Claude D. Pepper Older Americans Independence Center

Jeremy Walston, M.D.
Principal Investigator
Karen Bandeen-Roche, Ph.D.
Principal Investigator
Brian Buta, MHS
Program Administrator

Frailty is an age-related condition with a multifaceted etiology, in which older adults lose capacity to cope with stressors and become remarkably vulnerable to declines in health and functioning, loss of independence, and early mortality. Since its inception, the Johns Hopkins University (JHU) Older Americans Independence Center (OAIC) has pursued a highly productive program for the study of frailty through population-based, clinical, and biological research and for the training of the next generation of frailty-focused investigators. This has helped to create a vibrant and growing center with scientific vigor and a rich, diverse interdisciplinary milieu of experienced faculty and successful trainees focused on frailty research. The goals of this program are to ameliorate and prevent frailty, and by doing so, improve the health, well-being, and independence of older adults. During the current cycle this OAIC supported large bodies of research advancing understanding of the biology underlying frailty, the interplay between frailty and cognition, important distinctions in frailty manifestation for different assessments and subpopulations, implications of frailty for health management—overall, and in clinical subspecialties, and the development of interventions. Nonetheless, given the rapidly growing population of Americans over age 70, there remains an urgent need for further scholarship and its translation into modalities that facilitate the maintenance of independence. We envision great potential to further accelerate intervention development and delivery to older adults who can most benefit by increasing our attention to new areas of burgeoning opportunity: engineered / technological interventions, methods for pre-frailty ascertainment, and disparities in frailty and its ascertainment. We are dedicated both to further pursuing this work, and to infusing all of our work with the determination to address frailty and its health consequences equitably in older Americans.

This renewal application, hence, aims both to further our long-running progress and to expand into new areas where progress also is crucial if the Center’s goals are to be met. The proposed OAIC benefits from experienced and committed frailty-focused leadership, interdisciplinary expertise, an active engagement in the OAIC network, and strong institutional commitment to research on aging and frailty at Johns Hopkins University. Its mission remains to make fundamental discoveries related to the genesis of 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 and research fields 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. We propose to accomplish it through tried and true strategies already present in this OAIC, the innovations we identify above, and the following specific aims—each to be pursued overall and through a specific lens on health equity:

1) To develop, lead and advance effective frailty-focused interdisciplinary research programs that promote the maintenance of independence. This will include a new focus on engineering approaches, heightened priority on health equity, and emerging use of merged / massive cohort studies to investigate novel risk factors.

2) To translate new knowledge generated in this OAIC into targeted prevention and treatment strategies that help older adults maintain independence. This includes implementation of frailty into clinical practice, preventative strategies, new engineered technologies, and community-based interventions.

3) To provide the highest quality expertise, support, infrastructure and technology in biological, bioengineering, engineering, data analytic and clinical research methodologies to OAIC supported trainees and investigators. Four robust resource cores have been established to provide these resources to supported 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, Clinical Translation cores, and a new Technological Assessment and Solutions core. New expertise will be provided in machine learning and technology, and omics data science expertise will be strengthened.

5) To provide tailored training and mentorship to junior investigators interested in developing careers focused on frailty in older adults. The leadership team is committed to providing ongoing scientific, leadership, and career training to the next generation of frailty-focused investigators.

6) To attract a diverse group of outstanding investigators and trainees to frailty research from across the Johns Hopkins University and beyond. We will augment our prior successful efforts by providing leadership, locally, nationally, through the engagement of a diverse group of OAIC scholars, and through our OAIC Network, to promote and encourage research, educational and training activities related to frailty.

Leadership and Administrative Core (LAC)
Leader 1:    Karen Bandeen-Roche, PhD
Leader 2:    Jeremy Walston, MD
This Johns Hopkins University (JHU) Older Americans Independence Center (OAIC) Leadership and Administrative Core (LAC) was designed to provide the scientific leadership, organization and infrastructure necessary to lead and oversee the frailty-focused activities of this OAIC. The overall goal of the LAC is to ensure the ongoing success of this OAIC in stimulating and sustaining the next generation of frailty-related science and the next generation of frailty-focused investigators. The aims of this LAC are to: 1) provide the interdisciplinary intellectual leadership needed to stimulate and sustain the development of innovative frailty-focused research addressing diverse populations, facilitate translation between basic and clinical research on frailty, develop innovative intervention and prevention strategies from these biological and clinical discoveries, and ensure effective, high impact utilization of each OAIC core; 2) identify and attract the next generation of frailty-focused research leaders from diverse backgrounds at JHU and facilitate training, career development and access to resources to promote their emergence as independent, interdisciplinary investigators in this field; 3) organize independent panels for review of: Resource Core Developmental Projects, Pilot/Exploratory Studies, and for the selection of specific junior faculty to receive salary support from the Research Education Component, and progress towards OAIC goals, conducted annually by an External Advisory Board; 4) lead, administer, and oversee core functions to assure productivity, cost effectiveness, integration, and quality of all aspects of this OAIC program, and to well steward OAIC resources; 5) prepare reports for non-competing renewal applications, annually, and administrative documents as needed, including data safety monitoring documentation; 6) organize and conduct scientific sessions to propel the frailty-focused science and career development of participants in OAIC retreats, research in progress meetings, and research planning meetings; and 7) maximize JHU OAIC scholarly visibility locally and nationally via local programming and participation in the OAIC network, the annual OAIC scientific meeting and annual scientific meetings of aging or frailty focused organizations, and through OAIC-led information and dissemination resources. This Core will set goals with all other cores and ensure that goals are met. It will lead visioning discussions among the multidisciplinary Leadership Council as to scientific direction and clinical relevance; provide institutional leadership in identifying the investigators and mechanisms to accomplish the Center’s scientific goals; and provide leadership and organization to ensure the successful development and implementation of the infrastructure and new methods needed to support investigators in furthering research on frailty and its translation to increase the independence of older adults.

Research Education Component (REC)
Leader 1:    Gary Gerstenblith, MD
Leader 2:    Esther Oh, MD, PhD
The long-term objective of the Research Education Component (REC) is the establishment of a cadre of well-trained, highly motivated junior faculty who will become leaders and mentors in scholarship on frailty and aging and its translation to maintain independence, health and robustness for older adults. The REC accomplishes this objective through four specific aims: 1) It provides an education program combining subject-area, methodological and leadership training together with mentorship having both team-based and one-on-one elements and a mentored research project, so as to promote, benchmark, and assure research progress and career development. 2) It partners with the Leadership Council to identify, attract, and select outstanding junior faculty from a diversity of disciplines with the interest and potential to become future scholarly leaders on frailty and aging. 3) It provides the research infrastructure, salary support and protected time essential to enable the selected trainees to successfully bridge the critical transition to independent grant funding. 4) It creates a welcoming academic home and ‘stimulus zone’ for junior faculty, postdoctoral fellows, and predoctoral students invested in frailty-related scholarship through a variety of forums for ongoing networking and intellectual enrichment where they can interact with each other together and senior OAIC faculty. Forums provided complement structured mentorship plans for supported faculty and include monthly sessions in which REC-, PESC- and DP-supported faculty present research-in-progress, twice-monthly meetings of the Frailty and Multisystem Dysregulation research working group, and sponsorship of other working group meetings, seminars and guest lectures in collaboration with partnering institutional resources on aging. REC-supported faculty receive full mentorial and material support from each resource core, as appropriate to their interests and needs. Information dissemination infrastructure overseen by the LAC provides supported faculty with avenues by which to disseminate their findings. Resources are prioritized, first, to K-eligible individuals, followed by R-eligible individuals and then to other trainees so as to direct Core efforts to provide support at a key transitional point, when research careers are often in jeopardy because of lack of funding and research infrastructure. The leadership of this Core and the OAIC as a whole will continue to emphasize training across disciplines and that bridges basic science and clinical investigation. Demographic diversity and inclusion are prioritized: A new working group will help us ascend yet further in this area. The overall approach we propose has achieved notable success as evidenced by the accomplishments and success in receipt of career development awards of previously supported faculty.

Pilot / Exploratory Studies Core (PESC)
Leader 1:    Neal Fedarko, PhD
The overall goal of the Pilot / Exploratory Studies Core (PESC) is to cultivate and support cutting edge pilot and exploratory studies that will advance the development of effective prevention and/or therapies for frailty and hence facilitate independence in older adults. The PESC Core leaders, in close collaboration with other core leaders and congruent with the scientific vision of the OAIC, sets scientific goals for the next stages of pilot frailty research. They then work to identify investigators whose expertise and career goals would be applicable to furthering etiological and interventional knowledge in the targeted areas. Pilot and exploratory studies that can collect data required in order to select or design the future large-scale or confirmatory studies needed to establish frailty mechanisms, improve measurement and diagnosis, determine etiologies, or develop novel treatment approaches are prioritized. Studies selected for funding in the first year of this cycle include a study that uses video-based pose estimation to develop an automated, quantitative frailty and pre-frailty assessment in older adults, a multimodal approach to finding genetic signatures of frailty in TOPMed population studies, and a pilot study of provision of digital access to older, frail and underserved patients awaiting kidney transplant to facilitate improved health care in this most vulnerable group. The specific aims of the PESC are to 1) solicit, select, and support pilot studies that advance the science and translation of frailty research, 2) to support the development of well-designed and informative pilot studies, 3) to provide and conduct longitudinal mentorship to supported investigators as well as provide oversight through completion of the pilot award and pursuit of funding for the next stage of research, 4) to further guide the translation of any pilot study results, and 5) to expand the research environment and network of frailty-focused investigators needed to accomplish the overall OAIC goals. These aims will be carried out in close collaboration with biostatistics, biological mechanisms, and clinical translational and recruitment core leaders to ensure optimal design and access to core resources needed for study success. A new Technology Assessment and Solutions Core (RC4) will bring new and unique engineering focused studies into this core. This core will also guide the translation of pilot work into a deeper understanding of the basic biology and population implications of frailty and into interventions that will prevent or treat frailty hence help maintain independence.

Resource Core 1 (RC1): Biostatistics Core (RC1)
Leader 1:    Qian-Li Xue, PhD
Leader 2:    Karen Bandeen-Roche, PhD
Since mid-2003, this OAIC Biostatistics Core (RC1) has dedicated critically needed resources toward the quantitative challenges of research on frailty. Partnering in OAIC leadership, and working closely with other OAIC resource cores, it has helped develop the careers of an interdisciplinary cohort of junior faculty supported by the Research Education Component (REC)—and beyond—and ensured expert design and analysis of pilot, external, and de novo studies needed to advance science on frailty. It now proposes to continue in these efforts, by providing: (1) mentorship for junior faculty supported by our REC, and our broader OAIC, in developing careers focused on frailty and aging; (2) new data and computing infrastructure and software, including web-based data housing and acquisition tools; (3) expertise for science on frailty, through support for the design, statistical analysis, and data management of research projects, and through making available new data analytic methodologies that are essential to studying the complex syndrome of frailty; and (4) leadership and visibility for frailty-related scientific and health promotion endeavors at Johns Hopkins, throughout the OAIC network, and in the broader gerontological community. Our support and leadership in these areas have been significant and wide-reaching, and could not be provided without the resources of this Core. The leadership is experienced, expert, deeply immersed in scholarship on aging, and visible in both gerontology and statistics. The Core will continue to support every REC and pilot-supported investigator as per their need. The Core synergizes actively with other OAIC resource cores, as evidenced by progress over the last cycle. Our team includes a statistical genomics expert to enhance our collaborations with the Biological Mechanisms Core (RC2). We also have engaged an internal consultant with expertise in signal intensive measurement to enhance our interactions with our new Technological Assessment and Solutions Core (RC4). We will continue to provide design and analytic expertise and support a Registry collaboratively with the Clinical Translation Core (RC3). Regarding new methodologies: research will develop approaches needed to better (i) assess prefrailty, hence identify at-risk persons early enough to intervene successfully; (ii) delineate heterogeneous etiology underlying frailty; (iii) design studies to assess frailty intervention; (iv) characterize attributable fraction of frailty risk factors over the lifecourse, and (v) address frailty disparities. By efforts along all these lines, this Core will contribute crucially to the success of this OAIC in answering a next generation of questions on frailty, and achieving findings' translation toward increased independence of older persons.

Resource Core 2 (RC2): Biological Mechanisms Core (RC2)
Leader 1:    Peter Abadir, MD, PhD
Leader 2:    Dan Arking, PhD
The identification of the etiologies of frailty and age-related vulnerability remains a crucial challenge for gerontological research. Key to this challenge are the development of a better understanding of the underlying biological basis that contributes to frailty and the identification of key biological pathways for the development of interventions that might help prevent or alleviate frailty and loss of independence. The goal of Johns Hopkins Older Americans Independence Center (OAIC) Biological Mechanisms Core (RC-2) is to enable the next generation of frailty-related etiological discovery and to promote the translation of these discoveries into clinically relevant diagnostic, preventive, and treatment modalities. This will be achieved through the provision of high-quality biological and bioengineering measurement expertise, incorporation of new technologies, analytical and computational expertise for genetics and omics analyses, and infrastructure necessary to attain this goal. In order to comprehensively encompass the biological expertise necessary to study frailty-related etiology, we have engaged a leadership team and internal consultants with complementary and synergistic biological and translational expertise needed to unravel the complex biological mechanisms that underpin frailty. They also all bring mentorship skills for trainees, and infrastructure to RC-2 and national prominence to frailty research. The specific aims of RC-2 are to: 1) provide state of the art scientific expertise, infrastructure, and technology necessary to advance biological and etiological research related to frailty, 2) provide access to biological samples from human subjects and from animal models necessary to test hypotheses related to frailty, 3) facilitate the translation of biological findings into interventions or prevention-focused clinical studies, 4) provide training, mentorship, and guidance to promising junior investigators around biological mechanisms that impact frailty, and 5) provide institutional and external visibility for RC-2 related science and activities. Our aims will be accomplished through close communication between the core leaders and their laboratories, close partnership with the other OAIC cores, and the engagement of expert consultants in the highly relevant areas of mitochondrial measurement, metabolomics, epigenetics, mouse model development, nanotechnologies for diagnostic and treatment development, and the development of multi-omic analyses related to frailty. By providing these resources, RC-2 will foster high quality research that elucidates clinically relevant biological pathways that underlie frailty and related interventions that hold promise to attenuate frailty, related conditions, and the loss of independence.

