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Approved Concepts

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

September 2021 Council

Approved concepts in this round:

Cell Specific Impact of Liquid-Liquid Phase Separation in Aging and AD/ADRD

Protein aggregation has been a long-standing hallmark of neurodegenerative diseases, such as Alzheimer’s disease (AD) and Alzheimer’s disease related dementias (ADRD). For these conditions, there is a wide variety of proteins implicated in aggregation and disease, including such proteins as tau, TDP-43, and FUS. A common link between these proteins is that they all undergo liquid-liquid phase transitions (LLPS) to form biomolecular condensates (BMCs) under normal biological conditions to function properly. While classical organelles are surrounded by phospholipid bilayers, BMCs are membraneless organelles where proteins, RNA, DNA, and other cellular molecules are brought into close proximity to promote their interactions and to enhance their bioreactivity. Another factor that can influence BMC formation is the nuclear pore complex (NPC), which can transport proteins and nucleic acids in and out of the nucleus. The NPC has been shown to disaggregate proteins after aberrant BMC formation and can also impact the three-dimensional architecture of the genome to regulate gene expression. Despite an abundance of evidence connecting BMCs to neurodegenerative diseases, we still have a poor understanding of how BMC formation is regulated in different cell types and how different disease conditions may alter or influence normal BMC activity.

Emerging evidence has created a unique nexus between nuclear BMC function, cytoplasmic BMC function, the nuclear pore complex and how aging and neurodegenerative diseases may alter these normal functions. Many proteins that aggregate in AD/ADRD undergo transport in and out of the nucleus via the NPC, and the NPC has been shown to help disaggregate these proteins. Additionally, as aging occurs the NPC functions less efficiently, leading to improper transport in and out of the nucleus, which could lead to mislocalization of BMC associated proteins. Aging and cellular stress have also been linked to aberrant BMC formation and disease onset. Despite this growing evidence, there are still basic science questions to answer on how BMC formation is regulated within the cell and what makes certain cells or proteins more susceptible to aberrant BMC activity. For example, what types of modifications drive tau BMC formation and what changes occur to promote tau aggregation in AD? Furthermore, does tau form the same type of BMCs in different cell types or are there cell specific conditions that promote or dissolve BMC formation that may impact disease onset? The purpose of this concept and possible future funding opportunity announcement is to provide researchers an opportunity to gain preliminary data on how different cells or disease conditions may impact BMC formation, either cytoplasmic or nuclear, and what role the NPC may play.

Scientific/Research Contacts

Paul Barrett, Ph.D.
Division of Neuroscience
Email Paul Barrett

Viviana Perez, Ph.D.
Division of Aging Biology
Email Viviana Perez

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

The Claude D. Pepper Older Americans Independence Center (OAIC) program supports centers of research excellence and research training leading to improved or maintained functional independence in older adults. The OAIC Coordinating Center facilitates interactions and collaboration among OAICs and serves as a conduit for translating OAIC objectives and findings. Functions of the OAIC Coordinating Center include developing and maintaining a website for scientific exchange, sponsoring the annual OAIC investigators’ meeting, sharing research resources, curating a registry of data, imaging and biospecimens from clinical aging research studies at OAIC sites, logistical and educational support for OAIC investigators, and advancing translation of OAIC discoveries. In addition to the functions described above, the OAIC Coordinating Center may also build on its existing efforts by:

  • Providing support to OAICs to facilitate compliance with NIH data sharing and clinical research policies
  • Improving the annual directory interface to enhance its use as a vehicle for collaboration
  • Expanding the scope and broadening participation in the annual OAIC investigators meeting
  • Expanding the registry of clinical aging research data, specimens, and imaging
  • Coordinating aging research consultation services across OAIC sites
  • Developing guidance for core measurement sets in clinical aging studies

Scientific/Research Contacts

Basil Eldadah, M.D.
Division of Geriatrics and Clinical Gerontology
Email Basil Eldadah

Winnie Rossi, M.A.
Division of Geriatrics and Clinical Gerontology
Email Winnie Rossi

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Cytosolic DNA Sensing as An Integrating Point of the Aging Hallmarks

Aging is a process that involves many cellular changes characterized by a set of molecular hallmarks. Since their discovery, studies have led to a comprehensive understanding of the individual aging hallmarks or associated pathways. However, the interactions of different aging hallmarks and whether those interactions are consequential for aging remain poorly understood. While cytosolic DNAs, a relatively newly identified hallmark, have been increasingly recognized as important players in aging, much about them remains largely unknown. In the past a few years, it has been well-documented that the accumulation of cytosolic DNA is associated with aging and cellular senescence and contributes to the deterioration of cellular and physiological functions.

This concept’s goal is to advance our understanding of cytosolic DNAs as an integrator of interactions among the aging hallmarks and as an instigator of the downstream cascade of events that lead to cellular senescence and inflammaging. This concept encourages researchers to collaborate for needed expertise, especially in the areas of new or advanced technologies that could be transformative in enabling researchers to address critical mechanistic questions relevant to cytosolic DNAs and aging hallmarks. This concept intends to cover the following topics:

  • Investigating the origins and identities of cytosolic DNAs, how they are generated and accumulated, and their associated changes in aging hallmarks.
  • Determining the additive or synergistic effects of different aging hallmarks on the accumulation of cytosolic DNAs, and vice versa.
  • Investigating whether there are any common or special features among the cytosolic DNAs of different origin and their relationship with different aging hallmarks.
  • Determining the causal or correlative relationship between the cytosolic DNAs and aging hallmarks – their temporal sequence and the threshold of these events that lead to cellular and physiological dysfunctions in aging.
  • Examine whether and how these cytosolic DNAs induce other signals, in addition to cGAS-STING pathway and SASP production, and contribute to the cellular dysfunction in aging.

Scientific/Research Contact

Max Guo, Ph.D.
Division of Aging Biology
Email Max Guo

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Health Equity and the Cost of Novel Treatments for Alzheimer’s Disease and Related Dementias

As the population with Alzheimer’s disease and Alzheimer’s disease related dementias (AD/ADRD) grows, related health inequity and cost of care issues are of great concern. While racial and ethnic differences have been documented in the costs of AD/ADRD disease management, paid caregiving, and impacts of unpaid caregiving, less attention has been granted to quantifying the cost of treating Alzheimer’s disease with new medications or repurposed drugs and the health equity implications of access to such drugs. Failure to address the costs and benefits of new or repurposed pharmacological agents could lead to unnecessary delays in drug delivery.

This concept aims to support studies on the health equity implications of access to novel pharmacological treatments for AD/ADRD. It will support projects to conduct stakeholder engagement with underrepresented groups, followed by simulation modeling on the costs and health outcomes of new therapeutics in the U.S. population. Applicants will propose and apply methods to account for known racial and ethnic disparities treatment engagement and access. In the first phase, multidisciplinary teams will conduct rigorous stakeholder analysis with racial and ethnic sub-groups designed to understand the groups’ attitudes towards new drugs, and what outcomes are of most importance to the potential users of new drugs. In the second phase, the grantees will develop cost models and disseminate findings. This initiative will provide critical information to inform the design of access policies, such as co-payment and deductibles, for novel AD drugs. This effort will support and work to address drug access disparities in this area as these therapeutics transition to routine use.

