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

Principal Investigator    Jeremy Walston, M.D.  410-550-1003  jwalston@jhmi.edu
Principal Investigator    Karen Bandeen-Roche, Ph.D.  410-955-3067  kbandee1@jhu.edu
Program Administrator    Brian Buta, MHS  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 articulated in this application.

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 more than 15 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 nearly 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 1000 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 leaders, Dr. Robert Wise, who has considerable expertise in the development, implementation, and conduct of clinical physiological studies and clinical trials and who ended his tenure as leader in 2018. Dr. Todd Brown, an endocrinologist with considerable human subjects research expertise and who plays a leading role in the ICTR at Johns Hopkins, now 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 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 have developed a state-of-the art Information Dissemination Core (IDC) with a highly experienced partner: 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 provides 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
 
Sabra Lewsey, MD
Assistant Professor / Division of Cardiology
Understanding frailty risk factors in older individuals with heart failure with preserved ejection fraction.
Heart failure is increasingly a problem of older individuals and it shares several similarities to age associated frailty, including fatigue, exercise intolerance, sterile inflammation and skeletal muscle energetic changes. Nearly 6.5 million American adults are living with heart failure and more than half of these individuals have heart failure with preserved ejection fraction (HFpEF). HFpEF is the predominant form of heart failure in older persons and carries a poor prognosis, with 75% mortality within five years of a heart failure hospitalization. Unfortunately, no therapies are currently approved by the FDA to treat HFpEF. Frailty is increasingly recognized in the aging HFpEF population with prevalence estimates as high as 94%. HFpEF, like frailty, is a systemic pro-inflammatory state and is associated with increased catabolic cytokines, [i.e. tumor necrosis factor (TNF)-a, interleukin (IL)-6], which may promote muscle wasting in older adults. Sarcopenia, the loss of muscle mass and muscle strength, is directly related to functional impairment, falls, and loss of autonomy in aging and frailty and has largely been described in heart failure with reduced ejection fraction (HFrEF). Though sarcopenia and systemic inflammation are commonly described in HFpEF, their relative contribution to functional limitations in older individuals with HFpEF, at high risk of frailty, remains unclear. We propose here to examine the contribution of sarcopenia, inflammation, and SM energetic/mitochondrial abnormalities to exercise intolerance in younger and older individuals with HFpEF and at high risk of frailty. In preliminary studies, we observed reduced SM mitochondrial oxidative capacity and several-fold faster SM high-energy phosphate (HEP) decline during exercise in frail older adults and these SM energetic abnormalities correlated with early fatigue, conventional measures of exercise intolerance, and increased muscle lipids. This proposal will protect the time of the PI (Lewsey) to probe the potential mechanisms responsible for altered SM high-energy phosphates in older individuals with HFpEF at high risk of frailty. We propose to test the hypothesis that systemic inflammation and sarcopenia are central contributors to SM energetic abnormalities, fatigue and exercise intolerance in HFpEF, and that this effect is more profound in older individuals. We will test this hypothesis using magnetic resonance imaging/spectroscopy (MRI/MRS), conventional measures of global functional capacity, and established measures of inflammation in a cohort of 55 HFpEF patients that have already undergone 31P MRS/MRI. The specific aims are: Aim 1: To probe the factors underlying EI and SM energetic abnormalities in HFpEF patients, we will test the hypothesis that SM energetic abnormalities and sarcopenia in HFpEF are related to biomarkers of inflammation. Aim 2: To determine the relative importance of age on SM energetics and EI in HFpEF patients, we will compare older versus younger people with HFpEF and then relate SM energetics to EI in older versus younger populations. We hypothesize that abnormalities in SM energetics, mitochondrial function and EI will be more profound in older versus younger HFpEF patients, matched for diabetes and other co-morbidities, and that EI and frailty are closely associated with sarcopenia and elevated inflammation in older HFpEF (>65 years old) as compared to younger HFpEF patients. This will be tested in an existing HFpEF dataset across the age spectrum.
  • Diversity supplement to R01 (PI: Dr. Weiss). Funded.

