THE JOHNS HOPKINS UNIVERSITY
Claude D. Pepper Older Americans Independence Center

Jeremy Walston, M.D.
Principal Investigator
  410-550-1003   jwalston@jhmi.edu
Karen Bandeen-Roche, Ph.D.
Principal Investigator
  410-955-3067   kbandee1@jhu.edu
Brian Buta, MHS
Program Administrator
  410-502-3412   bbuta@jhu.edu
     
CENTER DESCRIPTION

Since its inception in 2003, the Johns Hopkins University (JHU) Older Americans Independence Center (OAIC) has pursued a rigorous and distinctive scientific approach considering physical frailty as a biologically-rooted state of decreased resiliency and reserve, which induces a syndromic phenotype and specific etiological mechanisms. As evidenced by peer-reviewed publications and associated NIH grant funding, this specific conceptualization of frailty has provided a highly productive framework for population-based, clinical, and biological discovery, for the development of potential prevention and treatment strategies, and for the training of junior investigators for academic careers in frailty and aging research.

This center’s mission remains, in many respects, as it has been throughout the life of our OAIC: To make fundamental etiological discoveries related to frailty, move these towards frailty-focused interventions, develop evidence-based guidelines for the prevention and management of adverse outcomes in frail older individuals, identify new investigators dedicated to these ends, and provide supported investigators with the expertise, resources, and training necessary to lead the next generation of frailty-related scholarship and practice. Given the rapidly growing interest in frailty, its detection, its management, and the critical mass of frailty-related knowledge that this OAIC has generated, we have launched an Information Dissemination Core (IDC) to enable our OAIC to more comprehensively disseminate frailty-related findings so as to better impact clinical and public health practice.

We pursue our mission through the following specific aims:

  1. To stimulate, lead and develop effective frailty-focused interdisciplinary research programs that promote the maintenance of independence. This has helped to create a vibrant and growing center with scientific vigor and a rich interdisciplinary milieu of experienced faculty and successful trainees focused on frailty research.
  2. To translate the new knowledge generated in this OAIC into targeted prevention and treatment strategies that help older adults maintain independence. An existing clinical translational resource core, an IDC, and the national OAIC network facilitate this effort.
  3. To provide the highest quality expertise, support, infrastructure and technology in biological, data analytic and clinical research methodologies to OAIC investigators.
  4. To support the development of new and innovative methodologies, research strategies and technologies essential to the study of frailty. Aims 3 and 4 are organized through Biostatistics, Biological Mechanisms, and Clinical Translational cores.
  5. To provide tailored training and mentorship to junior investigators interested in developing careers focused on frailty in older adults. We continue with a leadership team that has demonstrated expertise and commitment to training the next generation of investigators.
  6. To attract outstanding investigators and trainees to frailty research from across the Johns Hopkins University and beyond. We augment our successful local approach to this by providing highly visible educational and training activities on a local and national level, and through the IDC.

CORES
Leadership and Administrative Core (LAC)
Leader 1:    Karen Bandeen-Roche, PhD   kbandee1@jhu.edu
Leader 2:    Jeremy Walston, MD   jwalston@jhmi.edu
The Leadership/Administrative Core (LAC) spearheads the vision for the Johns Hopkins Older Americans Independence Center (JHU OAIC), sets goals through which to implement it, and assures energy and quality in accomplishing goals. It leads in identifying the next generation of research on frailty that should be created, supports research planning and recruitment of investigators, and sets and monitors progress benchmarks. It is the OAIC base for recruiting and nurturing a critical mass of investigators dedicated to the creation of high impact, innovative research essential to the prevention and treatment of frailty in older adults. It administrates the OAIC and its Cores for soundness of operations and accomplishes required reporting. It promotes a stimulating intellectual environment around scholarship on frailty so as to attract outstanding researchers and knit them into an interdisciplinary community. It creates visibility for the accomplishments of the OAIC locally and globally: In the current cycle it leverages a new Information Dissemination Core (IDC) to amplify these efforts. The LAC is led by OAIC Co-Principal Investigators with broad interdisciplinary scientific expertise and institutional reach. They work closely with the other OAIC Cores Directors, and with a diverse Leadership Council and Internal Advisory Committee to develop and promote a frailty-focused agenda across the Johns Hopkins University. An experienced External Advisory Board reviews this OAIC annually, and provides crucial feedback and additional scientific vision. The LAC provides essential leadership in planning, integrating, sustaining, implementing and monitoring OAIC operations. Its goals are to envision and then support research leading to new strategies to enhance independence in older Americans and to create a new generation of research leaders in the field.

Research Education Component (REC)
Leader 1:    Gary Gerstenblith, MD   gblith@jhmi.edu
The purpose of the Research Education Core (REC) is to foster the career development of junior faculty from multiple disciplines into academic scientists in gerontology and geriatrics, focusing on the theme of exercise and activity rehabilitation and recovery research. The REC supports mentor-based research training and education to promote the career development of REC Scholars as well as other junior faculty, fellows, and students pursuing research careers in aging. The UM-OAIC has a successful history of mentored training that crosses traditional disciplinary boundaries to develop novel research for improving function and independence in older persons. This has enriched the cadre of scientists at UM and elsewhere conducting aging research in exercise and rehabilitation science.

Pilot and Exploratory Studies Core (PESC)
Leader 1:    Neal Fedarko, PhD   ndarko@jhmi.edu
The major goal of Pilot and Exploratory Studies Core (PESC) is to cultivate and support innovative pilot and exploratory studies that are needed to develop crucial larger scale and confirmatory studies to advance the development of effective prevention and/or therapies for frailty, and hence facilitate independence in older adults. The PESC provides funding, access to biostatistical, biological, and clinical research core resources, and mentoring and oversight pilot and exploratory studies. Because of the importance of these studies to the development of new scientific priorities, additional resources are provided to this core to help maximize flexibility, efficiency, and rapid development of areas of focus for this OAIC. The PESC Core, in close collaboration with the OAIC Leadership Council, sets ideas the next stages of research most essential to advancing science on frailty, and then works to identify investigators whose expertise and career goals are applicable to furthering knowledge in these target areas. The leadership and resources of these cores are then focused on the development, conduct and eventual translation of high impact pilot studies. The proposed studies must be novel and either hypothesis-driven or focused on development of methods needed to validly address hypotheses: they ideally address potential mechanisms, etiologies, or screening approaches for frailty, or lay groundwork for evaluating potential therapies to prevent or treat the frailty and its consequences and hence maintain independence. It is expected that PESC-supported studies establish preliminary data that will lead to substantive, long term external funding that can bring the research initiated to completion. Given our roadmap goals of accelerating translation of frailty to increase healthspan in clinical and public health settings, elucidating the biological underpinnings and role of multisystem dysregulation in frailty and resilience, and improving ascertainment of frailty measurement in settings that challenge measurement, special focus was given to these areas for the PESC studies funded by our OAIC.

Resource Core 1 (RC1): Biostatistics Core (RC1)
Leader 1:    Qian-Li Xue, PhD    qxue1@jhu.edu
Leader 2:    Karen Bandeen-Roche, PhD   kbandee1@jhu.edu
The Johns Hopkins Older Americans Independence Center (OAIC) has empowered by many-fold the creation of significant research, training and practice paradigms for addressing frailty in older adults. The functions supplied by this Biostatistics Core have been central in this. They include: our key roles in the mentorship and training of junior colleagues in the statistics of frailty and aging; our development and dissemination of emerging resources and technologies for data management and analysis; our provision of database and statistical expertise and support to scholarship on frailty and aging, needed methodological innovation, and collaborative intellectual leadership for the creation and translation of research on frailty. Outcomes of this Core, in collaboration in this OAIC and beyond, include advancement of knowledge on the ascertainment, biological and etiological underpinnings, health consequences, and treatment of frailty, research surmounting significant methodological challenges to the study of frailty, and the creation of intellectual capital and infrastructure for further advances. These have laid crucial groundwork for intervening on frailty. For nearly 20 years our Biostatistics Core has dedicated a critical mass of leadership from gerontologically informed biostatisticians toward the amelioration of frailty in older adults through our OAIC, and its leadership has dedicated the same to research on aging for 30+ years. Our leadership and our external advisory committee consider it crucial that this Core continue to contribute to the OAIC’s overarching aims through the intellectual innovation, collaboration and support it provides. 

Resource Core 2 (RC2): Biological Mechanisms Core (RC2)
Leader 1:    Peter Abadir, MD, PhD   pabadir1@jhmi.edu
Leader 2:    Dan Arking, PhD   darking@jhmi.edu
Advances in in understanding of molecular and physiological processes that influence aging phenotypes, and in methodologies that help to measure these changes, have greatly improved our ability to identify biological pathways that are potentially relevant to the etiology of frailty.  The major goal of this core is to promote molecular and biological studies of aging and frailty-relevant pathways, and to translate these findings into relevant diagnostic, preventive and treatment strategies. Building on our prior cycles, mitochondrial biology, chronic inflammation, renin angiotensin system, and genetics continue to be a core expertise content offered to investigators from within the core.  We have also gained expertise and collaborators at Johns Hopkins who have considerable “omics” and in computational biology expertise.   These technologies have provided a logical basis for searching and identifying specific biomarkers associated with human phenotypes and diseases; they can not only provide markers for human disease that are useful for nosology in heterogeneous clinical phenotypes but, more importantly, provide deep insight into pathophysiology and disease mechanisms that will form the bases for future diagnostics and treatments.   Consequently, the rationale for RC-2 is to provide the expertise, technology access and infrastructure, mentoring, and training necessary to facilitate the highest quality etiologic research in frailty.

Resource Core 3 (RC3): Clinical Translation and Recruitment Core (RC3)
Leader 1:    Todd Brown, MD   tbrown27@jhmi.edu
In order to more effectively meet JHU OAIC’s goal of translating frailty-related etiological discoveries into clinical studies that help maintain independence in older adults, and to overcome the substantial barriers to success in clinical investigation for junior investigators,  the leadership of this OAIC made a strategic decision to develop this resource core. RC-3 provides to supported OAIC investigators: 1) comprehensive training and mentorship in clinical research that spans from study design through implementation through outcome interpretation, 2) clinical research space and assistance with all aspects of forms and protocol development, data collection, and recruitment of human subjects,  3) an active registry of more than 650 older adults who have consented to be contacted for aging and frailty related studies, and 4) synergy with other cores in order to optimize all aspects of frailty-related study design, data collection, and biological measurement and junior faculty training.  This synergy is greatly augmented by our core leader, Dr. Todd Brown, an endocrinologist with considerable human subjects research expertise and leader in the ICTR at Johns Hopkins, who leads RC-3.  The daily operations are led by a highly skilled and experienced research program manager with expertise in the measurement of frailty, mobility, and cognition, as well as expertise in protocol development and implementation and in subject recruitment and retention, in coordination with our OAIC administrator and Drs. Brown and Walston.  This initiative, which is closely aligned with the JHU Division of Geriatric Medicine and Gerontology's goals of better integrating clinical practice with clinical research, is funded in part by philanthropic resources. 

Information Dissemination Core (IDC)
Leader 1:    Jeremy Walston, MD   jwalston@jhmi.edu
To improve the reach and use of the evidence-based knowledge on frailty that emanates from JHU OAIC-supported research and elsewhere, we developed a state-of-the art Information Dissemination Core (IDC) with a highly experienced partner: the Johns Hopkins Center for Communication Programs (CCP). CCP has long standing, high-profile expertise and experience in knowledge management (KM) and dissemination science, with clients including USAID, The Bill and Melinda Gates Foundation, and UNICEF. The development of this close partnership between knowledge management experts at CCP and the frailty related content experts who lead this OAIC provided a highly rigorous yet accessible approach to more efficiently and effectively disseminate frailty-related findings and recommendations to a broader audience using cutting edge approaches. We envision that this audience will include researchers, students, clinicians, professional societies and foundations, policymakers, and older adults seeking information on frailty. Indeed, our overarching goal is to have this IDC become a national and international ‘go-to’ resource for the latest information and resources related to frailty science from this OAIC and as well as other authoritative sources: We seek ultimately to accelerate incorporation of best practices for addressing frailty in health practice and promotion, so as to benefit older adults. 

CAREER DEVELOPMENT
REC Scholar, Research & Grants Funded During Pepper Supported Time Years /
Publications
 
Melissa deCardi Hladek PhD, CRNP, FNP-BC
Assistant Professor / Johns Hopkins School of Nursing
Using Human-Centered Design to Adapt CAPABLE as a Prehabilitation Intervention for Adults with Frailty Awaiting Kidney Transplant
Over 700,000 Americans live with end-stage renal disease (ESRD), disproportionally affecting older adults, minority groups and those with lower socioeconomic status. ESRD is best treated with kidney transplant (KT) which increases life expectancy, functional ability and quality of life. Frailty is associated with higher KT waitlist mortality and worse KT surgical and post-surgical outcomes. As such, frailty is increasingly being evaluated in pre-surgical settings to plan for post-surgery recovery. There is an urgent need to further understand and intervene on the co-occurrence of frailty and KT. Beyond the need to improve surgical outcomes, there are stark health disparities in patients awaiting KT. Due to medical comorbidities, socio-economic constraints, or incomplete testing, Black and Hispanic individuals are more likely to change from active waitlist status (meaning able to receive a KT at any time) to inactive waitlist status (not currently eligible to receive KT) and are more likely to remain classified as inactive longer. There is an urgent need to further understand this disparity and create interventions to lessen it. Person-environment fit posits that improving a person’s lived environment will facilitate optimal individual functioning. CAPABLE is an evidence-based intervention that helps functionally limited, low-income older adults successfully age in their homes with better function and quality of life. It has been tested with in-center hemodialysis patients (N=12) which showed meaningful improvements in function and social network scores. This model, however, has not been applied to KT waitlist populations. We propose adapting CAPABLE as a KT prehabilitation program to accomplish two things: 1) To resolve barriers to being classified as active on the KT waitlist and 2) as a surgical prehabilitation intervention targeting the pre-frail/ frail KT waitlist population. We will accomplish this through a 3-phase human-centered design process, which engages the end users of the intervention throughout the research process to tailor interventions to their needs, behaviors and preferences. This work will form the basis for a future K01 proposal to pilot test the CAPABLE-KT prehab adaptation and R01 level funding to expand into other surgical populations conducting a larger community-based, comparative effectiveness trial. The proposed and subsequent studies will help inform the role of person-environment- focused prehabilitation interventions in surgical outcomes for vulnerable, frail populations.
2021-2023 /
1 (total)
1 (1st/Sr)
 
Gizem Keceli, PhD
Postdoctoral Fellow / Johns Hopkins School of Medicine, Division of Cardiology
Dissecting the Mechanisms Whereby Tryptophan Metabolites Alter Myocardial Function
Cardiovascular diseases (CVD) are a significant cause of morbidity and mortality in the elderly population and represent an important risk factor for frailty. Furthermore, frail patients have a heightened propensity to suffer from adverse outcomes of CVD. Studies emphasize the role of the altered kynurenine (kyn) pathway in the aging process and reveal its link to frailty. In recent clinical reports, increased levels of kyn and/or its metabolites, formed via degradation of the essential amino acid tryptophan, are associated with heart diseases and atherosclerosis. However, if these metabolites directly affect cardiac function is not known. In my pilot studies, kyn significantly impaired cardiac function. Similarly, in isolated cardiac cells, kyn infusion decreased the shortening ability and increased oxidative stress, an important contributor to many age-related CVD. Accordingly, I hypothesized that activated tryptophan degradation escalates ROS formation, jeopardizing cardiovascular function and prompting abnormal cell growth. In Aim1, I will explore whether kyn or its metabolites impact cardiac function directly by determining the functional parameters and ROS levels in isolated hearts/cells. In Aim2, I will investigate if kyn or its metabolites' accumulation induces abnormal growth of cardiac cells and examine the implicated mechanisms underlying kyn-induced alterations. The short-term goal is to gain insight into the potentially detrimental effects of the activated kynurenine pathway on cardiac function and determine whether, via enhanced ROS production, it drives maladaptive hypertrophy and loss of myocyte function. Overall, these studies will provide a better understanding of the reasons underpinning increased CVD risk in frailty and age-related cardiac dysfunction, thus facilitating new therapies.
2021-2023 /
1 (total)
1 (1st/Sr)
 
Lolita Nidadavolu, M.D., Ph.D.
Assistant Professor / Johns Hopkins University School of Medicine
Identifying mechanisms by which circulating-cell free DNA contribute to increased TNFR1 in frailty
Frailty, characterized by vulnerability to physical and psychosocial stressors, is an aging-related syndrome that contributes to increased mortality and is associated with changes in cell and tissue homeostasis (apoptosis, necrosis) and increased inflammation, in particular tumor necrosis factor receptor 1 (TNFR1). Circulating cell-free DNA (ccf-DNA) from genomic and mitochondrial DNA are released as a result of these cell death processes and the relative size of mitochondrial ccf-DNA fragments is related to different mechanisms of cell death. Our preliminary data shows strong associations between cell necrosis-associated mitochondrial ccf-DNA and serum TNFR1 levels as well as between TNFR1 levels and age-related physical decline. Mitochondrial ccf-DNA fragments are detected by innate immune system DNA sensors such as the cyclic GMP-AMP synthetase-stimulator of interferon genes (cGAS-STING) pathway, which is theorized to lead to upregulation in TNFR1. This proposal hypothesizes that frailty-associated increases in TNFR1 are mediated by higher levels of necrosis-associated mitochondrial ccf-DNA and upregulation in STING signaling. Aim 1 will characterize changes in the cGAS-STING signaling pathway with aging and frailty. Aim 2 will measure changes in robust older adult peripheral monocyte TNFR1 expression following treatment with necrosis-associated mitochondrial ccf-DNA from frail individuals and will examine how cGAS-STING mediates this relationship. The overall goal of this project is to identify innate immune system pathways for future intervention studies that can help attenuate frailty-associated chronic inflammation.
2021-2023 /
4 (total)
1 (1st/Sr)
 