Scientific/Research Contacts

Priscilla Novak, Ph.D.
Division of Behavioral and Social Research
Email Priscilla Novak

John Phillips, Ph.D.
Division of Behavioral and Social Research
Email John Phillips

Partha Bhattacharyya, Ph.D.
Division of Behavioral and Social Research
Email Partha Bhattacharyya

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Inter-organelle Communication as a Platform to Interrogate the Interactions of Hallmarks of Aging

Emerging evidence has pointed to organelle-organelle membrane contact sites as critical hubs for the transfer of ions, metabolites, lipids, and proteins between organelles and they have been shown to be involved in organelle biogenesis and dynamics. As inter-organelle communication is important in coordinating adaptative responses to intra- and extracellular stresses and maintaining cellular homeostasis, it is becoming clear that interactions between organelles undergo a cascade of decline in cellular aging. The biological hallmarks of aging, which have outlined major molecular and cellular processes that contribute to aging, have been studied primarily as processes of aging in isolation from each other. Inter-organelle communication provides a platform to interrogate novel interactions of aging hallmarks and associated mechanisms. Studies have begun to identify novel inter-organelle communication that can be understood as interactions of hallmarks of aging, however, additional research is needed to deepen our mechanistic understanding of the broad impact on cellular, tissue and organismal homeostasis. To date, much of the work on inter-organelle communication has been focused on identifying new contact sites and protein molecules involved in the interactions of apposing organelles in the context of physiology and disease. NIA aims to promote this nascent, exciting area of research on the extent of organelle communication that shapes the interactions of aging hallmarks.

NIA seeks comprehensive, multi-disciplinary research projects in the following areas:

  • Identification and characterization of novel organelle communication impacting the interactions of aging hallmarks
  • Evaluation of pro-longevity interventions in the context of direct or indirect organelle communication
  • Investigation of genetic and environmental factors involved in “re-wiring” of inter-organelle communication
  • Characterization of regulatory roles of inter-organelle communication in influencing the aging process at the organ and organismal levels
  • Development of systems-level imaging and microscopic technology to map organelle communication in aging relevant models (to provide information needed to drive more hypothesis-driven studies)

Scientific/Research Contacts

Yih-Woei Fridell, Ph.D.
Division of Aging Biology
Email Yih-Woei Fridell

Paul Barrett, Ph.D.
Division of Neuroscience
Email Paul Barrett

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Lipids in Brain Aging and AD/ADRD

Evidence for the important roles of lipids in brain aging and Alzheimer’s disease and Alzheimer’s disease related dementias (AD/ADRD) has been building slowly for decades. Recent research has revealed a number of important insights related to altered lipid profiles and lipid turnover; the role of lipid droplets in neurodegeneration and normal aging processes; lipid metabolism and AD; and the role of lipid-rich white matter in learning and brain function. Yet, there is still much to be discovered about the implications of these findings and the role of lipids in brain aging and AD/ADRD. Addressing outstanding questions on lipids in the aging brain could lead to important insights into age-related decline and vulnerability to neurodegeneration and AD.

This concept aims to promote research that investigates outstanding questions regarding lipids in brain aging using approaches spanning from cellular and animal models to human studies, including:

  • The effect of lipid droplets on brain aging and AD, including whether their accumulation is pathological or protective;
  • The interaction of the periphery with lipids in the aging brain, including whether these could be targets for future biomarkers;
  • The influence of ApoE and lipid-mediated signaling on brain aging and AD/ADRD progression, including the effects of APOE status, other AD risk factors, and sex differences; and,
  • The contribution of myelin lipids and their signaling to brain aging and AD/ADRD.

Scientific/Research Contact

Amanda DiBattista, Ph.D.
Division of Neuroscience
Email Amanda DiBattista

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Mapping Interconnectivity Among Hallmarks of Aging Under Lifespan Modifications

The hallmarks of aging, including genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication, were first described by López-Otín in 2013. Since then, there has been a significant amount of scientific evidence generated on the role of individual hallmarks on aging, and how they are involved in loss of function and the etiology of age-related diseases. Currently, it is a subject of ongoing research whether a specific hallmark by itself could be the primary driver of all aging phenotypes or if different combinations of interactions produce different aging phenotypes. Taken together, emerging evidence points to complex interactions as being the likely driver of aging. Lingering questions remain about whether there are hierarchies among the hallmarks that underlie different changes with age, or whether there is a threshold beyond which these hallmarks — and/or their interactions — overwhelm compensatory mechanisms and therefore become tipping points in the aging process.

This concept will solicit research projects to increase our understanding of the interactions among hallmarks of aging and their regulation in the following areas:

  • Characterization of the interactions among hallmarks of aging in various cells/tissues across the normal lifespan, to provide information about timing and priority (hierarchy)
  • Evaluation of whether the interactions between the hallmarks are an adaptive response to maintain health at different stages of life
  • Characterization of these interactions to determine if a threshold mechanism exists that leads to specific aging phenotypes
  • Investigation of which interaction(s) among the hallmarks is(are) necessary and sufficient to change the aging trajectory
  • Evaluation of the impact of lifespan-extending interventions on multiple hallmarks of aging at the single-cell level in different tissues as a means to uncover interactions from the onset of interventions started at different times over the life course

Scientific/Research Contact

Viviana Perez, Ph.D.
Division of Aging Biology
Email Viviana Perez

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Mechanisms of Brain Hypoperfusion in AD/ADRD

Cerebral blood flow (CBF) reductions are an early symptom of Alzheimer’s disease, and studies suggest that the severity of impairment in the CBF correlates with the severity of cognitive deficits. These observations have been replicated across a wide range of mouse models of AD. Despite the crucial impact of reduced blood flow in the brain (hypoperfusion) on cognitive symptoms and brain pathology in AD, there remains a limited understanding of the underlying molecular and cellular mechanisms and of the potential therapeutic benefit of CBF rescue. While some studies have investigated this question, there is a limited understanding of the molecular and cellular mechanisms underlying microvascular dysfunctions in AD. Since brain hypoperfusion exacerbates AD pathology and cognitive decline, it has been postulated that there is a vicious cycle of mutually reinforcing damage between β-amyloid-mediated pathology and CBF impairment; breaking this cycle by improving CBF could slow development and/or progression of AD.  Recent studies highlight both the importance of brain hypoperfusion in AD/ADRD and present some unanswered questions and controversies regarding cerebral blood flow in the context of neurodegenerative diseases. A deeper mechanistic understanding of changes in the cerebral blood flow in AD/ADRD could facilitate the development of innovative therapies for AD.

The goal of this concept is to understand the molecular and cellular mechanisms underlying the cerebral blood flow reduction in AD/ADRD. It will encourage studies of brain hypoperfusion in animal models of AD/ADRD, human studies which interrogate molecular and cellular mechanisms in association with hypoperfusion, as well as cellular models that recapitulate hypoperfusion in relation to neurodegeneration. If developed into a funding opportunity, this effort will solicit applications for projects designed to:

  • Determine the impact of blood brain barrier permeability on CBF and approaches to modulate vascular permeability in brain capillaries;
  • Establish mechanisms of pericyte constriction;
  • Understand leukocyte-endothelial interactions in the microvasculature;
  • Understand convergent causes and the interplay between different kinds of microvascular dysfunction in AD/ADRD;
  • Further develop cell-specific inducible knockout strategies to probe the involvement of different vascular and mural cells in CBF in the context of neurodegenerative diseases.