Resource Core 3 (RC3): Clinical Translation and Recruitment Core (RC3)
Leader 1:    Todd Brown, MD
The Johns Hopkins University (JHU) Older Americans Independence Center (OAIC) proposes to offer a resource core entitled Clinical Translation Core, or Resource Core 3 (RC3). This core—now in its 10th year—was designed to accelerate the translation of important biological findings related to frailty into clinical studies, and because of the need to train and support junior investigators proposing clinical investigations in frail, older adults. This initiative is closely aligned with the JHU Division of Geriatric Medicine and Gerontology's goals of integrating frailty-related research into clinical practice. The specific aims of RC3 are 1) to provide supported OAIC investigators with comprehensive training, mentorship and access to expertise in clinical research, 2) to provide the oversight necessary to ensure optimal and safe performance of clinical studies, 3) to provide clinical research space and assistance with all aspects of protocol development, data collection, and recruitment of human subjects as needed, and 4) to maintain and further develop an active registry of older adults characterized for frailty and consented to be contacted for additional aging and frailty related studies. A core leader with substantial clinical research expertise in aging and HIV-related metabolic studies, and who also leads a core and infrastructure in the JHU Institute of Clinical and Translational Research (ICTR), will facilitate the development, implementation, and conduct of both clinical physiological studies and clinical trials in this core. A highly skilled and experienced research program manager with expertise in recruitment of minoritized older adults and in the measurement of frailty and mobility, along with a team of experienced recruiters, will facilitate completion of Core aims. These aims will be carried out in close collaboration with the leaders of all other resource cores. Additional resources are provided by the ICTR, which will help ensure optimal study design, implementation, and interpretation of results, and Fast Forward, a translationally-focused unit at JHU will facilitate health technology development. This core will play a crucial role in the training of junior investigators engaged in Research Education Component (REC) activities and in pilot/exploratory studies, conduct developmental research as needed and will newly engage community advisory boards to maximize research relevance and potential to increase health equity. RC3 will continue to accelerate the pace of translation of the important biological findings being generated in this OAIC into frailty-related clinical studies that promote the maintenance of independence in older adults.

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

Resource Core 4 (RC4): Technological Assessment and Solutions (RC4)
Leader 1:    Najim Dehak
Leader 2:    Vadim Zipunnikov
Advances in the uses of engineered technologies and AI, including electronic mobile digital health (EMDH) technologies in health care, hold great promise for improving the older adult well-being and the care of frail older adults. The overarching goal of the Technological Assessment and Solutions Core (RC4) is to develop a novel ecosystem that promotes the development, testing, implementation, and dissemination of novel technologies and new uses of artificial intelligence for frailty-related purposes. This ecosystem will be created by bringing engineers, bioengineers, Gerontologists, Geriatricians and other clinical investigators together into built infrastructure that facilitates the development and testing of novel approaches to health care in frailty. This core will bridge the existing deep expertise in clinical investigation related to frailty to the deep expertise in EMDH technologies, robotics, and AI that exists at Johns Hopkins. Examples of projects that could be supported by this core include 1) robotic assistance with medication 2) treatment adherence the development of novel mobility and fall prevention technologies, 3) measurement improvements in frailty diagnostics through technology-assisted measurement of gait, activity, and other functional signals; 4) leveraging AI to build frailty assessments from these signals are also envisioned, and 5) remotely deployed technological interventions and measurement modalities could provide rich opportunities to expand reach to underserved older adults. This resource core, in collaboration with RC1, 2, and 3, proposes to support 2 pilot studies in this proposal. The specific aims of RC4 are: 1) to provide state-of-the-art engineering and technology application expertise to facilitate and support a broad array of translational frailty research; 2) to provide access to relevant technologies, and the necessary infrastructure to study frailty; 3) to facilitate the translation of RC4 frailty-related and focused technologies and uses of AI into intervention- or prevention-focused clinical studies in collaboration with the leadership of other resource cores; 4) to provide training, mentorship, and guidance to a diverse group of the most promising junior investigators who can contribute to frailty research, and to assure that RC4-developed technology are accessible to underserved populations of older adults; 5) To provide access to business development as relevant and local and national visibility for RC4-related science and activities.

REC Scholar, Research & Grants Funded During Pepper Supported Time Years /
Thomas Laskow, MD
Assistant Professor / School of Medicine, Division of Geriatric Medicine and Gerontology
Physical Frailty, Inflammation, and Response to Clinical Stressors
Physical frailty has been associated with adverse outcomes in response to a range of clinical stressors among older adults and prior studies have identified an association between physical frailty and markers of inflammation and dysregulated immune response. Less is known about the significance and convergence of physical frailty and inflammation in the context of clinical stressors, despite the fact that a core aim of identifying a phenotype for physical frailty is to better understand and anticipate adverse outcomes in older adults and clarify the biology that underlies these risks. This study will evaluate the relationship between inflammation and physical function measures such as physical frailty in the setting of older adults undergoing a defined clinical stressor. The study will utilize, biospecimens, measures of physical frailty, and related measures of physical function collected during the currently enrolling SPRING study, a multi-arm prospective study characterizing physical resilience in older adults undergoing one of 3 clinical stressors: total knee replacement, allogeneic bone marrow transplant, or living with advanced chronic kidney disease. The relationship between these physical function and inflammatory measures will be evaluated, both at baseline and at one-year follow up. By clarifying the interplay of frailty and inflammation in the context of real-world clinical stressors, this research could contribute to the care of older adults who experience such stressors, both through better risk stratification and through biologically informed interventions to promote physical resilience.
2022-2024 /
0 (total)
0 (1st/Sr)
Qinchuan Wang
Assistant Professor / School of Medicine, Division of Geriatric Medicine and Gerontology
CaMKII oxidation links oxidative stress to inflammation, frailty, and premature death
Inflammation is a key component of immunity against infections, which is necessary for the survival of organisms. However, inflammation can also cause self-damage, and aging-associated chronic inflammation contributes to frailty, diseases, and death. What sustains chronic inflammation in aging and how chronic inflammation promotes aging are incompletely understood. We hypothesize that the oxidative activation of the a2+/Calmodulin-dependent protein kinase II (ox-CaMKII) promotes chronic inflammation in aging. Our studies will determine the underlying mechanisms by which inflammation becomes harmful during aging and delineate a novel molecular pathway with therapeutic potential. We will use a recently established Drosophila melanogaster model to test our hypothesis that CaMKII oxidation activates age-associated inflammation through the master regulator of inflammation, NF-kB. We will also test two potential downstream pathways by which inflammation causes functional deterioration and premature death.
  • Glenn and AFAR Junior Faculty Award, CaMKII as a Cause of Age-Related Sarcopenia. PI: Qinchuan Wang.

2022-2024 /
0 (total)
0 (1st/Sr)
Melissa deCardi Hladek PhD, CRNP, FNP-BC
Assistant Professor / Johns Hopkins School of Nursing
Using Human-Centered Design to Adapt CAPABLE as a Prehabilitation Intervention for Adults with Frailty Awaiting Kidney Transplant
Over 700,000 Americans live with end-stage renal disease (ESRD), disproportionally affecting older adults, minority groups and those with lower socioeconomic status. ESRD is best treated with kidney transplant (KT) which increases life expectancy, functional ability and quality of life. Frailty is associated with higher KT waitlist mortality and worse KT surgical and post-surgical outcomes. As such, frailty is increasingly being evaluated in pre-surgical settings to plan for post-surgery recovery. There is an urgent need to further understand and intervene on the co-occurrence of frailty and KT. Beyond the need to improve surgical outcomes, there are stark health disparities in patients awaiting KT. Due to medical comorbidities, socio-economic constraints, or incomplete testing, Black and Hispanic individuals are more likely to change from active waitlist status (meaning able to receive a KT at any time) to inactive waitlist status (not currently eligible to receive KT) and are more likely to remain classified as inactive longer. There is an urgent need to further understand this disparity and create interventions to lessen it. Person-environment fit posits that improving a person’s lived environment will facilitate optimal individual functioning. CAPABLE is an evidence-based intervention that helps functionally limited, low-income older adults successfully age in their homes with better function and quality of life. It has been tested with in-center hemodialysis patients (N=12) which showed meaningful improvements in function and social network scores. This model, however, has not been applied to KT waitlist populations. We propose adapting CAPABLE as a KT prehabilitation program to accomplish two things: 1) To resolve barriers to being classified as active on the KT waitlist and 2) as a surgical prehabilitation intervention targeting the pre-frail/ frail KT waitlist population. We will accomplish this through a 3-phase human-centered design process, which engages the end users of the intervention throughout the research process to tailor interventions to their needs, behaviors and preferences. This work will form the basis for a future K01 proposal to pilot test the CAPABLE-KT prehab adaptation and R01 level funding to expand into other surgical populations conducting a larger community-based, comparative effectiveness trial. The proposed and subsequent studies will help inform the role of person-environment- focused prehabilitation interventions in surgical outcomes for vulnerable, frail populations.
  • K23, NIDDK, Addressing Inactive Kidney Transplant Waitlist Status through Adapting a Tailored Psycho-Social-Environmental Program. PI: Melissa Hladek.

2021-2023 /
5 (total)
1 (1st/Sr)
Gizem Keceli, PhD
Postdoctoral Fellow / Johns Hopkins School of Medicine, Division of Cardiology
Dissecting the Mechanisms Whereby Tryptophan Metabolites Alter Myocardial Function
Cardiovascular diseases (CVD) are a significant cause of morbidity and mortality in the elderly population and represent an important risk factor for frailty. Furthermore, frail patients have a heightened propensity to suffer from adverse outcomes of CVD. Studies emphasize the role of the altered kynurenine (kyn) pathway in the aging process and reveal its link to frailty. In recent clinical reports, increased levels of kyn and/or its metabolites, formed via degradation of the essential amino acid tryptophan, are associated with heart diseases and atherosclerosis. However, if these metabolites directly affect cardiac function is not known. In my pilot studies, kyn significantly impaired cardiac function. Similarly, in isolated cardiac cells, kyn infusion decreased the shortening ability and increased oxidative stress, an important contributor to many age-related CVD. Accordingly, I hypothesized that activated tryptophan degradation escalates ROS formation, jeopardizing cardiovascular function and prompting abnormal cell growth. In Aim1, I will explore whether kyn or its metabolites impact cardiac function directly by determining the functional parameters and ROS levels in isolated hearts/cells. In Aim2, I will investigate if kyn or its metabolites' accumulation induces abnormal growth of cardiac cells and examine the implicated mechanisms underlying kyn-induced alterations. The short-term goal is to gain insight into the potentially detrimental effects of the activated kynurenine pathway on cardiac function and determine whether, via enhanced ROS production, it drives maladaptive hypertrophy and loss of myocyte function. Overall, these studies will provide a better understanding of the reasons underpinning increased CVD risk in frailty and age-related cardiac dysfunction, thus facilitating new therapies.
2021-2023 /
1 (total)
1 (1st/Sr)
Lolita Nidadavolu, M.D., Ph.D.
Assistant Professor / Johns Hopkins University School of Medicine
Identifying mechanisms by which circulating-cell free DNA contribute to increased TNFR1 in frailty
Frailty, characterized by vulnerability to physical and psychosocial stressors, is an aging-related syndrome that contributes to increased mortality and is associated with changes in cell and tissue homeostasis (apoptosis, necrosis) and increased inflammation, in particular tumor necrosis factor receptor 1 (TNFR1). Circulating cell-free DNA (ccf-DNA) from genomic and mitochondrial DNA are released as a result of these cell death processes and the relative size of mitochondrial ccf-DNA fragments is related to different mechanisms of cell death. Our preliminary data shows strong associations between cell necrosis-associated mitochondrial ccf-DNA and serum TNFR1 levels as well as between TNFR1 levels and age-related physical decline. Mitochondrial ccf-DNA fragments are detected by innate immune system DNA sensors such as the cyclic GMP-AMP synthetase-stimulator of interferon genes (cGAS-STING) pathway, which is theorized to lead to upregulation in TNFR1. This proposal hypothesizes that frailty-associated increases in TNFR1 are mediated by higher levels of necrosis-associated mitochondrial ccf-DNA and upregulation in STING signaling. Aim 1 will characterize changes in the cGAS-STING signaling pathway with aging and frailty. Aim 2 will measure changes in robust older adult peripheral monocyte TNFR1 expression following treatment with necrosis-associated mitochondrial ccf-DNA from frail individuals and will examine how cGAS-STING mediates this relationship. The overall goal of this project is to identify innate immune system pathways for future intervention studies that can help attenuate frailty-associated chronic inflammation.
2021-2023 /
4 (total)
1 (1st/Sr)
Nicholas R. Rowan, MD
Assistant Professor / Johns Hopkins Department of Otolaryngology-Head and Neck Surgery
The implications of olfaction with frailty, a population-based and exploratory investigation
The ability to smell, olfaction, is an understudied sensory function with significant implications in health and aging. Olfactory dysfunction (OD) is incredibly common, afflicting approximately one fourth of the global population, and markedly increases with age. While OD has inherent dangers, such as placing individuals at increased risk of environmental hazards, disruption of this special sense has substantial psychosocial and well-being implications in the aged population. Olfaction has been identified as a bellwether of mortality, and there is mounting evidence that OD is a harbinger of multisystem, physical frailty. Often times overlooked, olfaction may represent a novel physiologic measure of frailty and mechanism to identify impending critical transitions in the continuum of frailty. The inherent neuroplasticity of this special sense also represents a modifiable risk factor and an attractive intervention target for vulnerable aging adults. In an effort to better understand appropriate olfactory screening measures and olfaction-related targets for interventional studies, we aim to utilize a robust, nationally-representative database that includes multiple measures of olfaction and phenotypic frailty assessments. Through this approach, differences between self-reported OD and more detailed psychophysical olfactory assessments will be examined. We will also evaluate validated self-reported metrics and novel psychophysical subdomain scores in a cross-sectional case-control cohort. Intrinsic differences in the underlying neurophysiologic mechanisms of these unique subdomains will provide insight into the underlying pathogenesis of olfactory dysfunction and its relationship to frailty. By employing innovative approaches to characterize olfactory deficits, substantiated by detailed psychophysical assessments, our results will offer mechanistic insight for olfactory loss in older adults and serve as a springboard for future interventional investigations aimed at the mitigation of OD and frailty in this population.
2021-2023 /
2 (total)
0 (1st/Sr)

