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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.

January 2020 Council

Approved concepts in this round:

Late Onset of Alzheimer’s Disease (LOAD) Family-Based Study (FBS)

Analysis of families with multiple members affected (3 or more diagnosed) with Alzheimer’s Disease (AD) provides distinct advantages for characterizing the impact of genetic variants on disease risk:

  • Multiplex families are likely to be enriched for genetic variants associated with increased risk, providing increased statistical power to estimate effects.
  • Family members at risk are regularly followed, facilitating prospective investigation of the effects of genetic variants on age-at-onset and modifying effects of antecedent risk and protective factors.
  • Finally, family data can provide information regarding the influence of known variants on the rate and residual heritability of disease progression.

The NIA LOAD FBS—an integral component of the Alzheimer’s Disease Sequencing Project (ADSP)—began in 2003 with the collection and longitudinal follow up of large multiply affected families. To date the ADSP has sequenced 1,164 multi-ethnic families with 3,929 subjects having whole genome sequencing. The ADSP Follow-Up Study (FUS) heavily engages resources provided by the NIA LOAD FBS and depends upon the longitudinal follow-up of families and the collection of additional families.

The ADSP FUS expects to sequence at least 500 additional multi-ethnic families with the most informative members. The next wave of the NIA-LOAD FBS will extend recruitment within families to other affected members, and future generations of relatives in the age range for collecting baseline data. Characterization of additional relatives’ risk factors and autopsy recruitment will benefit the field and expand the scientific value of the NIA-LOAD FBS.

The NIA LOAD FBS will extend the collection of biological materials beyond those for genetic studies to peripheral blood mononuclear cells (PBMC) for stem cell modeling; plasma for studies of metabolomics, proteomics and biomarker research; and brain autopsy materials for bulk RNA-Seq. These biological materials will be made available to the larger scientific community through NCRAD. Genetic, genomic, and related phenotypic data will be made available through NIAGADS.

As an essential research resource, the NIA LOAD FBS is a key provider of biological materials and clinical data on large multiplex families not only for the ADSP, but also for the Alzheimer Disease Genetics Consortium, the Consortium for Alzheimer's Disease Research, and the network of NIA sponsored Alzheimer's Disease Centers. NIA LOAD FBS PIs actively collaborate with investigators with interest in AD genetics. The NIA LOAD FBS will continue to prioritize coordination with other components of essential ADSP infrastructure and support in the form of biological materials and clinical data for NIA-funded genetic studies. Future success of the initiative depends upon keeping the relationships together.

Scientific/Research Contact:

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

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Development of Cost-Effective and Customizable Training and Education Platforms for AD/ADRD Caregivers that Focus on Addressing Financial Management and Legal Planning

By the close of this decade, the number of family caregivers of adults is expected to increase to 45 million while the number of individuals potentially requiring care is thought to reach 117 million. In 2013 alone, approximately 37 billion hours of care—with an estimated value of $470 billion—was provided by 40 million family caregivers. Caregivers of persons with Alzheimer’s disease (AD) and AD-related dementia (ADRD)—PwD—are faced with additional burden and represent a community in dire need of caregiver education and training platforms.

This imbalance—between the number of estimated caregivers and those seeking care—is exacerbated by the diverse array of duties performed by family caregivers. These duties are broad and varied depending on the PwD’s condition. These include aiding with instrumental activities of daily living (e.g. financial/budget management) among other responsibilities. Caregivers, largely unpaid and without formal training, typically provide this suite of services with very little assistance and consequently experience high levels of emotional, financial, and physical burdens.

Factors contributing to high levels of emotional, monetary, and physical burden for caregivers include among others, the large investment of time and energy in providing care, the absence of formal medical/nursing training, and financial strain from serving as an unpaid caregiver. Compounding these issues is the fact that many caregivers must withdraw from the labor force which could lead them to forgo insurance, promotions, retirement benefits and pensions. The need to alleviate these burdens is underscored by a National Alliance for Caregiving and AARP Public Policy Institute survey which found that nearly 85% of caregivers mentioned a greater need for information about the care services they were providing with more than 40% desiring information on how to manage their stress levels. Of note, caregivers respond with great interest to the prospect of technological tools to help their caregiving but only a small percentage of caregivers currently use tech-enabled services for their daily tasks.