Scientific/Research Contact

Miroslaw “Mack” Mackiewicz, Ph.D.
Division of Neuroscience
Email Mack Mackiewicz

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Noncoding RNAs in Alzheimer’s Disease and Related Dementias

A large body of literature has shown that noncoding RNAs (ncRNAs) play crucial regulatory roles in multiple molecular and cellular processes. They are also emerging as an important player in the complex biology underlying neurodegenerative disorders, but their implication in Alzheimer’s disease and Alzheimer’s disease related dementias (AD/ADRD) remains largely unknown. Preclinical data indicate that targeting microRNAs could help reinstate protein homeostasis and memory function in AD, representing a new avenue for patient stratification and therapy. Despite growing interest in exploring ncRNA-based therapeutics and diagnostics, their pertinence as potential biomarkers and drug targets for AD/ADRD remains uncertain until we gain a systematic and deeper understanding of the biology of ncRNAs and how they regulate cellular and pathophysiological processes in diseases. There is enormous potential by targeting ncRNAs to identify novel mechanisms to inform the design of diagnostics and therapeutics.

This initiative is to stimulate research in noncoding RNAs to investigate the causality, directionality, mechanisms, and therapeutic potential of ncRNAs implicated in AD/ADRD. Specific research areas that of great interest include:

  • Characterize functional significance of ncRNAs in specific temporal and spatial contexts, in physiological and pathological conditions, and during disease stages of AD/ADRD.
  • Decipher causal roles of ncRNAs involved in pathogenic protein aggregation, neuroinflammation, and other pathophysiologic processes in AD/ADRD.
  • Identify targets (protein/DNA/RNA) ncRNAs interact with, and cell types and states ncRNAs operate in. Investigate functional outcomes of these molecular interactions.
  • Elucidate molecular and cellular mechanisms underlying alterations of ncRNAs implicated in the pathogenesis of cognitive decline and AD/ADRD.
  • Discover translational insights into ncRNA-based diagnostics and therapeutics to estimate AD risk, predict disease trajectory, improve patient stratification, and inform drug development.

Scientific/Research Contact

Alison Yao, Ph.D.
Division of Neuroscience
Email Alison Yao

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Pharmacokinetic and Pharmacodynamic (PK/PD) Studies of mTOR inhibitors on Aging-related Indications

Although rapamycin has been shown to prolong lifespan in the model organisms, including mammals, there are very limited preclinical and clinical data on the effects of other mTOR inhibitors on aging-related indications. Results from a few completed clinical trials on the effects of mTOR inhibitors on aging-related indications indicate some positive effects of these drugs on response to vaccination and viral infection in older persons. Overall, in doses used in these trials, the drugs were well tolerated. However, effects on clinical measures such as age-related chronic diseases, frailty, cognitive and physical performance, or self-perceived health have not been studied.

To advance research on these and other similar indications, there is an urgent need to address important gaps in pharmacokinetic and pharmacodynamic information on mTOR inhibitors in populations other than cancer patients, organ transplantation patients, or arterial stent patients. In these populations, mTOR inhibitors are generally given concurrently with other drugs or administered nonsystemically. Thus, there is limited knowledge of mTOR clinical pharmacology in conducting translational clinical trials for diseases and conditions associated with aging. Such information would enhance the ability to design future trials and interpret their results. Trials submitted in response to this opportunity will generate the much-needed data on pharmacokinetics and pharmacodynamics of different mTOR inhibitors in older adults who have, or are at risk for, diseases and conditions associated with aging. These data will be used to inform designs of future trials on the effects of mTOR inhibitors in older adults.

Scientific/Research Contact

Irina Sazonova, Ph.D.
Division of Geriatrics and Clinical Gerontology
Email Irina Sazonova

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Resources to Promote Coordination and Collaboration across Deeply Phenotyped Longitudinal Behavioral and Social Studies of Aging

NIA’s Division of Behavioral and Social Research (BSR) supports many deeply phenotyped, psychologically rich, small- to mid-size longitudinal studies which, collectively, span the full life course. The studies amass rich and wide-ranging data on behavioral and psychological processes related to personality, stress, emotion, social relationships, self-regulation, decision-making, and health behaviors to investigate the direct factors and mediators affecting health and well-being in later life. Many of these studies also collect detailed cognitive assessments, incorporate real-time experience sampling or daily diary protocols, and include biomarker and neuroimaging assessments. These approaches allow collection of precise and detailed data for hypothesis generation and provide opportunities for fine-grained mapping of individual trajectories of aging and life-span development. These smaller, longitudinal behavioral studies have been developed by independent investigators, utilize unique designs, and have been funded as stand-alone research projects.

In contrast to the nationally representative, population-based longitudinal studies supported by NIA, which have been successfully supported by research infrastructure that encourages coordination and collaboration, these smaller studies have not to date benefitted from such an infrastructure. As such, they represent an untapped resource.Establishing links across individual studies could address replication questions, allow findings to be extended to new contexts, and offer greater potential to identify important behavioral, psychological, and social factors that moderate healthspan and lifespan. This concept is designed to support research infrastructure to build collaboration and coordination opportunities across these smaller studies through activities such as:

  • Outreach to investigators and support for meetings that will stimulate collaborative work.
  • Methodological consultation services for investigators.
  • Creation of a publicly available web-based, meta-data catalogue to describe existing datasets, identify studies with overlapping measures or compatible designs, and support cross-project co-analysis.
  • Pilot support for collaborative teams to leverage existing studies to answer new questions, address replication and generalizability issues, and provide training for the next generation of investigators.

Scientific/Research Contacts

Janine Simmons, M.D., Ph.D.
Division of Behavioral and Social Research
Email Janine Simmons

Lis Nielsen, Ph.D.
Division of Behavioral and Social Research
Email Lis Nielsen

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Screening for Cognitive Impairment: Decision-making

In early 2020, the U.S. Preventive Services Task Force (USPSTF) released an “I Statement” summarizing their analysis of the benefits and costs of screening for cognitive impairment in older adults, concluding that more research is needed to make a recommendation for or against screening. That the evidence on this point is still considered inconclusive following a decade of investigator-initiated research on the topic suggests that a more programmatic approach will be required. Overall, the USPSTF concluded that “More research is needed on the effect of screening and early detection of cognitive impairment (MCI and mild to moderate dementia) on important patient, caregiver, and societal outcomes, including decision-making, advance planning, and caregiver outcomes.” NIA already supports a large and growing research portfolio both in the development of caregiving interventions as well as the society-level burden of dementia, with relatively much less work being done on individual level outcomes of the persons living with cognitive impairment. This concept seeks to fill the research gap by supporting the further development and validation of measurement tools that could be used to screen for deficits related to decision-making, planning, and other important outcomes and assess changes that could be useful in the context of future interventions. The target population for these tools will be persons who are or will be living with cognitive impairment.