2020-2021  0 (0 1st/Sr)
Jude Phillip, PhD
Instructor / Department of Biomedical Engineering
Development and validation of dynamic cell-based biomarkers of healthy ageing
Ageing can be defined as the accumulation of dysfunction with the passage of time that limits the ability of organisms, organs and tissues to absorb and rebound after perturbations and stressors. In humans, normal ageing is associated with diverse physiological changes that influence the magnitude and rates of progressive decline among individuals. A growing body of evidence demonstrates that the interactions between intrinsic and extrinsic factors, such as molecular states (e.g. epigenomic) and macroscopic stressors (e.g. disparities and socio-economic factors), contribute to the ageing processes. However, it is unclear how the underlying molecular states of an individual relate to the observed clinical outlook of individuals. To address this, we postulate that studying age-associated changes at the intermediate length scale of cells—between the larger length scale of organs and tissues and the smaller length scales of molecules—may provide the missing link to understand the inter-relation of these ageing scales. Populations of cells typically display dynamic and heterogeneous phenotypes in the context of health and disease. As integrators of molecular signals (e.g. genetic, epigenetic), cells provide a mesoscale view of ageing that likely prelude the manifestation of dysfunctions and diseases at the clinical level. Recently, we have shown that biophysical properties of cells, such as cell morphology and mechanics encode essential ageing information, and as such can be used as robust biomarkers of ageing4. However, it is unclear how this information is encoded, and its potential role in developing novel approaches for precision health. To address this, we hypothesize that the propagation of ageing phenotypes at the cellular level is encoded, and driven in part by cellular heterogeneity, with an age-dependent re-distribution of cells among phenotypically defined states. Building on previous results, we propose the following aim that are based on dynamic measurements of age-dependent cell movements, to probe cross-sectional and longitudinal ageing trajectories in the context of health. Aim 1. Using our validated single-cell imaging technologies, we will develop a mechanistic understanding of how motility patterns of dermal fibroblasts constitute robust cell-based biomarkers of healthy ageing. • Using a large gender-balanced cohort (n=100), we will track and analyze single-cell motility patterns of primary dermal fibroblasts obtained from de-identified healthy donors, with a chronological age range from 20 to 98 years. • Using novel single-cell analysis tools together with machine learning approaches, we will develop robust software solutions and methods to: a. Classify age-dependent ‘cell motility states’ based on spatial and activity patterns of cell movements (i.e. how cells move—spatial, and the manner in which they move (consistent versus sporadic)—activity. b. Determine the magnitude of cellular heterogeneity and identify how fractional re-distribution of cells among motility states drive the propagation of ageing phenotypes at the cellular level. c. Identify how the fractional abundances of cells within each motility state define age-dependent phenotypes in healthy individuals, and in the long term for diseases such as frailty. d. Identify drug targets capable of reversing/augmenting age-dependent cell phenotypes upon exposure to a small custom library of drugs (n=30 drugs, subset from the anti-aging compound library from Selleck Chem) targeting mainly cytoskeletal and metabolic pathways. This approach will serve as a way to boast the translational potential of our findings for pre-clinical applications.
2020-2021  1 (1 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)

PILOT/EXPLORATORY PROJECTS (9 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.

 
DEVELOPMENT PROJECTS (3 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: Development and Validation of Age-, Sex-, and Race-specific Thresholds for the Physical Frailty Phenotype Criteria Among Kidney Transplant Candidates and Recipients
  Leader: Nadia M. Chu, PhD
  Core(s): Resource Core 1 (RC1): Biostatistics Core (RC1)
 

The physical frailty phenotype (PFP) is a measure of frailty recognized for its clinical utility. Frailty, based on the current PFP criteria, is common and associated with adverse outcomes among adult kidney transplant (KT) candidates and recipients. However, older and African American candidates/recipients are disproportionately impacted by frailty. Despite differences found between age and racial subgroups in KT, recent studies in community-dwelling older adults suggest that these variations may be partially due to measurement error, such that PFP criteria may assess frailty differentially between subgroups, resulting in potential misclassification. Given that KT populations comprise of a wider age-range and a greater prevalence of males and minority groups, this potential misclassification of individuals as frail could make it especially challenging for clinicians to identify candidates that can withstand surgery and benefit from KT. Our overall goal for this study will be to generate age-, sex-, and race-specific PFP criteria thresholds for KT candidates and recipients by leveraging an ongoing, prospective, multi-center NIA-funded R01 on frailty and aging in ESRD of 7,803 candidates and 1,383 recipients (aged ?18) linked to the national registry of all KT candidates and recipients. Specifically, we will aim to (1) test if age-, sex-, and race-specific thresholds for PFP criteria are needed among KT candidates and recipients; (2) calculate nationally-representative thresholds for continuous PFP components among KT candidates and recipients and create an updated PFP; and (3) compare predictive validity of the original PFP and the updated PFP (incorporating new nationally-representative thresholds) against adverse outcomes including waitlist mortality, longer length of stay, graft loss and post-KT mortality. Linkage to the national registry provides the unique opportunity to translate measures that were collected at the cohort-level and project them to the national-level in order to calculate nationally-representative thresholds for the PFP criteria using creative statistical methodologies. By doing so, we will reduce misclassification in future studies examining predictors, mechanisms, and consequences of frailty, which can have a direct impact on clinical practice by improving risk stratification, identifying frail candidates for prehabilitation, and improving equitable access to KT, particularly for older, robust candidates. Findings from this study will support the American Society of Transplantation’s goal to establish a standard, validated measure of frailty in solid organ transplantation. Additionally, with expert guidance from the OAIC Biostatistics Core, study findings will provide a benchmark for the operationalization of frailty and a blueprint for gerontologists on how to identify appropriate thresholds to improve geriatric assessments.  