Family caregivers face substantial barriers in personally incorporating technology as a tool to assist them in their caregiving tasks. Some of these barriers include : (a) mismatch between existing technological solutions and stated caregiver needs (b) available tools may not be personalized (or customizable) and lack cultural relevance, and (c) existing technologies are perceived by family caregivers as sole use (i.e. absence of a single platform), too expensive, difficult to use due to complexities in design and function, and only useful in rarely encountered circumstances (e.g. emergencies).

Given the barriers contributing to low-uptake and adoption rates of technology-enabled solutions for family caregivers, there are currently few solutions targeted to family caregivers across the socioeconomic spectrum. This, along with projections that there will be approximately 120 million family caregivers, represents an opportunity and unmet need for solutions that fill in key gaps in service

To address the fractionated nature by which solutions are available to family caregivers in addition to the paltry number of solutions that adapt to expertise levels, specific care demands, and needs of family caregivers, we are seeking solutions that create an integrated web-and-mobile educational platform for family caregivers. The solution should be cost-conscious, scalable, employ a user-centered design approach to promote accessibility for individuals across the socioeconomic spectrum and for individuals with varying levels of technological sophistication, and a solution generalizable to caregivers of non-dementia persons. Proposed products that address legal and estate decision making as well as financial management are of particular interest. While this funding opportunity will support platforms that target caregivers of PwD, it is expected that funded platforms would have applicability beyond dementia.

This concept is supported by both NIA and the HHS Administration for Community Living (ACL) and this collaborative concept was spearheaded by the listed scientific/research contacts

Scientific/Research Contacts:

Todd Haim, PhD
Chief, Office of Small Business Research
National Institute on Aging
Telephone: 301-480-7867
E-mail Todd Haim, Ph.D.

Vijeth Iyengar, PhD
Brain Health Lead & Technical Advisor to the Deputy Assistant Secretary for Aging
Administration for Community Living
Telephone: 202-795-7347
E-mail Vijeth Iyengar, Ph.D.

Dana Plude, PhD
Deputy Director, Division of Behavioral and Social Research (DBSR)
National Institute on Aging
Telephone: 301-435-2309
Email Dana Plude, Ph.D.

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Advancing Research for the Prevention of Multiple Chronic Conditions and Their Consequences

Multimorbidity—also referred to as multiple chronic conditions (MCCs)—is defined as the co-occurrence of two or more chronic health conditions, but the measurement of co-occurring morbidities has not been standardized or optimized. The prevalence of MCCs is rising in the United States and worldwide. According to National Health and Nutrition Examination Survey data, 60% of adults aged 20 and older in 2014 had two or more chronic conditions, an increase from 46% in 1998. An estimated two thirds of older adults have two or more chronic conditions.

Furthermore, other sub-groups of the U.S. population experience a disproportionate burden of MCCs and health inequities related to MCCs. Women, African Americans, Hispanics, and non-Hispanic Whites have the highest prevalence of MCCs. Asians/Pacific Islanders experience the highest mortality and cost per case compared to all other groups. Minority populations also tend to experience earlier onset of MCCs compared with majority populations. Limitations in measurement and methods have hampered progress in this research arena.

The Cochrane Collaboration (2016) review of interventions designed to address co-occurring MCCs among adults across the prevention-to-treatment-continuum showed mixed results on efficacy. Areas identified that need more research include clinical outcomes, use of health services, medication adherence, patient-related health behaviors/risk behaviors, behaviors of healthcare providers related to care delivery, and health care costs. Multimorbidity interventions showed some promise in improving depression outcomes when depression was one of the co-occurring morbidities.

