-related cognitive decline as well as cognitive reserve and resilience, as compared to cognitive impairment or dementia. Nevertheless, the assembled investigators noted that there was no bright line between normal age-related cognitive decline and more clearly pathological processes, and in many (but not all) cases the possible mechanisms of resilience could be the same. However, a significant barrier to progress in the field was the lack of clear and universally accepted definitions of important concepts related to cognitive reserve and resilience (including those signature terms).

Scientific/Research Contacts

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

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

Dementia Care and Caregiver Support Interventions

More than 200 dementia care interventions have been determined to be efficacious in randomized clinical trials. However, few of these interventions have been successfully implemented and disseminated in the real world. This problem is not unique to dementia care interventions; rather, this is a universal problem across many diverse behavioral intervention development fields, from mental health interventions to substance abuse treatment. Indeed, it is so common that a term was created to describe this phenomenon: the "implementation cliff."

Many factors are involved in creating this gap between efficacy and effectiveness. Research done on behavioral interventions conducted in efficacy trials tends to involve a well-defined intervention that is administered by interventionists who are trained by experts, and fidelity is ensured with intensive supervision and/or monitoring. Research done on behavioral interventions conducted in pragmatic effectiveness trials tends to involve interventions that must be flexibly administered, and are often adapted or modified. Pragmatic clinical trials, by their very nature, cannot involve expert trainers, but often materials to train community interventionists have not been developed prior to conducting the trial. Similarly, intensive supervision and/or monitoring is not realistic in pragmatic trials, so fidelity of administration cannot be ensured.

NIA had made substantial commitments to funding research on caregiver interventions, but there is very little research that specifically targets this gap. That is, very little research is supported by NIA to adapt interventions appropriately for the community settings for which they are aimed, prior to conducting pragmatic effectiveness trials. Research support is also needed for intervention developers to develop materials to train community providers to administer efficacious interventions. Given that flexible administration of interventions is essential in the real world, and hence is frequently noted in pragmatic trials, to ensure the delivery of interventions with fidelity, interventionists need to understand the principles of the interventions they deliver.

Understanding these principles has been highlighted by the NIH Science of Behavior Change initiative, but knowledge of these principles has not been a focus of intervention development studies across NIH in general, in within NIA in particular. Directly supporting use-informed basic research as part of early-stage intervention development (Stage I, II, and III; intervention creation/adaptation, intervention efficacy testing, and intervention efficacy testing in the real world, respectively), to ascertain the underlying principles of interventions needs to be addressed to ensure that interventions can be delivered flexibly but correctly (i.e., with "fidelity") in pragmatic trials.

Laying the groundwork for pragmatic trials in dementia care can be accomplished by directly supporting early-stage behavioral intervention development clinical trials aimed at adapting/modifying interventions for the real world, examining the principles underlying these interventions, developing methods to ensure fidelity of delivery, and developing training procedures for community interventions. Efficacious interventions for which this groundwork has already been laid may then be tested for effectiveness in real-world pragmatic trials (Stage IV). This initiative is intended to replace the clinical trials portion of PAR-15-348, "Research on Informal and Formal Caregiving for Alzheimer's Disease (R01)." This initiative is timely because over 200 caregiver and care interventions already exist, but these science-based interventions are not being delivered to the people who need them. This initiative can help to speed up the rate that these behavioral interventions make their way through the intervention development pipeline so that they can be effectively delivered in the community.

Scientific/Research Contact

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

Sleep disorders and circadian clock disruption in Alzheimer's disease and other dementias of aging

An estimated 70 million people in the United States suffer from a sleep disorder. While about 30 million Americans experience chronic insomnia, and approximately 18 million suffer from sleep apnea, it is estimated that fewer than 50 percent are diagnosed. Difficulties with sleep are common complaints among the elderly, with up to 50 percent or more older Americans reporting chronic sleep problems.

Older adults with Alzheimer's disease (AD) often exhibit sleep disturbances and circadian clock disruptions. Although this has been interpreted as a consequence of AD, there is evidence that sleep disturbances may contribute to AD risk. For example, it has been demonstrated that preclinical signs of AD are often associated with poor sleep quality. Moreover, Aβ accumulation in the brain predicts and exacerbates sleep disruption in humans and in animal models; experimental manipulations to increase sleep result in decreased Aβ deposition. Such findings provide support for interventions that improve sleep in older adults to reduce the risk of developing AD. Effective interventions exist to improve sleep, and these could be tested as a possible means to prevent AD.

While it appears that there is a bidirectional relationship between chronic sleep and circadian disruption with AD pathogenesis, and previous studies have strongly suggested that humans with AD and mice with Aβ pathology develop sleep and circadian dysfunction, very little is known about the molecular and cellular mechanisms involved. Studies suggest synaptic activity-driven Aβ release is lower during sleep, supported by the observation that slow-wave sleep disruption increases cerebrospinal fluid Aβ levels. There are data demonstrating that the clearance of Aβ from the brain is facilitated through the glymphatic pathway during sleep. It has been proposed that metabolic dyshomeostasis, such as mitochondrial dysfunction, induced by disrupted sleep promotes a feed-forward neuronal injury that hastens AD onset and progression through its effects on Aβ and tau. There are suggestions that Aβ pathology impairs the function of the core circadian clock in microglia in vivo, and that disruption of the circadian clock gene function in glial cells exacerbates neuroinflammation and sensitizes the brain to downstream AD-related injury.