Past Scholars
Alden Gross, PhD, Epidemiology (2014-2016)
Charles H. Brown IV, MD , Anesthesiology and Critical Care Medicine (2014-2016)
Charles H. Brown IV, MD , Anesthesiology and Critical Care Medicine (2014-2016)
Rani Hasan, MD, MHS, Cardiology (2015-2018)
Tae Chung, MD, Physical Medicine and Rehabilitation (2016-2018)
Abdulla Damluji, MD, PhD, Cardiology (2017-2019)
Orla Sheehan, MD, PhD, Geriatric Medicine (2018-2020)
Pei-Hsun Wu, PhD, Institute for NanoBioTechnology (2018-2020)
Bharath Ambale-Venkatesh, PhD, Radiology and Radiological Science (2018-2020)
Reyhan Westbrook, PhD, Geriatric Medicine (2018-2020)
Keenan Walker, PhD, Neorology (2019-2019)
Sabra Lewsey, MD, Division of Cardiology (2020-2021)
Jude Phillip, PhD, Department of Biomedical Engineering (2020-2021)
Jenny Pena Dias, Endocrinology/Medicine (2022-2022)

1. Project Title: Pilot Behavioral Intervention to Address Pain and Frailty in Older African-American Women
  Leader: Janiece Taylor, PhD, RN, Mary Catherine Beach, PhD; Sarah L. Szanton PhD, ANP, FAAN, Roland J. Thorpe Jr., PhD
  Older African American women are crucial to target for intervention not only because of their heightened frailty prevalence, but because they are at higher risk of pain than other racial/ethnic groups and African American men and have exacerbated relationship and outcomes of frailty and pain. They often experience difficulties communicating with health care providers, moreover, that may interfere with treatment of symptoms related to pain and frailty: Communication intervention has well documented potential to lessen these difficulties and result in better disease management. Specific aims of this study are: 1) To pilot a tailored behavioral activation intervention focused on improving frailty, chronic pain, and depressive symptoms among community dwelling older African American women and collect summary data needed to design a confirmatory intervention trial. Strategies will be non-pharmacologic and aim to improve communication, physical activity and education. 2) To determine a) feasibility and acceptability of the intervention b) if strategies and evaluation techniques were appropriate.
2. Project Title: Exploratory Study of Metabolomics Energy Signatures in Frailty
  Leader: Anne Le, MD, Reyhan Westbrook, PhD
  Building on a small PES awarded to Drs. Le and Westbrook that utilized a frail mouse model previously characterized in RC-2, altered metabolomics signatures were identified that suggest that TCA cycle processes are a component of dysregulated energy utilization in frailty. Given this background, we hypothesize that specific patterns of altered energy metabolites linked to glucose metabolism through mitochondrial bioenergetics, biosynthesis, and redox homeostasis pathways can help to distinguish frail from non-frail older adults, and that the circulating concentrations of metabolites related to glucose metabolism are measurably different between frail and non-frail older adults. Utilizing research resources from all three resource cores, and Dr. Le’s established metabolomics measurement infrastructure (Metabolomics facility) and expertise in energy metabolism measurement, the following specific aims were proposed: 1) To utilize metabolomics measurement to reconstruct the relevant metabolic pathways of glucose metabolism related to bioenergetics, biosynthesis, and redox homeostasis, and determine differences between frail and non-frail participants, and 2) To identify the most promising biomarkers for a frailty-related energetic signature and plan for a future targeted validation study of diagnostic utility and biological discovery.
3. Project Title: Association between Sleep Deficiency and Frailty: What harms most?
  Leader: Naresh Punjabi, MD, PhD, Jiawei Bai, PhD
  Epidemiologic surveys show that at least 50% of adults over 65 years in age have sleep-related complaints. Sleep disturbance has been associated with neurohormonal, circadian, and homeostatic alterations: As many such changes have been evidenced by this OAIC and others to also underlie frailty, it reasonable to expect interconnections between sleep quality and frailty. We hypothesize that disordered sleep heightens risk for frailty onset and believe that intervention to improve sleep can prevent or buffer frailty. Prior studies indicate that poor sleep quality is associated with frailty. These predominantly have assessed sleep, however, by either self-report or relatively crude summaries (e.g. time in sleep states) of actigraphy or polysomnography data. This project uses data from the community-based Sleep Heart Health Study (SHHS) to extract power spectral “curves” summarizing the history of the overnight sleep EEG, by functional principal components analysis (fPCA), and identify sleep EEG signatures highly associated with frailty prevalence, incidence and transitions, and vice versa.
4. Project Title: PCSK9 Links Age and Frailty Inflammation to Endothelial Cell Dysfunction
  Leader: Thorsten Leucker, MD, PhD, Gary Gerstenblith, MD.
  One of the most significant aspects of aging is the marked increase in mortality and significant lifelong disability due to coronary vascular and cerebrovascular disease respectively. There is heterogeneity in that risk with a significant increase in older individuals with frailty and those with the prediabetes, both of which are increased with age and independently associated with vascular disease. Many preclinical and clinical studies indicate that inflammation is a common predisposing factor but the link between inflammation and vascular disease in older adults and particularly in those with frailty and pre-diabetes is not well characterized. Decreased endothelial cell (EC) production and release of nitric oxide (NO), which has potent anti-atherosclerotic effects is a driver of the development and progression of atherosclerotic vascular disease. Beyond its role in cholesterol homeostasis, proprotein convertase subtilisin/kexin type 9 (PCSK9, is associated with the future risk of cardiovascular diseases. Laboratory studies of isolated ECs demonstrate that inflammatory stimuli increase EC PCSK9 and, in separate experiments, that increased PCSK9 decreases endothelial nitric oxide synthase (eNOS) and NO bioavailability, decreases which indicate EC dysfunction independent of low-density lipoprotein cholesterol (LDL-C). This research will examine whether PCSK9 links proinflammatory stimuli with EC dysfunction by studying in vivo endothelial- dependent vascular function and in vitro basic studies of ECs. A comparison of the in vivo and in vitro results will also provide information regarding the extent to which vascular dysfunction in the older groups is related to systemic, circulating factors and to mitochondrial dysfunction. In addition to association, we will examine causality by using PCSK9 targeted small interfering RNA in the above basic studies. The significance of the research to the field of aging, therefore, is the opportunity it offers to understand whether EC PCSK9 is one mediator of the known cardiovascular risk associated with inflammation in older individuals, which then would provide a target of intervention as PCSK9 antibodies are available for clinical use.
5. Project Title: Daily physical activity patterns and the modifying role of inflammatory markers in frailty
  Leader: Amal Wanigatunga, PhD, MPH, Jennifer A. Schrack, PhD, Lawrence J. Appel, MD, MPH, Dr. Robert H. Christenson, PhD
  Frailty is a common medical syndrome of increased vulnerability in adults aged 70 years and older that is often accompanied by low daily physical activity (PA) and high chronic inflammation. Currently, the method by which low PA is quantified and defined relies on coarse measures of self-reported time spent in a few daily activities, leaving a large knowledge gap regarding the true manifestation of PA decrements in frailty. Moreover, chronic inflammatory markers such as interleukin-6 (IL-6) and C-reactive protein (CRP) have been linked to components of frailty, including high fatigability and functional decline, making it plausible that degradation of daily PA patterns may be connected to rising circulation of both IL-6 and CRP. This warrants further investigation into inflammation as a possible underlying mechanism connecting detailed measures of PA and the onset and progression of frailty with aging. Findings from such investigation would lay the groundwork towards building the clinical utility of measuring physical activity in non-laboratory, community-dwelling settings to detect and intervene on trajectories towards frailty and accelerated aging in ever-expanding older adult populations. The proposed research aims to examine (1) whether total daily PA and patterns of daily PA accumulation differ by frailty status (non-frail, pre-frail, and frail), and (2) whether chronic inflammation modifies this association. We hypothesize that free-living PA patterns are deteriorated and diminished in those who exhibit pre-frail and frail phenotypes, compared to non-frail individuals. Further, we hypothesize that these sophisticated measures of PA are sensitive to rising chronic inflammation (IL-6 and CRP) typically present in frail older adults. The proposed research provides an exciting opportunity to use cutting-edge methods to extract unique patterns of PA accumulation from objectively measured PA and assess whether greater deterioration in these PA patterns are seen with higher inflammation and frailty states.
6. Project Title: Effects of Neurotoxic Kynurenines on Peripheral Nerve Regeneration
  Leader: Tae Chung, MD
  Age-related muscle weakness is a critical component of frailty in older adults, and independently predicts morbidity and mortality in late life. Over the past decades, various changes in aging neuromuscular system, such as partial denervation at neuromuscular junction (NMJ), reducing number of motor neurons, and fiber type switching, have been described, but the underlying molecular pathway that links the degeneration of neuromuscular system to overall reduction of morbidity/mortality with aging has not been elucidated to date. In a recent metabolomics study, we have identified alterations in the kynurenine pathway in frail older animal and human subjects. We also found that those kynurenine intermediates strongly correlate to the markers of frailty and chronic inflammation. Kynurenine pathway is a major pathway for tryptophan degradation that eventually leads to NAD synthesis, and interestingly, a few intermediates in the kynurenine pathway are known to be potently neurotoxic, and involved in some age-related neurodegenerative diseases, such as Alzheimer and Parkinson diseases. In addition, kynurenine pathway has been known to play a critical role in immune tolerance and cancer surveillance6, suggesting that alteration of kynurenine pathway may contribute to the immune senescence and increased morbidity/mortality in late life. Taken together, we hypothesized that alteration in kynurenine pathway is the major underlying pathway of age-related muscle weakness, eventually leading to increased morbidity/mortality in late life. To further investigate the influence of kynurenine pathway in frailty and aging, we have utilized a genetically altered mouse, Quinolinate phosphoribosyl transferase (QPRT) knock-out (KO), known to have elevated levels of the potent neurotoxic kynurenine metabolites, quinolinic acid (QUIN), in the nerve tissues and serum. In an NIA K08-funded proposal, we have been longitudinally tracking the neuromuscular functions of QPRT KO vs wild type mice over the entire lifespan. Our preliminary results have shown that QPRT KO mice have greater degree of NMJ denervation and reduced peak isometric strength as compared to the background-matching wild type mice after middle age. Additionally, QPRT KO mice also showed premature signs of frailty, such as weight loss, reduced lean mass, and poor glucose tolerance after middle age. The above results suggest that increased QUIN is related to degeneration of both motor neuron and skeletal muscle, leading to frailty phenotype. To further investigate the casual relationship between QUIN and neuromuscular dysfunction, we propose the following pilot experiments, using kynurenine inhibitors, JM6 that is known to reduce the levels of QUIN by inhibiting upstream enzyme, kynurenine 3-monooxygenase (KMO). Specific Aims: Aim1: To investigate the toxicity of QUIN on peripheral nerve and skeletal muscle regeneration Hypothesis: Regeneration of both nerve and muscle will be delayed in QPRT KO mice due to neuromyotoxicity of QUIN Subaim1: to compare the speed of nerve regeneration between QPRT KO and wild type mice after ligation of tibial nerve Subaim2: to compare the speed of muscle regeneration between QPRT KO and wild type mice after cardiotoxin injection to gastrocnemius muscle. Aim2: To determine if JM6 may facilitate the regeneration of peripheral nerve axon and skeletal muscle in QPRT KO mice Hypothesis: JM6 will facilitate the regeneration of peripheral nerve and skeletal muscle in QPRT KO mice Subaim1: compare the speed of nerve regeneration between QPRT KO and QPRT KO with JM6 after ligation of tibial nerve Subaim2: to compare the speed of muscle regeneration between QPRT KO and QPRT KO with JM6 after cardiotoxin injection to gastrocnemius muscle. The results from the current study will be used as preliminary data for NIH R01 application and justification for chronic administration of JM6 to prevent frailty phenotype in QPRT KO mice. In the future studies, we will manipulate kynurenine pathway at different points both genetically and pharmacologically, to identify the optimal target for the prevention of age-related muscle weakness, frailty, and eventually prolongation of lifespan.
7. Project Title: The Effects of Tryptophan Degradation Pathway Manipulation on Metabolism, Healthspan and Lifespan in Mice
  Leader: Reyhan Westbrook, PhD
  Chronically activated inflammatory pathways are strong predictors of age-related morbidity including disability, physical frailty, mild cognitive impairment1 and morality2. Despite this, the underlying molecular mechanisms that connect chronic inflammation (CI) to these common conditions are poorly characterized. We have recently identified metabolites in the tryptophan degradation pathway (TDP), known as kynurenines, as potential mediators of the effects of CI on functional decline in a mouse model and in older human subjects. Using targeted metabolomics, we showed that kynurenines correlate strongly with inflammation and decreased physical function in both mice and humans, and that the neurotoxic & cytotoxic metabolite 3-hydroxykynurenine (3HK) is elevated in the blood of frail older adults. Inflammatory cytokines activate indolamine 2,3 dioxygenase (IDO) which converts tryptophan to kynurenine, and kynurenine monooxygenase (KMO) which converts kynurenine to 3HK, thus cytokines increase the production of potentially deleterious kynurenines. We postulate that CI raises 3HK to toxic levels causing damage to tissues, including nerves and muscles, leading to accelerated decline in physical function and decreased lifespan. TDP blockade and reduced dietary tryptophan have increased lifespan in Drosophila and in mice, respectively. In this proposed study, we will elucidate the role kynurenines play in the development of age related functional decline by 1) determining if exogenously increased levels of 3HK lead to impaired physiology, functional decline and early mortality in C57BL/6 mice, and 2) determining if blocking the TDP using an inhibitor, improves physical function, delays age-related physiological changes, and increases lifespan in both C57BL/6 mice and in a mouse model of CI. To assess effects on healthspan, we will longitudinally measure physiological and physical function including grip strength testing, indirect calorimetry, spontaneous activity monitoring, body composition analysis, muscle contractility analysis and insulin/glucose tolerance testing. To assess kidney toxicity, we will measure blood urea and creatinine levels. We will longitudinally profile the metabolome, measure levels of circulating cytokines, and perform ex vivo neuromuscular junction analysis and senescent cell quantification in these mice. Specific Aims: Aim 1: To determine the effects of treatment with the cytotoxic TDP intermediate, 3-hydroxykynurenine, initiated in adult (10 month old) C57BL/6 mice on lifespan and healthspan. Hypothesis: Increased circulating levels of 3HK accelerate functional decline, pathophysiological metabolic changes, and mortality in C57BL/6 mice. Aim 2: Determine the effects of TDP blockade initiated in adult (10 month old) C57BL/6 mice and in chronically inflamed IL10tm mice on lifespan and healthspan using the IDO inhibitor 1- methyl-D-tryptophan. Hypothesis: Treatment with 1-methyl-D-tryptophan initiated at 10 months can prevent or delay functional decline, pathophysiological metabolic changes, and mortality in C57Bl/6 mice and in chronically inflamed IL10tm mice which have known kynurenine elevation. These approaches will allow us to more fully articulate the impact of kynurenines on function, metabolism, body composition, and inflammation in older mice, and facilitate the future development of translational approaches in human subjects. With this work we will gain insight on the mechanisms of decreased physical function associated with chronic inflammation and aging as well as guide the development of interventions that mitigate the effects of chronic inflammation on functional decline.
8. Project Title: Analysis of lamin A/C-associated proteins in the frail (IL10-KO) heart.
  Leader: Kathy Wilson, PhD