Nicholas R. Rowan, MD
Assistant Professor / Johns Hopkins Department of Otolaryngology-Head and Neck Surgery
The implications of olfaction with frailty, a population-based and exploratory investigation
The ability to smell, olfaction, is an understudied sensory function with significant implications in health and aging. Olfactory dysfunction (OD) is incredibly common, afflicting approximately one fourth of the global population, and markedly increases with age. While OD has inherent dangers, such as placing individuals at increased risk of environmental hazards, disruption of this special sense has substantial psychosocial and well-being implications in the aged population. Olfaction has been identified as a bellwether of mortality, and there is mounting evidence that OD is a harbinger of multisystem, physical frailty. Often times overlooked, olfaction may represent a novel physiologic measure of frailty and mechanism to identify impending critical transitions in the continuum of frailty. The inherent neuroplasticity of this special sense also represents a modifiable risk factor and an attractive intervention target for vulnerable aging adults. In an effort to better understand appropriate olfactory screening measures and olfaction-related targets for interventional studies, we aim to utilize a robust, nationally-representative database that includes multiple measures of olfaction and phenotypic frailty assessments. Through this approach, differences between self-reported OD and more detailed psychophysical olfactory assessments will be examined. We will also evaluate validated self-reported metrics and novel psychophysical subdomain scores in a cross-sectional case-control cohort. Intrinsic differences in the underlying neurophysiologic mechanisms of these unique subdomains will provide insight into the underlying pathogenesis of olfactory dysfunction and its relationship to frailty. By employing innovative approaches to characterize olfactory deficits, substantiated by detailed psychophysical assessments, our results will offer mechanistic insight for olfactory loss in older adults and serve as a springboard for future interventional investigations aimed at the mitigation of OD and frailty in this population.
2021-2023 /
2 (total)
0 (1st/Sr)
 

Past Scholars
Alden Gross, PhD, Epidemiology (2014-2016)
Charles H. Brown IV, MD , Anesthesiology and Critical Care Medicine (2014-2016)
Charles H. Brown IV, MD , Anesthesiology and Critical Care Medicine (2014-2016)
Rani Hasan, MD, MHS, Cardiology (2015-2018)
Tae Chung, MD, Physical Medicine and Rehabilitation (2016-2018)
Abdulla Damluji, MD, PhD, Cardiology (2017-2019)
Orla Sheehan, MD, PhD, Geriatric Medicine (2018-2020)
Pei-Hsun Wu, PhD, Institute for NanoBioTechnology (2018-2020)
Bharath Ambale-Venkatesh, PhD, Radiology and Radiological Science (2018-2020)
Reyhan Westbrook, PhD, Geriatric Medicine (2018-2020)
Keenan Walker, PhD, Neorology (2019-2019)
Sabra Lewsey, MD, Division of Cardiology (2020-2021)
Jude Phillip, PhD, Department of Biomedical Engineering (2020-2021)

PILOT/EXPLORATORY PROJECTS (11 Pilot Projects Listed)
1. Project Title: Pilot Behavioral Intervention to Address Pain and Frailty in Older African-American Women
  Leader: Janiece Taylor, PhD, RN, Mary Catherine Beach, PhD; Sarah L. Szanton PhD, ANP, FAAN, Roland J. Thorpe Jr., PhD
  Older African American women are crucial to target for intervention not only because of their heightened frailty prevalence, but because they are at higher risk of pain than other racial/ethnic groups and African American men and have exacerbated relationship and outcomes of frailty and pain. They often experience difficulties communicating with health care providers, moreover, that may interfere with treatment of symptoms related to pain and frailty: Communication intervention has well documented potential to lessen these difficulties and result in better disease management. Specific aims of this study are: 1) To pilot a tailored behavioral activation intervention focused on improving frailty, chronic pain, and depressive symptoms among community dwelling older African American women and collect summary data needed to design a confirmatory intervention trial. Strategies will be non-pharmacologic and aim to improve communication, physical activity and education. 2) To determine a) feasibility and acceptability of the intervention b) if strategies and evaluation techniques were appropriate.
 
2. Project Title: Exploratory Study of Metabolomics Energy Signatures in Frailty
  Leader: Anne Le, MD, Reyhan Westbrook, PhD
  Building on a small PES awarded to Drs. Le and Westbrook that utilized a frail mouse model previously characterized in RC-2, altered metabolomics signatures were identified that suggest that TCA cycle processes are a component of dysregulated energy utilization in frailty. Given this background, we hypothesize that specific patterns of altered energy metabolites linked to glucose metabolism through mitochondrial bioenergetics, biosynthesis, and redox homeostasis pathways can help to distinguish frail from non-frail older adults, and that the circulating concentrations of metabolites related to glucose metabolism are measurably different between frail and non-frail older adults. Utilizing research resources from all three resource cores, and Dr. Le’s established metabolomics measurement infrastructure (Metabolomics facility) and expertise in energy metabolism measurement, the following specific aims were proposed: 1) To utilize metabolomics measurement to reconstruct the relevant metabolic pathways of glucose metabolism related to bioenergetics, biosynthesis, and redox homeostasis, and determine differences between frail and non-frail participants, and 2) To identify the most promising biomarkers for a frailty-related energetic signature and plan for a future targeted validation study of diagnostic utility and biological discovery.
 
3. Project Title: Association between Sleep Deficiency and Frailty: What harms most?
  Leader: Naresh Punjabi, MD, PhD, Jiawei Bai, PhD
  Epidemiologic surveys show that at least 50% of adults over 65 years in age have sleep-related complaints. Sleep disturbance has been associated with neurohormonal, circadian, and homeostatic alterations: As many such changes have been evidenced by this OAIC and others to also underlie frailty, it reasonable to expect interconnections between sleep quality and frailty. We hypothesize that disordered sleep heightens risk for frailty onset and believe that intervention to improve sleep can prevent or buffer frailty. Prior studies indicate that poor sleep quality is associated with frailty. These predominantly have assessed sleep, however, by either self-report or relatively crude summaries (e.g. time in sleep states) of actigraphy or polysomnography data. This project uses data from the community-based Sleep Heart Health Study (SHHS) to extract power spectral “curves” summarizing the history of the overnight sleep EEG, by functional principal components analysis (fPCA), and identify sleep EEG signatures highly associated with frailty prevalence, incidence and transitions, and vice versa.
 
4. Project Title: PCSK9 Links Age and Frailty Inflammation to Endothelial Cell Dysfunction
  Leader: Thorsten Leucker, MD, PhD, Gary Gerstenblith, MD.
  One of the most significant aspects of aging is the marked increase in mortality and significant lifelong disability due to coronary vascular and cerebrovascular disease respectively. There is heterogeneity in that risk with a significant increase in older individuals with frailty and those with the prediabetes, both of which are increased with age and independently associated with vascular disease. Many preclinical and clinical studies indicate that inflammation is a common predisposing factor but the link between inflammation and vascular disease in older adults and particularly in those with frailty and pre-diabetes is not well characterized. Decreased endothelial cell (EC) production and release of nitric oxide (NO), which has potent anti-atherosclerotic effects is a driver of the development and progression of atherosclerotic vascular disease. Beyond its role in cholesterol homeostasis, proprotein convertase subtilisin/kexin type 9 (PCSK9, is associated with the future risk of cardiovascular diseases. Laboratory studies of isolated ECs demonstrate that inflammatory stimuli increase EC PCSK9 and, in separate experiments, that increased PCSK9 decreases endothelial nitric oxide synthase (eNOS) and NO bioavailability, decreases which indicate EC dysfunction independent of low-density lipoprotein cholesterol (LDL-C). This research will examine whether PCSK9 links proinflammatory stimuli with EC dysfunction by studying in vivo endothelial- dependent vascular function and in vitro basic studies of ECs. A comparison of the in vivo and in vitro results will also provide information regarding the extent to which vascular dysfunction in the older groups is related to systemic, circulating factors and to mitochondrial dysfunction. In addition to association, we will examine causality by using PCSK9 targeted small interfering RNA in the above basic studies. The significance of the research to the field of aging, therefore, is the opportunity it offers to understand whether EC PCSK9 is one mediator of the known cardiovascular risk associated with inflammation in older individuals, which then would provide a target of intervention as PCSK9 antibodies are available for clinical use.
 
5. Project Title: Daily physical activity patterns and the modifying role of inflammatory markers in frailty
  Leader: Amal Wanigatunga, PhD, MPH, Jennifer A. Schrack, PhD, Lawrence J. Appel, MD, MPH, Dr. Robert H. Christenson, PhD
  Frailty is a common medical syndrome of increased vulnerability in adults aged 70 years and older that is often accompanied by low daily physical activity (PA) and high chronic inflammation. Currently, the method by which low PA is quantified and defined relies on coarse measures of self-reported time spent in a few daily activities, leaving a large knowledge gap regarding the true manifestation of PA decrements in frailty. Moreover, chronic inflammatory markers such as interleukin-6 (IL-6) and C-reactive protein (CRP) have been linked to components of frailty, including high fatigability and functional decline, making it plausible that degradation of daily PA patterns may be connected to rising circulation of both IL-6 and CRP. This warrants further investigation into inflammation as a possible underlying mechanism connecting detailed measures of PA and the onset and progression of frailty with aging. Findings from such investigation would lay the groundwork towards building the clinical utility of measuring physical activity in non-laboratory, community-dwelling settings to detect and intervene on trajectories towards frailty and accelerated aging in ever-expanding older adult populations. The proposed research aims to examine (1) whether total daily PA and patterns of daily PA accumulation differ by frailty status (non-frail, pre-frail, and frail), and (2) whether chronic inflammation modifies this association. We hypothesize that free-living PA patterns are deteriorated and diminished in those who exhibit pre-frail and frail phenotypes, compared to non-frail individuals. Further, we hypothesize that these sophisticated measures of PA are sensitive to rising chronic inflammation (IL-6 and CRP) typically present in frail older adults. The proposed research provides an exciting opportunity to use cutting-edge methods to extract unique patterns of PA accumulation from objectively measured PA and assess whether greater deterioration in these PA patterns are seen with higher inflammation and frailty states.
 
6. Project Title: Effects of Neurotoxic Kynurenines on Peripheral Nerve Regeneration
  Leader: Tae Chung, MD
  Age-related muscle weakness is a critical component of frailty in older adults, and independently predicts morbidity and mortality in late life. Over the past decades, various changes in aging neuromuscular system, such as partial denervation at neuromuscular junction (NMJ), reducing number of motor neurons, and fiber type switching, have been described, but the underlying molecular pathway that links the degeneration of neuromuscular system to overall reduction of morbidity/mortality with aging has not been elucidated to date. In a recent metabolomics study, we have identified alterations in the kynurenine pathway in frail older animal and human subjects. We also found that those kynurenine intermediates strongly correlate to the markers of frailty and chronic inflammation. Kynurenine pathway is a major pathway for tryptophan degradation that eventually leads to NAD synthesis, and interestingly, a few intermediates in the kynurenine pathway are known to be potently neurotoxic, and involved in some age-related neurodegenerative diseases, such as Alzheimer and Parkinson diseases. In addition, kynurenine pathway has been known to play a critical role in immune tolerance and cancer surveillance6, suggesting that alteration of kynurenine pathway may contribute to the immune senescence and increased morbidity/mortality in late life. Taken together, we hypothesized that alteration in kynurenine pathway is the major underlying pathway of age-related muscle weakness, eventually leading to increased morbidity/mortality in late life. To further investigate the influence of kynurenine pathway in frailty and aging, we have utilized a genetically altered mouse, Quinolinate phosphoribosyl transferase (QPRT) knock-out (KO), known to have elevated levels of the potent neurotoxic kynurenine metabolites, quinolinic acid (QUIN), in the nerve tissues and serum. In an NIA K08-funded proposal, we have been longitudinally tracking the neuromuscular functions of QPRT KO vs wild type mice over the entire lifespan. Our preliminary results have shown that QPRT KO mice have greater degree of NMJ denervation and reduced peak isometric strength as compared to the background-matching wild type mice after middle age. Additionally, QPRT KO mice also showed premature signs of frailty, such as weight loss, reduced lean mass, and poor glucose tolerance after middle age. The above results suggest that increased QUIN is related to degeneration of both motor neuron and skeletal muscle, leading to frailty phenotype. To further investigate the casual relationship between QUIN and neuromuscular dysfunction, we propose the following pilot experiments, using kynurenine inhibitors, JM6 that is known to reduce the levels of QUIN by inhibiting upstream enzyme, kynurenine 3-monooxygenase (KMO). Specific Aims: Aim1: To investigate the toxicity of QUIN on peripheral nerve and skeletal muscle regeneration Hypothesis: Regeneration of both nerve and muscle will be delayed in QPRT KO mice due to neuromyotoxicity of QUIN Subaim1: to compare the speed of nerve regeneration between QPRT KO and wild type mice after ligation of tibial nerve Subaim2: to compare the speed of muscle regeneration between QPRT KO and wild type mice after cardiotoxin injection to gastrocnemius muscle. Aim2: To determine if JM6 may facilitate the regeneration of peripheral nerve axon and skeletal muscle in QPRT KO mice Hypothesis: JM6 will facilitate the regeneration of peripheral nerve and skeletal muscle in QPRT KO mice Subaim1: compare the speed of nerve regeneration between QPRT KO and QPRT KO with JM6 after ligation of tibial nerve Subaim2: to compare the speed of muscle regeneration between QPRT KO and QPRT KO with JM6 after cardiotoxin injection to gastrocnemius muscle. The results from the current study will be used as preliminary data for NIH R01 application and justification for chronic administration of JM6 to prevent frailty phenotype in QPRT KO mice. In the future studies, we will manipulate kynurenine pathway at different points both genetically and pharmacologically, to identify the optimal target for the prevention of age-related muscle weakness, frailty, and eventually prolongation of lifespan.
 
7. Project Title: The Effects of Tryptophan Degradation Pathway Manipulation on Metabolism, Healthspan and Lifespan in Mice
  Leader: Reyhan Westbrook, PhD
  Chronically activated inflammatory pathways are strong predictors of age-related morbidity including disability, physical frailty, mild cognitive impairment1 and morality2. Despite this, the underlying molecular mechanisms that connect chronic inflammation (CI) to these common conditions are poorly characterized. We have recently identified metabolites in the tryptophan degradation pathway (TDP), known as kynurenines, as potential mediators of the effects of CI on functional decline in a mouse model and in older human subjects. Using targeted metabolomics, we showed that kynurenines correlate strongly with inflammation and decreased physical function in both mice and humans, and that the neurotoxic & cytotoxic metabolite 3-hydroxykynurenine (3HK) is elevated in the blood of frail older adults. Inflammatory cytokines activate indolamine 2,3 dioxygenase (IDO) which converts tryptophan to kynurenine, and kynurenine monooxygenase (KMO) which converts kynurenine to 3HK, thus cytokines increase the production of potentially deleterious kynurenines. We postulate that CI raises 3HK to toxic levels causing damage to tissues, including nerves and muscles, leading to accelerated decline in physical function and decreased lifespan. TDP blockade and reduced dietary tryptophan have increased lifespan in Drosophila and in mice, respectively. In this proposed study, we will elucidate the role kynurenines play in the development of age related functional decline by 1) determining if exogenously increased levels of 3HK lead to impaired physiology, functional decline and early mortality in C57BL/6 mice, and 2) determining if blocking the TDP using an inhibitor, improves physical function, delays age-related physiological changes, and increases lifespan in both C57BL/6 mice and in a mouse model of CI. To assess effects on healthspan, we will longitudinally measure physiological and physical function including grip strength testing, indirect calorimetry, spontaneous activity monitoring, body composition analysis, muscle contractility analysis and insulin/glucose tolerance testing. To assess kidney toxicity, we will measure blood urea and creatinine levels. We will longitudinally profile the metabolome, measure levels of circulating cytokines, and perform ex vivo neuromuscular junction analysis and senescent cell quantification in these mice. Specific Aims: Aim 1: To determine the effects of treatment with the cytotoxic TDP intermediate, 3-hydroxykynurenine, initiated in adult (10 month old) C57BL/6 mice on lifespan and healthspan. Hypothesis: Increased circulating levels of 3HK accelerate functional decline, pathophysiological metabolic changes, and mortality in C57BL/6 mice. Aim 2: Determine the effects of TDP blockade initiated in adult (10 month old) C57BL/6 mice and in chronically inflamed IL10tm mice on lifespan and healthspan using the IDO inhibitor 1- methyl-D-tryptophan. Hypothesis: Treatment with 1-methyl-D-tryptophan initiated at 10 months can prevent or delay functional decline, pathophysiological metabolic changes, and mortality in C57Bl/6 mice and in chronically inflamed IL10tm mice which have known kynurenine elevation. These approaches will allow us to more fully articulate the impact of kynurenines on function, metabolism, body composition, and inflammation in older mice, and facilitate the future development of translational approaches in human subjects. With this work we will gain insight on the mechanisms of decreased physical function associated with chronic inflammation and aging as well as guide the development of interventions that mitigate the effects of chronic inflammation on functional decline.
 
8. Project Title: Analysis of lamin A/C-associated proteins in the frail (IL10-KO) heart.
  Leader: Kathy Wilson, PhD
  We hypothesize that signaling and gene-regulatory complexes that depend on A-type lamins are functionally perturbed in IL10-KO mice. This hypothesis is based on our mass spectrometry multiplex identification and quantification of proteins that co-immunoprecipitated with lamins A/C from old (21-22 months) IL10-KO vs control mouse hearts, skeletal muscle and brain. This pilot study will focus on the heart data, which revealed two groups of proteins proposed to associate with lamin A/C: Proposed novel partners (proteins not known to associate with lamin A/C). This group of 20 candidates includes two exciting proteins: Perm1 and Fam210A. Perm1 is a ~100 kDa intrinsically disordered (‘transformer’) protein, highly expressed in heart and skeletal muscle, that regulates genes required for endurance exercise, mitochondrial biogenesis and oxidative capacity in muscle (Cho et al., 2016; Cho et al., 2019), as discovered by our Hopkins collaborator Natasha Kralli. Equally interesting is Fam210A, which is genetically linked to grip strength, sarcopenia and bone fractures (Tanaka et al., 2018; Trajanoska et al., 2018; Tanaka et al., 2020), and is unstudied in the heart. Known or proposed partners for which lamin A/C association significantly decreased in frail hearts (log2-fold changes with p-values <0.05). This group includes MLIP (muscle LMNA-interacting protein), which directly binds lamin A, regulates mTOR signaling in the heart and is required for cardiac adaptation (Cattin et al., 2015), and transcriptional regulators that function in the nucleus and are important for cardiac health, including YBX1 (Choong et al., 2019), PDLIM5 (Elbediwy et al., 2018) and NDRG2 (Sun et al., 2013). Aim 1. Biochemical foundation for lamin A/C-dependent molecular changes in the frail heart. We will prioritize 20 potential partners based on functional annotation of our mass spectrometry results, and then screen for direct binding to lamin A/C or emerin, the intrinsically-disordered nuclear membrane protein that partners with lamin A to support signaling and gene-regulatory complexes important for heart and muscle. (a) Complete our functional annotation of the heart proteome and prioritize proteins for further study. (b) Test 20 prioritized candidates for direct binding to lamin A or emerin. Aim 2. Validation: screen top-20 candidates in frail-vs-control hearts for changes in expression, localization or association with lamin A/C. (a) Western blot lysates from frail vs control hearts (n=5 each) using antibodies specific for each candidate to determine if expression changes in frailty. (b) Validate lamin A/C association by co-immunoprecipitation from frail vs control hearts, or by APEX co-localization (immunofluorescence) in tissue sections. Aim 3. Tools for the molecular characterization of the frailty-relevant protein Fam210A. Determine if the Fam210 isoform(s) identified in the heart proteome include the transmembrane domain, predict any folded or intrinsically-disordered domains, and use this information to: (a) generate recombinant Fam210A for biochemical studies, and (b) generate adenovirus-deliverable TurboID-Fam210A constructs to independently identify Fam210A-proximal proteins in cardiomyocytes.
 