In this area, the ability of research to provide useful evidence in either observational or interventional studies relies heavily on the quality and consistency of the outcome measures used. This project will focus on the development of a taxonomy of higher-level skills that support autonomy and daily life for people living with cognitive impairment, the creation of a more detailed mapping between those skills and daily life activities, and the design and validation of reliable and valid instruments to measure those skills. Future work can then develop and test interventions on those skills most amenable to intervention and determine whether earlier screening led to superior outcomes due to application of these interventions, thus also providing concrete evidence of the value of screening.

Scientific/Research Contacts

Jonathan King, Ph.D.
Division of Behavioral and Social Research
Email Jonathan King

Nina Silverberg, Ph.D.
Division of Neuroscience
Email Nina Silverberg

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Understanding Place-Based Health Inequalities in Mid-Life

The National Academies of Sciences, Engineering, and Medicine recently released “High and Rising Mortality Rates Among Working Age Adults,” a Consensus Study Report primarily supported by NIA’s Division of Behavioral and Social Research. The Study finds that recent declines in US life expectancy were the result of two mortality trends among the “working age” population (i.e., aged 25-64). First, working age mortality increased for drug- and alcohol-related causes and suicide beginning in the 1990s. Second, mortality declines in other causes of death, most notably cardiometabolic diseases, stalled among the working age population after 2010. This Study also identified large differences in life expectancy by place – i.e., U.S. Census regions, metropolitan areas, states, and counties. In many cases, place-based inequalities, including inequalities across the urban-rural continuum, have grown over the past several decades. These troubling domestic trends are coupled with declines in the nation’s life expectancy rankings, as life expectancy for both non-Hispanic whites and Blacks/African Americans have fallen further and further behind peer countries.

While the Consensus Study is rich in descriptions of levels of (and trends in) health inequalities by place, it does not provide definitive answers as to what social, economic, behavioral, and policy factors are responsible for these patterns. Understanding the fundamental causes of such inequalities — and the mechanisms through which they impact health — is essential to redressing them. Addressing place-based health inequalities requires data analysis and/or data infrastructure investments and enhancements to existing studies. As such, this concept proposes support for studies that will:

  1. Clarify the unique and interactive roles of social, economic, behavioral, and policy factors that drive place-based health disparities (levels and trends);
  2. Examine intersections between place and sociodemographic characteristics (e.g., gender, race, ethnicity, etc.) to better understand and address processes driving other health disparities; and/or,
  3. Include data collection and data enhancements to support the first two efforts.

Scientific/Research Contacts

Amelia Karraker, Ph.D.
Division of Behavioral and Social Research
E-mail Amelia Karraker

Frank Bandiera, Ph.D.
Division of Behavioral and Social Research
Email Frank Bandiera

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Understanding the Role of Bilingualism in Cognitive Reserve and Resilience in Aging and AD/ADRD

Bilingualism has been hypothesized to strengthen structural and functional connections in the aging brain in areas important for language and executive function. However, research findings in this area have been mixed and complicated by environmental and sociocultural factors like health equity in diverse populations, age of second language acquisition, aspects of language use, socioeconomic status, education, and recency of immigration. Better understanding of the complex interactions between neural, environmental, and sociocultural factors and the role of bilingualism in healthy aging and in Alzheimer’s disease and Alzheimer’s disease related dementias (AD/ADRD) may lead to new intervention targets and provide insight into the role of language in the aging brain. Lessons learned through this research could also help refine or develop interventions designed to build or stimulate cognitive reserve.

Given the unsettled state of research in this area, there is a need for more prospective, hypothesis-driven research to help build a theoretical framework and more clearly identify if and how bilingualism impacts brain function. In addition, multidisciplinary and multimodal approaches are needed to explore whether and how bilingualism exerts effects on cognitive reserve and resilience.

Scientific/Research Contacts

Matt Sutterer, Ph.D.
Division of Neuroscience
Email Matt Sutterer

Jonathan W. King, Ph.D.
Division of Behavioral and Social Research
Email Jonathan King

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May 2021 Council

Approved concepts in this round:

Diversifying the Therapeutic Pipeline for AD/ADRD: Drug Discovery for Novel Targets

The development of effective AD/ADRD therapies has proven to be difficult. One reason is that past AD drug development has been based on a narrow understanding of the disease centered on the amyloid hypothesis. In contrast to this conventional wisdom, growing amounts of new data suggest that clinical AD is a highly heterogeneous, multimodal, and multicomponent disease caused by a combination of genetic and environmental factors acting to perturb molecular networks across multiple interrelated biological pathways. These new discoveries, coupled with the failure of numerous anti-amyloid drugs, have highlighted the need for alternative therapeutic approaches that require the identification of next generation, nascent AD/ADRD drug targets. To improve and diversify the AD/ADRD drug development pipeline, the next generation targets must be preclinically validated, prioritized, and advanced into drug discovery campaigns.

To address the need for next generation AD/ADRD drug targets, NIA has spearheaded the launching of several target discovery initiatives (e.g. AMP-AD, M2OVE-AD, and Resilience-AD), which are aimed at discovering nascent, candidate therapeutic targets. Recently, NIA launched TREAT-AD for the development of target enablement packages (TEPs) for the characterization and experimental validation of these candidate drug targets. In 2016 NIA launched MODEL-AD, which is missioned to create and characterize late-onset AD (LOAD) mouse models that better recapitulate human LOAD.

This initiative will capitalize on the discoveries of AMP-AD and other target discovery programs, leverage the TEPs made available through TREAT-AD, and utilize the new LOAD models created by MODEL-AD for determining the efficacy of the emergent therapeutic agents in the most appropriate mouse model. The R61 will support feasibility studies (i.e., rigorous preclinical target validation) and R33 will support drug discovery/development of small molecules and biologics. In addition, the initiative will emphasize requirements for rigorous study design of preclinical efficacy testing studies and transparent reporting. If successful the initiative will improve, diversify, and reinvigorate the AD/ADRD drug development pipeline through the discovery of novel small molecule and biologic agents against preclinically validated, next generation drug targets.

Scientific/Research Contacts

Zane Martin
Division of Neuroscience
National Institute on Aging
Telephone: 301-827-7130
Email Zane Martin

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

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Limited Competition: Renewal of the Caenorhabditis Intervention Testing Program (U01) and Its Data Coordinating Center (U24)

This FOA calls for renewal and scientific scope expansion of the Caenorhabditis Interventions Testing Program (CITP), a flagship program to support rigor and reproducibility in studies with laboratory animals. It aims to test potential intervention strategies that may moderate or alleviate health declines associated with aging across genetically diverse species and strains of Caenorhabditis (worms used to explore genetic and cellular mechanisms of longevity, learning and memory.) Interventions (compounds) are proposed for screening by the research community and then selected by an independent NIA-supported access panel of CITP.

