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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 2019 Council

Approved concepts in this round:

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

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

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

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

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

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

Scientific/Research Contact

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

Implementation Research on Hypertension Control to Prevent Dementia and Cognitive Decline

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

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

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

Demonstration projects using multiple strategies for system level interventions may provide innovative approaches to address and overcome important barriers. They can address known disparities in hypertension care and outcomes. Health care systems have interest in participating in studies that may potentially impact the care they deliver, including pragmatic clinical trials.

We define pragmatic trials as trials “primarily designed to determine the effects of an intervention under the usual conditions in which it will be applied”, which is in contrast with explanatory trials that “are primarily designed to determine the effects of an intervention under ideal circumstances”1. Pragmatic trials are also well-suited for testing how readily practice guidelines can be implemented in health care systems, and for assessing outcomes of implementation across a broad and diverse range of patient subgroups.

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

Scientific/Research Contact

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

Lipid Signaling in Healthspan and Longevity Regulation

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

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

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

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

Scientific/Research Contact

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

Paul B. Beeson Emerging Leaders Career Development Award in Aging

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

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

Scientific/Research Contact

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

Research Infrastructure Development for Interdisciplinary Aging Studies Program

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

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

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

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

The recently approved concept now allows renewal of these FOAs.

Scientific/Research Contact

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

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

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

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

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

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

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

Scientific/Research Contacts

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

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

The Biological Mechanisms of Metformin Effects on Aging and Longevity

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

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

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

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

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

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

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

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

Scientific/Research Contact

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

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

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

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

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

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

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

Scientific/Research Contacts

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

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

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February 2019 Council

Approved concepts in this round:

Aging, Driving and Early Detection of Dementia

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

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

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

Scientific/Research Contact

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

Basic Biology of Aging in Reproductive Tissues

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

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

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

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

Scientific/Research Contacts

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

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

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

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

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

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

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

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

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

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

Scientific/Research Contact

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

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

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

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

Given the anticipated demand for and shortage of paid caregivers over the next decade, specifically home health and personal care aides2, this topic is a timely opportunity to understand the health impact of these settings. The initiative will add to the body of evidence focusing on the availability and accessibility of LTSS as well as optimizing health-related outcomes for PWD, including less reliance on anti-psychotic drugs, reduced wandering, greater social engagement, decreased delirium, and improved quality of life. Services of great importance, but that are under-studied include home health care and adult day services. Research should address availability of these non-residential home and community-based health services that impact both the immediate quality of life for persons living in the community with dementia as well as the likelihood of nursing home admission for persons with dementia. The initiative will encourage addressing disparities in access to services such as adult day and home health care.

2Bureau of Labor Statistics. “Occupational Outlook Handbook: Fastest Growing Occupations.” U.S. Department of Labor. (accessed December 13, 2018).

Scientific/Research Contact

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

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

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

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

Scientific/Research Contact

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

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

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

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

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

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

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

Scientific/Research Contacts

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

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

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

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

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

Examples of individual OAIC themes include:

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

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

Each OAIC has an organizational structure involving the following cores:

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

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

Scientific/Research Contact

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

Genome Center for Alzheimer’s Disease (GCAD)

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

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

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

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

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

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

Scientific/Research Contact

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

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

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

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

Scientific/Research Contacts

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

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

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

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

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

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

Scientific/Research Contact

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

Infectious Etiology of Alzheimer's Disease

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

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

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

The initiative will:

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

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

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

Scientific/Research Contacts

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

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

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

Innovations to Foster Healthy Longevity in Low-Income Settings

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

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

Scientific/Research Contact

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

Interpersonal Processes in AD/ADRD Clinical Settings

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

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

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

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

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

Scientific/Research Contact

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

Lucidity in Dementia

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

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

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

Scientific/Research Contacts

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

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

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

Non-invasive Neurostimulation in AD/ADRD

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

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

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

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

Scientific/Research Contact

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

NRSA Short-Term Institutional Research Training Grant

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

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

Scientific/Research Contact

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

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

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

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

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

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

Scientific/Research Contact

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

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

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

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

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

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

Scientific/Research Contacts

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

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

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

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

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

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

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

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

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

Scientific/Research Contact

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

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

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

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

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

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

Scientific/Research Contact

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

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

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

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

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

Scientific/Research Contact

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

Science of Behavior Change (SOBC) Resource and Coordinating Center

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

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

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

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

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

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

Scientific/Research Contact

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

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

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

The initiative will:

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

Scientific/Research Contact

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

Tailoring Interventions to Improve Preventive Health Service Use

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

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

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

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

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

Scientific/Research Contact

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

Transition to Aging Research Award for Predoctoral Students

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

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

Scientific/Research Contact

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

Understanding Senescence in Brain Aging and Alzheimer’s Disease

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

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

Scientific/Research Contact

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

Back to contents

May 2018 Council

Approved concepts in this round:

A Census of Cells and Circuits in the Aging Brain

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

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

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

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

Scientific/Research Contact

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

Alzheimer’s Disease Genetics Consortium

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

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

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

New initiatives may include:

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

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

Scientific/Research Contact

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

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

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

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

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

Scientific/Research Contacts

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

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

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

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

Scientific/Research Contacts

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

Exploring Molecular Links Between Dietary Interventions and Circadian Rhythm

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

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

Scientific/Research Contact

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

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

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

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

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

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

Scientific/Research Contacts

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

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

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

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

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

Scientific/Research Contacts

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

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

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

Low-Cost Detection of Cognitive Decline in Clinical Settings

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

Development Work:

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

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

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

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

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

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

Scientific/Research Contacts

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

Marmosets as a Translational Model for Aging Research

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

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

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

Scientific/Research Contacts

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

Microbiome and Aging: Impact on Health and Disease

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

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

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

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

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

Scientific/Research Contacts

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

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

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

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

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

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

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

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

Scientific/Research Contacts

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

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

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

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

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

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

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

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

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

Scientific/Research Contacts

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

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