9. Project Title: Resilience and Multifactorial Stressors Among Older Adults During the COVID-19 Pandemic
  Leader: Alden Gross, PhD
  The COVID-19 pandemic represents a complex stressor for older adults. Though our understanding of COVID-19 pathogenesis is evolving, evidence is accumulating that both age-related physiologic changes and age-associated multimorbidity drive increased hospitalization, ICU admissions, and death seen among older people with this infection (Verity 2020, Zhang 2020, Garg 2020). In addition to its direct impact via infection, older adults also face indirect stressors related to COVID-19 mitigation strategies. These indirect stressors include increased sedentary activity, stress, and nutritional challenges, and decreased access to medical care (Schrack 2020). Additionally, many older adults, in practicing social distancing, also may face increased loneliness and social isolation--experiences known to increase risk for anxiety and depression (Santini 2020). Against this backdrop, modern gerontological thinking recognizes the importance not only of vulnerability, but also ability to withstand or rebound from stressors when evaluating how older adults respond to COVID-19. By understanding the underpinnings of resilience and frailty, we can better understand the needs, interventions, and targeting strategies that can best support the health of older adults during and after the COVID-19 pandemic. In this study, we propose to characterize the multifaceted COVID-19 stressor in older adults living in the Baltimore area through a quantitative survey and qualitative interviews. We will leverage two existing cohorts to measure key aspects of the complex stressor that older adults are facing during the pandemic including direct stressors and indirect stressors. We will relate these stressors to clinical and psychosocial outcomes including stress levels measured objectively using measurements from salivary cortisol, and explore how resilience and frailty affect these relationships. In qualitative surveys of a subset of participants, we will explore perceptions and experiences of older adults as to how the COVID-19 pandemic may have been a stressor impacting their health, social interactions, finances and care of existing chronic medical conditions; and strategies they use to cope with these stressors. Ultimately, we hope to identify targets for interventions to lessen stressor impacts in this and future crises facing older adults. The proposed specific aims are: Specific Aim 1: To characterize the complex stressor older adults face during the COVID-19 pandemic and identify clinically relevant impacts. We will survey: (a) direct and indirect pandemic effects--direct: COVID-19 exposure, infection, hospitalization; indirect: changes and disruptions to daily life and health care, psychosocial effects and coping, social networks, food/medication access; (b) hypothesized outcomes of stressors: physical function, pain, fatigue, depression and anxiety symptoms, loneliness, health behavior changes, worsening chronic medical conditions, nonCOVID-19-related hospitalizations, frailty status and changes, perceived and objective (via serial home salivary cortisol) stress. Specific Aim 2: To characterize associations of clinical outcomes with (a) COVID-19 stressors and (b) sociodemographic and psychosocial factors hypothesized to partially determine resilience. Specific Aim 3: To explore direct associations of pre-pandemic measures of frailty and resilience with outcomes (Aim 1), and potential effect modification of these by stressor type and intensity. Specific Aim 4: To explore in qualitative interviews the perceptions and experiences of older adults as to how the COVID-19 pandemic may have been a stressor impacting their health, social interactions, finances and care of existing chronic medical conditions; and strategies they use to cope with these stressors. If successful, we will identify targets for interventions to lessen stressor impacts in future crises facing older adults.
 
10. Project Title: A Pilot Study to Identify Frail Patients Prior to Surgery and Implement a Novel Social Work- Focused Preoperative Intervention
  Leader: Lee Goeddel MD, MPH
  Older patients have increased complications after surgery. Although many older adults fare well postoperatively, frail and vulnerable patients seem to be at highest risk. Multiple studies have demonstrated the association between preoperative frailty assessment and post-operative outcomes. These studies have not assessed the associations between individual components of frailty assessment and outcome to better target intervention. Additionally, the majority of preoperative interventions have focused primarily on physical activity with limited outcome benefit. Psychosocial risk factors have been increasingly associated with poor outcome after surgery in this high-risk population. There is a critical need to identify and develop interventions that can improve outcomes for frail patients undergoing surgery. This OAIC proposal focuses on first identifying patients who might benefit from a novel Social Work intervention (by assessing the association of subcomponents of a commonly utilized assessment of frailty with postoperative outcomes), and secondly, the implementation and evaluation of a novel preoperative Social Work intervention to improve postoperative outcomes. We propose three aims of limited scope. In Aim 1, we will retrospectively analyze the subcomponents of the Edmonton Frailty Score (EFS) and the association with postoperative outcomes in a population of 4100 patients. This information will allow us to identify patients who might benefit from the novel Social Work intervention described in Aim 2. In Aim 2, we will assess the feasibility and barriers to implementing a social work intervention in the Johns Hopkins Center for Perioperative Optimization. Patients are identified for social work assessment and plan with EFS36. For the second half of the study, patients will be evaluated with the Physical Frailty Phenotype Assessment and the EFS to assess the feasibility and additional utility of social work intervention in frail patients. Aim 3 will evaluate the postoperative outcomes of the cohort of patients that undergo the social work intervention compared to historical matched controls from Aim 1.
 
11. Project Title: Identification of emergent patterns of monocyte morphologies and functional heterogeneity in frail and non-frail adults
  Leader: Jude M. Phillip, PhD
  During ageing, physiological changes and dysfunctions propagate, eventually manifesting as diseases later in life. In many older adults (>65 years), chronic low-grade inflammation typically associates with adverse outcomes, and is strongly linked to geriatric syndromes such as frailty. Recent studies have shown that potential sources of inflammation include the accumulation of senescent cells within ageing tissues, and from the age associated increase in cellular and protein fragments that are inadequately cleared from the body, (i.e. circulating cell-free DNA). Furthermore, this increased pro-inflammation phenotype induce deficiencies in immune activity and surveillance, likely contributing to the frailty-associated phenotypes in older adults. To address this, we propose to study frailty-induced changes in blood-derived monocytes from older adults (>65 years). For this proof-of-principle study, we hypothesize that frailty-associated inflammation drives the emergence of defective cellular phenotypes and decreased heterogeneity within circulating monocyte compartments. In this proposal we will focus on two interconnected goals: (a) develop and optimize an image-based platform to identify and classify functional cell morphologies and heterogeneity of circulating monocytes from frail and non-frail older adults (Aim 1A), and (b) develop a computational model based on morphological changes to describe how cytoskeletal signaling pathway activities associate with the resultant morphological phenotypes (Aim 1B). This study will form the framework to guide future confirmatory studies, which will enhance our understanding of frailty-associated monocyte phenotypes, and provide new learning opportunities from transfer-learning approaches for additional cell types, including other immune subtypes and fibroblasts. Successfully attaining this pilot funding will allow us to generate critical preliminary data needed to pursue external funding through R01/R21 mechanisms from the NIA.
 
DEVELOPMENT PROJECTS (4 Development Projects Listed)
1. Project Title: Characterizing Longitudinal Interdependence among Multiple Multi-System Dysregulation (MSD) Biomarkers
  Leader: Karen Bandeen-Roche, PhD
  Core(s): Resource Core 1 (RC1): Biostatistics Core (RC1)
 

MSD has long been hypothesized as a determinant of frailty but rarely has been assessed other than through counts of dysregulated systems taken cross-sectionally. This DP lays groundwork for its study as a dynamic process through specific aims to: (1) Characterize longitudinal interdependence among biomarkers of systems thought to underlie frailty; (2) Derive summary measures of longitudinal dysregulation in multiple systems; (3) Validate measures resulting from (2) by assessing their associations with frailty and mortality, and whether they are stronger predictors of frailty than the count measure.  

 
2. Project Title: Development of an aptamer to selectively target the angiotensin autoantibody
  Leader: Peter Abadir, MD, Neal Fedarko, PhD
  Core(s): Resource Core 2 (RC2): Biological Mechanisms Core (RC2)
 

Prior RC-2 studies have focused on the angiotensin system as a potential contributor to frailty and as a target for intervention development. A recent publication in part supported by RC-1, 2, and 3 described agonistic autoantibodies (aAbs) against the Angiotensin Type 1 Receptor (AT1R) whose serum levels increased in older
adults and were associated with inflammatory cytokines, hypertension, adverse health outcomes and frailty. Aptamers are oligonucleotides that bind their targets with high affinity and specificity and are currently used for
in vitro diagnostics, biosensor technologies, and targeted therapies. RNA aptamer agents can be engineered as allosterically modulated ribozymes - where binding to the targeted aAb activates the selfcleaving ribozyme domain and a fluorescence quencher is removed, yielding a fluorescent signal. This DP seeks to develop the lead agents necessary for creating a unique high throughput diagnostic/prognostic quantitative assay.  

 
3. Project Title: Implementation of preoperative frailty assessment in older surgical populations.
  Leader: Frederick Sieber, MD
  Core(s):
  The data is compelling that assessment of frailty is germane to determining surgical risk. There are two common means of frailty assessments, the phenotypic model and the deficit accumulation model. When assessing for frailty in the same population, phenotypic frailty instruments and deficit accumulation instruments of frailty display some overlap among subjects, but the populations defined are different. To help define the use of each frailty assessment in clinical practice, this proposal will first examine the use of both the phenotype model (“light-touch” Frailty Screen, LTFS) and the deficit accumulation model (Edmonton Frail Scale, EFS) within a surgical clinic to examine the level of agreement between the two assessments. In addition, relationships between individual domains assessed by the EFS and the frailty phenotype will be determined. Next, outcomes will be compared between the two models in the same surgical population. This comparison will be used to determine the ability of both assessments to predict postoperative outcomes and garnish support for the targeted use of these assessments in the preoperative workflow for patients ? 65 years. In addition, it will guide the development of domain specific interventions that may ultimately influence postoperative outcomes. Once the analysis is completed, we will use the well-defined Johns Hopkins Translating Evidence into Practice (TRIP) model to guide implementation of both assessments into clinical practice/workflow as a routine part of the pre-operative assessment of surgical patients ? 65 years of age across the John Hopkins Health System. This development grant will include incorporation of EHR documentation and dashboard creation for ease of analysis.
 
4. Project Title: Effects of Kynurenine Pathway Manipulation on the Metabolome of Drosophila
  Leader: Mariann Gabrawy, PhD & Reyhan Westbrook, PhD
  Core(s):
  Chronic inflammation is associated with physical frailty and functional decline in older adults; however, the molecular mechanisms of this linkage are not understood. Through findings from translational studies on both aged and chronically inflamed mice, as well as on aged and frail older adults, we have identified metabolites of the kynurenine pathway (KP) as potential mediators of systemic damage caused by chronic inflammation. Tryptophan metabolism is an important precursor to several bioactive metabolites including serotonin and NAD+. Tryptophan metabolism is highly conserved throughout nature and fluxes of this pathway are linked to longevity in numerous species. In humans, overproduction of downstream kynurenines such as 3-hydroxykynurenine (3-HK) and 3-hydroxyanthranillic acid (3-HAA) is linked to diseases such as cardiovascular disease, neurodegenerative disease, and frailty while blockade of the KP increases life span of Drosophila melanogaster. We used line DGRP_229 to elucidate the role of altered levels of kynurenines on physical performance and life span. Our results show that flies treated with 3-HK or 3-HAA have reduced climbing speed, endurance, and life span. Flies treated with a combination of ?-methyltryptophan (?-MT) plus nicotinamide (NAM) or nicotinamide riboside (NR) have greater speed, endurance, and life span than those treated with each metabolite alone. Motor neuron density is commensurate with the above treatments. We conclude that promotion of the KP accelerates functional decline and reduces life span while blockade of the KP, with NAD+ supplementation, attenuates the effect of age on functional decline and increases life span in an age-specific, synergistic manner. We have demonstrated, for the first time, that a combination of blocking the KP while supplementing its product, NAD+ (?-MT+NAM or ?-MT+NR), can increase life span and preserve physical function in Drosophila. Our work provides the foundation for future studies in mice and in humans. In order to understand the etiological linkages between KP manipulations and the resulting changes in physical function and life span, it is necessary to understand how our treatments affected the levels of 1) KP metabolites and 2) other molecular pathways including those involved in energy metabolism.
 
RESEARCH (25 Projects Listed)
1. Project Title: VISION LOSS AND COGNITION: TESTING THE SENSORY CONSEQUENCE HYPOTHESIS
  Leader(s): SWENOR, BONNIELIN
    THE JOHNS HOPKINS UNIVERSITY
    NIH K01AG052640 / ( 2017 - 2022 )
  Core(s):
  ABSTRACTThis is an application for a K01 Research Career Development Award. The goal of the proposed project is toprovide the candidate with advanced skills needed to establish an independent research program examiningthe relationship between vision loss and cognitive decline in older individuals. To facilitate this long-term goalthe candidate will: (1) characterize the longitudinal relationship between objective measures of visual functionand cognition in older adults, (2) determine the relationship between vision loss and brain volume and corticalthickness in older adults, and the role brain volume and thickness may play in the vision-cognition relationship,and (3) assess the association between vision loss and participation in cognitively stimulating activities,exploring this participation as a mediator of the vision-cognition relationship. The candidate proposes acomprehensive training plan, combining formal coursework, meetings and tutorials overseen by her mentors,participation in applied training experiences, and involvement in seminars and workshops. Specific traininggoals include: (1) receive training in the neuropsychological and clinical assessment of older individuals, (2)develop neuroimaging analyses skills, (3) receive training in the neuroscience of vision, (4) gain advancedknowledge of mediation and experimental study design and analyses, and (5) continued training in theresponsible conduct of research. The training plan will be executed in coordination with the set of researchactivities, mentioned above, that are based on preliminary data collected by the applicant. The preliminary datashow that reduced visual functioning is associated cross-sectionally with: (1) lower executive function, memory,and language test scores, and (2) reduced gray and white matter volumes, in the visual cortex and frontallobes. The candidate will expand on these findings, using longitudinal data from participants in the BaltimoreLongitudinal Study on Aging (BLSA) who are 60 years and older. The aim of the project is to test the `sensoryloss consequence hypothesis', using a multi-domain approach to examine the vision-cognition relationship.The primary hypotheses to be examined are that: (1) reduced visual function is associated with greaterdeclines in executive function, memory, and language test scores, and an increased risk of incident dementia,(2) reduced visual function is associated with reduced brain volume and thickness in regions of interest withinthe frontal cortex and visual pathways, which mediate the vision-cognition relationship, and (3) age-relatedvision loss is associated with a reduction in the frequency and variety of participation in cognitively stimulatingactivities, which also influences the vision-cognition relationship in older adults. Results from this research willbe used to develop a subsequent R01 research proposal that will facilitate the candidate's transition to anindependent researcher.
 
2. Project Title: Frailty, Post-Transplant Delirium, and Neurocognitive Underpinnings of Alzheimers
  Leader(s): CHU, NADIA MIKHAIL
    JOHNS HOPKINS UNIVERSITY
    NIH K01AG064040 / ( 2020 - 2025 )
  Core(s):
  PROJECT SUMMARY Kidney transplantation (KT) is a growing treatment for older adults with end-stage renal disease (ESRD). Even after careful pre-operative cognitive screening, post-KT incidence of Alzheimer's disease and related dementias (ADRD) is high. Presence of diagnosed ADRD increases the risk of graft loss, and more than doubles post-KT mortality risk; thus, understanding post-KT ADRD is of great clinical significance. Prior studies have suggested that ADRD may be a down-stream corollary of post-operative delirium, an acute decline and fluctuation in behaviors related to attentional capacity that is often preventable in older surgical patients. In fact, our preliminary data from medical claims suggested that older KT recipients with post-KT delirium were 5-fold more likely to be diagnosed with downstream ADRD. Therefore, we assessed 72 KT recipients initially free of cognitive impairment for delirium using the Delirium Rating Scale (DRS-98) and Confusion Assessment Method (CAM), and found that 93% experienced post-KT sub-syndromal delirium symptoms, 64% had moderate delirium, and 15% had severe delirium. The relationship between delirium components (severity, duration, subtypes) and domain-specific cognitive decline is understudied, but could lend insight into neurocognitive underpinnings of the potential delirium-ADRD link. Frailty (low physiologic reserve), comorbidity may be common substrates linking delirium and ADRD, but few underlying mechanisms have been identified. We hypothesize that post-KT delirium, as a marker of cognitive reserve, interfaces with frailty and KT-specific health-related stressors to accelerate cognitive decline and ADRD progression. Older KT recipients are an ideal population to clarify this association; they have a high prevalence of comorbidities and frailty and are screened to be free of dementia prior to KT. We will leverage an ongoing, prospective R01-funded study of frailty and aging in KT recipients. In this K01, we will add novel CAM measures that will be reviewed by a new delirium consensus panel and establish a consensus committee to identify ADRD cases for 500 older (age=50) KT recipients in this cohort. I will work closely with my highly supportive, multidisciplinary advisory team to meet my training goals and accomplish my aims: 1) To assess whether post-KT delirium incidence is associated with steeper global and domain-specific cognitive decline and increased ADRD risk among older KT recipients; 2) To test whether delirium duration, CAM severity, and sub-type are associated with steeper global and domain-specific cognitive decline and increased ADRD risk among older KT recipients; 3) To assess whether post-KT delirium mediates the relationship between pre- and peri-KT factors and ADRD risk. Our findings will help clarify the role of post-operative delirium in cognitive decline and ADRD risk among the highly susceptible surgical population of older KT recipients, and will lend clues into potential underlying mechanisms of the delirium-ADRD relationship.
 