 
RESEARCH (26 Projects Listed)
1. Project Title: INTERSECTION OF PHYSIOLOGIC FRAILTY AND COGNITIVE PERFORMANCE IN OLDER ADULTS: AN INTEGRATIVE DATA ANALYSIS
  Leader(s): GROSS, ALDEN L.
    THE JOHNS HOPKINS UNIVERSITY
    NIH K01AG050699 / (2016-2021)
  Core(s):
  DESCRIPTION (provided by applicant): Alden L. Gross is an Assistant Professor in the Department of Epidemiology at the Johns Hopkins Bloomberg School of Public Health. He seeks a mentored career development award to obtain critical knowledge skills in the biology of aging, particularly as it relates to frailty in older adults, and necessary research experience foran independent career a...
 
2. 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 b...
 
3. 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 f...
 
4. 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 pat...
 
5. 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 evaluat...
 
6. Project Title: MONITORING CEREBRAL AUTOREGULATION IN PATIENTS UNDERGOING TRAUMATIC HIP FRACTURE SURGERY TO IMPROVE POSTOPERATIVE OUTCOMES
  Leader(s): BROWN, CHARLES HUGH
    THE JOHNS HOPKINS UNIVERSITY
    NIH K76AG057020 / (2017-2021)
  Core(s):
  PROJECT SUMMARY/ABSTRACTBackground: Surgery for hip fracture can be devastating for older adults, with complications includingdelirium, increased risk of dementia, and inability to walk. As an anesthesiologist and clinician-scientist, I havefocused on reducing delirium after surgery. In this proposal, I will build the foundation for a research careerfocused on the broader goals of reducing neuroco...
 
7. 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 ex...
 
8. 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 disea...
 
9. 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 l...
 
10. 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 unde...
 
11. 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 ...
 
12. 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 spatia...
 
13. 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...
 
14. 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 ...
 
15. 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 li...
 
16. 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, le...
 
17. 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) medicatio...
 
18. Project Title: MITOCHONDRIAL DNA COPY NUMBER AND GENETIC VARIATION IN CORONARY HEART DISEASE
  Leader(s): ARKING, DAN E
    THE JOHNS HOPKINS UNIVERSITY
    NIH R01HL131573 / (2016-2021)
  Core(s):
  DESCRIPTION (provided by applicant): Coronary heart disease (CHD) continues to be a leading cause of mortality and morbidity worldwide. Age-related decline in mitochondrial function is a novel mechanism that may underlie multiple biological changes that increase the risk of atherosclerosis and CHD in the general population. We determined mtDNA copy number (mtDNA-CN) in whole blood, one ...
 
19. Project Title: MEASUREMENT OF COGNITIVE FUNCTION IN OLDER ADULTS WITH SENSORY LOSS
  Leader(s): SWENOR, BONNIELIN; DEAL, JENNIFER ANNE ;
    THE JOHNS HOPKINS UNIVERSITY
    NIH R21AG060243 / (2019-2021)
  Core(s):
  ABSTRACTThe goal of the proposed project is to determine if estimates of cognitive impairment and Alzheimer s diseaseand related dementias (ADRD) are biased among older adults with hearing or vision impairment. The impact ofthis this potential bias could be significant, as over 55% of Americans 60 years and older have either hearingor vision impairment. The specific aims of this research are to: (...
 
20. Project Title: A RANDOMIZED, BLINDED, PLACEBO-CONTROLLED CLINICAL TRIAL TO EVALUATE LONGEVERON MESENCHYMAL STEM CELL (LMSC) THERAPY FOR TREATING THE METABOLIC SYNDROME
  Leader(s): HARE, JOSHUA M; LENG, SEAN XIAO ; OLIVA, ANTHONY ANDREW ;
    LONGEVERON LLC
    NIH R42AG054322 / (2017-2021)
  Core(s):
  The metabolic syndrome (MetS) is a cluster of factors that increases the risks for cardiovascular disease, type 2diabetes mellitus, and mortality, and currently affects > 40% of US adults. MetS is associated with endothelialdysfunction, decreased circulating endothelial progenitor cells (EPCs), and a pro-inflammatory state. We havemade the exciting discovery that therapy with allogeneic mesenchyma...
 