There are several grants currently funded by NIA which encompass sleep, the circadian clock, and Alzheimer's disease. However, this portfolio is skewed toward research examining associations between disturbed sleep and cognitive decline, as well as imaging and cerebrospinal fluid biomarkers of Alzheimer's disease; these are patient-oriented, and predominantly cross-sectional studies on existing cohorts. As of July 2017, there were just two R01-type grants focused on the molecular and/or cellular mechanisms of sleep/circadian rhythms in AD.

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.

Sensory and motor system changes as predictors of preclinical Alzheimer's disease

Alzheimer's disease (AD) continues to be a critical health problem as the aging population grows. Approximately five million Americans age 65 and older suffer from AD, and it is projected that the number of new cases of AD will double by 2025. The neuropathological hallmarks of AD, including A-beta accumulation, tau aggregation, and neurofibrillary tangles may accumulate years before the cognitive symptoms become apparent. Based on these observations, intervening prior to detection of cognitive impairment might present an opportunity to modify the disease and decrease the risk of future cognitive decline. To this end, there have been significant efforts to identify and develop reliable biomarkers of early or preclinical AD.

Over the last decade there has been growing interest in noncognitive functional changes, such as sensory or motor changes, as potential predictors or biomarkers of preclinical AD. Evidence from epidemiological studies suggest that changes in olfaction, audition, and even gait speed may precede the onset of cognitive impairment and dementia by several years. Studies have also shown that sensory and motor regions of the central nervous system are affected by AD pathology. For example, AD pathology is found in the olfactory neural networks, visual neural system pathways, and motor neurons of the pyramidal and extrapyramidal motor pathways in AD patients. Additionally, AD pathology has been shown to appear in sensory association areas well before its appearance in regions involving memory, such as the entorhinal and hippocampal areas. However, despite the mounting evidence, sensory and motor changes have not gained much traction as biomarkers of preclinical AD primarily due of their lack of specificity. Sensory and motor changes are very common in normal aging as well as other neurodegenerative diseases.

There are, however, some data to suggest that assessment of multiple sensory and/or motor modalities in conjunction with other molecular, genetic, or imaging biomarkers may improve the diagnostic accuracy of preclinical AD but more research is needed. Further investigation is also needed to disentangle the sensory and motor changes associated with AD from those associated with normal aging to harness their potential as early, noninvasive AD biomarkers.

This initiative will fill a gap area that is not being sufficiently addressed by other NIA AD initiatives and follows on the heels of a recent report from the National Academies of Sciences, Engineering, and Medicine recommending methodological improvements to clinical trials aimed at preventing cognitive decline and dementia. These recommendations include initiating interventions at younger ages and allowing for longer follow-up periods. Identifying noninvasive biomarkers of preclinical AD would be crucial to improving AD prevention trials.

Scientific/Research Contact

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

Consequences of amyloid protein polymorphisms in AD

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 perhaps 10 or more, based on several recent publications. In fact, the type of molecular protein polymorphism detected in Aß fibrils can be also observed in other disease-associated aggregates such as α-synuclein, tau and IAPP, suggesting structural variation within various protein aggregates are not strictly by the amino acid sequences of amyloid-forming peptides or proteins. This is further supported by the study showing that the seeds of mutant tau fibrils are able to alter the growth of wild-type tau fibrils and the altered wild-type tau fibrils have the properties of mutant tau fibrils instead. 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.

Currently there is no clear correlation between molecular variation of amyloid polymorphs and the progression of neuropathologies in AD. However, many recent studies using in vitro seeding and solid-phase NMR suggest variations in Aß fibril structures in vivo could correlate with variations in AD phenotypes. For instance, it was found that a single predominant form of Aß40 fibril is most abundant in typical sporadic AD brains, whereas Aß40 fibrils observed in rapidly progressing AD have rather distinct additional structures. As a result, it has been postulated that Aß and other self-assembled protein polymorphs such as tau and α-synuclein might be functionally similar to prion strains that are associated with different pathological and clinical phenotypes. Together with other cellular and in vivo transgenic animal studies, initial observations further demonstrate that a single disease-associated protein could form different types of ordered aggregate structures and these proteins or amyloid polymorphs could then be stably maintained and propagated in vivo with distinct pathological phenotypes.

Understanding the direct correlation between variations in Aß and tau strains and patient-to-patient variations in AD could potentially lead to the development of structure-specific Aß and tau imaging agents. If certain Aß or tau structures can be found in patients who progress from MCI to AD, while other structures are found in patients with nonprogressing MCI or in asymptomatic elderly people, then developing of PET imaging agents and antibodies that bind selectively to the AD-related Aß and tau conformers would be highly desirable. In parallel, this type of approach could also provide new insights into developing a new class of small molecules that can redirect the disease aggregation process of Aß and PHF tau into other types of aggregates.

In summary, the goal of this RFA is to identify molecular and cellular mechanisms underlying the formation of these protein conformers in AD and the potential of these variations in disease pathology and transmission. This FOA will also encourage both unbiased and hypothesis-driven approaches to characterize the regulation of biochemical and cellular process that are responsible for time course, clinical presentation, and neuropathological accumulation of these amyloid polymorphs.

Scientific/Research Contact

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