This funding opportunity will use U01 (screening compounds) and U24 (Data Coordinating Center) mechanisms, inviting applications for a limited competition and set aside to achieve these objectives:

  • Lifespan Studies and Midlife Health Indicators. The CITP is expected to determine the effects of selected compounds on diverse species and strains of Caenorhabditis for lifespan extension and health benefits.
  • Reporters of Aging Hallmarks. The CITP is expected to develop reporters of key aging hallmarks in genetically diverse Caenorhabditis strains. These reporter strains will be used for screening of compounds.
  • Effects of Compounds Related to Alzheimer’s Disease or Related Dementias (AD/ADRD). Compounds may be nominated from screens against AD/ADRD. The CITP would test them under objectives 1 and 2, above, and a set of genetically engineered Caenorhabditis related to neuronal changes associated with AD/ADRD.

The goal of this program, as with the (mouse) Intervention Testing Program, is to establish “ground truths” about compounds that have robust effects on lifespan, or on hallmarks of aging, and provide accessible high-quality data potentially useful for novel hypotheses and which may spur further research in biology of aging.

Scientific/Research Contacts

Max Guo
Division of Aging Biology
National Institute on Aging
Telephone: 301-402-7747

Email Max Guo

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Reissue of the Alzheimer’s Drug Development Program

Alzheimer's disease is the most common cause of dementia in older people and is among the greatest healthcare challenges of the century. Delaying symptom onset by five years could reduce disease prevalence by as much as 50% and significantly reduce the disease’s health care costs and burden on families. Unfortunately, the clinically available therapies fall short of this requirement and provide only limited and temporary relief of symptoms. To avert this large and escalating public health crisis, new therapies that effectively prevent, slow the progression, or improve the symptoms of Alzheimer’s are urgently needed.

In 2006, NIA launched the Alzheimer’s Drug Development Program (ADDP) to address the unmet need for therapeutics, counteract the biopharma investment gap, and stimulate drug development. The ADDP is designed to offer academic and biotech researchers funding for drug development activities that can be conducted in their own laboratories, or in collaboration with contract research organizations that specialize in drug development activities. Between fiscal year 2007 and FY 2019, the ADDP funded 32 drug development projects. Of these, nine projects have transitioned to the clinic, with four in Phase I and five in Phase II. Since the end of FY 2019, an additional nine drug development projects have been funded through the ADDP. This concept calls for a reissue of the ADDP to continue to build on the gains made in the first fifteen years of the program.

Scientific/Research Contacts

Lorenzo Refolo
Division of Neuroscience
National Institute on Aging
Telephone: 301-594-7576
Email Lorenzo Refolo

Jean Yuan
Division of Neuroscience
National Institute on Aging
Telephone: 301-496-9350
Email Jean Yuan

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Small Business Innovation Research (SBIR) Research Contract Topics

This proposal will add three NIA topics to the NIH Parent SBIR contract solicitation PHS-2022. Use of the contract mechanism allows solicitation of topics that stimulate innovation and address unmet scientific priorities that are ripe for innovation while providing NIA with the ability to specify expected deliverables.

Geroscience-based Chronic Wound Treatment Product Development

Delayed wound healing increases the risk of recurrent infection and tissue necrosis, resulting in disability, hospitalization, and mortality among older adults. While NIA has regularly funded chronic wound healing product development, the ability to specify deliverables will ensure more optimal, geroscience-based wound healing SBIR grant applications. Development of wound treatments that incorporate modalities such as stem cell therapies, senolytics, or inflammation modulators can address the incidence of chronic wounds that do not follow a normal healing process and increase with age.

The Development of Mechanism-based Adult Stem Cell Treatments to Combat Aging Pathologies

There are now over 600 U.S. companies focused on stem cell-based treatments, yet there is a relative lack of mechanistic-based therapeutic discovery, which is critical for optimal development. This project will support research directed at developing mechanism-based therapeutics with defined alterations of cellular and/or molecular processes (senescence, inflammation, metabolism, DNA repair etc.) to facilitate aging tissue regeneration at the molecular, cellular, tissue, or organism level.

Improving CNS Gene Delivery Systems for AD/ADRD Therapy Development

There is a need for further efforts to specifically improve the safety and efficacy of gene delivery systems. Improved gene delivery systems are needed to overcome current challenges and better penetrate the blood-brain barrier, enhance stability and bioavailability, decrease immunogenicity, and improve cell-type targeting. As part of the AMP-AD initiative, this project will help improve, diversify, and reinvigorate the AD/ADRD drug development pipeline and may represent a key area for innovation.

Scientific/Research Contacts

Armineh Ghazarian
Office of Small Business Research
National Institute on Aging
Telephone: 301-827-6219
Email Armineh Ghazarian

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January 2021 Council

Approved concepts in this round:

Data enhancements and analyses to clarify the relationship between education and cognitive function [including Alzheimer's disease/Alzheimer's disease related dementias (AD/ADRD) and dementia]

One of the most-robust findings in Alzheimer’s disease and Alzheimer’s disease-related dementia research is that higher levels of education are associated with lower risk of AD/ADRD. However, key questions about this relationship remain. Most longitudinal studies of aging examining education only contain measures of years of schooling, obscuring the pathways that might link educational experiences and cognitive function. Studies of cognitive aging and AD/ADRD typically lack information on other dimensions of education that may drive and/or modify observed associations between years of education and cognitive function.

Measures of educational quality, content, and success, along with measures that capture aspects of schools as social institutions could help further understanding of the education-cognition relationship. Adding enhanced measures of educational experiences to longitudinal studies of aging may also help explain differences in cognitive health in later life by race/ethnicity, urban-rural status, and other demographic factors that often pattern health disparities.

In the same vein, many studies with rich educational measures have only limited measures of cognitive function in early and/or later life, leaving such studies currently underutilized by the AD/ADRD research community. NIA has made major investments in several studies that might elucidate the relationship between education and ADRD risk. Some of these studies have cohorts entering ages where the beginning of cognitive change may be detectable with adequately sensitive measures. Others are poised to go back into the field in the near future, making now an especially efficient and appropriate time to support data enhancements.

An RFA is proposed to support data enhancements in measures of education beyond years of education, cognitive function, or both, and/or analyses that incorporate these measures in order to clarify the relationship between education and cognition, including the extent to which the relationship is causal (and if so, under what conditions and for whom).

Scientific/Research Contact

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

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Data management coordinating center (DMCC) and a collaborative research space for translational research on exceptional longevity (EL)

NIA currently supports several cooperative agreement projects on exceptional longevity (EL) in humans which include the Longevity Consortium (LC), Long-Life Family Study (LLFS), Longevity Genomics (LG) and the Integrative Longevity Omics (ILO) project. These studies focus on the discovery of genetic and other protective factors influencing EL and their translation into possible therapeutic targets for healthy aging. Until now, these projects have been mostly inward facing and functioned independently of each other. In the absence of a centralized infrastructure for research coordination/data management, opportunities for synergisms and potential outside partnerships have been missed.

Equally critical to advancing translational research on EL is the availability of a collaborative research space to consolidate and increase the access and use of complex biological data and other research resources generated by the ongoing EL studies and related efforts. This need for better data integration and exchange will only increase since large volumes of omics data will be generated by the EL projects in coming years. Substantial computing resources are also needed to develop and test new analytical algorithms on large multidimensional data sources.