21. Project Title: TRANSITIONS TO FAMILY CAREGIVING AND ITS IMPACT ON HEALTH INDICATORS
  Leader(s): ROTH, DAVID L
    THE JOHNS HOPKINS UNIVERSITY
    NIH RF1AG050609 / (2016-2021)
  Core(s):
  DESCRIPTION (provided by applicant): The growth of the older adult population, increased prevalence of many disabling conditions, and high costs of institutional care are placing heavy demands on family members to provide informal caregiving services to adults with disabilities. Many previous studies have characterized caregiving as a chronic stress experience associated with poorer hea...
 
22. 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. Hyp...
 
23. 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 ...
 
24. 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-thro...
 
25. 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 approximat...
 
26. 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...
 
PUBLICATIONS
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: | AltScore: 8.7
  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. 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: 2 | AltScore: 6.95
  4. 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: | AltScore: 7.55
  5. 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
  6. 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
    pii: glab083. https://doi.org/10.1093/gerona/glab083 | PMID: 33721909
    Citations: | AltScore: 1
  7. 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
    Citations: 1 | AltScore: 1
  8. 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: | AltScore: 33.208
  9. 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: | AltScore: 0.75
  10. 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
    Citations: | AltScore: NA
  11. 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
  12. 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: | AltScore: 73
  13. 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: | AltScore: NA
  14. 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: | AltScore: 16.35
  15. 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
  16. 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
    https://doi.org/10.1111/jgs.17290 | PMID: 34118059
    Citations: | AltScore: 40.15
  17. 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
    Citations: | AltScore: 1.5
 