3. Project Title: Effects of Genetic and Pharmacological Kynurenine Pathway Suppression on Healthspan, Lifespan, and Cellular Changes Associated with Aging in Mice
  Leader(s): WESTBROOK, REYHAN M.
    JOHNS HOPKINS UNIVERSITY
    NIH K01AG076873 / ( 2022 - 2027 )
  Core(s):
  Title: Impact of Genetic and Pharmacological Kynurenine Pathway Suppression on Healthspan, Lifespan and Cellular Changes Associated With Aging in Mice PROJECT SUMMARY/ASTRACT (30 LINES OF TEXT) Through findings from translational studies on both aged and chronically inflamed mice, as well as on aged and frail older adults, we have identified metabolites of the kynurenine pathway (KP) as potential mediators of systemic damage caused by chronic inflammation. We recently identified that KP metabolites including kynurenine, kynurenic acid, 3-hydroxykynurenine and quinolinic acid were significantly elevated in the serum of older mice and robust and frail older adults, and that this was linked to functional decline and neurodegeneration. The family of molecules known as `kynurenines' are derived from the amino acid tryptophan and are precursors for the important electron carrier and coenzyme molecule NAD+. Kynurenines possess unique bioactive properties and some have pathological potential. For example quinolinic acid (QA) and 3-hydroxykynurenine (3-HK) are neuro- and cytotoxic and induce oxidative stress while kynurenine (KYN) and kynurenic acid (KA) are ligands for the aryl hydrocarbon receptor (AhR), whose signaling activity is linked to immunosuppression, senescence and impaired autophagy. Conversely, genetically inhibiting the KP extends lifespan in C. elegans and Drosophila, and pharmacological KP blockade increases lifespan in Drosophila. Reduced dietary tryptophan extends lifespan in rodents, but it is unknown if genetic or pharmacological KP blockade improves healthspan or extends lifespan in mice. In this study, we aim to evaluate the hypothesis that genetically and pharmacologically suppressing levels of KP metabolites can delay functional decline, pathophysiological metabolic changes, mortality and cellular changes associated with aging in mice. To understand the effects of KP suppression on aging, we will determine the effect of suppressing the oxidative stress inducing kynurenines, 3-HK and QA, using kynurenine 3-monooxygenase knock out mice (KMO -/-, Aim 1). We will also determine the effect of suppressing both oxidative stress inducing kynurenines, 3-HK and QA, as well as AhR agonist kynurenines, KYN and KA using the indolamine 2,3 dioxygenase knockout mouse (Ido -/-, Aim 2). We will then determine if pharmacological suppression of toxic kynurenines and AhR ligands can delay aging in mice using 1-methyltryptophan (Aim 3). Additionally, we will determine if pairing all of these KP suppression strategies with NAD+ supplementation will synergistically benefit healthspan, lifespan and characteristics of aging in mice. These studies will inform on the role of the KP in functional decline and aging and the therapeutic potential of KP suppression as an anti-aging intervention.
 
4. Project Title: The START trial: a proof-of-concept sedentary reduction program for prefrail older adults
  Leader(s): WANIGATUNGA, AMAL ASIRI
    JOHNS HOPKINS UNIVERSITY
    NIH K01AG076967 / ( 2022 - 2027 )
  Core(s):
  PROJECT SUMMARY Frailty is a syndromic state of vulnerability that puts adults aged =65 years at heightened risk of adverse health outcomes. An estimated 50% of older Americans are prefrail a pre-clinical stage of frailty that might be more amenable to intervention efforts than frailty. Increasing physical activity is a promising intervention to better manage/help reverse the multisystem dysregulation that drives frailty and sequalae. However, initiating and maintaining habitual physical activity is difficult for sedentary older adults, particularly those encumbered by health challenges. The 2018 US Physical Activity Guidelines recommends that all adults perform =150 minutes/week of physical activity and reduce sedentary behaviors. Yet, traditional approaches to increase physical activity do little to address sedentary behavior reduction, especially for older adults. Lower sedentary behavior is associated with improved biological and psychosocial health independent of meeting physical activity guidelines. Thus, there remains a critical need to implement and evaluate a structured way to reduce sedentary behavior as a potential pathway for habitual physical activity engagement. Using novel objectively measured physical activity metrics, our research group has shown that daily sedentary time, either in total or accrued in a prolonged manner, is associated with frailty. Our observation evidence shows that: 1) daily, non- exercise physical activity declines and becomes more fragmented with age (less continuous activity with longer sedentary bouts), 2) higher daily sedentary time and activity fragmentation are both associated with higher frailty incidence, and 3) sedentary time is positively associated with frailty-related markers of inflammation. We propose a pilot study in which we randomize 60 prefrail community-dwelling older adults to receive one of two interventions, each designed to gradually reduce sedentary time: 1) continuously to form a 30-minute walking bout, or 2) in a bouted manner to form three 10-minute walking bouts. Project goals are to: a) explore the effectiveness within and between interventions to decrease objectively measured sedentary time over 2 months; b) assess decreased sedentary time s association with i) patient-reported outcomes and ii) frailty- related inflammatory markers. The primary outcome is accelerometer-determined sedentary time. Secondary outcomes include activity fragmentation, patient-reported outcomes, and inflammatory markers. With a transdisciplinary mentoring panel, my career development plan builds on my expertise in aging and physical activity epidemiology to gain proficiency in: 1) developing and implementing clinical trials for older adults, 2) designing interventions to improve health behaviors, 3) conducting frailty and inflammation related research and 4) gaining competencies to become an effective PI and leader. This project utilizes the infrastructure of the Johns Hopkins Institute for Clinical and Translational Research (ICTR) and Beacham Center for Geriatric Medicine which have strong records of supporting early-stage faculty. This award will facilitate my transition to an independent investigator and will also provide informative data for R21 and R01 applications.
 
5. Project Title: ALTERATION OF KYNURENINE PATHWAY IN AGE-ASSOCIATED MUSCLE WEAKNESS
  Leader(s): CHUNG, TAE HWAN
    THE JOHNS HOPKINS UNIVERSITY
    NIH K08AG058483 / ( 2018 - 2023 )
  Core(s):
  PROJECT SUMMARY Decline in skeletal muscle function with aging is a major determinant of disability and morbidity in late life.However, the neurobiology of such decline in skeletal muscle function in normal aging is poorly understood.The proposed K08 project is a critical step towards to understanding the underlying mechanism of age-relateddecline of skeletal muscle function. This study uniquely focuses on the intersection between kynureninemetabolic pathway, motor neuron, neuromuscular junction (NMJ), and skeletal muscle function. Kynureninepathway is a major route to the synthesis of Nicotinamide adenine dinucleotide (NAD), a critical coenzyme thatbalances redox status of all living cells. Many intermediate metabolites of kynurenine pathway are known to bepotent neurotoxins, and involved in various age-related neurodegenerative diseases. The preliminary studiesof this project showed alterations of kynurenine pathway in aging peripheral neuromuscular system. Herein, itis hypothesized that age-related alterations in kynurenine pathway contributes to neurodegeneration in spinalmotor neurons, eventually causing age-associated muscle weakness. Aim1 propose to identify key alterationsin the kynurenine pathway in the aging spinal motor neurons, using mass spectrometry, PCR, and Westernblot techniques. Aim2 propose to determine the neurotoxicity of kynurenine pathway in aging neuromuscularsystem both in vitro and in vivo models. Finally, Aim3 tests the effects of pharmacological inhibition of akynurenine metabolite synthesis. The findings from this study will likely identify molecular targets for age-associated muscle weakness, and used for future translational study. The proposal will take place in the Johns Hopkins School of Medicine under the mentorship of JeremyWalston, MD, Ahmet Hoke, MD, PhD, and Robert Schwarcz, PhD. An integrated career development andmentoring plan has been also proposed to ensure Dr. Chung s successful transition to independence. Thetraining goals are focused on development of Dr. Chung s expertise in kynurenine neurobiology, variousmolecular techniques in neuroscience research, and translational gerontology. The strength of the proposalcomes from the collaboration between all of his mentors who have world-renowned expertise in aging frailty(Dr. Walston), peripheral neurodegeneration (Dr. Hoke), and kynurenine neurobiology (Dr. Schwarcz).
 
6. Project Title: ASSOCIATION OF FRAILITY WITH POST THYROIDECTOMY ALTERATIONS IN VOICE, SWALLOWING, AND QUALITY OF LIFE
  Leader(s): MATHUR, AARTI
    THE JOHNS HOPKINS UNIVERSITY
    NIH K23AG053429 / ( 2017 - 2022 )
  Core(s):
  Project SummaryThis project aims to evaluate the association of frailty with post-operative changes in voice, swallowing, andquality of life following thyroidectomy in older adults. Specifically, Aim 1 is to evaluate the effect ofthyroidectomy on voice, swallowing, and quality of life in older adults. The literature suggests that thesealterations occur at a relatively high frequency in younger patients. We aim to quantify frequency andmagnitude of changes in voice, swallowing, and QOL using subjective assessment with surveys and semi-structured patient interviews. Additionally we aim to correlate this with objective data obtained from speech-language pathology evaluations using videostroboscopy and videofluoroscopy. In Aim 2, we will explore theassociations between a frailty phenotype with pre-operative findings, thyroid-specific markers, and post-thyroidectomy alterations in voice, swallowing or decline in QOL. In addition to exploring the role of frailty topredict these alterations and identify a high-risk group, we will also explore the utility of thyroid or laryngealspecific markers to augment the predictive power of frailty. In Aim 3, we hope to investigate the role of pre-operative interventions including tracheal traction exercises and voice therapy to reduce the incidence ofimpact of post-operative alterations. We will randomize patients to intervention or usual care and evaluate thefrequency of alterations after thyroidectomy. This work represents an interdisciplinary approach to establishalterations in voice and swallowing that occur after thyroidectomy in older individuals, the impact of thesechanges on quality of life, and an attempt to reduce post-surgical disability. Findings from this study will informthe design of 2 future clinical trials aimed at 1) evaluating pre-operative interventions to reduce surgicaldisability after thyroidectomy and 2) creating a patient-reported outcome measurement tool specifically forolder adults undergoing thyroidectomy.
 
7. Project Title: Frailty and Resiliency in Older Adults with Acute Myocardial Infarction
  Leader(s): DAMLUJI, ABDULLA AL
    INOVA HEALTH CARE SERVICES
    NIH K23HL153771 / ( 2020 - 2025 )
  Core(s):
  The purpose of this research is to support the development of Dr. Abdulla Damluji into an independent investigator focused on studying geriatric syndromes during cardiovascular intervention. The K23 award will allow the development of a fundamental skillset including: the design and methods for analysis of interventions, understanding and proper application of frailty and resiliency assessments, designing pilot prospective studies, and enhancing knowledge of geriatrics and gerontology. Skills will be obtained through coursework, workshops, seminars, scientific meetings and mentored research. The overall goals are: 1) identify a simple universal bedside frailty test for clinical decision-making and 2) become an NIH-investigator prepared to conduct a clinical trial aimed to evaluate the comparative effectiveness of different treatments of acute myocardial infarction (AMI) in a heterogenous population of older adults living with frailty and lack of resiliency. Two thirds of all patients with cardiovascular disease (CVD) are older than 60 years of age, and >85% of patients over age 85 years live with some form of CVD. Of those older patients admitted with acute AMI, a majority experience frailty, a syndrome of decreased physiologic reserve and vulnerability to stressors. Moreover, some of these frail patients lack physical resiliency, the ability to rebound back and recover from a major health crisis. Critical gaps in knowledge in cardiovascular care for older adults, particularly those with frailty and lack of resiliency, have been identified. These gaps need to be addressed in order to provide the best possible care to a growing older patient population. This proposal examines the hypothesis that frailty and resiliency influence the treatment choice and health outcome after AMI. Aim1 evaluates the prevalence of frailty in U.S. among older AMI patients by treatment [percutaneous coronary intervention (PCI), coronary artery bypass graft (CABG) surgery, or guideline-directed medical therapy (GDMT)] using the validated claims-based frailty index. Aim 2 examines the role of frailty in treatment response to PCI and CABG. Aim 3 validates the diagnostic accuracy of a bedside 4-item frailty scale and assesses whether this diagnostic tool, used in combination with resiliency measurements, can predict health outcomes at 1-year follow-up. The institutional environments at both the Inova Heart and Vascular Institute (IHVI) and Johns Hopkins University (JHU) are ideal for conducting cardiovascular outcomes research. The mentorship consists of leaders with expertise directly relevant to the career goals of the applicant: Christopher M O Connor, MD (IHVI; expert in experimental design); Dr Wayne Batchelor (IHVI: interventional cardiologist); Jodi B Segal, MD, MPH (JHU: internist/epidemiologist; expertise in clinical effectiveness), and Gary Gerstenblith (JHU: geriatric cardiology). Resources at IHVI include bioinformatics laboratory, grant management office, and a state-of-the-art research office. At JHU, resources include the Bloomberg School of Public Health, Graduate Training Program in Clinical Investigation, JHU Pepper Center Biostatistical and Research Education Cores, and the Welch Medical Library.
 
8. Project Title: PATIENT-CENTERED CARE FOR OLDER ADULTS WITH MULTIPLE CHRONIC CONDITIONS: RESEARCH AND MENTORING PROGRAM
  Leader(s): BOYD, CYNTHIA MELINDA
    THE JOHNS HOPKINS UNIVERSITY
    NIH K24AG056578 / ( 2017 - 2022 )
  Core(s):
  Project SummaryThe aims of this proposal are to 1) develop the candidate's capacity for research, leadership, and mentorshipthrough career development in clinical trials, building and leading national collaborations, and mentoring, 2) toexpand her mentorship of promising junior investigators in patient-oriented aging research, and 3) to pursue aninnovative research direction to develop and evaluate person-centered interventions to optimize medicationuse in older people with multiple chronic conditions that will serve as a platform to engage an expanding groupof mentees. The candidate, a geriatrician who practices in a primary care clinic, has established a nationally-and internationally-recognized, high impact, well-funded independent clinical research program with anoutstanding publication record. In the 14 years since completing her geriatrics fellowship, she has establishedherself as a successful mentor of trainees from all levels who have published high-impact research, obtainedfunding and necessary research skills, and continue to conduct patient-oriented research. The candidate hasdeveloped a robust research portfolio focused on patient-centered care for older adults, particularly those withmultiple chronic conditions. The candidate's work to date has been transformative both within aging and inother fields by shifting attention from a disease-specific approach to care to one that recognizes that most olderadults live with multiple chronic conditions. The candidate has a strong track record of research funding fromAHRQ, PCORI and the NIA to improve the generation and synthesis of evidence to better inform the care ofpeople with multiple chronic conditions, and to develop patient- and family-centered approaches to care ofolder adults with multiple chronic conditions. This proposal will provide the candidate with protected time toincrease her expertise, expand her mentoring program, and develop new research focused on optimalmedication prescribing to improve patient-centered outcomes for this population. The candidate will furtherdevelop a formal mentoring program for the engagement and development of high-caliber mentees who willserve as the next generation of leaders in patient-oriented research for aging populations. She will work witheach mentee to implement a focused career development plan in which they complete research projects anddevelop skills including grant and scientific writing, study design, and presentation skills necessary to besuccessful independent patient-oriented investigators. The outstanding environment for aging research andclinical research training at Johns Hopkins is fundamental to this proposal.
 
9. Project Title: IMPROVING CANCER SCREENING IN OLDER ADULTS WITH LIMITED LIFE EXPECTANCY
  Leader(s): SCHOENBORN, NANCY
    THE JOHNS HOPKINS UNIVERSITY
    NIH K76AG059984 / ( 2018 - 2022 )
  Core(s):
  PROJECT SUMMARYBackground: Cancer screening can lower cancer-related mortality and morbidity but may be associated withsignificant harms and burdens in older adults. There is often a lag-time of 10 years before patients screenedfor breast, colorectal, or prostate cancers actually benefit. On the other hand, multiple harms from screeningcan occur in the short-term. Older adults with limited life expectancy continue to receive cancer screening athigh rates even though it exposes them to the harms of screening with little chance of benefit. Clinicians are amajor driver of over-screening but why they often continue to recommend cancer screening in older adults withlimited life expectancy is unknown. This proposal aims to improve the cancer screening of older adults by 1)identifying the factors that facilitate or hinder clinician recommendations to stop routine screening in olderadults with limited life expectancy, and 2) better supporting clinicians to appropriately incorporate lifeexpectancy in their screening recommendations.Research proposal: Aim 1 will use qualitative methods to understand the range of factors that facilitate orhinder clinicians from recommending screening cessation in older adults with limited life expectancy. Aim 2 willtest these factors in a national physician survey to determine and quantify their effects on physicians'screening recommendations in older adults with limited life expectancy. Aim 3 will then develop and pilot test anovel multi-modal intervention to target the factors that significantly contribute to over-screening. Theintervention will be developed with input from clinicians and older adults and will use multiple, overlappingstrategies that may include decision support, communication coaching, and clinician feedback.Career development plan: The candidate is a geriatrician who has already demonstrated national andinstitutional leadership in research and a strong track record of academic scholarship with numerous highimpact publications and early investigator grants. Her long-term career goal is to be a research leader focusedon incorporating life expectancy to inform patient-centered, individualized preventive care decisions for olderadults. She has laid out a comprehensive, feasible career development plan that will enable her to transitioninto an independent investigator and research leader. She proposes to learn new skills in decision support,clinical trial design, and implementation science, in addition to continued development of leadership skills. Shehas assembled an exemplary mentoring team with expertise in the subject area and the relevant researchmethods and works in a rich research environment with tremendous resources to support her development.Summary: The proposal addresses an important research gap and produces a novel intervention that mayhave major impact to improve the cancer screening of older adults. The results from this proposal will support asubsequent large-scale clinical trial to test the intervention. This proposal will also further foster the careerdevelopment of the candidate into a research leader focused on individualized preventive care in older adults.
 