The availability of a limited data commons would create a computing resource that will enable investigators to explore new analytical approaches and tools. Incorporating the EL portal on the AD Knowledge Portal platform will increase the use and exchange of EL data, an important step towards the development of a more comprehensive collaborative research infrastructure.

Scientific/Research Contact

Chhanda Dutta
Division of Geriatrics and Clinical Gerontology
National Institute on Aging
Telephone: 301-496-4161
E-mail Chhanda Dutta

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Development and maintenance of a multigenotypic aged mouse colony (Contract renewal)

This is a proposal to renew the existing contract supporting the NIA’s aged mouse colony. NIA supports basic biomedical research through several programs which require animals as models of the aging process. These programs include immunology, endocrinology, pharmacology, neurobiology, exercise physiology, behavior, genetics, and nutrition. As more is learned about the genetic and physiological components of aging, a need is also arising for animal models in which to test the therapeutic potential of drug and nutritional interventions.

Most academic laboratories do not have the funds or facilities to raise aged animals, and aged rodents are not routinely available commercially. For over two decades, this resource has successfully facilitated studies by providing of genetically defined, barrier-reared aged mice free of charge to the research community. The program requires the review of experts in aging research, rodent animal models and rodent veterinary medicine. This contract renewal will continue all current functions of this unique infrastructure resource for research in the biology of aging.

Scientific/Research Contact

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

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Early and late-stage clinical trials for the spectrum of AD/ADRD and age-related cognitive decline (Re-issue)

The early and late-stage clinical trials FOAs have been the primary avenue for NIA-supported clinical trials focusing on Alzheimer’s disease and Alzheimer’s disease-related dementias (AD/ADRD) and age-related cognitive decline. The NIA currently supports over 200 early- and late-stage AD/ADRD clinical trials, the majority of which were supported via the current and prior versions of this FOA. Until now, the early and late-stage clinical trials FOAs had been separate funding opportunities that went to a single special emphasis panel for review. In this most recent re-issue, we are planning to combine these FOAs into a single FOA covering Phases I-III pharmacological and non-pharmacological clinical trials, as well as clinical trials supporting activities.

The goals of this re-issued FOA are:

  • To invite research grant applications that provide clinical testing (Phase I to III) of promising pharmacological and non-pharmacological interventions for cognitive and neuropsychiatric symptoms in individuals with age-related cognitive decline or AD/ADRD across the spectrum from pre-symptomatic to more severe stages of disease, and
  • To stimulate studies to enhance trial design and methods. Moreover, timely and broad sharing of trial data and biosamples is a key component of this FOA.

Scientific/Research Contacts

Laurie Ryan, Ph.D.
Division of Neuroscience
National Institute on Aging
Email Laurie Ryan

Kristina McLinden, Ph.D.
Division of Neuroscience
National Institute on Aging
Email Kristina McLinden

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Elucidating the roles of transposable elements in AD/ADRD and aging

Nearly half of the human genome is comprised of transposable elements (TEs). Although the majority of TEs have been rendered immobile due to accumulation of mutations during evolution, activation of TEs could have deleterious effects by disrupting the transcriptional landscape and triggering immunologic or other responses. Although the link between TE activation and neurodegeneration or aging has been established, mechanisms underlying these observed associations are largely unknown and the causal relationship remains elusive. Growing evidence demonstrates that the human genome and transcriptome destabilize due to dysregulation and activation of TEs, which is a phenotype observed in many neurodegenerative diseases including Alzheimer’s disease (AD), and during aging and cellular senescence. Recent discoveries related to human endogenous retroviruses, TDP-43, and retrotransposable elements demonstrate that dysregulation of TEs plays critical roles in the pathophysiology of neurodegeneration and aging.

Determining the roles of TEs in AD/ADRD and aging is an emerging field with many great challenges. This FOA will provide targeted support of critical research into the mechanisms underlying activation and regulation of TEs and their causal contributions in AD/ADRD and aging. Targeting TEs will open a new avenue to reveal novel mechanistic insights to expand diagnostic and therapeutic strategies for AD/ADRD and other aging-related diseases. Outcomes of this initiative would significantly improve our understanding of TEs in the following areas:

  • Discover molecular and cellular mechanisms of TE regulation and activation in the context of cell and tissue specificity, disease states, cellular and pathophysiological phenotypes of AD/ADRD, cellular senescence, and aging process.
  • Investigate causal effects and mechanisms underlying TE activation and pathologic protein aggregation such as Tau, TDP-43, Aβ, α-synuclein etc.
  • Define functional role and causal relationship between TE activity and neuroinflammation, inflammaging, or SASP. Identify mechanisms underpinning innate and adaptive immune responses on TEs and HERVs.
  • Elucidate functional roles of TEs contributing to cellular dysfunction or molecular alterations leading to genome instability, neurotoxicity, apoptosis, or cellular senescence.
  • Characterize functional consequences of TE activation that interacts with co-morbidities such as viral infection, vascular compromise, aging, and proteinopathies. Investigate the impacts of these interactions on cellular functions, aging hallmarks, and disease susceptibility and severity.
  • Explore therapeutic interventions interfering TE-mediated molecular pathways and cellular processes. Test TE regulation strategies for improving aging and disease trajectories.

Scientific/Research Contacts

Alison Yao, Ph.D.
Division of Neuroscience
National Institute on Aging
Email Alison Yao

Max Guo, Ph.D.
Division of Aging Biology
National Institute on Aging
Email Max Guo

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High resolution mapping of biomolecules in aging and Alzheimer's brains

The spatial and abnormal distribution of misfolded proteins together with other lipids and small metabolites are thought to play a critical role in the onset of late and sporadic Alzheimer’s disease (AD). However, there is currently no reliable way to determine the accumulation and distribution of various small biomolecules together with pathological hallmarks from the surface of brain sections at all stages of AD. The overall goal of this concept is to generate brain cell type and regional three-dimensional (3D) representations or atlases of biomolecules that change in normal aging and in AD. Specifically, this proposal will encourage interdisciplinary approaches using an emerging mass spectrometry (MS) imaging technology to map and understand the biodistribution, metabolism and accumulation of small biological molecules, such as lipids, neuropeptides and carbohydrates, during the course of aging and Alzheimer’s disease. Traditionally, most “omics” and mass spectrometry-related experiments are commonly conducted through using homogenized brain tissues which are models for investigating the changes of global gene expression and protein composition. Recent single cell “omics” experiments are beginning to characterize neural and glial cell types with some spatial and anatomical details, but they are not addressing neurochemical changes and heterogeneity across an entire brain tissue. Therefore, this initiative proposes to establish a 3D biomolecular atlas of human brain in AD. The biomolecular maps could then be integrated with optical imaging technologies and gene expression profiles of cells in various brain regions to provide comprehensive markers for a detailed brain atlas of aging and AD brains.