2020
  1. Associations of Actigraphic Sleep Parameters With Fatigability in Older Adults.
    Alfini AJ, Schrack JA, Urbanek JK, Wanigatunga AA, Wanigatunga SK, Zipunnikov V, Ferrucci L, Simonsick EM, Spira AP
    J Gerontol A Biol Sci Med Sci, 2020 Sep 16, 75(9): e95-e102
    https://doi.org/10.1093/gerona/glaa137 | PMID: 32502253 | PMCID: PMC7494020
    Citations: 4 | AltScore: 1
  2. Physical Frailty Phenotype Criteria and their Synergistic Association on Cognitive Functioning.
    Chu NM, Bandeen-Roche K, Xue QL, Carlson MC, Sharrett AR, Gross AL
    J Gerontol A Biol Sci Med Sci, 2020 Oct 15
    pii: glaa267. https://doi.org/10.1093/gerona/glaa267 | PMID: 33057609
    Citations: | AltScore: NA
  3. Frailty Prevalence in Younger End-Stage Kidney Disease Patients Undergoing Dialysis and Transplantation.
    Chu NM, Chen X, Norman SP, Fitzpatrick J, Sozio SM, Jaar BG, Frey A, Estrella MM, Xue QL, Parekh RS, Segev DL, McAdams-DeMarco MA
    Am J Nephrol, 2020 Jul 8, 51(7): 501-510
    https://doi.org/10.1159/000508576 | PMID: 32640462 | PMCID: PMC7442041
    Citations: 3 | AltScore: 3.2
  4. Brain Renin-Angiotensin System at the Intersect of Physical and Cognitive Frailty.
    Cosarderelioglu C, Nidadavolu LS, George CJ, Oh ES, Bennett DA, Walston JD, Abadir PM
    Front Neurosci, 2020, 14: 586314
    https://doi.org/10.3389/fnins.2020.586314 | PMID: 33117127 | PMCID: PMC7561440
    Citations: 2 | AltScore: 21.95
  5. Transcatheter Aortic Valve Replacement in Low-Population Density Areas: Assessing Healthcare Access for Older Adults With Severe Aortic Stenosis.
    Damluji AA, Fabbro M 2nd, Epstein RH, Rayer S, Wang Y, Moscucci M, Cohen MG, Carroll JD, Messenger JC, Resar JR, Cohen DJ, Sherwood MW, O'Connor CM, Batchelor W
    Circ Cardiovasc Qual Outcomes, 2020 Aug, 13(8): e006245
    https://doi.org/10.1161/CIRCOUTCOMES.119.006245 | PMID: 32813564 | PMCID: PMC7590951
    Citations: | AltScore: 33.95
  6. Sarcopenia and health-related quality of life in older adults after transcatheter aortic valve replacement.
    Damluji AA, Rodriguez G, Noel T, Davis L, Dahya V, Tehrani B, Epps K, Sherwood M, Sarin E, Walston J, Bandeen-Roche K, Resar JR, Brown TT, Gerstenblith G, O'Connor CM, Batchelor W
    Am Heart J, 2020 Jun, 224: 171-181
    https://doi.org/10.1016/j.ahj.2020.03.021 | PMID: 32416332 | PMCID: PMC8132132
    Citations: | AltScore: 6.45
  7. U.S. National Profile of Older Adults with Cognitive Impairment Alone, Physical Frailty Alone, and Both.
    Ge ML, Carlson MC, Bandeen-Roche K, Chu NM, Tian J, Kasper JD, Xue QL
    J Am Geriatr Soc, 2020 Dec, 68(12): 2822-2830
    https://doi.org/10.1111/jgs.16769 | PMID: 32860219 | PMCID: PMC7774869
    Citations: 1 | AltScore: 8.9
  8. Plasma levels of corticosterone, tumor necrosis factor receptor 1 and interleukin 6 are influenced by age, sex and chronic inflammation in mice treated with acute temperature stress.
    Ge N, Westbrook R, Langdon J, Yang H, Marx R, Abadir P, Xue QL, Walston JD
    Exp Gerontol, 2020 Dec, 142: 111136
    https://doi.org/10.1016/j.exger.2020.111136 | PMID: 33164891 | PMCID: PMC7705815
    Citations: | AltScore: NA
  9. Derivation of a measure of physiological multisystem dysregulation: Results from WHAS and health ABC.
    Gross AL, Carlson MC, Chu NM, McAdams-DeMarco MA, Mungas D, Simonsick EM, Varadhan R, Xue QL, Walston J, Bandeen-Roche K
    Mech Ageing Dev, 2020 May 11, 188: 111258
    https://doi.org/10.1016/j.mad.2020.111258 | PMID: 32423871 | PMCID: PMC7375911
    Citations: | AltScore: 5.05
  10. Clinically Meaningful Change for Physical Performance: Perspectives of the ICFSR Task Force.
    Guralnik J, Bandeen-Roche K, Bhasin SAR, Eremenco S, Landi F, Muscedere J, Perera S, Reginster JY, Woodhouse L, Vellas B
    J Frailty Aging, 2020, 9(1): 9-13
    https://doi.org/10.14283/jfa.2019.33 | PMID: 32150208 | PMCID: PMC7286121
    Citations: 3 | AltScore: 28.7
  11. An overview of frailty in kidney transplantation: measurement, management and future considerations.