  We hypothesize that signaling and gene-regulatory complexes that depend on A-type lamins are functionally perturbed in IL10-KO mice. This hypothesis is based on our mass spectrometry multiplex identification and quantification of proteins that co-immunoprecipitated with lamins A/C from old (21-22 months) IL10-KO vs control mouse hearts, skeletal muscle and brain. This pilot study will focus on the heart data, which revealed two groups of proteins proposed to associate with lamin A/C: Proposed novel partners (proteins not known to associate with lamin A/C). This group of 20 candidates includes two exciting proteins: Perm1 and Fam210A. Perm1 is a ~100 kDa intrinsically disordered (‘transformer’) protein, highly expressed in heart and skeletal muscle, that regulates genes required for endurance exercise, mitochondrial biogenesis and oxidative capacity in muscle (Cho et al., 2016; Cho et al., 2019), as discovered by our Hopkins collaborator Natasha Kralli. Equally interesting is Fam210A, which is genetically linked to grip strength, sarcopenia and bone fractures (Tanaka et al., 2018; Trajanoska et al., 2018; Tanaka et al., 2020), and is unstudied in the heart. Known or proposed partners for which lamin A/C association significantly decreased in frail hearts (log2-fold changes with p-values <0.05). This group includes MLIP (muscle LMNA-interacting protein), which directly binds lamin A, regulates mTOR signaling in the heart and is required for cardiac adaptation (Cattin et al., 2015), and transcriptional regulators that function in the nucleus and are important for cardiac health, including YBX1 (Choong et al., 2019), PDLIM5 (Elbediwy et al., 2018) and NDRG2 (Sun et al., 2013). Aim 1. Biochemical foundation for lamin A/C-dependent molecular changes in the frail heart. We will prioritize 20 potential partners based on functional annotation of our mass spectrometry results, and then screen for direct binding to lamin A/C or emerin, the intrinsically-disordered nuclear membrane protein that partners with lamin A to support signaling and gene-regulatory complexes important for heart and muscle. (a) Complete our functional annotation of the heart proteome and prioritize proteins for further study. (b) Test 20 prioritized candidates for direct binding to lamin A or emerin. Aim 2. Validation: screen top-20 candidates in frail-vs-control hearts for changes in expression, localization or association with lamin A/C. (a) Western blot lysates from frail vs control hearts (n=5 each) using antibodies specific for each candidate to determine if expression changes in frailty. (b) Validate lamin A/C association by co-immunoprecipitation from frail vs control hearts, or by APEX co-localization (immunofluorescence) in tissue sections. Aim 3. Tools for the molecular characterization of the frailty-relevant protein Fam210A. Determine if the Fam210 isoform(s) identified in the heart proteome include the transmembrane domain, predict any folded or intrinsically-disordered domains, and use this information to: (a) generate recombinant Fam210A for biochemical studies, and (b) generate adenovirus-deliverable TurboID-Fam210A constructs to independently identify Fam210A-proximal proteins in cardiomyocytes.
9. Project Title: Resilience and Multifactorial Stressors Among Older Adults During the COVID-19 Pandemic
  Leader: Alden Gross, PhD
  The COVID-19 pandemic represents a complex stressor for older adults. Though our understanding of COVID-19 pathogenesis is evolving, evidence is accumulating that both age-related physiologic changes and age-associated multimorbidity drive increased hospitalization, ICU admissions, and death seen among older people with this infection (Verity 2020, Zhang 2020, Garg 2020). In addition to its direct impact via infection, older adults also face indirect stressors related to COVID-19 mitigation strategies. These indirect stressors include increased sedentary activity, stress, and nutritional challenges, and decreased access to medical care (Schrack 2020). Additionally, many older adults, in practicing social distancing, also may face increased loneliness and social isolation--experiences known to increase risk for anxiety and depression (Santini 2020). Against this backdrop, modern gerontological thinking recognizes the importance not only of vulnerability, but also ability to withstand or rebound from stressors when evaluating how older adults respond to COVID-19. By understanding the underpinnings of resilience and frailty, we can better understand the needs, interventions, and targeting strategies that can best support the health of older adults during and after the COVID-19 pandemic. In this study, we propose to characterize the multifaceted COVID-19 stressor in older adults living in the Baltimore area through a quantitative survey and qualitative interviews. We will leverage two existing cohorts to measure key aspects of the complex stressor that older adults are facing during the pandemic including direct stressors and indirect stressors. We will relate these stressors to clinical and psychosocial outcomes including stress levels measured objectively using measurements from salivary cortisol, and explore how resilience and frailty affect these relationships. In qualitative surveys of a subset of participants, we will explore perceptions and experiences of older adults as to how the COVID-19 pandemic may have been a stressor impacting their health, social interactions, finances and care of existing chronic medical conditions; and strategies they use to cope with these stressors. Ultimately, we hope to identify targets for interventions to lessen stressor impacts in this and future crises facing older adults. The proposed specific aims are: Specific Aim 1: To characterize the complex stressor older adults face during the COVID-19 pandemic and identify clinically relevant impacts. We will survey: (a) direct and indirect pandemic effects--direct: COVID-19 exposure, infection, hospitalization; indirect: changes and disruptions to daily life and health care, psychosocial effects and coping, social networks, food/medication access; (b) hypothesized outcomes of stressors: physical function, pain, fatigue, depression and anxiety symptoms, loneliness, health behavior changes, worsening chronic medical conditions, nonCOVID-19-related hospitalizations, frailty status and changes, perceived and objective (via serial home salivary cortisol) stress. Specific Aim 2: To characterize associations of clinical outcomes with (a) COVID-19 stressors and (b) sociodemographic and psychosocial factors hypothesized to partially determine resilience. Specific Aim 3: To explore direct associations of pre-pandemic measures of frailty and resilience with outcomes (Aim 1), and potential effect modification of these by stressor type and intensity. Specific Aim 4: To explore in qualitative interviews the perceptions and experiences of older adults as to how the COVID-19 pandemic may have been a stressor impacting their health, social interactions, finances and care of existing chronic medical conditions; and strategies they use to cope with these stressors. If successful, we will identify targets for interventions to lessen stressor impacts in future crises facing older adults.
10. Project Title: A Pilot Study to Identify Frail Patients Prior to Surgery and Implement a Novel Social Work- Focused Preoperative Intervention
  Leader: Lee Goeddel MD, MPH
  Older patients have increased complications after surgery. Although many older adults fare well postoperatively, frail and vulnerable patients seem to be at highest risk. Multiple studies have demonstrated the association between preoperative frailty assessment and post-operative outcomes. These studies have not assessed the associations between individual components of frailty assessment and outcome to better target intervention. Additionally, the majority of preoperative interventions have focused primarily on physical activity with limited outcome benefit. Psychosocial risk factors have been increasingly associated with poor outcome after surgery in this high-risk population. There is a critical need to identify and develop interventions that can improve outcomes for frail patients undergoing surgery. This OAIC proposal focuses on first identifying patients who might benefit from a novel Social Work intervention (by assessing the association of subcomponents of a commonly utilized assessment of frailty with postoperative outcomes), and secondly, the implementation and evaluation of a novel preoperative Social Work intervention to improve postoperative outcomes. We propose three aims of limited scope. In Aim 1, we will retrospectively analyze the subcomponents of the Edmonton Frailty Score (EFS) and the association with postoperative outcomes in a population of 4100 patients. This information will allow us to identify patients who might benefit from the novel Social Work intervention described in Aim 2. In Aim 2, we will assess the feasibility and barriers to implementing a social work intervention in the Johns Hopkins Center for Perioperative Optimization. Patients are identified for social work assessment and plan with EFS36. For the second half of the study, patients will be evaluated with the Physical Frailty Phenotype Assessment and the EFS to assess the feasibility and additional utility of social work intervention in frail patients. Aim 3 will evaluate the postoperative outcomes of the cohort of patients that undergo the social work intervention compared to historical matched controls from Aim 1.
11. Project Title: Identification of emergent patterns of monocyte morphologies and functional heterogeneity in frail and non-frail adults
  Leader: Jude M. Phillip, PhD
  During ageing, physiological changes and dysfunctions propagate, eventually manifesting as diseases later in life. In many older adults (>65 years), chronic low-grade inflammation typically associates with adverse outcomes, and is strongly linked to geriatric syndromes such as frailty. Recent studies have shown that potential sources of inflammation include the accumulation of senescent cells within ageing tissues, and from the age associated increase in cellular and protein fragments that are inadequately cleared from the body, (i.e. circulating cell-free DNA). Furthermore, this increased pro-inflammation phenotype induce deficiencies in immune activity and surveillance, likely contributing to the frailty-associated phenotypes in older adults. To address this, we propose to study frailty-induced changes in blood-derived monocytes from older adults (>65 years). For this proof-of-principle study, we hypothesize that frailty-associated inflammation drives the emergence of defective cellular phenotypes and decreased heterogeneity within circulating monocyte compartments. In this proposal we will focus on two interconnected goals: (a) develop and optimize an image-based platform to identify and classify functional cell morphologies and heterogeneity of circulating monocytes from frail and non-frail older adults (Aim 1A), and (b) develop a computational model based on morphological changes to describe how cytoskeletal signaling pathway activities associate with the resultant morphological phenotypes (Aim 1B). This study will form the framework to guide future confirmatory studies, which will enhance our understanding of frailty-associated monocyte phenotypes, and provide new learning opportunities from transfer-learning approaches for additional cell types, including other immune subtypes and fibroblasts. Successfully attaining this pilot funding will allow us to generate critical preliminary data needed to pursue external funding through R01/R21 mechanisms from the NIA.
12. Project Title: The Effects of a Proof-of-Concept Sedentary Reduction Program on Metabolism in Prefrail Older Adults
  Leader: Amal Wanigatunga, PhD
  The proposed pilot seeks to enhance a K01 project (K01AG076967; PI: Wanigatunga) that aims to evaluate sedentary behavior reduction interventions in prefrail older adults in two important ways by: 1) adding secondary outcomes of glucose and lipid metabolism biomarkers and 2) testing the feasibility of remotely monitoring physical activity continuously for 2 months in prefrail older adults. The Older Americans Independence Center (OAIC) Pilot Core aims are to: OAIC Aim 1: Assess the dose-response relationship between changes in sedentary time and biomarkers of glucose and lipid metabolism, including glucose, insulin, total cholesterol, low-density lipoprotein (LDL), triglycerides, and high-density lipoprotein (HDL) OAIC Hypothesis 1. Decreased daily sedentary time is associated with decreased levels of blood glucose, insulin, total cholesterol, LDLs, triglycerides and increased HDLs over 2 months. OAIC Aim 2: Determine the dose-response and diurnal relationships between changes in sedentary time and blood glucose continuously monitored over 24 hours for 14 consecutive days using a Libre Pro sensor OAIC Hypothesis 2. Decreased sedentary time is associated with decreased overall glucose and different time-of-day glucose levels (e.g., faster returns to pre-meal glucose levels). OAIC Exploratory Aim 3: Explore the feasibility of a protocol to monitor accelerometry 24 hours/day for 60 consecutive days using a fully remote Actigraph Centrepoint system that provides study staff access to real time monitoring of device wear and activity volume and characteristics
13. Project Title: Investigating changes in monocyte-macrophage phenotype and inflammation in older frail adults
  Leader: Nicola M. Heller, Ph.D., and Franco R. D’Alessio, M.D.
  Frailty in older adults increases risk of morbidity and mortality and it is a good predictor of worse health outcomes. Prevention of frailty is therefore of critical importance in raising life expectancy, quality of life and decreasing healthcare costs. Understanding the dysregulation of the cellular and molecular processes that underpin frailty and identifying hallmark cellular characteristics and biomarkers of those dysregulated processes is key to intervention. Chronic inflammation and impaired healing capacity are features of an aging immune system. Tissue reparative macrophages are essential to resolution of inflammation and tissue repair. We found that macrophages from old mice cannot convert to the tissue reparative phenotype as macrophages from young animals do. Therefore, we hypothesize that impairment of conversion to the tissue reparative macrophage phenotype occurs in old frail adults and correlates with frailty and chronic inflammation. To test this idea, we propose three Specific Aims using previously collected and cryopreserved peripheral blood mononuclear cells from old frail, old robust and young healthy donors. First, we will measure the ability of monocyte-derived macrophages to convert to the tissue reparative phenotype in vitro. We will compare gene and surface marker expression of the tissue reparative phenotype in monocyte-derived macrophages from young healthy, old robust and old frail individuals. Second, we will correlate the amount of expression of the tissue reparative phenotype in vitro with frailty scores and proinflammatory cytokines in the serum of the same donors in the three groups. Third, we will use scRNA-Seq to explore whether monocytes, the circulating precursors of tissue macrophages, from old frail adults show alterations in abundance or gene expression profiles compared to old robust or young healthy adults. The scRNA-Seq data will also allow us insights into changes in other immune cell populations and gene expression in the cells of the peripheral blood of old frail adults. With these preliminary data, our goal is to apply for a larger National Institute on Aging (NIA) award to investigate more thoroughly the cellular and molecular mechanisms in monocyte-macrophages that contribute to frailty in older adults. Our long-term objective is to find new cellular markers of frailty – monocytemacrophage dysfunction - and then find new approaches to slow or stop worsening of the frail state by targeting immune system dysfunction in older adults.
14. Project Title: Artificial intelligence-based phenotypic biosignals of frailty
  Leader: Najim Dehak, PhD, and Laureano Moro-Velazquez, PhD
  Frailty is a clinical state characterized by dysregulation in multiple physiological systems related to cognitive and motor aspects, resulting in an increased vulnerability to stressors for the frail individual. However, cognitive and motor biosignals remain unexplored to predict frailty onset. Moreover, the relationship between physical frailty and cognition has not been deeply studied. In this proposal, we hypothesize that quantitative phenotypic biosignals (voice, speech, handwriting, eye movement, and gait) can provide digital biomarkers to assess frailty in the elderly population. Consequently, our goal is to enroll a cohort of frail and robust subjects older than 64 years and record phenotypic biosignals as well as clinical data. We will use digital biomarkers extracted from the biosignals and study their relationship with frailty and their relationship with the cognitive state of the participants. The rationale behind the use of the proposed biosignals is that they provide a window on motor and cognitive function and are tightly related to multiple physiological mechanisms that drive the frail phenotype. Our first aim will be to determine the correlation between phenotypic biosignals and established frailty scores in the participants. Our second aim will be to study relationships between biosignals and physical frailty in subjects with and without cognitive impairment.
DEVELOPMENT PROJECTS (7 Development Projects Listed)
1. Project Title: Characterizing Longitudinal Interdependence among Multiple Multi-System Dysregulation (MSD) Biomarkers
  Leader: Karen Bandeen-Roche, PhD
  Core(s): Resource Core 1 (RC1): Biostatistics Core (RC1)