10. Project Title: THE JOHNS HOPKINS ALZHEIMER'S DISEASE RESOURCE CENTER FOR MINORITY AGING RESEARCH
  Leader(s): REBOK, GEORGE W.; THORPE, ROLAND J ;
    THE JOHNS HOPKINS UNIVERSITY
    NIH P30AG059298 / ( 2018 - 2023 )
  Core(s):
  The Schools of Medicine, Nursing, and Public Health of the Johns Hopkins University areproposing a new Alzheimer's-related Resources Center for Minority Aging Research (AD-RCMAR) in response to RFA-AG-18-002. The aims of this application are to: (1) mentor early-stage investigators from underrepresented backgrounds in minority aging and health disparitiesresearch, with a focus on Alzheimer's disease and related disorders (ADRD), using a life courseperspective encompassing biological, behavioral, and community factors contributing tocognitive impairment and dementia in older minority adults; (2) conduct epidemiological,preventive, and intervention research that addresses ADRD in later life within a multi-levelframework that encompasses individuals, families, social networks, and communities; and 3)engage communities and health care providers especially family caregivers, primary carepractices, communities of faith, and community organizations as our partners in recognizingdementia and developing interventions with the potential to prevent cognitive decline andreduce ADRD dementia risk and disparities in minority older adults. The Johns Hopkins AD-RCMAR consists of: (1) an Administrative Core whose function is to provide governance and anadministrative structure, to support research, to foster interactions between Cores and otherCenters, and to ensure RCMAR Scientists develop mentoring relationships across the affiliateddepartments, schools, the intramural program at NIA in Baltimore, and nationally; (2) aResearch Education Component to foster diverse junior investigators and mid-careerinvestigators transitioning into ADRD-relevant research through support for individual pilotprojects, career mentoring, scholar-to-scholar interactions, and role modeling; (3) a Community-Liaison and Recruitment Core to ensure the relevance of the ADRD research and to increaseknowledge of engagement of community members in the research enterprise with the creationof a Community Resource Institute as a venue for community-investigator interaction; and (4) anAnalysis Core as a foundation for methodological and statistical mentoring, including educationand mentoring in mixed-methods research. An Executive Committee includes communityrepresentatives and a Scientific Advisory Panel consists of distinguished investigators withrelevant expertise in minority aging, disparities, and ADRD. A pilot project program supportedby all Cores to facilitate the development of RCMAR Scientists includes three initial pilotprojects focusing on recruitment of minority populations for ADRD research, early diagnoses ofdementia, and intervention development related to ADRD-related driving disparities.
 
11. Project Title: Utilizing Technology and AI Approaches to Facilitate Independence and Resilience in Older Adults
  Leader(s): CHELLAPPA, RAMA ; ABADIR, PETER M.; HAGER, GREGORY DONALD; WALSTON, JEREMY D;
    JOHNS HOPKINS UNIVERSITY
    NIH P30AG073104 / ( 2021 - 2026 )
  Core(s):
  The overarching goal of this application is to build an Artificial Intelligence (AI) and Technology Collaboratory (AITC) ecosystem that will serve as a national resource to promote the development and implementation of novel AI and technology approaches to improve care and health outcomes for older Americans. The specific aims are: 1) To engage AI and geriatric/gerontology investigators from across the country and to identify, validate, test, and develop new AI and technologies relevant to improving the health and wellbeing of older adults through crucial pilot study mechanisms; 2) To serve as a national resource center that stimulates and leads the development and implementation of effective novel AI and technology approaches and products that will promote the health, wellbeing and independence of all older Americans; 3) To support the engagement of stakeholders in AI research; 4) To build an ecosystem of overlapping innovation and business, academic, and communities- of-practice networks ; and 5) To provide highest quality expertise, support, and infrastructure needed to disseminate technical and policy guidelines and best practices for effectively incorporating AI approaches and technology for older Americans, in partnership with private industry, angel investors, venture capital firms, and healthcare systems. This AITC is directed by a multi-PI interdisciplinary team led by two world-class experienced investigators who have long worked successfully in the fields of AI and technology development areas partnered with investigators who have long and successfully worked at the translational interface that connects real-world medical, cognitive, and functional declines that impact older adults with medical and technological solutions. Each of these investigators has a complementary skill set and a long track records of organizing transdisciplinary teams and consortiums of investigators around core themes. This interdisciplinary, accomplished, and highly visible leadership team will work together to develop vision for the next generation of AI in aging science and to build a scientifically and culturally diverse community of AI scholars and trainees around Aging. To achieve our goals, we designed the JHU AITC to have robust scientific and technological expertise that are described in eight core components. This infrastructure will support the implementation of stakeholder input and the identification of relevant technologies and investigators locally and nationally through a vetting and feasibility testing process of both technology and data processes. It will include a pilot testing phase and related oversight process. We have also established a key partnership with the Iowa office of Rural Health and Veterans Rural Health Resource Centers Leadership and with organizations within Johns Hopkins University that focus on improvements in the health and well-being of older adults in underserved urban communities. Connections with key academic, industry partners have also been established to accelerate the development of relevant technologies into products. This team is dedicated to developing the next AI scientific advances and disseminating resulting strategies into practice and policy that will maximize health, well-being, and independence for older adults.
 
12. Project Title: NEIGHBORHOODS, COGNITIVE AGING AND MODIFIABLE RISK FACTORS
  Leader(s): CARLSON, MICHELLE C
    THE JOHNS HOPKINS UNIVERSITY
    NIH R01AG055404 / ( 2018 - 2022 )
  Core(s):
  The role of modifiable risk factors (RF), like physical activity (PA), sleep quality, social engagement, andcardiovascular (CV) risk is receiving greater attention to promote the cognitive health of an aging populationand reduce risk of Alzheimer's disease. Each of these risk factors is known to be influenced by environmentalsources, such as neighborhood walkability, safety, noise, and access to low-cost transportation, retail, andhealthy food sources. However, little is known about the role of neighborhood factors as drivers of cognitiveaging and risk for Alzheimer's disease. If neighborhood matters, adaptations in the use of availableinfrastructures have the potential to impact thousands at a time. Those neighborhood factors that most impactindividual RF and cognitive health to reduce Alzheimer's disease risk may further differ by race and sex.Evaluating the role of neighborhood characteristics on cognitive health is difficult to interpret from more widelyused cross-sectional data due to residual confounding. Therefore, investigating how residentially stable olderadults are affected by their local stable and changing contexts and how older adults who relocate to a newneighborhood may respond to their new context by changing health behaviors requires long-term study duringthe last 1/3 of life years prior to the onset of Alzheimer's disease. The Cardiovascular Health Study (CHS)represents an ideal cohort for studying interactions between individual health and neighborhood risk factors forvarious reasons. First, participants were well characterized for key modifiable RF, above, as well as cognition,and mobility. Second, the cohort is nationally representative, bi-racial and spans socioeconomically diverse,urban and rural neighborhoods, allowing us to examine the relation between individual risk and variability inneighborhood factors. Third, our proposal seeks to address the research challenges and opportunitiesarticulated in the NIA Health Disparities Research Framework by examining interactions between environment,biology and behavior. We hypothesize that long-term exposure to neighborhood disadvantage may serve asa common cause of individual risk factors and neurocognitive and functional health, particularly insocio-demographically at-risk groups. Specific aims are to characterize associations between long-termneighborhood exposures and: 1) individual rates of decline and impairment in cognition and physical function;2) individual risk factors (PA, sleep quality, social engagement and CV burden) for Alzheimer's disease, whichmay mediate neighborhood differences in cognitive and functional risk, and; 3) whether specific neighborhoodexposures account for racial and sex differences in cognitive and functional risk. Addressing these questions inthe CHS provides an unmatched opportunity to examine the influence of a range of neighborhood factors onlong-term trajectories of cognitive and functional aging prior to the onset of Alzheimer's disease. This work willinform future design of multi-level approaches to target those neighborhood factors impacting multiple RF tooptimize healthful activity, reduce health disparities, and help adults remain active and age in place.1
 
13. Project Title: AGING, COGNITION, AND HEARING EVALUATION IN ELDERS (ACHIEVE) RANDOMIZED TRIAL
  Leader(s): LIN, FRANK R; CORESH, JOSEF ;
    THE JOHNS HOPKINS UNIVERSITY
    NIH R01AG055426 / ( 2017 - 2022 )
  Core(s):
  Novel approaches to reduce the risk of age-related cognitive decline, Alzheimer s disease (AD), and otherdementias in older adults are urgently needed given the aging of the population. Epidemiologic studiesdemonstrate that peripheral hearing loss in older adults is strongly and independently associated withaccelerated cognitive decline and incident dementia. Hypothesized mechanistic pathways underlying thisobserved association include the effects of poor hearing and distorted peripheral encoding of sound oncognitive load, brain structure/function, and/or reduced social engagement. Importantly, these pathways maybe modifiable with comprehensive hearing loss treatment consisting of the use of hearing technologies(hearing aids, other integrated hearing assistive devices) and rehabilitative training. To date, however, therehas never been a randomized trial that has investigated whether such therapies could reduce cognitive declineand the risk of Alzheimer s disease and other dementias in older adults. Over the past two years, we havedeveloped the Aging, Cognition, and Hearing Evaluation in Elders (ACHIEVE) randomized trial. The ACHIEVEtrial will recruit 750 70-84 year-old cognitively-normal older adults with hearing loss who will be randomized 1:1to the hearing intervention (hearing needs assessment, fitting of hearing devices, education/counseling) orcontrol intervention (individualized successful aging education sessions with a health educator coveringhealthy aging topics). The trial will be powered to detect a minimum of a 0.30 standard deviation (SD)difference in the annual rate of cognitive decline between the hearing intervention and the successful agingintervention arms over a 3-year follow-up period. The ACHIEVE study brings together a multidisciplinary groupof investigators and leverages the existing research infrastructure, scientific expertise, and well-characterizedparticipant cohort of the Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NCS). TheACHIEVE trial has the following aims: Aim 1 To determine the effect of hearing rehabilitative interventionversus a successful aging control intervention on rates of cognitive decline (primary outcome measure) in 70-84 year-old cognitively-normal older adults with hearing loss. Aim 2 To determine the effect of hearingrehabilitative intervention versus a successful aging control intervention on secondary outcome measures ofadjudicated incident dementia, physical and social functioning, health-related quality of life, and physicalactivity. Secondary Aims: 1) To investigate whether hearing rehabilitative intervention alters establishedtrajectories of cognitive decline in participants recruited from ARIC-NCS. 2) To investigate the effect of hearingrehabilitative intervention on rates of cognitive decline in persons with Alzheimer s disease risk factors andbiomarkers. Given that nearly two-thirds of all adults 70 years and older have a clinically-significant hearingloss, conducting the ACHIEVE study to determine if existing hearing rehabilitative interventions can reduce therate of cognitive decline in older adults is of substantial public health importance.
 
14. Project Title: ESRD-SPECIFIC PHYSIOLOGIC RESERVE: IMPROVING GERIATRIC TRANSPLANT PROGNOSTICATION - DIVERSITY SUPPLEMENT
  Leader(s): MCADAMS DEMARCO, MARA A.
    THE JOHNS HOPKINS UNIVERSITY
    NIH R01AG055781 / ( 2017 - 2022 )
  Core(s):
  Older adults with end stage renal disease (ESRD) who receive kidney transplantation (KT) double their lifeexpectancy. The new kidney allocation system, designed to better match longevity of recipients and allografts,has been in effect for 2 years. During this time, access to KT among older adults has plummeted; with ratesdeclining 10% for candidates aged 61-70 and 24% for those aged >70. The core problem is that the UnitedNetwork for Organ Sharing (UNOS) decided that longevity matching for the new allocation system would bebased on Estimated Post-Transplant Survival (EPTS), a simple model that only includes chronologic age,diabetes, time on dialysis, and prior transplant. EPTS has poor predictive power among older recipients; the c-statistic of EPTS for older recipients is 0.59, which is lower than the c-statistic of 0.67 for younger recipients.We hypothesize that a measure of physiologic reserve will more accurately stratify risk among older KTrecipients than chronologic age. Our preliminary work suggests that the Fried frailty phenotype, is associatedwith poor post-KT outcomes. While our findings are encouraging, it is unlikely that this construct captures allthe dimensions of physiologic reserve associated with ESRD. It is likely that some attributes of the Fried frailtyphenotype are not even relevant for this population. We believe an ESRD-specific measure of physiologicreserve, beyond frailty and/or other conventional measures, would greatly improve risk stratification.UNOS and the transplant community might be reluctant to add a new variable to the purposefully parsimoniousEPTS score, which was debated for 15 years. Our novel approach, supported by the upcoming UNOSpresident, is to replace chronologic age with physiologic age in the model. The overarching goal of ourresearch will be to develop a physiologic age calculator and test whether replacing chronologic age withphysiologic age improves prognostication for older adults with ESRD.To achieve these goals, we will leverage existing data and collect new data within an ongoing longitudinalcohort study of 5,500 ESRD patients. We will abstract new data on components of physiologic reserve from theparent study and enroll an additional 2,342 new ESRD patients in an ancillary study which will directly measurethe physiologic reserve components that cannot be abstracted. We will test the following aims: 1) To elicit andevaluate novel constructs that might quantify physiologic reserve in older ESRD patients; 2) To create a valid,reliable, and generalizable measure of physiologic reserve for ESRD patients; 3) To test if replacingchronologic age with physiologic age improves prognostication in older recipients.This work would improve prognostication for older adults with ESRD, which would benefit patient selection,informed consent, and case-mix adjusted transplant center report cards. Our novel approach to replacingchronologic age with physiologic age has the support of UNOS leadership and could have an immediateimpact on organ allocation and prioritization, possibly improving access for older KT candidates.
 
15. Project Title: DOES VESTIBULAR LOSS PREDICT FALLS IN PATIENTS WITH ALZHEIMER'S DISEASE?
  Leader(s): AGRAWAL, YURI
    THE JOHNS HOPKINS UNIVERSITY
    NIH R01AG057667 / ( 2018 - 2023 )
  Core(s):
  Project summaryThis project investigates whether vestibular loss predicts falls in patients with Alzheimer s disease (AD).The proposed research is an observational study of 150 patients with AD to evaluate the associationbetween baseline vestibular function and 2-year incidence of falls. We will also explore whether vestibularfunction is associated with balance and gait function, as well as spatial cognitive function, as potentialmechanisms by which vestibular function contributes to fall risk. Specifically, Aim 1 is to determinewhether vestibular loss predicts falls in patients with mild-moderate AD. We hypothesize that poorervestibular function at baseline predicts a higher 2-year incidence of falls. Additionally, we hypothesize thatthe attributable risk of falls associated with vestibular loss will be substantial enough (>~10%) to warrantfurther investigation of vestibular therapy as a clinically significant modifier of fall risk. Aim 2 is to evaluatewhether vestibular loss in AD predicts impaired static and dynamic balance, measured using the BergBalance Scale (BBS) and the Timed-Up-and-Go (TUG) test. We hypothesize that greater reduction investibular function over the 2-year follow-up period predicts greater decline in BBS and TUG performance.Aim 3 is to evaluate whether vestibular loss in AD predicts impaired spatial cognitive skills. We willadminister cognitive tests of spatial cognition (including the Money Road Map test, the Card Rotationstest, the Visual Form Discrimination test and the Clock Drawing test), and we will also query participantsand caregivers about difficulty with driving, losing objects, getting lost and wandering behaviors asfunctional manifestations of impaired spatial cognition in AD patients. We hypothesize that greaterreduction in vestibular function over the 2-year follow-up period predicts greater decline in spatial cognitivetest scores, and a higher incidence of functional spatial cognitive impairment. Moreover, we hypothesizethat impaired balance measures (from Aim 2) and impaired spatial cognitive skills will both be independentmediators of the association between vestibular loss and incident falls. To accomplish these aims, we willleverage well-established resources at Johns Hopkins including the Johns Hopkins Alzheimer s DiseaseResearch Center and the Memory and Alzheimer s Treatment Center. Falls are a major source ofmorbidity in AD and current interventions are not uniformly effective. If our observational studiesdemonstrate that vestibular loss is associated with poorer balance and spatial cognition and incident falls,these results will inform the design of interventional trials to prevent falls in AD patients.
 
16. Project Title: FRAILTY, HIV INFECTION, INJECTION DRUG USE AND THE INFLAMMATORY-MICROBIOME
  Leader(s): PIGGOTT, DAMANI
    THE JOHNS HOPKINS UNIVERSITY
    NIH R01AG060825 / ( 2018 - 2023 )
  Core(s):
  PROJECT SUMMARY/ABSTRACTWith effective antiretroviral therapy (ART), life expectancy for HIV-infected persons has markedly improved, yetmarked deficits in survival remain for HIV-infected persons with a history of injecting drugs (PWID). Disparitiesamong PWID have been attributed in part to a shifting spectrum of disease to aging-associated conditionsdriven by persistent inflammation even with ART. Frailty is an important aging-related state of vulnerability tostress, with an increased burden in HIV infection, strongly associated with heightened inflammation, andpredictive of premature mortality and aging-related morbidity among PWID. Injecting drugs itself can increasethe severity of inflammation in HIV. The human gut microbial ecosystem (gut microbiome) critically regulatesinflammation and immunity. Alterations in the gut microbiome (gut dysbiosis) together with associateddisruptions of gut structure and immune integrity constitute an inflammatory-microbiome signature (gutdysbiosis, increased gut permeability, translocation of microbial products, immune activation, heightenedinflammation) linked to adverse aging-associated inflammatory conditions and disease. Proposed is asystematic investigation of the role of HIV infection and injection drug use (IDU) in defining the inflammatory-microbiome signature and determination of the relationship of this signature to frailty. Through assessments ofthe fecal and mucosal microbiome in the AIDS Linked to the IntraVenous Experience (ALIVE) cohort of HIV-infected and epidemiologically comparable HIV-uninfected PWID, we will determine how HIV infection andactive IDU alter microbiome composition and function and the relationship of these changes to inflammationand frailty progression over time. Using a germ free murine model, we will further define the frail humanmicrobial communities and gene products that precipitate inflammation. These studies will facilitate elucidationof gut microbial determinants of frailty among HIV-infected PWID and could significantly inform microbiotamodulation strategies to reduce frailty-associated inflammation beyond ART. Understanding the role of the gutmicrobiome in relation to HIV, injection drug use, and frailty remains a critical next step to reducing the markeddisparities in clinical outcomes among HIV-infected PWID.
 