    Harhay MN, Rao MK, Woodside KJ, Johansen KL, Lentine KL, Tullius SG, Parsons RF, Alhamad T, Berger J, Cheng XS, Lappin J, Lynch R, Parajuli S, Tan JC, Segev DL, Kaplan B, Kobashigawa J, Dadhania DM, McAdams-DeMarco MA
    Nephrol Dial Transplant, 2020 Jul 1, 35(7): 1099-1112
    https://doi.org/10.1093/ndt/gfaa016 | PMID: 32191296 | PMCID: PMC7417002
    Citations: 3 | AltScore: 44.4
  12. Development and validation of an inflammatory-frailty index for kidney transplantation.
    Haugen CE, Gross A, Chu NM, Norman SP, Brennan DC, Xue QL, Walston J, Segev DL, McAdams-DeMarco M
    J Gerontol A Biol Sci Med Sci, 2020 Jul 3, 76(3): 470-477
    pii: glaa167. https://doi.org/10.1093/gerona/glaa167 | PMID: 32619229 | PMCID: PMC7907494
    Citations: 1 | AltScore: 3
  13. High coping self-efficacy associated with lower odds of pre-frailty/frailty in older adults with chronic disease.
    Hladek MD, Gill J, Bandeen-Roche K, Walston J, Allen J, Hinkle JL, Lorig K, Szanton SL
    Aging Ment Health, 2020 Dec, 24(12): 1956-1962
    https://doi.org/10.1080/13607863.2019.1639136 | PMID: 31290680 | PMCID: PMC8098714
    Citations: 1 | AltScore: NA
  14. The Association between Frailty and Uncorrected Refractive Error in Older Adults.
    Lee MJ, Varadaraj V, Tian J, Bandeen-Roche K, Swenor BK
    Ophthalmic Epidemiol, 2020 Jun, 27(3): 219-225
    https://doi.org/10.1080/09286586.2020.1716380 | PMID: 31952461 | PMCID: PMC7080595
    Citations: | AltScore: NA
  15. Spinal Anesthesia for Geriatric Lumbar Spine Surgery: A Comparative Case Series.
    Lessing NL, Edwards CC 2nd, Dean CL, Waxter OH, Lin C, Curto RA, Brown CH 4th
    Int J Spine Surg, 2020 Oct, 14(5): 713-721
    https://doi.org/10.14444/7103 | PMID: 33046538 | PMCID: PMC7671447
    Citations: 1 | AltScore: NA
  16. Stable ischemic heart disease: how to keep it that way.
    Leucker TM, Schulman SP, Gerstenblith G
    J Clin Invest, 2020 Mar 2, 130(3): 1055-1057
    https://doi.org/10.1172/JCI135959 | PMID: 31985489 | PMCID: PMC7269554
    Citations: 1 | AltScore: 8.65
  17. Exercise intolerance and rapid skeletal muscle energetic decline in human age-associated frailty.
    Lewsey SC, Weiss K, Sch?r M, Zhang Y, Bottomley PA, Samuel TJ, Xue QL, Steinberg A, Walston JD, Gerstenblith G, Weiss RG
    JCI Insight, 2020 Oct 15, 5(20):
    pii: 141246. https://doi.org/10.1172/jci.insight.141246 | PMID: 32941181 | PMCID: PMC7605538
    Citations: 2 | AltScore: 44.45
  18. Linking early life risk factors to frailty in old age: evidence from the China Health and Retirement Longitudinal Study.
    Li Y, Xue QL, Odden MC, Chen X, Wu C
    Age Ageing, 2020 Feb 27, 49(2): 208-217
    https://doi.org/10.1093/ageing/afz160 | PMID: 31957780 | PMCID: PMC7047816
    Citations: 3 | AltScore: 12.4
  19. Evaluation of mitochondrial DNA copy number estimation techniques.
    Longchamps RJ, Castellani CA, Yang SY, Newcomb CE, Sumpter JA, Lane J, Grove ML, Guallar E, Pankratz N, Taylor KD, Rotter JI, Boerwinkle E, Arking DE
    PLoS One, 2020, 15(1): e0228166
    https://doi.org/10.1371/journal.pone.0228166 | PMID: 32004343 | PMCID: PMC6994099
    Citations: 9 | AltScore: 1.5
  20. Targeted deletion of interleukin-6 in a mouse model of chronic inflammation demonstrates opposing roles in aging: benefit and harm.
    Ma L, Nidadavolu LS, Yang H, Langdon J, Westbrook R, Tsui BMW, Lee TS, Hinson J, Ling S, Marx-Rattner R, Wu Y, Nguyen T, Tan J, Khadeer M, Moaddel R, Le A, Walston JD, Abadir PM
    J Gerontol A Biol Sci Med Sci, 2020 Jun 26, 76(2): 211-215
    pii: glaa156. https://doi.org/10.1093/gerona/glaa156 | PMID: 32585682 | PMCID: PMC7812426
    Citations: 2 | AltScore: 46.75
  21. IL10 deficiency promotes alveolar enlargement and lymphoid dysmorphogenesis in the aged murine lung.
    Malinina A, Dikeman D, Westbrook R, Moats M, Gidner S, Poonyagariyagorn H, Walston J, Neptune ER
    Aging Cell, 2020 Apr, 19(4): e13130
    https://doi.org/10.1111/acel.13130 | PMID: 32170906 | PMCID: PMC7189990
    Citations: 4 | AltScore: 0.25
  22. Perceptions and Practices Regarding Frailty in Kidney Transplantation: Results of a National Survey.