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

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

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

3. Project Title: Implementation of preoperative frailty assessment in older surgical populations.
  Leader: Frederick Sieber, MD
  The data is compelling that assessment of frailty is germane to determining surgical risk. There are two common means of frailty assessments, the phenotypic model and the deficit accumulation model. When assessing for frailty in the same population, phenotypic frailty instruments and deficit accumulation instruments of frailty display some overlap among subjects, but the populations defined are different. To help define the use of each frailty assessment in clinical practice, this proposal will first examine the use of both the phenotype model (“light-touch” Frailty Screen, LTFS) and the deficit accumulation model (Edmonton Frail Scale, EFS) within a surgical clinic to examine the level of agreement between the two assessments. In addition, relationships between individual domains assessed by the EFS and the frailty phenotype will be determined. Next, outcomes will be compared between the two models in the same surgical population. This comparison will be used to determine the ability of both assessments to predict postoperative outcomes and garnish support for the targeted use of these assessments in the preoperative workflow for patients ? 65 years. In addition, it will guide the development of domain specific interventions that may ultimately influence postoperative outcomes. Once the analysis is completed, we will use the well-defined Johns Hopkins Translating Evidence into Practice (TRIP) model to guide implementation of both assessments into clinical practice/workflow as a routine part of the pre-operative assessment of surgical patients ? 65 years of age across the John Hopkins Health System. This development grant will include incorporation of EHR documentation and dashboard creation for ease of analysis.
4. Project Title: Effects of Kynurenine Pathway Manipulation on the Metabolome of Drosophila
  Leader: Mariann Gabrawy, PhD & Reyhan Westbrook, PhD
  Chronic inflammation is associated with physical frailty and functional decline in older adults; however, the molecular mechanisms of this linkage are not understood. Through findings from translational studies on both aged and chronically inflamed mice, as well as on aged and frail older adults, we have identified metabolites of the kynurenine pathway (KP) as potential mediators of systemic damage caused by chronic inflammation. Tryptophan metabolism is an important precursor to several bioactive metabolites including serotonin and NAD+. Tryptophan metabolism is highly conserved throughout nature and fluxes of this pathway are linked to longevity in numerous species. In humans, overproduction of downstream kynurenines such as 3-hydroxykynurenine (3-HK) and 3-hydroxyanthranillic acid (3-HAA) is linked to diseases such as cardiovascular disease, neurodegenerative disease, and frailty while blockade of the KP increases life span of Drosophila melanogaster. We used line DGRP_229 to elucidate the role of altered levels of kynurenines on physical performance and life span. Our results show that flies treated with 3-HK or 3-HAA have reduced climbing speed, endurance, and life span. Flies treated with a combination of ?-methyltryptophan (?-MT) plus nicotinamide (NAM) or nicotinamide riboside (NR) have greater speed, endurance, and life span than those treated with each metabolite alone. Motor neuron density is commensurate with the above treatments. We conclude that promotion of the KP accelerates functional decline and reduces life span while blockade of the KP, with NAD+ supplementation, attenuates the effect of age on functional decline and increases life span in an age-specific, synergistic manner. We have demonstrated, for the first time, that a combination of blocking the KP while supplementing its product, NAD+ (?-MT+NAM or ?-MT+NR), can increase life span and preserve physical function in Drosophila. Our work provides the foundation for future studies in mice and in humans. In order to understand the etiological linkages between KP manipulations and the resulting changes in physical function and life span, it is necessary to understand how our treatments affected the levels of 1) KP metabolites and 2) other molecular pathways including those involved in energy metabolism.
5. Project Title: Improving Data Infrastructure and Care Planning for Patients Enrolled in the Program for All-Inclusive Care for the Elderly (PACE)
  Leader: Qian-Li Xue, PhD
  The goal of this project is to improve communication within the Program for All-Inclusive Care for the Elderly (PACE) care team and between the care team and patient/caregiver by developing and testing a data integration and reporting system that can be used to facilitate personalized care planning, coordination, management, and communication, with the ultimate goal of improving health and quality of life of PACE patients and their informal caregivers. Hypotheses and specific aims: 1. To build a SQL database that serves as a data warehouse for integrating data from EPIC and PACE. 2. To develop a one-page report template that provides a user-friendly summary of clinical data routinely used by PACE for care-planning and communication. 3. To create a streamlined and color-coded care plan document that better communicates care priorities, as well as distinguish patient/caregiver-initiated vs. provider-initiated tasks. 4. To conduct questionnaire-based surveys with the PACE care team and patient/caregiver dyads to assess user experience of the new data report and documentation system.
6. Project Title: High-throughput screening of mitochondrial function
  Leader: Dan Arking, PhD
  Mitochondria, which are found in 10s to 1000s of copies per cell, are maternally inherited ancient bacterial symbionts that have maintained their own DNA (mtDNA). mtDNA contains 37 genes, including 13 that code for proteins, 2 for rRNAs, and 22 for tRNAs, while the remaining ~1500 genes required for mitochondrial (MT) function are encoded in the nuclear genome. Given the critical role of mitochondria in energy production via the oxidation phosphorylation (OXPHOS) pathway, decline in MT function has long been hypothesized to underlie multiple biological changes that increase vulnerability to chronic disease, and ultimately, to mortality. We and others have demonstrated that mtDNA copy number (mtDNA-CN) measured in peripheral blood cells, which is associated with MT enzyme activity and ATP production, declines longitudinally with age and is associated with general health among the elderly, including frailty susceptibility. Multiple mechanisms contribute to aging-related MT functional decline, including declines in energy (ATP) production, increased free radical production, altered rate of apoptosis and mitophagy, and altered fusion/fission. While mtDNA-CN has proven useful in implicating a role for mitochondria in various aging-related diseases, this measure is a relatively crude estimator of mitochondrial function, as it only captures the number of mtDNA molecules, which does not allow for direct measurement of mitochondrial function. Moreover, it does not distinguish between changes in the function of specific electron transport chain complexes, ROS production, or OXPHOS capacity. To make additional progress in the field, there is an urgent need for high-throughput mitochondrial functional assays that can identify changes in OXPHOS capacity, mitochondrial mass, and ROS, and that could be applied to both patient samples and used in cell culture to rapidly screen for changes in mitochondrial function in response to genetic and/or chemical perturbations.
7. Project Title: Development of a novel technology for the sustained delivery of valsartan and senolytics to frail older adults with chronic wounds
  Leader: Efrosini Kokkoli
  Non-healing, chronic wounds are a manifestation of multimorbidity and frailty that significantly diminish quality of life with increased risk of infection, amputation, and death, and require long-term treatment at high costs. The angiotensin system is a major hormonal system that contributes to the chronicity of diabetic wounds by keeping them stalled in the inflammatory phase and unable to progress to the proliferative or remodeling phases of healing. We recently demonstrated that a daily, topical reformulation of valsartan cream, an angiotensin receptor blocker, significantly accelerated healing in aged diabetic mice and pigs and regenerated skin of superior quality. Despite these impressive results, two major potential areas of improvement to this novel therapy remain: First, there remains a need to develop an extended release formulation that will maintain the level of local, active valsartan in the wound bed and reduce the frequency of necessary applications. Second, because senescent cells are a significant component of chronic wound base matrix, there remains great potential to target senescent cells in the wound base that could further accelerate chronic wound healing in older, frail adults. Based on these needs, we have devised a plan to develop and evaluate a combination treatment for chronic wounds that consists of a fast release of senolytic agents (dasatinib + quercetin) combined with a thermosensitive and biodegradable valsartan-loaded hydrogel. This is further supported by prior findings related to wound healing with topical valsartan, the recent development of a novel thermosensitive and biodegradable polymeric hydrogel that can be used as a tunable multi-drug delivery system, and our own new feasibility data that shows that an early prototype of this novel hydrogel showed an extended release of valsartan for 2 weeks. We propose the following Specific Aims to engineer a desperately needed solution for chronic wounds. In Aim 1, we will synthesize and characterize a thermosensitive and biodegradable hydrogel that encapsulates nanoemulsions loaded with dasatinib and quercetin senolytics, and valsartan. We will evaluate thermosensitivity and degradation of the hydrogel in the presence of the drugs, and the release profile of the drugs from the hydrogel. In Aim 2, we will evaluate hydrogels loaded with different drugs in an aged mouse model and focus on collecting safety and efficacy data.
RESEARCH (19 Projects Listed)
1. Project Title: Frailty, Post-Transplant Delirium, and Neurocognitive Underpinnings of Alzheimers
    NIH K01AG064040 / ( 2020 - 2025 )
  PROJECT SUMMARY Kidney transplantation (KT) is a growing treatment for older adults with end-stage renal disease (ESRD). Even after careful pre-operative cognitive screening, post-KT incidence of Alzheimer's disease and related dementias (ADRD) is high. Presence of diagnosed ADRD increases the risk of graft loss, and more than doubles post-KT mortality risk; thus, understanding post-KT ADRD is of great clinical significance. Prior studies have suggested that ADRD may be a down-stream corollary of post-operative delirium, an acute decline and fluctuation in behaviors related to attentional capacity that is often preventable in older surgical patients. In fact, our preliminary data from medical claims suggested that older KT recipients with post-KT delirium were 5-fold more likely to be diagnosed with downstream ADRD. Therefore, we assessed 72 KT recipients initially free of cognitive impairment for delirium using the Delirium Rating Scale (DRS-98) and Confusion Assessment Method (CAM), and found that 93% experienced post-KT sub-syndromal delirium symptoms, 64% had moderate delirium, and 15% had severe delirium. The relationship between delirium components (severity, duration, subtypes) and domain-specific cognitive decline is understudied, but could lend insight into neurocognitive underpinnings of the potential delirium-ADRD link. Frailty (low physiologic reserve), comorbidity may be common substrates linking delirium and ADRD, but few underlying mechanisms have been identified. We hypothesize that post-KT delirium, as a marker of cognitive reserve, interfaces with frailty and KT-specific health-related stressors to accelerate cognitive decline and ADRD progression. Older KT recipients are an ideal population to clarify this association; they have a high prevalence of comorbidities and frailty and are screened to be free of dementia prior to KT. We will leverage an ongoing, prospective R01-funded study of frailty and aging in KT recipients. In this K01, we will add novel CAM measures that will be reviewed by a new delirium consensus panel and establish a consensus committee to identify ADRD cases for 500 older (age=50) KT recipients in this cohort. I will work closely with my highly supportive, multidisciplinary advisory team to meet my training goals and accomplish my aims: 1) To assess whether post-KT delirium incidence is associated with steeper global and domain-specific cognitive decline and increased ADRD risk among older KT recipients; 2) To test whether delirium duration, CAM severity, and sub-type are associated with steeper global and domain-specific cognitive decline and increased ADRD risk among older KT recipients; 3) To assess whether post-KT delirium mediates the relationship between pre- and peri-KT factors and ADRD risk. Our findings will help clarify the role of post-operative delirium in cognitive decline and ADRD risk among the highly susceptible surgical population of older KT recipients, and will lend clues into potential underlying mechanisms of the delirium-ADRD relationship.
2. Project Title: Effects of Genetic and Pharmacological Kynurenine Pathway Suppression on Healthspan, Lifespan, and Cellular Changes Associated with Aging in Mice
    NIH K01AG076873 / ( 2022 - 2027 )