17. Project Title: CONTRIBUTION OF SENSORIMOTOR FUNCTION TO RISK AND PATHOGENIC MECHANISMS OF ALZHEIMER'S DISEASE AND RELATED DEMENTIAS
  Leader(s): SCHRACK, JENNIFER ANN; AGRAWAL, YURI ; LIN, FRANK R ;
    THE JOHNS HOPKINS UNIVERSITY
    NIH R01AG061786 / ( 2019 - 2023 )
  Core(s):
  PROJECT SUMMARYAlzheimer's disease (AD) is the most common cause of dementia. Underlying pathological and physiologicalchanges related to the onset and progression of AD are believed to emerge several years prior to clinicalmanifestations. Sensory impairments, gait abnormalities, and motor slowing may precede the diagnosis of ADby a decade or more, presenting the exciting possibility that changes in sensorimotor functioning may act asearly noninvasive biomarkers for AD. Previous work by our group has identified links between cognitiveperformance and sensory impairment and gait speed and variability, making them potential preclinical markersof early AD pathology. We propose to use up to 10 years of existing longitudinal data, and ongoing/new datacollection in approximately 1,000 older adults in the Baltimore Longitudinal Study of Aging (BLSA), to examinethe roles of sensory function, gait speed and variability, and free-living measures of daily physical activity (PA)as precursors to cognitive impairment. We will also determine the link between sensorimotor measures andbiomarkers of AD pathology, including A deposition using [11C]-Pittsburgh compound B positron emissiontomography, brain atrophy using structural magnetic resonance imaging (MRI), Tau and pTau from cerebrospinalfluid, and cognitive performance. We will further utilize the rich data resources of the BLSA to develop aparsimonius prediction model for risk of progression to MCI/AD, and validate its performance in theAtherosclerosis Risk in Communities (ARIC) study. A better understanding of the associations amongsensorimotor changes, subclinical AD pathology, and cognitive performance may elucidate a high-risk phenotypethat is associated with increased risk of poor cognitive outcomes over time and increase our understanding ofthe complex associations among declines in sensory, physical, and cognitive functioning with age. To this end,future intervention studies of AD prevention might screen for sensorimotor impairments as a high-risk phenotypereflective of increased risk for developing AD, which could serve as surrogate outcomes in clinical trials.Moreover, sensorimotor impairments may present feasible and modifiable targets for AD prevention byidentifying critical threshold(s) for implementation of assistive and rehabilitative technologies such as hearingaids, corrective lenses, surgical or pharmacologic procedures to correct hearing and/or vision impairment (e.g.,cataract surgery, cochlear implants), and physical therapy/timing and coordination of movement training tocorrect gait abnormalities.
 
18. Project Title: MITOCHONDRIAL ENERGETICS, EXERCISE INTOLERANCE AND FATIGABILITY IN OLDER PEOPLE WITH HIV
  Leader(s): WEISS, ROBERT G
    THE JOHNS HOPKINS UNIVERSITY
    NIH R01AG063661 / ( 2019 - 2024 )
  Core(s):
  People living with HIV infection (PLWH) are living longer but with advancing age experienceaccelerated functional decline (decreased strength, slowed gait, reduced exercise tolerance) and increasedfrailty, as compared to non-infected individuals. The syndromes of functional decline and frailty are associatedwith impaired quality of life, increased vulnerability to superimposed stresses, and the likelihood of prematuremorbidity and mortality. The mechanisms underlying this accelerated dysfunction and disability, however, arepoorly understood. The proposed project examines the contribution of altered skeletal muscle (SM)mitochondrial function and high energy phosphate metabolism to the related, but distinct syndromes of fatigue,exercise intolerance, and frailty often present in older PLWH. Considerable pre-clinical data and our pilotclinical studies using a 31P magnetic resonance spectroscopy (MRS) fatigability test during and following lower-extremity exercise suggest an energetic myopathy as a possible basis for the fatigue and decreasedperformance in older PLWH individuals. However the extent, underlying responsible factors, and functionalsignificance of altered SM mitochondrial bioenergetics in this population have not been characterized. Inaddition, two potential mechanisms responsible for altered SM high energy phosphate metabolism in otherpopulations, increased inflammation and SM lipid accumulation, have not been examined and related tomuscle energetics in PLWH and so these too will be examined. The central hypothesis is that impaired SMmitochondrial energy metabolism, initiated by aging and accelerated in the setting of contemporary HIV, is acentral contributor to the geriatric syndromes of fatigue, exercise intolerance, and frailty in older PLWH. Wepropose to use state-of-the art 31P MRS exercise testing, detailed muscle and whole body compositionmeasures, functional assessments during observed and free-living conditions, and biomarkers of inflammationand immune activation in 200 older (age>=60) women and men derived from four local NIH-sponsored cohortsto address these questions. The specific aims are 1) to define the scope of SM metabolic changes in olderwomen and men living with HIV, 2) to probe whether inflammation, skeletal fat and other underlying factors arerelated to the energetic abnormalities in older PLWH and 3) to determine the functional significance of SMenergetic changes in older PLWH by examining the relationships between the energetic changes and exercisetolerance and other functional assessments as well as the frailty phenotype. Fatigue, exercise intolerance, andfrailty are common in older PLWH and the underlying mechanisms remain poorly understood These novel,timely studies will provide new insights and guide future intervention strategies designed to attenuate orreverse mitochondrial and bioenergetic decline and thereby reduce the personal and societal toll of thesegeriatric conditions in older women and men living with HIV.
 
19. Project Title: HEMODIALYSIS-BASED INTERVENTIONS TO PRESERVE COGNITIVE FUNCTION
  Leader(s): MCADAMS DEMARCO, MARA A.
    THE JOHNS HOPKINS UNIVERSITY
    NIH R01DK114074 / ( 2018 - 2022 )
  Core(s):
  ABSTRACTOver 640,000 US adults suffer from ESRD, >95% of whom receive hemodialysis (HD) for the rest of their life oruntil transplantation. Kidney disease and HD significantly impact cognitive function, especially higher-orderexecutive function. Only 13% of HD patients have normal cognition; HD patients experience executive functionimpairment at a rate 3-fold higher than the general population, leading to hospitalization, disability, and death.Studies of older adults suggest that the only effective interventions for preserving executive function arecognitive training (CT) and/or exercise training (ET). These modalities have not been tested for executivefunction preservation in HD patients; even younger HD patients suffer substantial executive functionimpairment and could benefit from these interventions. HD frequency (3 sessions a week) and duration (4-6hours/session) makes HD patients a captive audience for intradialytic CT and/or ET to mitigate executivefunction decline. In preliminary studies, HD patients reported spending most of their time watching TV;intradialytic CT and/or ET could replace these passive activities. In preliminary studies, 87% of nephrologyproviders believed that their patients would be interested in intradialytic CT and 83% believed that theirpatients would be interested in intradialytic ET. Among HD patients, 67% wanted to improve their cognitionthrough CT and 71% wanted to improve their strength and cognition through ET while undergoing HD.To test the feasibility of intradialytic interventions, we conducted a pilot RCT of 20 HD patients, comparingstandard of care to CT or ET; even in this pilot, we found that intradialytic CT and ET preserved executivefunction. As expected, executive function in patients receiving standard of care declined substantially by 3months (difference=47.4 seconds, P=0.006); however, this decline was not seen among those receiving CT orET. Compared with standard of care, the difference in mean change was -46.72 seconds (95% CI: -91.12, -2.31; P=0.04) for CT and -56.21 seconds (95% CI: -105.86, -6.56; P=0.03) for ET. In just 3 months, CT and ETpreserved executive function compared to a striking decline with standard of care.To properly test the impact of intradialytic CT and/or ET, on the executive function decline associated with HD,we propose the following aims: 1) To conduct an RCT to evaluate executive function decline in the setting ofintradialytic CT and/or ET, 2) To quantify the effects of intradialytic CT and/or ET on ESRD-specific clinicaloutcomes, 3) To quantify the effects of intradialytic CT and/or ET, on patient-centered outcomes.Through this RCT, we will learn the impact of two potential non-pharmacological interventions, cognitive andexercise training, in preserving executive function during HD. If successful, this will improve HD outcomes of>640,000 adults with ESRD. For the first time, we will have validated, beneficial activities replace the typicalpassive activities of HD patients. Our findings will be implementable in dialysis centers across the country tohelp reduce the decline in executive function.
 
20. Project Title: DEVELOPING PERSONALIZED IMMUNOSUPPRESSION FOR OLDER KIDNEY TRANSPLANT RECIPIENTS
  Leader(s): MCADAMS DEMARCO, MARA A.
    THE JOHNS HOPKINS UNIVERSITY
    NIH R01DK120518 / ( 2018 - 2022 )
  Core(s):
  ABSTRACT>400,000 older adults (age =55) suffer from end-stage renal disease (ESRD). There has been a 5-foldincrease in the number of kidney transplants (KT) in this age group. Older recipients are a distinct group due toimpaired homeostasis, higher comorbidity burden, and immune system attenuation. These physiologic factorsinfluence older KT recipients response to immunosuppression (IS) medications, a lifelong treatment.The balance between short-term benefits and long-term adverse outcomes of IS can be challenging in olderKT recipients. Excellent short-term outcomes (1-year allograft survival>95% and acute rejection [AR]<15%) areachieved in younger patients with modern IS, but our preliminary findings suggest that older KT recipients areat 1.5x increased risk of poor IS tolerance. Older KT recipients are also more susceptible to long-term adverseoutcomes associated with the modern IS regimens like infections, malignancy, and new-onset diabetes aftertransplantation (NODAT) resulting in part from an attenuated immune response. Our preliminary findingssuggest that IS regimens with calcineurin inhibitors increase an older recipient s dementia risk. Yet, ourpreliminary data suggest that IS is not personalized; center practices account for 46% of IS regimen variation.While KT has been found to be cost saving for ESRD patients, the total KT cost is influenced by accumulatinglong-term adverse outcomes of IS in this population. IS is not chosen in a cost-blind environment; if the risksand benefits are similar, then cost-effectiveness is an important adjunct to IS regimen choice. The risks,benefits, and cost-effectiveness for an older KT recipient cannot simply be inferred from studies of youngerrecipients or from clinical trials that largely excluded older recipients. A comprehensive dataset with all keydata elements is needed to develop personalized IS for older KT recipients.To develop a personalized approach to IS for older KT recipients, we will integrate 3 novel datasets with>78,800 older KT recipients KT recipients (2005-2019): (1) national data from the Scientific Registry ofTransplant Recipients (SRTR); (2) Medicare claims to identify post-KT outcomes and costs; (3) pharmacyclaims to identify not only IS agents used but also novel lab data of metabolized IS levels (for 14,000 olderrecipients). Using this integrated data, we will: 1) compare the effects of IS regimens on efficacy, morbidity,and mortality for older KT recipients; 2) develop Markov models and calculate cost-effectiveness for ISregimens for older KT recipients; and 3) generate individualized reports of predicted efficacy, morbidity, andmortality along with IS regimen cost for practitioners to use for the clinical counseling of older KT recipients.Our goal is to provide evidence and communication tools to help move the field of transplantation away fromcenter-based protocols for IS to personalized IS for older KT recipients. The ability to predict trade-offs in ARand graft survival against long-term adverse outcomes for specific IS regimens in older KT recipients will allowpatients and physicians to customize IS choices in a cost-effective and more informed manner.!
 
21. Project Title: REPRODUCTIVE RISK FACTORS FOR ALZHEIMER'S DISEASE DEMENTIA AND PATHOLOGY
  Leader(s): MIELKE, MICHELLE M
    MAYO CLINIC
    NIH RF1AG055151 / ( 2017 - 2022 )
  Core(s):
  PROJECT SUMMARY/ABSTRACTRecent estimates suggest that almost two-thirds of the individuals diagnosed with Alzheimer s disease [AD]are women. The National Institutes of Health and the Alzheimer s Association have highlighted the critical needto understand sex differences in the risk factors and clinical progression of AD. Reproductive and hormonalfactors may be particularly important for women. Hypertensive pregnancy disorders [HPD] have beenassociated with subjective cognitive complaints or white matter lesions five to ten years after the HPD, but thelong-term effects of HPD on brain structure and cognitive function are unknown. Population-based studies areneeded to assess the contribution of HPD and subtype (i.e., preeclampsia) to the risk of cognitive decline, AD,and neuroimaging measures of amyloid-beta [A ], neurodegeneration, and cerebrovascular pathologies.Further, observational studies and clinical trials have examined the effects of early menopause (natural orsurgically-induced) and hormonal therapy [HT] on the risk of AD and other dementias. However, it is notcurrently known whether the effects of early menopause, HT use, and their interactions with APOE genotype,are associated with specific type(s) of brain pathology (i.e., A , neurodegeneration, cerebrovascular) becausemulti-modal imaging studies have not been conducted. The overall aims of this proposal are to elucidate theimpact of two hormonally-related sex-specific factors for women, pregnancy (e.g., number of pregnancies,HPD) and menopause (surgically-induced or natural), on the risk of cognitive decline, AD, and neuroimagingmeasures of A , neurodegeneration, and cerebrovascular pathologies. Because the literature and ourpreliminary data suggest that risk scores for cardiovascular disease and dementia are less predictive in womencompared to men, we also propose to incorporate these sex-specific factors to develop a more predictive riskscore of mild cognitive impairment and AD for women. To accomplish our goals, we will utilize two existinginfrastructures at the Mayo Clinic: the Mayo Clinic Study of Aging (MCSA; U01 AG006786) and the RochesterEpidemiology Project medical records-linkage system (REP; R01 AG034676). Using the REP, we will newlyabstract information on pregnancy and menopause for 2,370 women enrolled in the MCSA. Because fewstudies assessing pregnancy and menopause have also adjusted for putative confounding variables, we willalso abstract this data using the REP to determine whether these sex-specific conditions are independentpredictors of cognitive decline, AD, and neuroimaging measures of specific brain pathologies. Successfulcompletion of these aims will be a key step towards understanding whether these sex-specific factors areassociated with the risk of AD in women, to understanding whether these factors are related to a specific typeof brain pathology (i.e., A , neurodegeneration, cerebrovascular), and to developing a better risk score forpredicting cognitive impairment, dementia, and specific brain changes in women.
 
22. Project Title: ENERGY RESERVES, PHYSICAL ACTIVITY, AND ALZHEIMER'S DISEASE IN THE BALTIMORE LONGITUDINAL STUDY OF AGING
  Leader(s): SCHRACK, JENNIFER ANN
    THE JOHNS HOPKINS UNIVERSITY
    NIH U01AG057545 / ( 2017 - 2022 )
  Core(s):
  PROJECT SUMMARYAlzheimer s disease (AD) is the most common cause of dementia. Underlying pathological and physiologicalchanges related to the onset and progression of AD are believed to emerge several years prior to clinicalmanifestations. Gait abnormalities and motor slowing typically precede the diagnosis of AD by a decade ormore, presenting the exciting possibility that changes in gait may act as early noninvasive biomarkers for AD.Previous work by our group has identified key markers of impending and/or accelerated gait speed declinebased on physiological measures of the energy cost of slow walking, peak energy capacity, and quantities andpatterns of objectively measured free-living physical activity (PA), making them potential preclinical markers ofearly AD pathology. We propose to use 8 years of existing longitudinal data, and ongoing/new data collectionin nearly 1,000 older adults in the Baltimore Longitudinal Study of Aging (BLSA), to examine the roles ofaltered energy reserves, and reduced and fragmented daily PA as precursors to clinical markers of Alzheimer sdisease and neuronal injury, which include A deposition using [11C]-Pittsburgh compound B positron emissiontomography, brain atrophy using structural magnetic resonance imaging (MRI), and cognitive performance. Wewill also explore potential vascular mechanisms linking energy reserves and PA to these outcomes, includingcerebral blood flow, ankle brachial index, and pulse wave velocity, as well as the role of mediating or modifyingfactors such as inflammation and the apolipoprotein E genotype. The BLSA is a continuously enrolled cohortstudy of aging that already contains repeated measures of cognition and adjudication of cognitive status, inwhich a subset completes repeated MRI and PiB PET scans. Importantly, our preliminary cross-sectional datafrom the BLSA indicate strong associations among energy reserves, cognitive performance, b-amyloid burden,and diurnal patterns of daily PA. We propose to investigate the longitudinal associations among thesevariables to identify physiological thresholds of poor energy reserve and reduced and fragmented patterns ofdiurnal PA as early precursors to the onset and progression of AD pathology. A better understanding of theassociation between energy reserves/PA, subclinical AD pathology, and cognitive performance may elucidatea physiological threshold of diminished energy reserve that is associated with increased risk of poor cognitiveoutcomes over time, and increase our understanding of the complex association between declines in physicaland cognitive functioning with age. Moreover, uncovering patterns of daily free-living PA most commonlyassociated with this threshold will help define a phenotype of reduced and/or fragmented PA that signifiesimpending emergence and progression of AD. Given the proliferation of wearable devices to monitor PA in theconsumer and research markets, identifying changes in PA consistent with the development of AD pathologycould provide evidence for future wide-scale screening for early detection of persons at high risk of AD.
 
23. Project Title: VALIDATION OF NUCLEAR MORPHOLOGY AS A BIOMARKER OF AGING AND AGING-RELATED PHENOTYPES
  Leader(s): WIRTZ, DENIS
    THE JOHNS HOPKINS UNIVERSITY
    NIH U01AG060903 / ( 2018 - 2023 )
  Core(s):
  AbstractAlterations in the nuclear protein lamin and associated structures in the nucleus have beenidentified as a source of nuclear morphology changes that markedly impact overall cellularfunction. These changes in nuclear morphology are thought to drive molecular changes thatinfluence a wide range of aging-related phenotypes and chronic disease states. Importantly, wehave recently used high-throughput measurements of nuclear morphology to identify outstandingbiomarkers of chronological age. We hypothesize that these age-related changes in nuclearmorphology are highly correlated with chronological age in healthy individuals, and that a specificage-related biological change in lamin underlies this phenomenon. Building on our priordevelopment of these high-throughput and accurate measures of nuclear morphology, we proposehere to further develop this biological discovery and technology as a valid and reliable biomarkerof aging-related biological mechanisms. We hypothesize that changes in nuclear morphology canbe rapidly measured and that age-related alterations correlate with aging-related phenotypes anddisease states independently of chronological age, consistent with a measure of cellular biologicalage. To test these hypotheses and move results toward clinical utility, we have assembled a highlysynergistic, interdisciplinary team propose the following specific aims:Aim 1. Using our validated single-cell technologies, we will develop a mechanistic understandingof how descriptors of nuclear morphology in human dermal fibroblasts and B-lymphocytes arerobust biomarkers of aging in healthy individuals. Aim 2. Establish the accuracy and precisionwith which our proposed biomarkers identify chronological age for individuals with varyingdemographic, behavioral, and health characteristics. Aim 3. We will examine the strength withwhich morphological biomarkers discriminate individuals with adverse phenotypes and outcomesof aging, and at risk for the development of these, from healthy older adults, above and beyondchronological age.
 