Outcomes of this initiative may include:

  • Synthesizing multiparameter and mass spectrometry images into 3D biomolecular brain maps to understand the temporal and spatial relationship between early changes in key AD biochemical hallmarks and alterations of inflammation, lipid and energy metabolism, and synaptic dysfunction.
  • Defining the roles of various AD risk genes in different APOE isoforms in regulating 3D brain regional and cell type specific lipid distribution and signaling networks during the process of normal and pathological brain aging.
  • Establishing a brain small molecule 3D atlas to understand the alteration, transportation, and distribution of small molecules, such ATP/ADP, NADPH/NAD and GSH in regulating oxidative stress and brain energy metabolism in normal brain aging and AD.
  • Developing computational and analytical tools to integrate MS imaging and single-cell ‘omic measurements of brain tissue into “multiparameter’ images with anatomical information.
  • Optimizing high-throughput single cell imaging mass spectrometry and other imaging techniques for mapping and disease staging of normal and AD brains.
  • Developing tools to scale up to collect and analyze multimolecular images across subjects of different ages and across various 3-D brain imaging projects.

Scientific/Research Contact

Austin Yang, Ph.D.
Division of Neuroscience
National Institute on Aging
Email Austin Yang

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Leveraging existing large databases and cohorts to better understand the risks and benefits of long-term osteoporosis therapy and drug holiday

Osteoporosis is a common skeletal disorder in older adults causing loss of bone mass and bone deterioration that leads to increased fracture risk. Each year, about 2 million U.S. adults experience an osteoporotic or other low-trauma fracture, which often cause pain, disability, and impaired quality of life. Most fracture risks increase sharply with age and fracture burden is projected to increase in coming decades as the population ages.

Bisphosphonates (BP) are a first line of pharmacologic treatment for most women and men who have osteoporosis. They are effective when taken for 3-5 years by people who are at high risk of fracture. However, rare but serious adverse events such as atypical femoral fractures and osteonecrosis of the jaw have raised questions regarding their safety, especially in people who use the drugs long-term and who are at low risk for fracture. Reports of these rare adverse events led to a more than 50 percent decline in BP use from 2008 to 2012, as well as low therapy adherence by patients prescribed oral BPs. These trends have raised concern in the medical and professional communities that patients who need pharmacologic intervention are not receiving or taking it, which may lead to a rise in fracture rate.

Most data regarding the appropriate use, benefits and risks of BPs and other fracture prevention drugs come from the clinical trials that led to regulatory approval, generally for treatment duration of 3-5 years. There are limited data on the appropriate long-term use of these drugs beyond this original trial period. Data is likewise scarce on interrupted therapy (drug holidays). It is not known which patients will benefit or may be harmed from continued drug intervention, the appropriate criteria to be put on drug holiday, how to identify at-risk patients and properly treat them, and how to predict their outcomes.

The proposed concept will support the assembly of and support for multi-disciplinary teams to manage large datasets and propose innovative analytical methods to examine this complex interaction on the benefits and risks of long-term osteoporotic drug therapy and management of patient’s outcomes.

Scientific/Research Contact

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

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Pilot studies for the spectrum of AD/ADRD and age-related cognitive decline

NIA’s current clinical trials pipeline for age-related cognitive decline and AD/ADRD consists of two announcements: Early-Stage Clinical Trials for the Spectrum of Alzheimer’s Disease and Age-related Cognitive Decline FOA (PAR-18-877) and Late Stage Clinical Trials for the Spectrum of Alzheimer's Disease and Age-related Cognitive Decline (PAR-18-878). However, to be competitive under the Early-Stage clinical trials FOA, applicants generally must demonstrate some preliminary data. Some PIs lack pilot data at all, or have data from diseases or populations that may not be directly relevant for AD/ADRD trials. In those cases, the only option available to applicants is to apply to the NIH Parent R21, from which applications routed to standing study sections that may lack aging and AD/ADRD clinical trials expertise. This approach can result in less rigorous review and much lower success rates.

We are proposing to extend NIA’s clinical trials pipeline and create an R21 clinical trials FOA focused on gathering directly relevant pilot data specifically for AD/ADRD and age-related cognitive decline clinical trials. Pilot data should be focused on addressing issues of feasibility, safety, tolerability/acceptability. Pilot data under can also be useful further inform aspects of subject selection, trial design, and trial endpoints. The goal of these pilot data is to de-risk novel interventions and approaches, and to improve the likelihood of success at the R01 level. This FOA will further demonstrate NIA’s commitment to developing novel interventions for AD/ADRD and age-related cognitive decline and supporting emerging researchers in AD/ADRD.

Scientific/Research Contact

Kristina McLinden, Ph.D.
Division of Neuroscience
National Institute on Aging
Email Kristina McLinden

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Transition to aging and AD/ADRD career development award

Given the highly competitive academic landscape, transition awards that provide NIH funding for the first three years of the independent research career can significantly increase the candidate’s competitiveness for transition to faculty positions and demonstrate the merits of their research plans as viewed by peer review. Due to the strict K99 eligibility criteria (including a 4-year eligibility window) many postdocs miss the opportunity to apply for this grant and transition into faculty position. There is a need for another NIA program that specifically provides support to the talented, mentored intramural and extramural aging scholars to establish and sustain a successful, and independent research career in aging and AD/ADRD. This new career development award (K22) will be open to mentored intramural and extramural researchers who have not yet received major NIH funding (such as R01 or other K awards). Researchers will work with their current mentor and put together a complete application including research and career development plans for their independent phase. Applicants recommended for funding will have one year to secure a tenure-track (or equivalent) position and submit their transition package which includes offer letter and information on their startup package, institutional commitment, and updated bio-sketch, research, and training plans. This approach will fill a gap of transition awards for candidates ready for a transition including those that have more than four years of postdoctoral experience.

Scientific/Research Contact

NIA Training Officer
Division of Extramural Activities
National Institute on Aging
Email the NIA Training Officer

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The role of adaptive immunity in etiology of Alzheimer’s disease

While the role of innate immunity and microglia in the pathogenesis of Alzheimer’s disease (AD) has been extensively studied, much less is known about the peripheral innate and adaptive branch of immunology in AD. It was nearly three decades ago when the first observations of T cells in AD brains were reported. In the years since, contrasting reports demonstrated the presence or absence of T cells in AD brain with a common ‘thread’ that T cells infiltrating the brain parenchyma in AD do not associate with either plaque or tangle pathology. Today, although still controversial, there is a growing body of evidence on the importance of the adaptive immune system in AD/ADRD pathogenesis. There is a need to understand the heterogeneity of Aβ-specific T cell responses in different genetic backgrounds and MHC context and the role of CD4+ T cell types in AD/ADRD pathogenesis. Recent studies highlight both the importance of adaptive immunity in AD/ADRD as well as some unanswered questions and controversies regarding adaptive immune responses in the context of neurodegenerative diseases. A deeper mechanistic understanding of the immune processes that are at play could facilitate the development of innovative immunotherapies for AD.