    McAdams-DeMarco MA, Van Pilsum Rasmussen SE, Chu NM, Agoons D, Parsons RF, Alhamad T, Johansen KL, Tullius SG, Lynch R, Harhay MN, Rao MK, Berger J, Cooper M, Tan JC, Cheng XS, Woodside KJ, Parajuli S, Lentine KL, Kaplan B, Segev DL, Kobashigawa JA, Dadhania D, AST Kidney Pancreas Community of Practice Workgroup.
    Transplantation, 2020 Feb, 104(2): 349-356
    https://doi.org/10.1097/TP.0000000000002779 | PMID: 31343576 | PMCID: PMC6834867
    Citations: 5 | AltScore: 7.65
  23. Functional Outcomes of Frail Patients After Cardiac Surgery: An Observational Study.
    Nakano M, Nomura Y, Suffredini G, Bush B, Tian J, Yamaguchi A, Walston J, Hasan R, Mandal K, Schena S, Hogue CW, Brown CH 4th
    Anesth Analg, 2020 Jun, 130(6): 1534-1544
    https://doi.org/10.1213/ANE.0000000000004786 | PMID: 32384343 | PMCID: PMC7641106
    Citations: 1 | AltScore: NA
  24. Frailty transitions, inflammation and mortality among persons aging with HIV infection and injection drug use.
    Piggott DA, Bandeen-Roche K, Mehta SH, Brown TT, Yang H, Walston JD, Leng SX, Kirk GD
    AIDS, 2020 Apr 13, 34(8): 1217-1225
    https://doi.org/10.1097/QAD.0000000000002527 | PMID: 32287069
    Citations: 4 | AltScore: 5.5
  25. The transition to family caregiving and its effect on biomarkers of inflammation.
    Roth DL, Haley WE, Sheehan OC, Huang J, Rhodes JD, Durda P, Howard VJ, Walston JD, Cushman M
    Proc Natl Acad Sci U S A, 2020 Jul 14, 117(28): 16258-16263
    https://doi.org/10.1073/pnas.2000792117 | PMID: 32581123 | PMCID: PMC7368336
    Citations: | AltScore: 68
  26. Longitudinal Association Between Perceived Fatigability and Cognitive Function in Older Adults: Results from the Baltimore Longitudinal Study of Aging.
    Salerno EA, Wanigatunga AA, An Y, Urbanek JK, Simonsick EM, Ferrucci L, Resnick SM, Schrack JA
    J Gerontol A Biol Sci Med Sci, 2020 Sep 16, 75(9): e67-e73
    https://doi.org/10.1093/gerona/glz287 | PMID: 31828289 | PMCID: PMC7494023
    Citations: 1 | AltScore: 14.25
  27. Longitudinal Association Between Energy Regulation and Fatigability in Mid-to-Late Life.
    Schrack JA, Wanigatunga AA, Zipunnikov V, Kuo PL, Simonsick EM, Ferrucci L
    J Gerontol A Biol Sci Med Sci, 2020 Sep 16, 75(9): e74-e80
    https://doi.org/10.1093/gerona/glaa011 | PMID: 31942600 | PMCID: PMC7494036
    Citations: 1 | AltScore: NA
  28. Visual Impairment and Frailty: Examining an Understudied Relationship.
    Swenor BK, Lee MJ, Tian J, Varadaraj V, Bandeen-Roche K
    J Gerontol A Biol Sci Med Sci, 2020 Feb 14, 75(3): 596-602
    https://doi.org/10.1093/gerona/glz182 | PMID: 31419280 | PMCID: PMC7328203
    Citations: 2 | AltScore: 1
  29. Aging With Vision Loss: A Framework for Assessing the Impact of Visual Impairment on Older Adults.
    Swenor BK, Lee MJ, Varadaraj V, Whitson HE, Ramulu PY
    Gerontologist, 2020 Aug 14, 60(6): 989-995
    https://doi.org/10.1093/geront/gnz117 | PMID: 31504483 | PMCID: PMC7427480
    Citations: 5 | AltScore: 1.5
  30. Pain in low-income older women with disabilities: a qualitative descriptive study.
    Taylor JL, Drazich BF, Roberts L, Okoye S, Rivers E, Wenzel J, Wright R, Beach MC, Szanton SL
    J Women Aging, 2020 Jul-Aug, 32(4): 402-423
    https://doi.org/10.1080/08952841.2020.1763895 | PMID: 32475259 | PMCID: PMC7934966
    Citations: | AltScore: 2.5
  31. A Standardized and Comprehensive Approach to the Management of Cardiogenic Shock.
    Tehrani BN, Truesdell AG, Psotka MA, Rosner C, Singh R, Sinha SS, Damluji AA, Batchelor WB
    JACC Heart Fail, 2020 Nov, 8(11): 879-891
    https://doi.org/10.1016/j.jchf.2020.09.005 | PMID: 33121700 | PMCID: PMC8167900
    Citations: 2 | AltScore: 82.5
  32. Dissecting the Racial/Ethnic Disparity in Frailty in a Nationally Representative Cohort Study with Respect to Health, Income, and Measurement.
    Usher T, Buta B, Thorpe RJ, Huang J, Samuel LJ, Kasper JD, Bandeen-Roche K
    J Gerontol A Biol Sci Med Sci, 2020 Mar 9, 76(1): 69-76
    pii: glaa061. https://doi.org/10.1093/gerona/glaa061 | PMID: 32147727 | PMCID: PMC7756712
    Citations: | AltScore: 18.9