24. Project Title: SEX AND AGE DIFFERENCES IN IMMUNITY TO INFLUENZA (SADII)
  Leader(s): KLEIN, SABRA L.
    THE JOHNS HOPKINS UNIVERSITY
    NIH U54AG062333 / ( 2018 - 2023 )
  Core(s):
  SEX AND AGE DIFFERENCES IN IMMUNITY TO INFLUENZA (SADII) SUMMARYThe NIH Office of Research on Women s Health (ORWH) should support a Specialized Center of ResearchExcellence (SCORE) on sex differences in influenza immunity because despite having antivirals and vaccines,influenza remains a significant public health threat, causing approximately 100,000 hospitalizations, 30,000deaths, and approximately $7 billion in lost productivity in the United States, alone. Sex and age are emergingas two host variables that significantly impact the pathogenesis of influenza virus infection and responses toinfluenza vaccines. The Sex and Age Differences in Immunity to Influenza (SADII, pronounced sade) SCOREwill leverage the internationally recognized research, resources, and educational opportunities at JohnsHopkins University to transform women s health and impact the development of and policy decisions aboutinfluenza vaccine programs, including universal influenza vaccines. The overarching hypothesis being testedthrough the SADII SCORE Research Projects is that female-biased vaccine-induced immunity to influenzaviruses is age-dependent and reflects both hormonal and genetic differences between the sexes that impactimmune responses (i.e., both effector and memory) to influenza vaccine antigens. SADII will bring togetherinvestigators focused on 1) seasonal influenza vaccination in an existing age and sex stratified humanpopulation; 2) animal models that can test hypotheses and mechanisms of action that are inferred from studiesin human populations; and 3) the contributions of age, frailty, sex, and gender to vaccine outcomes usingquantitative and qualitative statistical models. By using the combined expertise in our research groups, SADIIis uniquely positioned to identify the biological basis behind sex and age differences in immune responses toinfluenza vaccination and disseminate those findings to the broader research, clinical, and public healthcommunities. The overarching mission of the SADII SCORE will be achieved through the following SpecificAims: 1) To provide leadership and oversight of the SADII SCORE and collaboration with other entities atJohns Hopkins and elsewhere to develop a translational research program focused on sex and age differencesin immunology and infectious diseases; 2) To systematically evaluate sex differences in vaccine-inducedimmune responses across the life course using translational approaches involving human studies andmechanistic animal models; and 3) To meet the career enhancement needs of diverse translational scientistsstudying sex differences at Johns Hopkins and beyond. We are prepared to transform women s health, sex,and gender research into a signature initiative at Johns Hopkins and in the fields of microbiology andimmunology.
 
25. Project Title: CHARACTERIZING RESILIENCIES TO PHYSICAL STRESSORS IN OLDER ADULTS: A DYNAMICAL PHYSIOLOGICAL SYSTEMS APPROACH
  Leader(s): WALSTON, JEREMY DAVID; BANDEEN-ROCHE, KAREN J. ; VARADHAN, RAVI ;
    THE JOHNS HOPKINS UNIVERSITY
    NIH UH3AG056933 / ( 2019 - 2022 )
  Core(s):
  Project SummaryWhen confronted with a major physical stressor, some older adults are able to recover, with minimal decline,their physical and cognitive function, while others suffer precipitous, irreversible declines in function. This is thecentral notion behind resiliency. Little is known about the intrinsic (e.g., physiologic and molecular processes)and extrinsic (e.g., health behaviors) factors that impact resiliency. A two-phase study is proposed here toaddress this gap in our understanding. In phase 1, data will be generated to characterize age-related changesin physical resiliencies, their determinants, and their outcomes. Phase 2 will involve construction and validationof measures of resiliency; assessment of their predictive and clinical value; and investigation of age-relatedbiological mechanisms determining specific resiliencies.Phase 1 Specific Aims:1. To define, develop and refine phenotypic measures of resiliency responses to three pre-defined physical stressors: hip replacement surgery, initiation of hemodialysis, and bone marrow transplantation for hematologic malignancy.2. To develop and pilot test candidate indicators of physical resiliency to include static and dynamic, as well as global and stressor-specific, measures.3. To identify pre-stressor determinants of resilience, including measures of disease states, psychosocial factors, and molecular measures, and to characterize their measurement and statistical properties.4. To synthesize data developed in Aims 1-3 to inform the design of Phase 2 studies.Phase 2 Specific Aims:1. For each of clinical stressor to be studied: To build and evaluate assessments of resiliency incorporating measures identified in phase 1. Promising candidate measures will be cross-validated and their accuracy in predicting short- and long-term resilient stressor response rigorously characterized. The relative predictive value of global vs. specific, static vs. dynamic, and solely EHR-based versus broader resiliency measures will be assessed.2. To characterize and assess age-related biological mechanisms that contribute to resilience or lack thereof that are specific to each clinical stressor, as well as mechanisms that are common across three specific physical stressors in older adults.3. In preparation for the conduct of intervention studies: to cross-validate measures of resiliency at an external institution and to design pilot studies of strategies to bolster resiliencies based on clinical findings and biological mechanisms identified in Phase 1.
 
PUBLICATIONS
2022
  1. Telomere shortening and the transition to family caregiving in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study.
    Armstrong ND, Irvin MR, Haley WE, Blinka MD, Kamin Mukaz D, Patki A, Rutherford Siegel S, Shalev I, Durda P, Mathias RA, Walston JD, Roth DL
    PLoS One, 2022, 17(6): e0268689
    https://doi.org/10.1371/journal.pone.0268689 | PMID: 35657918 | PMCID: PMC9165822
    Citations: | AltScore: NA
  2. The effects of vitamin D supplementation on frailty in older adults at risk for falls.
    Cai Y, Wanigatunga AA, Mitchell CM, Urbanek JK, Miller ER 3rd, Juraschek SP, Michos ED, Kalyani RR, Roth DL, Appel LJ, Schrack JA
    BMC Geriatr, 2022 Apr 10, 22(1): 312
    https://doi.org/10.1186/s12877-022-02888-w | PMID: 35399053 | PMCID: PMC8994906
    Citations: | AltScore: 32.15
  3. Moving toward clinical implementation of the physical frailty phenotype in kidney transplantation.
    Chen X, Shafaat O, Liu Y, King EA, Weiss CR, Xue QL, Walston JD, Segev DL, DeMarco MA
    Am J Transplant, 2022 Apr 29
    https://doi.org/10.1111/ajt.17080 | PMID: 35486021
    Citations: | AltScore: NA
  4. Revision of frailty assessment in kidney transplant recipients: Replacing unintentional weight loss with CT-assessed sarcopenia in the physical frailty phenotype.
    Chen X, Shafaat O, Liu Y, King EA, Weiss CR, Xue QL, Walston JD, Segev DL, McAdams-DeMarco MA
    Am J Transplant, 2022 Apr, 22(4): 1145-1157
    https://doi.org/10.1111/ajt.16934 | PMID: 34953170 | PMCID: PMC8983565
    Citations: | AltScore: 11.65
  5. Long-term Trajectories of Frailty and its Components after Kidney Transplantation.
    Chu NM, Ruck J, Chen X, Xue QL, Norman SP, Segev DL, McAdams-DeMarco MA
    J Gerontol A Biol Sci Med Sci, 2022 Feb 20
    pii: glac051. https://doi.org/10.1093/gerona/glac051 | PMID: 35184167
    Citations: | AltScore: NA
  6. New horizons in evidence-based care for older people: individual participant data meta-analysis.
    Clegg A, Bandeen-Roche K, Farrin A, Forster A, Gill TM, Gladman J, Kerse N, Lindley R, McManus RJ, Melis R, Mujica-Mota R, Raina P, Rockwood K, Teh R, van der Windt D, Witham M
    Age Ageing, 2022 Apr 1, 51(4):
    pii: afac090. https://doi.org/10.1093/ageing/afac090 | PMID: 35460409 | PMCID: PMC9034697
    Citations: | AltScore: 49.93
  7. Higher Angiotensin II Type 1 Receptor Levels and Activity in the Postmortem Brains of Older Persons with Alzheimer's Dementia.
    Cosarderelioglu C, Nidadavolu LS, George CJ, Marx-Rattner R, Powell L, Xue QL, Tian J, Salib J, Oh ES, Ferrucci L, Dincer P, Bennett DA, Walston JD, Abadir PM
    J Gerontol A Biol Sci Med Sci, 2022 Apr 1, 77(4): 664-672
    https://doi.org/10.1093/gerona/glab376 | PMID: 34914835 | PMCID: PMC8974324
    Citations: 1 | AltScore: 15.55
  8. The Influence of Frailty on Cardiovascular Disease: The Time for a \Frailty Academic Research Consortium\ Is Now!
    Damluji AA, Cohen MG
    Circ Cardiovasc Interv, 2022 Jan, 15(1): e011669
    https://doi.org/10.1161/CIRCINTERVENTIONS.121.011669 | PMID: 35041458 | PMCID: PMC8852245
    Citations: | AltScore: 16.75
  9. At the Crossroad Between Skeletal and Cardiac Muscle Cells.
    deFilippi CR, Damluji AA
    Circulation, 2022 Jun 14, 145(24): 1780-1783
    https://doi.org/10.1161/CIRCULATIONAHA.122.059935 | PMID: 35696457 | PMCID: PMC9202001
    Citations: | AltScore: 13
  10. Exploring the Experiences of Co-morbid Pain and Depression in Older African American Women and Their Preferred Management Strategies.
    Drazich BF, Jenkins E, Nkimbeng M, Abshire Saylor M, Szanton SL, Wright R, Beach MC, Taylor JL
    Front Pain Res (Lausanne), 2022, 3: 845513
    https://doi.org/10.3389/fpain.2022.845513 | PMID: 35295801 | PMCID: PMC8915555
    Citations: | AltScore: NA
  11. Genome-Wide Analysis in Drosophila Reveals the Genetic Basis of Variation in Age-Specific Physical Performance and Response to ACE Inhibition.
    Gabrawy MM, Khosravian N, Morcos GS, Morozova TV, Jezek M, Walston JD, Huang W, Abadir PM, Leips J
    Genes (Basel), 2022 Jan 14, 13(1):
    pii: 143. https://doi.org/10.3390/genes13010143 | PMID: 35052483 | PMCID: PMC8775566
    Citations: 1 | AltScore: 11.75
  12. Frailty in Patients Undergoing Surgery for Brain Tumors: A Systematic Review of the Literature.
    Huq S, Liu J, Romano R, Seal S, Khalafallah AM, Walston JD, Mukherjee D
    World Neurosurg, 2022 Jul 14
    pii: S1878-8750(22)00986-X. https://doi.org/10.1016/j.wneu.2022.07.039 | PMID: 35843574
    Citations: | AltScore: NA
  13. Interventions for Frailty Among Older Adults With Cardiovascular Disease: JACC?State-of-the-Art Review.
    Ijaz N, Buta B, Xue QL, Mohess DT, Bushan A, Tran H, Batchelor W, deFilippi CR, Walston JD, Bandeen-Roche K, Forman DE, Resar JR, O'Connor CM, Gerstenblith G, Damluji AA
    J Am Coll Cardiol, 2022 Feb 8, 79(5): 482-503
    https://doi.org/10.1016/j.jacc.2021.11.029 | PMID: 35115105 | PMCID: PMC8852369
    Citations: 2 | AltScore: 89.58
  14. Mitochondrial Creatine Kinase Attenuates Pathologic Remodeling in Heart Failure.
    Keceli G, Gupta A, Sourdon J, Gabr R, Sch?r M, Dey S, Tocchetti CG, Stuber A, Agrimi J, Zhang Y, Leppo M, Steenbergen C, Lai S, Yanek LR, O'Rourke B, Gerstenblith G, Bottomley PA, Wang Y, Paolocci N, Weiss RG
    Circ Res, 2022 Mar 4, 130(5): 741-759
    https://doi.org/10.1161/CIRCRESAHA.121.319648 | PMID: 35109669 | PMCID: PMC8897235
    Citations: | AltScore: 3.85
  15. Serum concentrations of losartan metabolites correlate with improved physical function in a pilot study of prefrail older adults.
    Lee JL, Zhang C, Westbrook R, Gabrawy MM, Nidadavolu L, Yang H, Marx R, Wu Y, Anders NM, Ma L, Bichara MD, Kwak MJ, Buta B, Khadeer M, Yenokyan G, Tian J, Xue QL, Siragy HM, Carey RM, de Cabo R, Ferrucci L, Moaddel R, Rudek MA, Le A, Walston JD, Abadir PM
    J Gerontol A Biol Sci Med Sci, 2022 May 3
    pii: glac102. https://doi.org/10.1093/gerona/glac102 | PMID: 35511890
    Citations: | AltScore: 25.2
  16. Improvements of Disability Outcomes in CAPABLE Older Adults Differ by Financial Strain Status.
    Liu M, Xue QL, Samuel L, Gitlin LN, Guralnik J, Leff B, Szanton SL
    J Appl Gerontol, 2022 Feb, 41(2): 471-477
    https://doi.org/10.1177/0733464820975551 | PMID: 33267710 | PMCID: PMC8169719
    Citations: 1 | AltScore: 0.75
  17. Valsartan and sacubitril combination treatment enhances collagen production in older adult human skin cells.
    Marin S, Godet I, Nidadavolu LS, Tian J, Dickinson LE, Walston JD, Gilkes DM, Abadir PM
    Exp Gerontol, 2022 Aug, 165: 111835
    https://doi.org/10.1016/j.exger.2022.111835 | PMID: 35598697
    Citations: | AltScore: 7.5
  18. The influence of heart failure on clinical and economic outcomes among older adults =75 years of age with acute myocardial infarction.
    Pasala S, Cooper LB, Psotka MA, Sinha SS, deFilippi CR, Tran H, Tehrani B, Sherwood M, Epps K, Batchelor W, Damluji AA
    Am Heart J, 2022 Apr, 246: 65-73
    https://doi.org/10.1016/j.ahj.2021.11.021 | PMID: 34922928 | PMCID: PMC8917998
    Citations: | AltScore: 9.2
  19. Transitions to Family Caregiving and Latent Variables of Systemic Inflammation Over Time.
    Roth DL, Bentley JP, Mukaz DK, Haley WE, Walston JD, Bandeen-Roche K
    Res Aging, 2022 Apr 15 1640275221084729
    https://doi.org/10.1177/01640275221084729 | PMID: 35422166
    Citations: | AltScore: 4.45
  20. Early identification of frailty: Developing an international delphi consensus on pre-frailty.
    Sezgin D, O'Donovan M, Woo J, Bandeen-Roche K, Liotta G, Fairhall N, Rodr?guez-Laso A, Ap?stolo J, Clarnette R, Holland C, Roller-Wirnsberger R, Illario M, Ma?as LR, Vollenbroek-Hutten M, Dogu BB, Balci C, Pernas FO, Paul C, Ahern E, Romero-Ortuno R, Molloy W, Cooney MT, O'Shea D, Cooke J, Lang D, Hendry A, Kennelly S, Rockwood K, Clegg A, Liew A, O'Caoimh R
    Arch Gerontol Geriatr, 2022 Mar-Apr, 99: 104586
    https://doi.org/10.1016/j.archger.2021.104586 | PMID: 34896797
    Citations: 3 | AltScore: 12.75
  21. Cardiogenic Shock From Heart Failure Versus Acute Myocardial Infarction: Clinical Characteristics, Hospital Course, and 1-Year Outcomes.
    Sinha SS, Rosner CM, Tehrani BN, Maini A, Truesdell AG, Lee SB, Bagchi P, Cameron J, Damluji AA, Desai M, Desai SS, Epps KC, deFilippi C, Flanagan MC, Genovese L, Moukhachen H, Park JJ, Psotka MA, Raja A, Shah P, Sherwood MW, Singh R, Tang D, Young KD, Welch T, O'Connor CM, Batchelor WB
    Circ Heart Fail, 2022 Jun, 15(6): e009279
    https://doi.org/10.1161/CIRCHEARTFAILURE.121.009279 | PMID: 35510546 | PMCID: PMC9286066
    Citations: | AltScore: 32.2
  22. Acute Myocardial Infarction and Cardiogenic Shock Interventional Approach to Management in the Cardiac Catheterization Laboratories.
    Tehrani BN, Damluji AA, Batchelor WB
    Curr Cardiol Rev, 2022, 18(2): 15-30
    https://doi.org/10.2174/1573403X17666211125090929 | PMID: 34823461
    Citations: 1 | AltScore: 3
  23. Association of Frailty Status and Dietary Patterns in a Nationally Representative Sample of United States Adults with Olfactory Dysfunction.
    Vohra V, Leland EM, Schlosser RJ, Kamath V, Rowan NR
    Nutrients, 2022 Mar 15, 14(6):
    pii: 1238. https://doi.org/10.3390/nu14061238 | PMID: 35334897 | PMCID: PMC8954153
    Citations: | AltScore: 3.7
 