The goal of this RFA is to explore the role of the adaptive immune system in the etiology of AD. Research areas of interest to be supported by the FOA may include: research on brain barriers, e.g. the blood brain and blood CSF barriers and meningeal lymphatics in the context of brain adaptive immunity and neurodegeneration; studies on the composition, phenotype and antigen specificity of T cells in the CNS during the neurodegenerative process; composition, phenotype and antigen-specificity of T cells across various brain compartments; characterization of T cells infiltrating protein aggregates in AD brain; characterization of antigen presenting cells and identity of MHC class I and II peptides from APC, microglia in particular; studies on interactions between innate and adaptive immunity during neurodegeneration, e.g. microglia phenotypes and disease progression following manipulations of regulatory T cells; characterization of B cells residing in AD brains and their roles in disease onset and progression; and studies on behavioral outcomes following manipulation of the adaptive immune system. The FOA opens the way to better understanding of brain immune surveillance and the generation of CNS-directed immune responses in neurodegenerative disorders, specifically the functional role adaptive immunity in AD onset and progression. It will shed light on the etiology of the immune imbalance, e.g. between peripheral adaptive and brain innate immune responses, typical of neurodegenerative disorders, with promising implications for therapy. These studies my help with AD diagnostics, risk stratification and discovery of immunotherapeutics.

Scientific/Research Contacts

Miroslaw “Mack” Mackiewicz, Ph.D.
Division of Neuroscience
National Institute on Aging
Email Mack Mackiewicz

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

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

Transformative artificial intelligence based strategies to identify determinants of exceptional healthspan and lifespan

Ongoing NIA-supported studies of exceptional longevity (EL) are in the process of generating a wealth of multi-omic data from exceptionally long-lived individuals and several non-human species with varied lifespans. These projects converge on the major goal of identifying protective genetic/omic based druggable targets to enhance healthy aging by analyzing datasets spanning the phenome, genome, epigenome, transcriptome, proteome, metabolome, and microbiome. The mass and complexity of such omic data generated by these and related NIH projects pose critical analytical challenges for identifying potential therapeutic targets.

Two crucial challenges are:

  • Integrative analyses of data from multiple types of omics, and
  • Integration of human omics data with data from other species with a wide range of life spans.

This concept will bring data scientists with artificial intelligence (AI) expertise into the aging field and stimulate the development of novel methods to integrate, extract, and interpret multi-omic and clinical data from human EL cohorts and multiple non-human species to discover new targets for extending health span and delaying the onset of chronic age-related disorders including dementias. The initiative is timely as a rich resource of multi-omic data will be available in a year or so and this wealth of information can be mined in depth by AI methodologies. The efforts of this initiative in data harmonization could also be leveraged with other harmonization efforts in other ongoing large-scale projects such as AMP AD and ADSP. Overall, this project is expected to enable new directions for translational longevity research.

Scientific/Research Contacts

Nalini Raghavachari, Ph.D.
Division of Geriatrics and Clinical Gerontology
National Institute on Aging
Email Nalini Raghavachari

Candace Kerr, Ph.D.
Division of Aging Biology
National Institute on Aging
Email Candace Kerr

Marilyn Miller, Ph.D.
Division of Neuroscience
National Institute on Aging
Email Marilyn Miller

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Screening and intervention for the maltreatment of older & vulnerable adults with Mild Cognitive Impairment and AD/ADRD and their families

The maltreatment of older adults is a significant public health problem. Elder Maltreatment (EM) includes: physical abuse, emotional or psychological abuse, sexual abuse, neglect or abandonment, and financial exploitation of older adults. Older adults rarely directly disclose maltreatment, and there are no unequivocal signs. Consequently, EM frequently goes undetected in clinical settings. In situations where people with Alzheimer’s disease and Alzheimer’s disease related dementia (AD/ADRD) disclose EM, issues of capacity and competency often cast doubt on the validity of their claims. In addition, clinicians may be faced with complex ethical challenges for both self and the patient. Allegations of EM can result in civil or criminal consequences. However, often no alternative caregiving options are available, and effective interventions for prevention and treatment intervention do not exist. Therefore, clinicians need screening tools to improve diagnostic accuracy and early detection of EM, as well as strategies for prevention and early intervention. Screening patients prior to or early in the course of cognitive decline can help clinicians to identify and provide a brief psychoeducational intervention to patients and families at risk for EM and to direct them to appropriate health and social services.

To these ends, this RFA will request R61/R33 research applications for studies that respond directly to priority research needs and gaps highlighted in the U.S. Preventive Services Task Force’s 2018 final recommendation statement on Intimate Partner Violence, Elder Abuse, and Abuse of Vulnerable Adults: Screening; specifically, for the development and validation of:

  1. Reliable and accurate EM screening instruments or assessments in primary care settings for older and vulnerable adults and medical visit companions, at the time of diagnosis of mild cognitive impairment or AD/ADRD and subsequent primary care encounters and
  2. Brief and effective point-of-care psychoeducational and behavioral interventions for the prevention of all subtypes of EM.

NIA will be particularly interested in applications proposing research that includes measures, and that develops screening tools and interventions, with and for people who have been underrepresented in AD/ADRD intervention research (e.g., racial and ethnic minorities, sexual and gender minority populations (as defined on the home page of NIH’s Sexual & Gender Minority Research Office | DPCPSI) older adults with disabilities and/or low literacy, non-English speakers, and those from socially, culturally, economically, or educationally disadvantaged backgrounds). Applications will be required (1) to use the PICOTS framework, by specifying the Population, Intervention, Comparators, Outcomes, Timing, and Setting, (2) to specify the steps taken to reduce the risk of sampling bias, selection bias, attrition bias, detection bias, performance bias, and observer bias, and (3) to assess individual-level variables in the decision to screen and patient consents, and concordance, in terms of a similarity, or shared identity, between the patient and provider.

Scientific/Research Contacts

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

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

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Social, behavioral and economic research on COVID-19 consortium and coordinating center

Note: This concept was approved electronically by the National Advisory Council on Aging in January 2021.

The COVID-19 pandemic is proving to have long term social, behavioral and economic impacts, so acquiring relevant longitudinal data is critical to study longer term direct and secondary health effects by making use of existing data resources. Specifically, the purpose of concept is to initiate FOAs to advance research on the impact of SARS-CoV-2 and associated mitigation efforts on individual, family, and community behavior; and on how subsequent economic disruption affects health-related outcomes, with close attention to underserved and vulnerable populations. To address these questions, this coordinating center and research grants will form a research consortium to access, extract, integrate, share, and analyze existing data from various sources with broad population coverage including underserved and vulnerable populations. The consortium coordinating center will promote use of common data constructs and support research, dissemination and data management activities. The research grants will serve to advance research on the impact of SARS-CoV-2 by leveraging/enhancing existing longitudinal data. Substantial NIH involvement is required to coordinate data collection along with existing activities supported by NIH and ensure collaboration among research awards. Examples of existing data include public health data; personal digital data; economic, labor, and commerce data; electronic health records, claims data, and ongoing health, demographic, and social surveys.

The consortium coordinating center will foster collaboration and synergies across consortia member projects and other NIH-funded projects that address these priorities. Investigators will work with the consortium coordinating center to enhance and share data resources used in proposed research both within the consortia group as well as with others for health research purposes. The coordinating center will also organize annual meetings of the consortium investigators to share results, foster harmonization among measures collected, identify new opportunities for interaction/collaboration, and share results with NIH and the public. Further, the consortium coordinating center will support the development of reports and analyses summarizing and integrating the findings/products of the consortia.

Scientific/Research Contact

John W. R. Phillips, PhD
Division of Behavioral and Social Research
National Institute on Aging
Email John Phillips

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