Additionally, interventions focused on functional status led to modest improvements in functional outcomes among those with MCCs. Finally, given that most chronic conditions share many risk factors and pathways, interventions for MCCs should focus on common risk factors, many of which are behavioral. However, few intervention studies have focused on the recent advances from geroscience and combined with an approach to addressing these risk factors.

This concept, a collaboration with the NIH Office of Disease Prevention, is intended to address two key gaps in measurement of MCC and related factors along with development of interventions to prevent, delay, or manage the progression of, co-occurring MCCs and their consequences. First, interventions focused on co-occurring MCCs and MCCs in vulnerable populations may be best targeted to risk factors that are common to multiple conditions (e.g. mental health, functional abilities and possibly others). The paucity of studies is primarily focused on treatment and indicate a need for more research related to interventions designed to prevent, delay or manage the progression of co-occurring MCCs in the population. Second, many of the MCC-related intervention studies and published research are focused on older adults, a period in life when co-occurring MCCs are most prevalent.

However, little research has focused on prevention of MCCs or on addressing risk factors for MCCs at different stages across the lifespan. Many groups called for interventions that incorporate partnership models involving collaborations between communities and health care systems, particularly within primary care. Populations that experience MCCs are diverse by race, ethnicity, socioeconomic status and other social determinants. Interventions developed to address risk factors for, or delay, the progression of co-occurring MCCs may be more effective in reaching the most at-risk populations through such partnership approaches.

Scientific/Research Contact:

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

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September 2019 Council

Approved concepts in this round:

Aging Research Dissertation Awards to Increase Diversity

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

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

Scientific/Research Contact:

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

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

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

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

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

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

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

Scientific/Research Contacts:

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

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

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Artificial Intelligence and Technology Centers for Aging Research

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

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

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

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

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

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

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

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

Scientific/Research Contact:

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

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Central and Peripheral Control of Balance in Older Adults

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

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

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

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

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

Scientific/Research Contacts:

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

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

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Emotional Well-Being: High Priority Research Networks

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

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

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

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

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

Scientific/Research Contact:

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

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Glial Plasticity in the Aging Brain

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

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

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

Scientific/Research Contact:

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

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

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

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

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

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

Scientific/Research Contact:

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

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Mechanisms of Rejuvenation and Accelerated Aging in Heterochronic Blood Exchange

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

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

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

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

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

Scientific/Research Contacts:

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

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

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

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

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

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

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

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

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

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

Scientific/Research Contacts:

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

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

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New/Unconventional Animal Models of Alzheimer’s Disease

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

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

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

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

Scientific/Research Contact:

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

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Oligomer Seed Bank Initiative

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

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

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

Outcomes of this initiatives might include:

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

Scientific/Research Contact:

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

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

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

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

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

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

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

Scientific/Research Contact:

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

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Prodromal α-Synucleinopathies Consortium

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

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

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

Scientific/Research Contacts:

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

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

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

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

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

Scientific/Research Contact:

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

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Stem Cell Aging and Oncogenic Transformation

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

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

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

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

Scientific/Research Contacts:

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

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

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May 2019 Council

Approved concepts in this round:

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

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

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

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

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

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

Scientific/Research Contact:

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

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Implementation Research on Hypertension Control to Prevent Dementia and Cognitive Decline

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

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

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

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

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

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

Scientific/Research Contact:

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

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Lipid Signaling in Healthspan and Longevity Regulation

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

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

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

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

Scientific/Research Contact:

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

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Paul B. Beeson Emerging Leaders Career Development Award in Aging

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

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

Scientific/Research Contact:

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

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Research Infrastructure Development for Interdisciplinary Aging Studies Program

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

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

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

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

The recently approved concept now allows renewal of these FOAs.

Scientific/Research Contact:

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

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

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

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

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

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

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

Scientific/Research Contacts:

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

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

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The Biological Mechanisms of Metformin Effects on Aging and Longevity

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

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

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

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

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

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

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

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

Scientific/Research Contact:

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

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

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

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

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

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

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

Scientific/Research Contacts:

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

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

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