2021
  1. Does study subject diversity influence cardiology research site performance?: Insights from 2 U.S. National Coronary Stent Registries.
    Batchelor WB, Damluji AA, Yong C, Fiuzat M, Barnett SD, Kandzari DE, Sherwood MW, Epps KC, Tehrani BN, Allocco DJ, Meredith IT, Lindenfeld J, O'Connor CM, Mehran R
    Am Heart J, 2021 Jun, 236: 37-48
    https://doi.org/10.1016/j.ahj.2021.02.003 | PMID: 33636137 | PMCID: PMC8188231
    Citations: 1 | AltScore: 9.8
  2. Developing a sensor-based mobile application for in-home frailty assessment: a qualitative study.
    Blinka MD, Buta B, Bader KD, Hanley C, Schoenborn NL, McNabney M, Xue QL
    BMC Geriatr, 2021 Feb 4, 21(1): 101
    https://doi.org/10.1186/s12877-021-02041-z | PMID: 33541276 | PMCID: PMC7863502
    Citations: 1 | AltScore: 8.68
  3. Visual Impairment and Objectively Measured Physical Activity in Middle-Aged and Older Adults.
    Cai Y, Schrack JA, Wang H, E JY, Wanigatunga AA, Agrawal Y, Urbanek JK, Simonsick EM, Ferrucci L, Swenor BK
    J Gerontol A Biol Sci Med Sci, 2021 Nov 15, 76(12): 2194-2203
    https://doi.org/10.1093/gerona/glab103 | PMID: 33837407 | PMCID: PMC8599058
    Citations: 3 | AltScore: NA
  4. Traits and treadmills: Association between personality and perceived fatigability in well-functioning community-dwelling older adults.
    Chan T, Wanigatunga AA, Terracciano A, Carlson MC, Bandeen-Roche K, Costa PT, Simonsick EM, Schrack JA
    Psychol Aging, 2021 Sep, 36(6): 710-717
    https://doi.org/10.1037/pag0000631 | PMID: 34516174 | PMCID: PMC8442749
    Citations: 1 | AltScore: NA
  5. Intrinsic Capacity as a Determinant of Physical Resilience in Older Adults.
    Chhetri JK, Xue QL, Ma L, Chan P, Varadhan R
    J Nutr Health Aging, 2021, 25(8): 1006-1011
    https://doi.org/10.1007/s12603-021-1629-z | PMID: 34545921 | PMCID: PMC8035602
    Citations: 7 | AltScore: 14.95
  6. Frailty-a risk factor of global and domain-specific cognitive decline among a nationally representative sample of community-dwelling older adult U.S. Medicare beneficiaries.
    Chu NM, Xue QL, McAdams-DeMarco MA, Carlson MC, Bandeen-Roche K, Gross AL
    Age Ageing, 2021 Jun 7, 50(5): 1569-1577
    pii: afab102. https://doi.org/10.1093/ageing/afab102 | PMID: 34097002 | PMCID: PMC8437073
    Citations: 1 | AltScore: 13.8
  7. Clinical Application of Serologic Testing for Coronavirus Disease 2019 in Contemporary Cardiovascular Practice.
    Damluji AA, Christenson RH, deFilippi C
    J Am Heart Assoc, 2021 Feb, 10(5): e019506
    https://doi.org/10.1161/JAHA.120.019506 | PMID: 33619984 | PMCID: PMC8174282
    Citations: 5 | AltScore: 6.95
  8. Frailty and cardiovascular outcomes in the National Health and Aging Trends Study.
    Damluji AA, Chung SE, Xue QL, Hasan RK, Moscucci M, Forman DE, Bandeen-Roche K, Batchelor W, Walston JD, Resar JR, Gerstenblith G
    Eur Heart J, 2021 Oct 1, 42(37): 3856-3865
    https://doi.org/10.1093/eurheartj/ehab468 | PMID: 34324648 | PMCID: PMC8487013
    Citations: 6 | AltScore: 69.95
  9. Physical Frailty Phenotype and the Development of Geriatric Syndromes in Older Adults with Coronary Heart Disease.
    Damluji AA, Chung SE, Xue QL, Hasan RK, Walston JD, Forman DE, Bandeen-Roche K, Moscucci M, Batchelor W, Resar JR, Gerstenblith G
    Am J Med, 2021 May, 134(5): 662-671.e1
    https://doi.org/10.1016/j.amjmed.2020.09.057 | PMID: 33242482 | PMCID: PMC8107119
    Citations: 6 | AltScore: 8.3
  10. Lies, damned lies, and statistics, but bleeding and acute limb ischemia are facts!
    Damluji AA, Gilchrist IC
    Catheter Cardiovasc Interv, 2021 May 1, 97(6): 1139-1140
    https://doi.org/10.1002/ccd.29726 | PMID: 33974740
    Citations: | AltScore: 3.95
  11. Serological Testing for COVID-19 Disease: Moving the Field of Serological Surveillance Forward.
    Damluji AA, Rajan D, Haymond A, deFilippi C
    J Appl Lab Med, 2021 Apr 29, 6(3): 584-587
    https://doi.org/10.1093/jalm/jfab018 | PMID: 33693726 | PMCID: PMC7989295
    Citations: 2 | AltScore: 1.75
  12. The physical frailty syndrome as a transition from homeostatic symphony to cacophony.
    Fried LP, Cohen AA, Xue QL, Walston J, Bandeen-Roche K, Varadhan R
    Nat Aging, 2021 Jan, 1(1): 36-46
    https://doi.org/10.1038/s43587-020-00017-z | PMID: 34476409 | PMCID: PMC8409463
    Citations: 5 | AltScore: 95.5
  13. Use of the p-values as a size-dependent function to address practical differences when analyzing large datasets.
    G?mez-de-Mariscal E, Guerrero V, Sneider A, Jayatilaka H, Phillip JM, Wirtz D, Mu?oz-Barrutia A
    Sci Rep, 2021 Oct 22, 11(1): 20942
    https://doi.org/10.1038/s41598-021-00199-5 | PMID: 34686696 | PMCID: PMC8536742
    Citations: | AltScore: 41.85
  14. Frailty, with or without Cognitive Impairment, is a Strong Predictor of Recurrent Falls in a US Population-Representative Sample of Older Adults.
    Ge ML, Simonsick EM, Dong BR, Kasper JD, Xue QL
    J Gerontol A Biol Sci Med Sci, 2021 Mar 15, 76(11): e354-e360
    pii: glab083. https://doi.org/10.1093/gerona/glab083 | PMID: 33721909 | PMCID: PMC8562403
    Citations: 5 | AltScore: 1.5
  15. Evidence from two cohorts for the frailty syndrome as an emergent state of parallel dysregulation in multiple physiological systems.
    Ghachem A, Fried LP, Legault V, Bandeen-Roche K, Presse N, Gaudreau P, Cohen AA
    Biogerontology, 2021 Feb, 22(1): 63-79
    https://doi.org/10.1007/s10522-020-09903-w | PMID: 33064226 | PMCID: PMC8557952
    Citations: 8 | AltScore: 1
  16. Strategies to Prevent or Remediate Cancer and Treatment-Related Aging.
    Guida JL, Agurs-Collins T, Ahles TA, Campisi J, Dale W, Demark-Wahnefried W, Dietrich J, Fuldner R, Gallicchio L, Green PA, Hurria A, Janelsins MC, Jhappan C, Kirkland JL, Kohanski R, Longo V, Meydani S, Mohile S, Niedernhofer LJ, Nelson C, Perna F, Schadler K, Scott JM, Schrack JA, Tracy RP, van Deursen J, Ness KK
    J Natl Cancer Inst, 2021 Feb 1, 113(2): 112-122
    https://doi.org/10.1093/jnci/djaa060 | PMID: 32348501 | PMCID: PMC7850536
    Citations: 9 | AltScore: 34.458
  17. Durability of Viral Neutralization in Asymptomatic Coronavirus Disease 2019 for at Least 60 Days.
    Haymond A, Damluji AA, Narayanan A, Mueller C, Reeder A, Alem F, Maxwell GL, Petricoin EF, Liotta L, deFilippi CR
    J Infect Dis, 2021 May 28, 223(10): 1677-1680
    https://doi.org/10.1093/infdis/jiab140 | PMID: 33718952 | PMCID: PMC7989428
    Citations: 2 | AltScore: 0.75
  18. Self-efficacy proxy predicts frailty incidence over time in non-institutionalized older adults.
    Hladek MD, Zhu J, Buta BJ, Szanton SL, Bandeen-Roche K, Walston JD, Xue QL
    J Am Geriatr Soc, 2021 Dec, 69(12): 3507-3518
    https://doi.org/10.1111/jgs.17417 | PMID: 34418062 | PMCID: PMC8648965
    Citations: 1 | AltScore: 15.85
  19. 2015-2016 Normative Data for the 3-m Usual Walk, Five Repeated Chair Stands, and Static Balance Components of the SPPB Among U.S. Older Adults Across Two Nationally Representative Data Sets: NSHAP and NHATS.
    Huisingh-Scheetz M, Buta B, Bandeen-Roche K, Huang ES, Varadhan R, Walston J, Wroblewski K, Schumm LP, Waite LJ
    J Gerontol B Psychol Sci Soc Sci, 2021 Dec 17, 76(Suppl 3): S299-S312
    https://doi.org/10.1093/geronb/gbab135 | PMID: 34918153 | PMCID: PMC8678433
    Citations: | AltScore: 2
  20. Lactoferrin for the treatment of age-associated inflammation - A pilot study.
    Laskow T, Langdon J, Abadir P, Xue QL, Walston J
    Physiol Int, 2021 Apr 9
    https://doi.org/10.1556/2060.2021.00010 | PMID: 33844642 | PMCID: PMC9211386
    Citations: | AltScore: NA
  21. Association Between Walking Energetics and Fragmented Physical Activity in Mid- to Late-Life.
    Liu F, Wanigatunga AA, Kuo PL, Zipunnikov V, Simonsick EM, Ferrucci L, Schrack JA
    J Gerontol A Biol Sci Med Sci, 2021 Sep 13, 76(10): e281-e289
    https://doi.org/10.1093/gerona/glab127 | PMID: 33963748 | PMCID: PMC8436987
    Citations: 1 | AltScore: 1.75
  22. Association of Mitochondrial Function, Substrate Utilization, and Anaerobic Metabolism With Age-Related Perceived Fatigability.
    Liu F, Wanigatunga AA, Zampino M, Knuth ND, Simonsick EM, Schrack JA, Ferrucci L
    J Gerontol A Biol Sci Med Sci, 2021 Feb 25, 76(3): 426-433
    https://doi.org/10.1093/gerona/glaa201 | PMID: 32803242 | PMCID: PMC8355455
    Citations: 2 | AltScore: 7.45
  23. Valsartan nano-filaments alter mitochondrial energetics and promote faster healing in diabetic rat wounds.
    Nidadavolu LS, Stern D, Lin R, Wang Y, Li Y, Wu Y, Marin S, Antonio MJ, Yenokyan G, Boronina T, Cole R, Foster DB, Talbot C, Jedrych J, Smith B, Rini D, Le A, Cui H, Walston JD, Abadir PM
    Wound Repair Regen, 2021 Nov, 29(6): 927-937
    https://doi.org/10.1111/wrr.12974 | PMID: 34669222 | PMCID: PMC8571056
    Citations: | AltScore: 7.1
  24. Underlying Vulnerabilities to the Cytokine Storm and Adverse COVID-19 Outcomes in the Aging Immune System.
    Nidadavolu LS, Walston JD
    J Gerontol A Biol Sci Med Sci, 2021 Feb 25, 76(3): e13-e18
    https://doi.org/10.1093/gerona/glaa209 | PMID: 32841329 | PMCID: PMC7546042
    Citations: 8 | AltScore: 7.85
  25. Midlife Cardiovascular Health and Robust versus Frail Late-Life Status: The Atherosclerosis Risk in Communities (ARIC) Study.
    Palta P, Griswold M, Ranadive R, Bandeen-Roche K, Folsom AR, Petruski-Ivleva N, Burgard S, Kucharska-Newton A, Windham BG
    J Gerontol A Biol Sci Med Sci, 2021 Oct 18, 77(6): 1222-1229
    pii: glab310. https://doi.org/10.1093/gerona/glab310 | PMID: 34661638 | PMCID: PMC9159655
    Citations: | AltScore: NA
  26. A robust unsupervised machine-learning method to quantify the morphological heterogeneity of cells and nuclei.
    Phillip JM, Han KS, Chen WC, Wirtz D, Wu PH
    Nat Protoc, 2021 Feb, 16(2): 754-774
    https://doi.org/10.1038/s41596-020-00432-x | PMID: 33424024 | PMCID: PMC8167883
    Citations: 9 | AltScore: 77.4
  27. Fractional re-distribution among cell motility states during ageing.
    Phillip JM, Zamponi N, Phillip MP, Daya J, McGovern S, Williams W, Tschudi K, Jayatilaka H, Wu PH, Walston J, Wirtz D
    Commun Biol, 2021 Jan 19, 4(1): 81
    https://doi.org/10.1038/s42003-020-01605-w | PMID: 33469145 | PMCID: PMC7815872
    Citations: 1 | AltScore: 11.65
  28. Pain in persons with dementia and the direct and indirect impacts on caregiver burden.
    Regier NG, Taylor JL, Szanton SL, Parmelee PA, Perrin N, Liu M, Jenkins E, Hodgson NA, Gitlin LN
    Geriatr Nurs, 2021 Mar-Apr, 42(2): 366-371
    https://doi.org/10.1016/j.gerinurse.2021.01.007 | PMID: 33571930 | PMCID: PMC8832466
    Citations: | AltScore: NA
  29. Myocarditis Temporally Associated With COVID-19 Vaccination.
    Rosner CM, Genovese L, Tehrani BN, Atkins M, Bakhshi H, Chaudhri S, Damluji AA, de Lemos JA, Desai SS, Emaminia A, Flanagan MC, Khera A, Maghsoudi A, Mekonnen G, Muthukumar A, Saeed IM, Sherwood MW, Sinha SS, O'Connor CM, deFilippi CR
    Circulation, 2021 Aug 10, 144(6): 502-505
    https://doi.org/10.1161/CIRCULATIONAHA.121.055891 | PMID: 34133885 | PMCID: PMC8340723
    Citations: 88 | AltScore: 731.22
  30. Abernethy Malformation with Massively Dilated Main Pulmonary Artery Manifesting as Acute Myocardial Infarction.
    Rout A, Chongthammakun V, Siegel YJ, Mendoza D, Damluji AA
    J Cardiovasc Imaging, 2021 Oct, 29(4): 379-381
    https://doi.org/10.4250/jcvi.2021.0011 | PMID: 34080337 | PMCID: PMC8592679
    Citations: | AltScore: NA
  31. Understanding surgical decision-making in older adults with differentiated thyroid cancer: A discrete choice experiment.
    Sutton W, Genberg B, Prescott JD, Segev DL, Zeiger MA, Bandeen-Roche K, Mathur A
    Surgery, 2021 Jan, 169(1): 14-21
    https://doi.org/10.1016/j.surg.2020.03.022 | PMID: 32475718 | PMCID: PMC7704531
    Citations: 1 | AltScore: 16.35
  32. Transradial access in acute myocardial infarction complicated by cardiogenic shock: Stratified analysis by shock severity.
    Tehrani BN, Damluji AA, Sherwood MW, Rosner C, Truesdell AG, Epps KC, Howard E, Barnett SD, Raja A, deFilippi CR, Murphy CE, O'Connor CM, Batchelor WB
    Catheter Cardiovasc Interv, 2021 Jun 1, 97(7): 1354-1366
    https://doi.org/10.1002/ccd.29098 | PMID: 32744434 | PMCID: PMC8165635
    Citations: 1 | AltScore: 1.5
  33. Objectively measured patterns of daily physical activity and phenotypic frailty.
    Wanigatunga AA, Cai Y, Urbanek JK, Mitchell CM, Roth DL, Miller ER, Michos ED, Juraschek SP, Walston J, Xue QL, Appel LJ, Schrack JA
    J Gerontol A Biol Sci Med Sci, 2021 Sep 25
    pii: glab278. https://doi.org/10.1093/gerona/glab278 | PMID: 34562073
    Citations: | AltScore: 12.55
  34. The effects of vitamin D supplementation on types of falls.
    Wanigatunga AA, Sternberg AL, Blackford AL, Cai Y, Mitchell CM, Roth DL, Miller ER 3rd, Szanton SL, Juraschek SP, Michos ED, Schrack JA, Appel LJ, STURDY Collaborative Research Group.
    J Am Geriatr Soc, 2021 Jun 12, 69(10): 2851-2864
    https://doi.org/10.1111/jgs.17290 | PMID: 34118059 | PMCID: PMC8497407
    Citations: 2 | AltScore: 49.9
  35. Association Between Brain Volumes and Patterns of Physical Activity in Community-Dwelling Older Adults.
    Wanigatunga AA, Wang H, An Y, Simonsick EM, Tian Q, Davatzikos C, Urbanek JK, Zipunnikov V, Spira AP, Ferrucci L, Resnick SM, Schrack JA
    J Gerontol A Biol Sci Med Sci, 2021 Jul 13, 76(8): 1504-1511
    https://doi.org/10.1093/gerona/glaa294 | PMID: 33230557 | PMCID: PMC8495900
    Citations: 2 | AltScore: 11.2
  36. Plasma metabolites associated with chronic kidney disease and renal function in adults from the Baltimore Longitudinal Study of Aging.
    Yamaguchi Y, Zampino M, Moaddel R, Chen TK, Tian Q, Ferrucci L, Semba RD
    Metabolomics, 2021 Jan 11, 17(1): 9
    https://doi.org/10.1007/s11306-020-01762-3 | PMID: 33428023 | PMCID: PMC9220986
    Citations: 4 | AltScore: 1.5


EXTERNAL ADVISORY BOARD MEMBERS

Harvey J. Cohen, M.D.
Walter Kempner Professor of Medicine, Director Emeritus, Center for the Study of Aging and Human Development, Chair Emeritus, Department of Medicine, Duke University Medical Center
Serving since 2003 (19 years)

Luigi Ferrucci, M.D., Ph.D.
Scientific Director, Senior Investigator, Longitudinal Studies Section, National Institute on Aging, National Institutes of Health
Serving since 2003 (19 years)

Joan E. Bailey-Wilson, Ph.D.
Head, Statistical Genetics Section; Co-Branch Chief, Inherited Disease Research Branch; National Human Genome Research Institute; National Institutes of Health
Serving since 2008 (14 years)

Gerald Beck, Ph.D.
Section Head, Clinical Trials; Design and Analysis, Department of Quantitative Health Sciences, Cleveland Clinic Foundation
Serving since 2013 (9 years)

Howard Bergman, M.D.
Assistant Dean, International Affairs, Faculty of Medicine and Health Sciences, Professor of Family Medicine, Medicine and Oncology and the Institute for Health and Social Policy, McGill University 
Serving since 2013 (9 years)


RECOGNITION AND AWARDS (2021-2022)

Recognition and Awards not specified.

MINORITY RESEARCH

General Brief Description of Minority Activities:

Janiece Taylor, PhD: Pilot Study. "Pilot Behavioral Intervention to Address Pain and Frailty in Older African-American Women."

Karen Bandeen-Roche, PhD: RC1 Development Project: includes analyses of frailty measurement variance by race in the National Health and Aging Trends Study.

Janiece Taylor, PhD, and Karen Bandeen-Roche, PhD: Small Pilot Study: "Focus groups to study racial differences in the frailty phenotype measure."




Minority Trainee(s):
  • Janiece Taylor, PhD, Assistant Professor
    Janiece Taylor, PhD: Pilot Study. "Pilot Behavioral Intervention to Address Pain and Frailty in Older African-American Women."
  • Jude Phillip, PhD, Assistant Professor
    Jude M. Phillip is an Assistant Professor of Biomedical Engineering, with a secondary appointment in Chemical & Biomolecular Engineering and a core member in the Institute for Nanobiotechnology (INBT) at Johns Hopkins University. His lab studies biological ageing dynamics in the context of health and disease. He combines fundamental engineering approaches with translational ageing and oncology research to develop strategies and technologies to probe ageing and identify mechanisms to modify ageing trajectories to drive heathy ageing.
  • Reyhan Westbrook, PhD, Instructor
    Division of Geriatric Medicine and Gerontology
  • Sabra Lewsey, MD, Assistant Professor
    Advanced Heart Failure and Transplant Cardiology, Cardiomyopathy, Congestive Heart Failure (CHF), Heart Failure

Minority Grant(s):