  Title: Impact of Genetic and Pharmacological Kynurenine Pathway Suppression on Healthspan, Lifespan and Cellular Changes Associated With Aging in Mice PROJECT SUMMARY/ASTRACT (30 LINES OF TEXT) Through findings from translational studies on both aged and chronically inflamed mice, as well as on aged and frail older adults, we have identified metabolites of the kynurenine pathway (KP) as potential mediators of systemic damage caused by chronic inflammation. We recently identified that KP metabolites including kynurenine, kynurenic acid, 3-hydroxykynurenine and quinolinic acid were significantly elevated in the serum of older mice and robust and frail older adults, and that this was linked to functional decline and neurodegeneration. The family of molecules known as `kynurenines' are derived from the amino acid tryptophan and are precursors for the important electron carrier and coenzyme molecule NAD+. Kynurenines possess unique bioactive properties and some have pathological potential. For example quinolinic acid (QA) and 3-hydroxykynurenine (3-HK) are neuro- and cytotoxic and induce oxidative stress while kynurenine (KYN) and kynurenic acid (KA) are ligands for the aryl hydrocarbon receptor (AhR), whose signaling activity is linked to immunosuppression, senescence and impaired autophagy. Conversely, genetically inhibiting the KP extends lifespan in C. elegans and Drosophila, and pharmacological KP blockade increases lifespan in Drosophila. Reduced dietary tryptophan extends lifespan in rodents, but it is unknown if genetic or pharmacological KP blockade improves healthspan or extends lifespan in mice. In this study, we aim to evaluate the hypothesis that genetically and pharmacologically suppressing levels of KP metabolites can delay functional decline, pathophysiological metabolic changes, mortality and cellular changes associated with aging in mice. To understand the effects of KP suppression on aging, we will determine the effect of suppressing the oxidative stress inducing kynurenines, 3-HK and QA, using kynurenine 3-monooxygenase knock out mice (KMO -/-, Aim 1). We will also determine the effect of suppressing both oxidative stress inducing kynurenines, 3-HK and QA, as well as AhR agonist kynurenines, KYN and KA using the indolamine 2,3 dioxygenase knockout mouse (Ido -/-, Aim 2). We will then determine if pharmacological suppression of toxic kynurenines and AhR ligands can delay aging in mice using 1-methyltryptophan (Aim 3). Additionally, we will determine if pairing all of these KP suppression strategies with NAD+ supplementation will synergistically benefit healthspan, lifespan and characteristics of aging in mice. These studies will inform on the role of the KP in functional decline and aging and the therapeutic potential of KP suppression as an anti-aging intervention.
3. Project Title: The START trial: a proof-of-concept sedentary reduction program for prefrail older adults
    NIH K01AG076967 / ( 2022 - 2027 )
  PROJECT SUMMARY Frailty is a syndromic state of vulnerability that puts adults aged =65 years at heightened risk of adverse health outcomes. An estimated 50% of older Americans are prefrail a pre-clinical stage of frailty that might be more amenable to intervention efforts than frailty. Increasing physical activity is a promising intervention to better manage/help reverse the multisystem dysregulation that drives frailty and sequalae. However, initiating and maintaining habitual physical activity is difficult for sedentary older adults, particularly those encumbered by health challenges. The 2018 US Physical Activity Guidelines recommends that all adults perform =150 minutes/week of physical activity and reduce sedentary behaviors. Yet, traditional approaches to increase physical activity do little to address sedentary behavior reduction, especially for older adults. Lower sedentary behavior is associated with improved biological and psychosocial health independent of meeting physical activity guidelines. Thus, there remains a critical need to implement and evaluate a structured way to reduce sedentary behavior as a potential pathway for habitual physical activity engagement. Using novel objectively measured physical activity metrics, our research group has shown that daily sedentary time, either in total or accrued in a prolonged manner, is associated with frailty. Our observation evidence shows that: 1) daily, non- exercise physical activity declines and becomes more fragmented with age (less continuous activity with longer sedentary bouts), 2) higher daily sedentary time and activity fragmentation are both associated with higher frailty incidence, and 3) sedentary time is positively associated with frailty-related markers of inflammation. We propose a pilot study in which we randomize 60 prefrail community-dwelling older adults to receive one of two interventions, each designed to gradually reduce sedentary time: 1) continuously to form a 30-minute walking bout, or 2) in a bouted manner to form three 10-minute walking bouts. Project goals are to: a) explore the effectiveness within and between interventions to decrease objectively measured sedentary time over 2 months; b) assess decreased sedentary time s association with i) patient-reported outcomes and ii) frailty- related inflammatory markers. The primary outcome is accelerometer-determined sedentary time. Secondary outcomes include activity fragmentation, patient-reported outcomes, and inflammatory markers. With a transdisciplinary mentoring panel, my career development plan builds on my expertise in aging and physical activity epidemiology to gain proficiency in: 1) developing and implementing clinical trials for older adults, 2) designing interventions to improve health behaviors, 3) conducting frailty and inflammation related research and 4) gaining competencies to become an effective PI and leader. This project utilizes the infrastructure of the Johns Hopkins Institute for Clinical and Translational Research (ICTR) and Beacham Center for Geriatric Medicine which have strong records of supporting early-stage faculty. This award will facilitate my transition to an independent investigator and will also provide informative data for R21 and R01 applications.
4. Project Title: Alteration in the hypothalamic-pituitary-gonadal axis and frailty in aging men with HIV
  Leader(s): PENA DIAS, JENNY
    NIH K01AG079680 / ( 2022 - 2026 )
  PROJECT SUMMARY/ABSTRACT People with human immunodeficiency virus (HIV), (PWH), are at increased risk of frailty, which increases the risk of adverse age-related outcomes, including falls, hospitalization and mortality. The mechanisms of frailty are not completely understood, particularly among PWH. The objectives of this proposal are to study the extent to which free testosterone and sex hormone binging globulin (SHBG) concentrations are associated with frailty and inflammation in men with HIV. We hypothesize that free testosterone and SHBG are key biomarkers for identifying PWH at the highest risk of frailty and who may benefit from intervention with anabolic agents. Our specific aims are to: 1) Determine the association of circulating free testosterone and SHBG with incident frailty using state-of-the-art hormone measurements among men with HIV, 2) Determine the association of diurnal variation in free testosterone with HIV serostatus in men and its association with systemic inflammation, 3) Determine the association of novel SHBG glycans with frailty among men with HIV. In Aim 1, we will measure serum free testosterone with state-of-the-art methods and SHBG in men with HIV who are part of the Multicenter AIDS Cohort Study (MACS), an ongoing prospective study since 1984 studying the natural and treated histories of HIV-1 infection in homosexual and bisexual men. We will determine the associations of these hormones with incident frailty, collected at semi-annual visits since 2007. In Aim 2, we will select men with and without HIV that have collected blood samples in AM and PM to assess diurnal variation in free testosterone and systemic inflammation [Interleukin 6 (IL6) and soluble TNF-alpha receptors II (sTNFRII)]. In Aim 3, we will study novel SHBG glycoforms in men with HIV, the identification and quantification of SHBG glycoforms will be performed by capillary electrophoresis and lectin microarray. The proposed research aims to provide new insights to the contribution of free testosterone and SHBG in frailty and its relationship with systemic inflammation. The goals during the award period include gaining advanced expertise in biostatistical methods, design and conduct epidemiological studies, as well as hands-on experience in the measurement of glycoforms from plasma proteins and interpretation of glycomic data through mentored research, tailored didactic coursework, and supervised performance of relevant laboratory techniques. Long-term goals include developing a career as an independent investigator in translational epidemiology and developing new approaches to treating and preventing age-related outcomes such as frailty in PWH.
  Leader(s): CHUNG, TAE HWAN
    NIH K08AG058483 / ( 2018 - 2023 )
  PROJECT SUMMARY Decline in skeletal muscle function with aging is a major determinant of disability and morbidity in late life.However, the neurobiology of such decline in skeletal muscle function in normal aging is poorly understood.The proposed K08 project is a critical step towards to understanding the underlying mechanism of age-relateddecline of skeletal muscle function. This study uniquely focuses on the intersection between kynureninemetabolic pathway, motor neuron, neuromuscular junction (NMJ), and skeletal muscle function. Kynureninepathway is a major route to the synthesis of Nicotinamide adenine dinucleotide (NAD), a critical coenzyme thatbalances redox status of all living cells. Many intermediate metabolites of kynurenine pathway are known to bepotent neurotoxins, and involved in various age-related neurodegenerative diseases. The preliminary studiesof this project showed alterations of kynurenine pathway in aging peripheral neuromuscular system. Herein, itis hypothesized that age-related alterations in kynurenine pathway contributes to neurodegeneration in spinalmotor neurons, eventually causing age-associated muscle weakness. Aim1 propose to identify key alterationsin the kynurenine pathway in the aging spinal motor neurons, using mass spectrometry, PCR, and Westernblot techniques. Aim2 propose to determine the neurotoxicity of kynurenine pathway in aging neuromuscularsystem both in vitro and in vivo models. Finally, Aim3 tests the effects of pharmacological inhibition of akynurenine metabolite synthesis. The findings from this study will likely identify molecular targets for age-associated muscle weakness, and used for future translational study. The proposal will take place in the Johns Hopkins School of Medicine under the mentorship of JeremyWalston, MD, Ahmet Hoke, MD, PhD, and Robert Schwarcz, PhD. An integrated career development andmentoring plan has been also proposed to ensure Dr. Chung s successful transition to independence. Thetraining goals are focused on development of Dr. Chung s expertise in kynurenine neurobiology, variousmolecular techniques in neuroscience research, and translational gerontology. The strength of the proposalcomes from the collaboration between all of his mentors who have world-renowned expertise in aging frailty(Dr. Walston), peripheral neurodegeneration (Dr. Hoke), and kynurenine neurobiology (Dr. Schwarcz).
6. Project Title: A Meal Delivery and Exercise Intervention to Increase Resilience in Homebound Older Adults
  Leader(s): LEE, JESSICA LAN
    NIH K23AG072042 / ( 2021 - 2026 )
  PROJECT SUMMARY/ABSTRACT Homebound older adults are often functionally dependent and at risk for placement in institutions such as nursing homes. The majority of older adults would prefer to age in place in their homes so research is needed to identify interventions that can help them maintain their autonomy. Frailty is an age-related syndrome highly predictive of functional decline and mortality, which is very prevalent in our preliminary studies of homebound older adults (56% frail, 44% prefrail, none were robust) and mainly driven by slow walking speed (88%). Because the homebound population is difficult to reach, there have been few studies and no clinical trials in this population. In our pilot randomized controlled trial of an exercise program administered by Meals on Wheels (MOW), 9 participants (5 treatment, 4 control) completed the 12-week study which showed that gait speed and total frailty score improved in the treatment group. The improvement in gait speed is particularly exciting given its prevalence in homebound older adults. In addition, there were no adverse events and the participants enjoyed the exercises as well as the convenience of the meal deliveries. To further evaluate the clinical changes seen in our trial, we assessed potential novel frailty biomarkers. These biomarkers could help identify frailty earlier than may be seen clinically and provide valuable information about the effects of frailty interventions. Inflammatory biomarkers such as interleukin-6 (IL-6), C-reactive protein (CRP), and tumor necrosis factor-alpha (TNF-a) have been associated with frailty status but not correlated with treatments. We preliminarily tested heat shock protein (HSP) 70, which induces muscle wasting in cancer cachexia, as well as macrophage inflammatory protein-1 (MIP-1 ), and soluble interleukin-6 receptor (sIL-6R) to see if they could be more specific frailty biomarkers. Our exercise group had decreased HSP70, MIP-1 , and sIL-6R when compared to the control group over 12 weeks. Thus we have 2 aims: 1) evaluate the effects of a home-based exercise program administered through MOW on gait speed and frailty status in frail/prefrail homebound older adults, and 2) assess the association between novel serum biomarkers (HSP70, MIP-1 , sIL-6R) and established but non-specific frailty biomarkers (IL-6, CRP, TNF-a) in frail/prefrail homebound older adults before and after the exercise intervention. Data from this project will be the catalyst for an R01 or equivalent award involving multi-pronged frailty interventions, targeting mechanistic and clinical pathways, with the goal of helping homebound older adults age in place. This career award would also provide training and mentorship for Dr. Jessica Lee to develop into a physician-scientist with independent funding. UTHealth has provided her with a supportive environment, individualized career development plan, and expert mentors with long-standing experience in geriatrics, clinical trials, exercise interventions, biomarkers, and biostatistics. As the medical director of a home-based primary care service, her goal is to become an expert in interventions to improve resilience in her homebound patients.