  33. Perceptions, Barriers, and Experiences With Successful Aging Before and After Kidney Transplantation: A Focus Group Study.
    Van Pilsum Rasmussen SE, Warsame F, Eno AK, Ying H, Covarrubias K, Haugen CE, Chu NM, Crews DC, Harhay MN, Schoenborn NL, Segev DL, McAdams-DeMarco MA
    Transplantation, 2020 Mar, 104(3): 603-612
    https://doi.org/10.1097/TP.0000000000002848 | PMID: 31283666 | PMCID: PMC6930354
    Citations: | AltScore: 2.7
  34. Association of peripheral inflammatory markers with connectivity in large-scale functional brain networks of non-demented older adults.
    Walker KA, Gross AL, Moghekar AR, Soldan A, Pettigrew C, Hou X, Lu H, Alfini AJ, Bilgel M, Miller MI, Albert MS, Walston J
    Brain Behav Immun, 2020 Jan 11, 87: 388-396
    pii: S0889-1591(19)31061-X. https://doi.org/10.1016/j.bbi.2020.01.006 | PMID: 31935468 | PMCID: PMC7316598
    Citations: | AltScore: 11.25
  35. Kynurenines link chronic inflammation to functional decline and physical frailty.
    Westbrook R, Chung T, Lovett J, Ward C, Joca H, Yang H, Khadeer M, Tian J, Xue QL, Le A, Ferrucci L, Moaddel R, de Cabo R, Hoke A, Walston J, Abadir PM
    JCI Insight, 2020 Aug 20, 5(16):
    pii: 136091. https://doi.org/10.1172/jci.insight.136091 | PMID: 32814718 | PMCID: PMC7455140
    Citations: 1 | AltScore: 34.6
  36. Single-cell morphology encodes metastatic potential.
    Wu PH, Gilkes DM, Phillip JM, Narkar A, Cheng TW, Marchand J, Lee MH, Li R, Wirtz D
    Sci Adv, 2020 Jan, 6(4): eaaw6938
    https://doi.org/10.1126/sciadv.aaw6938 | PMID: 32010778 | PMCID: PMC6976289
    Citations: 9 | AltScore: 64.45
  37. Frailty as an integrative marker of physiological vulnerability in the era of COVID-19.
    Xue QL
    BMC Med, 2020 Oct 23, 18(1): 333
    https://doi.org/10.1186/s12916-020-01809-1 | PMID: 33092582 | PMCID: PMC7581466
    Citations: 2 | AltScore: 4.3
  38. Progression of Physical Frailty and the Risk of All-Cause Mortality: Is There a Point of No Return?
    Xue QL, Bandeen-Roche K, Tian J, Kasper JD, Fried LP
    J Am Geriatr Soc, 2020 Dec 24, 69(4): 908-915
    https://doi.org/10.1111/jgs.16976 | PMID: 33368158 | PMCID: PMC8049969
    Citations: | AltScore: 36.23
  39. Discrepancy in Frailty Identification: Move Beyond Predictive Validity.
    Xue QL, Tian J, Walston JD, Chaves PHM, Newman AB, Bandeen-Roche K
    J Gerontol A Biol Sci Med Sci, 2020 Jan 20, 75(2): 387-393
    https://doi.org/10.1093/gerona/glz052 | PMID: 30789645 | PMCID: PMC7176056
    Citations: 5 | AltScore: 2.2
  40. Angiotensin II Blood Levels Are Associated with Smaller Hippocampal and Cortical Volumes in Cognitively Normal Older Adults.
    Yasar S, Moored KD, Adam A, Zabel F, Chuang YF, Varma VR, Carlson MC
    J Alzheimers Dis, 2020, 75(2): 521-529
    https://doi.org/10.3233/JAD-200118 | PMID: 32280103 | PMCID: PMC7293768
    Citations: 2 | AltScore: 10
  41. Mitochondrial DNA copy number and incident atrial fibrillation.
    Zhao D, Bartz TM, Sotoodehnia N, Post WS, Heckbert SR, Alonso A, Longchamps RJ, Castellani CA, Hong YS, Rotter JI, Lin HJ, O'Rourke B, Pankratz N, Lane JA, Yang SY, Guallar E, Arking DE
    BMC Med, 2020 Sep 16, 18(1): 246
    https://doi.org/10.1186/s12916-020-01715-6 | PMID: 32933497 | PMCID: PMC7493408
    Citations: | AltScore: NA


EXTERNAL ADVISORY BOARD MEMBERS

Harvey J. Cohen, M.D.
Division Chief of Geriatrics, Director of the Center for the Study of Aging and Human Development, Duke University Medical Center
Serving since 2003 (18 years)

Luigi Ferrucci, M.D., Ph.D.
NIA Scientific Director, Senior Investigator and Chief, Longitudinal Studies Section
Serving since 2003 (18 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 (13 years)

Gerald Beck, Ph.D.
Section Head, Clinical Trials; Design and Analysis, Department of Quantitative Health Sciences, Cleveland Clinic Foundation
Serving since 2013 (8 years)

Howard Bergman, M.D.
Professor of Family Medicine, Medicine and Oncology, Dr. Joseph Kaufmann Professor of Geriatric Medicine, McGill University
Serving since 2013 (8 years)


RECOGNITION AND AWARDS (2020-2021)

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):