7. Project Title: Addressing Inactive Kidney Transplant Waitlist Status through Adapting a Tailored Psycho-Social-Environmental Program
  Leader(s): HLADEK, MELISSA
    NIH K23DK133677 / ( 2023 - 2028 )
  PROJECT SUMMARY/ ABSTRACT Kidney transplantation (KT) is a growing treatment for older adults with end-stage renal disease (ESRD), but there is vast heterogeneity in KT outcomes. Older adults are more likely to be listed as inactive (on the waitlist but ineligible for KT), which is associated with increased waitlist mortality and worse post-surgical outcomes. Those awaiting KT also experience depressive symptoms, pain, loss of physical function, and social isolation, which can contribute to waitlist mortality and decrease chances of KT. As of April 2022, 94,249 people were awaiting KT with an estimated 44% currently inactive. There is a critical need for enhanced models of care to improve inactive waitlist outcomes. The purpose of this study is to adapt and pilot test the evidence-based Community Aging in Place- Advancing Better Living for Elders (CAPABLE) intervention to address barriers for KT waitlist activation which involve symptom burden, self-management, social support, health literacy, patient activation and home function. CAPABLE equips older adults to age in their homes using person-directed priorities and a strengths-based tailored approach by a nurse, occupational therapist and handy worker (PI: Szanton, co-primary mentor). CAPABLE improves function, pain, depressive symptoms, and quality of life while decreasing hospitalizations and nursing home admissions. CAPABLE also improves healthcare engagement and self-efficacy which are key components to remaining active on the KT waitlist. Our adapted CAPABLE Transplant model will extend services to include options for internet access, training, patient portal usage and patient-directed online social engagement to address the noted isolation. We hypothesize that decreasing patient and clinician reported barriers will decrease time inactive on the KT waitlist status. We plan to examine CAPABLE-Transplant among those with inactive KT waitlist status in a two-phase developmental study leveraging partnership with the JHU Comprehensive Transplant Center and an ongoing, prospective NIA R01-funded cohort study of individuals awaiting KT for recruitment (PI: McAdams-DeMarco, co-primary mentor) through the following aims: (1) To develop an adaptation of CAPABLE targeting those currently KT inactive, (2) To iteratively refine the CAPABLE -Transplant prototype for those currently KT inactive and, (3) To pilot test the CAPABLE-Transplant intervention in a 30 person 1:1 randomized waitlist control trial delivered over 16 weeks with outcomes (e.g. waitlist status, symptom burden, social networks) evaluated at 0,16, and 32 weeks post-randomization to test feasibility, acceptability, fidelity of CAPABLE-Transplant and estimate preliminary effects sizes for a future efficacy trial. To our knowledge, there are no other home-based programs that address patient-directed goals and the home environment among those inactive awaiting KT. This work will form the basis for a future R01 to expand to other KT centers and/or into other transplant populations conducting a larger community-based, efficacy trial.
8. Project Title: Frailty and Resiliency in Older Adults with Acute Myocardial Infarction
    NIH K23HL153771 / ( 2020 - 2025 )
  The purpose of this research is to support the development of Dr. Abdulla Damluji into an independent investigator focused on studying geriatric syndromes during cardiovascular intervention. The K23 award will allow the development of a fundamental skillset including: the design and methods for analysis of interventions, understanding and proper application of frailty and resiliency assessments, designing pilot prospective studies, and enhancing knowledge of geriatrics and gerontology. Skills will be obtained through coursework, workshops, seminars, scientific meetings and mentored research. The overall goals are: 1) identify a simple universal bedside frailty test for clinical decision-making and 2) become an NIH-investigator prepared to conduct a clinical trial aimed to evaluate the comparative effectiveness of different treatments of acute myocardial infarction (AMI) in a heterogenous population of older adults living with frailty and lack of resiliency. Two thirds of all patients with cardiovascular disease (CVD) are older than 60 years of age, and >85% of patients over age 85 years live with some form of CVD. Of those older patients admitted with acute AMI, a majority experience frailty, a syndrome of decreased physiologic reserve and vulnerability to stressors. Moreover, some of these frail patients lack physical resiliency, the ability to rebound back and recover from a major health crisis. Critical gaps in knowledge in cardiovascular care for older adults, particularly those with frailty and lack of resiliency, have been identified. These gaps need to be addressed in order to provide the best possible care to a growing older patient population. This proposal examines the hypothesis that frailty and resiliency influence the treatment choice and health outcome after AMI. Aim1 evaluates the prevalence of frailty in U.S. among older AMI patients by treatment [percutaneous coronary intervention (PCI), coronary artery bypass graft (CABG) surgery, or guideline-directed medical therapy (GDMT)] using the validated claims-based frailty index. Aim 2 examines the role of frailty in treatment response to PCI and CABG. Aim 3 validates the diagnostic accuracy of a bedside 4-item frailty scale and assesses whether this diagnostic tool, used in combination with resiliency measurements, can predict health outcomes at 1-year follow-up. The institutional environments at both the Inova Heart and Vascular Institute (IHVI) and Johns Hopkins University (JHU) are ideal for conducting cardiovascular outcomes research. The mentorship consists of leaders with expertise directly relevant to the career goals of the applicant: Christopher M O Connor, MD (IHVI; expert in experimental design); Dr Wayne Batchelor (IHVI: interventional cardiologist); Jodi B Segal, MD, MPH (JHU: internist/epidemiologist; expertise in clinical effectiveness), and Gary Gerstenblith (JHU: geriatric cardiology). Resources at IHVI include bioinformatics laboratory, grant management office, and a state-of-the-art research office. At JHU, resources include the Bloomberg School of Public Health, Graduate Training Program in Clinical Investigation, JHU Pepper Center Biostatistical and Research Education Cores, and the Welch Medical Library.
    NIH P30AG059298 / ( 2018 - 2023 )
  The Schools of Medicine, Nursing, and Public Health of the Johns Hopkins University areproposing a new Alzheimer's-related Resources Center for Minority Aging Research (AD-RCMAR) in response to RFA-AG-18-002. The aims of this application are to: (1) mentor early-stage investigators from underrepresented backgrounds in minority aging and health disparitiesresearch, with a focus on Alzheimer's disease and related disorders (ADRD), using a life courseperspective encompassing biological, behavioral, and community factors contributing tocognitive impairment and dementia in older minority adults; (2) conduct epidemiological,preventive, and intervention research that addresses ADRD in later life within a multi-levelframework that encompasses individuals, families, social networks, and communities; and 3)engage communities and health care providers especially family caregivers, primary carepractices, communities of faith, and community organizations as our partners in recognizingdementia and developing interventions with the potential to prevent cognitive decline andreduce ADRD dementia risk and disparities in minority older adults. The Johns Hopkins AD-RCMAR consists of: (1) an Administrative Core whose function is to provide governance and anadministrative structure, to support research, to foster interactions between Cores and otherCenters, and to ensure RCMAR Scientists develop mentoring relationships across the affiliateddepartments, schools, the intramural program at NIA in Baltimore, and nationally; (2) aResearch Education Component to foster diverse junior investigators and mid-careerinvestigators transitioning into ADRD-relevant research through support for individual pilotprojects, career mentoring, scholar-to-scholar interactions, and role modeling; (3) a Community-Liaison and Recruitment Core to ensure the relevance of the ADRD research and to increaseknowledge of engagement of community members in the research enterprise with the creationof a Community Resource Institute as a venue for community-investigator interaction; and (4) anAnalysis Core as a foundation for methodological and statistical mentoring, including educationand mentoring in mixed-methods research. An Executive Committee includes communityrepresentatives and a Scientific Advisory Panel consists of distinguished investigators withrelevant expertise in minority aging, disparities, and ADRD. A pilot project program supportedby all Cores to facilitate the development of RCMAR Scientists includes three initial pilotprojects focusing on recruitment of minority populations for ADRD research, early diagnoses ofdementia, and intervention development related to ADRD-related driving disparities.
10. Project Title: Utilizing Technology and AI Approaches to Facilitate Independence and Resilience in Older Adults
    NIH P30AG073104 / ( 2021 - 2026 )
  The overarching goal of this application is to build an Artificial Intelligence (AI) and Technology Collaboratory (AITC) ecosystem that will serve as a national resource to promote the development and implementation of novel AI and technology approaches to improve care and health outcomes for older Americans. The specific aims are: 1) To engage AI and geriatric/gerontology investigators from across the country and to identify, validate, test, and develop new AI and technologies relevant to improving the health and wellbeing of older adults through crucial pilot study mechanisms; 2) To serve as a national resource center that stimulates and leads the development and implementation of effective novel AI and technology approaches and products that will promote the health, wellbeing and independence of all older Americans; 3) To support the engagement of stakeholders in AI research; 4) To build an ecosystem of overlapping innovation and business, academic, and communities- of-practice networks ; and 5) To provide highest quality expertise, support, and infrastructure needed to disseminate technical and policy guidelines and best practices for effectively incorporating AI approaches and technology for older Americans, in partnership with private industry, angel investors, venture capital firms, and healthcare systems. This AITC is directed by a multi-PI interdisciplinary team led by two world-class experienced investigators who have long worked successfully in the fields of AI and technology development areas partnered with investigators who have long and successfully worked at the translational interface that connects real-world medical, cognitive, and functional declines that impact older adults with medical and technological solutions. Each of these investigators has a complementary skill set and a long track records of organizing transdisciplinary teams and consortiums of investigators around core themes. This interdisciplinary, accomplished, and highly visible leadership team will work together to develop vision for the next generation of AI in aging science and to build a scientifically and culturally diverse community of AI scholars and trainees around Aging. To achieve our goals, we designed the JHU AITC to have robust scientific and technological expertise that are described in eight core components. This infrastructure will support the implementation of stakeholder input and the identification of relevant technologies and investigators locally and nationally through a vetting and feasibility testing process of both technology and data processes. It will include a pilot testing phase and related oversight process. We have also established a key partnership with the Iowa office of Rural Health and Veterans Rural Health Resource Centers Leadership and with organizations within Johns Hopkins University that focus on improvements in the health and well-being of older adults in underserved urban communities. Connections with key academic, industry partners have also been established to accelerate the development of relevant technologies into products. This team is dedicated to developing the next AI scientific advances and disseminating resulting strategies into practice and policy that will maximize health, well-being, and independence for older adults.
  Leader(s): AGRAWAL, YURI
    NIH R01AG057667 / ( 2018 - 2023 )
  Project summaryThis project investigates whether vestibular loss predicts falls in patients with Alzheimer s disease (AD).The proposed research is an observational study of 150 patients with AD to evaluate the associationbetween baseline vestibular function and 2-year incidence of falls. We will also explore whether vestibularfunction is associated with balance and gait function, as well as spatial cognitive function, as potentialmechanisms by which vestibular function contributes to fall risk. Specifically, Aim 1 is to determinewhether vestibular loss predicts falls in patients with mild-moderate AD. We hypothesize that poorervestibular function at baseline predicts a higher 2-year incidence of falls. Additionally, we hypothesize thatthe attributable risk of falls associated with vestibular loss will be substantial enough (>~10%) to warrantfurther investigation of vestibular therapy as a clinically significant modifier of fall risk. Aim 2 is to evaluatewhether vestibular loss in AD predicts impaired static and dynamic balance, measured using the BergBalance Scale (BBS) and the Timed-Up-and-Go (TUG) test. We hypothesize that greater reduction investibular function over the 2-year follow-up period predicts greater decline in BBS and TUG performance.Aim 3 is to evaluate whether vestibular loss in AD predicts impaired spatial cognitive skills. We willadminister cognitive tests of spatial cognition (including the Money Road Map test, the Card Rotationstest, the Visual Form Discrimination test and the Clock Drawing test), and we will also query participantsand caregivers about difficulty with driving, losing objects, getting lost and wandering behaviors asfunctional manifestations of impaired spatial cognition in AD patients. We hypothesize that greaterreduction in vestibular function over the 2-year follow-up period predicts greater decline in spatial cognitivetest scores, and a higher incidence of functional spatial cognitive impairment. Moreover, we hypothesizethat impaired balance measures (from Aim 2) and impaired spatial cognitive skills will both be independentmediators of the association between vestibular loss and incident falls. To accomplish these aims, we willleverage well-established resources at Johns Hopkins including the Johns Hopkins Alzheimer s DiseaseResearch Center and the Memory and Alzheimer s Treatment Center. Falls are a major source ofmorbidity in AD and current interventions are not uniformly effective. If our observational studiesdemonstrate that vestibular loss is associated with poorer balance and spatial cognition and incident falls,these results will inform the design of interventional trials to prevent falls in AD patients.
  Leader(s): PIGGOTT, DAMANI
    NIH R01AG060825 / ( 2018 - 2023 )
  PROJECT SUMMARY/ABSTRACTWith effective antiretroviral therapy (ART), life expectancy for HIV-infected persons has markedly improved, yetmarked deficits in survival remain for HIV-infected persons with a history of injecting drugs (PWID). Disparitiesamong PWID have been attributed in part to a shifting spectrum of disease to aging-associated conditionsdriven by persistent inflammation even with ART. Frailty is an important aging-related state of vulnerability tostress, with an increased burden in HIV infection, strongly associated with heightened inflammation, andpredictive of premature mortality and aging-related morbidity among PWID. Injecting drugs itself can increasethe severity of inflammation in HIV. The human gut microbial ecosystem (gut microbiome) critically regulatesinflammation and immunity. Alterations in the gut microbiome (gut dysbiosis) together with associateddisruptions of gut structure and immune integrity constitute an inflammatory-microbiome signature (gutdysbiosis, increased gut permeability, translocation of microbial products, immune activation, heightenedinflammation) linked to adverse aging-associated inflammatory conditions and disease. Proposed is asystematic investigation of the role of HIV infection and injection drug use (IDU) in defining the inflammatory-microbiome signature and determination of the relationship of this signature to frailty. Through assessments ofthe fecal and mucosal microbiome in the AIDS Linked to the IntraVenous Experience (ALIVE) cohort of HIV-infected and epidemiologically comparable HIV-uninfected PWID, we will determine how HIV infection andactive IDU alter microbiome composition and function and the relationship of these changes to inflammationand frailty progression over time. Using a germ free murine model, we will further define the frail humanmicrobial communities and gene products that precipitate inflammation. These studies will facilitate elucidationof gut microbial determinants of frailty among HIV-infected PWID and could significantly inform microbiotamodulation strategies to reduce frailty-associated inflammation beyond ART. Understanding the role of the gutmicrobiome in relation to HIV, injection drug use, and frailty remains a critical next step to reducing the markeddisparities in clinical outcomes among HIV-infected PWID.
    NIH R01AG061786 / ( 2019 - 2023 )
  PROJECT SUMMARYAlzheimer's disease (AD) is the most common cause of dementia. Underlying pathological and physiologicalchanges related to the onset and progression of AD are believed to emerge several years prior to clinicalmanifestations. Sensory impairments, gait abnormalities, and motor slowing may precede the diagnosis of ADby a decade or more, presenting the exciting possibility that changes in sensorimotor functioning may act asearly noninvasive biomarkers for AD. Previous work by our group has identified links between cognitiveperformance and sensory impairment and gait speed and variability, making them potential preclinical markersof early AD pathology. We propose to use up to 10 years of existing longitudinal data, and ongoing/new datacollection in approximately 1,000 older adults in the Baltimore Longitudinal Study of Aging (BLSA), to examinethe roles of sensory function, gait speed and variability, and free-living measures of daily physical activity (PA)as precursors to cognitive impairment. We will also determine the link between sensorimotor measures andbiomarkers of AD pathology, including A deposition using [11C]-Pittsburgh compound B positron emissiontomography, brain atrophy using structural magnetic resonance imaging (MRI), Tau and pTau from cerebrospinalfluid, and cognitive performance. We will further utilize the rich data resources of the BLSA to develop aparsimonius prediction model for risk of progression to MCI/AD, and validate its performance in theAtherosclerosis Risk in Communities (ARIC) study. A better understanding of the associations amongsensorimotor changes, subclinical AD pathology, and cognitive performance may elucidate a high-risk phenotypethat is associated with increased risk of poor cognitive outcomes over time and increase our understanding ofthe complex associations among declines in sensory, physical, and cognitive functioning with age. To this end,future intervention studies of AD prevention might screen for sensorimotor impairments as a high-risk phenotypereflective of increased risk for developing AD, which could serve as surrogate outcomes in clinical trials.Moreover, sensorimotor impairments may present feasible and modifiable targets for AD prevention byidentifying critical threshold(s) for implementation of assistive and rehabilitative technologies such as hearingaids, corrective lenses, surgical or pharmacologic procedures to correct hearing and/or vision impairment (e.g.,cataract surgery, cochlear implants), and physical therapy/timing and coordination of movement training tocorrect gait abnormalities.
  Leader(s): WEISS, ROBERT G
    NIH R01AG063661 / ( 2019 - 2024 )
  People living with HIV infection (PLWH) are living longer but with advancing age experienceaccelerated functional decline (decreased strength, slowed gait, reduced exercise tolerance) and increasedfrailty, as compared to non-infected individuals. The syndromes of functional decline and frailty are associatedwith impaired quality of life, increased vulnerability to superimposed stresses, and the likelihood of prematuremorbidity and mortality. The mechanisms underlying this accelerated dysfunction and disability, however, arepoorly understood. The proposed project examines the contribution of altered skeletal muscle (SM)mitochondrial function and high energy phosphate metabolism to the related, but distinct syndromes of fatigue,exercise intolerance, and frailty often present in older PLWH. Considerable pre-clinical data and our pilotclinical studies using a 31P magnetic resonance spectroscopy (MRS) fatigability test during and following lower-extremity exercise suggest an energetic myopathy as a possible basis for the fatigue and decreasedperformance in older PLWH individuals. However the extent, underlying responsible factors, and functionalsignificance of altered SM mitochondrial bioenergetics in this population have not been characterized. Inaddition, two potential mechanisms responsible for altered SM high energy phosphate metabolism in otherpopulations, increased inflammation and SM lipid accumulation, have not been examined and related tomuscle energetics in PLWH and so these too will be examined. The central hypothesis is that impaired SMmitochondrial energy metabolism, initiated by aging and accelerated in the setting of contemporary HIV, is acentral contributor to the geriatric syndromes of fatigue, exercise intolerance, and frailty in older PLWH. Wepropose to use state-of-the art 31P MRS exercise testing, detailed muscle and whole body compositionmeasures, functional assessments during observed and free-living conditions, and biomarkers of inflammationand immune activation in 200 older (age>=60) women and men derived from four local NIH-sponsored cohortsto address these questions. The specific aims are 1) to define the scope of SM metabolic changes in olderwomen and men living with HIV, 2) to probe whether inflammation, skeletal fat and other underlying factors arerelated to the energetic abnormalities in older PLWH and 3) to determine the functional significance of SMenergetic changes in older PLWH by examining the relationships between the energetic changes and exercisetolerance and other functional assessments as well as the frailty phenotype. Fatigue, exercise intolerance, andfrailty are common in older PLWH and the underlying mechanisms remain poorly understood These novel,timely studies will provide new insights and guide future intervention strategies designed to attenuate orreverse mitochondrial and bioenergetic decline and thereby reduce the personal and societal toll of thesegeriatric conditions in older women and men living with HIV.
15. Project Title: Differential Regulation and Roles of A-type Lamins in Early G1
    NIH R01GM132427 / ( 2020 - 2024 )
  Summary Lamins A, C, B1 and B2 form nuclear intermediate filaments as major components of the dynamic genome- associated nucleoskeleton. Lamins associate with nuclear envelope (NE) membrane proteins, together forming nuclear lamina networks. Lamins and key partners (LEM-domain proteins and BANF1) are essential during exit from mitosis to ensure that chromosomes are coalesced, captured and properly organized within the daughter nucleus. During interphase, nuclear lamina networks have fascinating roles in the higher-order architecture of transcriptionally-inactive regions of the genome (heterochromatin). Silent regions of each chromosome, known as Lamina Associated Domains (LADs), are typically located near the NE. There are clear correlations between LAD organization, epigenomic regulation, and the functional three-dimensional (3D) folding of the genome. A-type lamins (encoded by LMNA) have key roles in LAD organization. LMNA gives rise to two major somatic isoforms, lamin A and lamin C, by alternative mRNA splicing. Because the first 566 residues of human lamin A and lamin C are identical, they were long thought to function redundantly. However new reports show lamin A and lamin C form separate filaments, associate differentially with nuclear pore complexes and have distinct metabolic phenotypes. We discovered lamin C is required for LADs to associate with the NE during interphase. Furthermore, lamin C is specifically and strikingly nucleoplasmic during telophase and early-G1, in stark contrast to lamin A at the nascent NE. Although lamin C is not LAD- associated in early-G1, we found lamin C associates with LADs as they return to their tethered positions at the NE. We propose lamin C is required for LAD recruitment to the NE, and will test this hypothesis in cells specifically downregulated for lamin C or lamin A. We can detect distinct yet overlapping proteomes in unsynchronized cells, comprising emerin and LAP2beta at the nuclear membrane, lamins and soluble partners ( connectome ), and a novel LAD-associated proteome. We hypothesize that lamin C specifically interacts with LADs or LAD-associated proteins during exit from mitosis as a pathway to re-establish the tissue-specific positioning of silent chromatin (LADs) at the NE. Our models predict distinct proteomes for lamin C vs lamin A during mitotic exit, distinct changes in the LAD proteome during mitotic exit, and perturbed LAD organization or LAD recruitment to the NE in cells that lack lamin C during mitotic exit. We will test these models by super- resolution imaging of lamins and LADs in single cells, directed proteomics, genome organization mapping and functional studies in cells downregulated for either lamin C, lamin A or validated proteins identified in this work. This work is expected to fill major gaps in understanding how genome architecture is established after mitosis, and functional differences between lamin A and lamin C that may also be relevant to the mechanisms of diseases linked to LMNA.
16. Project Title: Cerebral Autoregulation in the Cardiac Surgery Intensive Care Unit: Associations with Postoperative Delirium, Cognitive Change, and Biomarkers of Brain Injury
    NIH RF1AG072387 / ( 2021 - 2024 )
  PROJECT SUMMARY/ABSTRACT Delirium occurs in up to 50% of patients after cardiac surgery and is associated with cognitive decline and Alzheimer s disease and related dementias (ADRD). However, the underlying mechanisms for these complications are elusive. Further, the extent to which events in the early postoperative period increase risk for delirium, cognitive decline, and ADRD is unclear. The goal of this proposal is to examine cerebrovascular contributions to delirium / cognitive decline, with a focus on cerebral perfusion in the cardiac surgery intensive care unit (ICU). Given the wide variations in blood pressure in the ICU, coupled with the high prevalence of cerebrovascular disease, cerebral malperfusion in the ICU may contribute to delirium and cognitive decline. Current practice of targeting empiric mean arterial pressure (MAP) goals in the perioperative period may be inadequate for individual patients. Our group has championed a more personalized method based on cerebral autoregulation monitoring. Through the process of cerebral autoregulation, the brain is regulated to maintain a constant cerebral blood flow across a range of MAP. However, when MAP exceeds limits of autoregulation or when autoregulation is impaired, compensatory mechanisms fail and inadequate or excessive cerebral blood flow results. Our work in the cardiac surgery operating room has shown several results that emphasize the importance of individualizing blood pressure goals. First, the MAPs at the limits of autoregulation vary widely in patients, and both impaired autoregulation and MAP outside the limits of autoregulation are associated with organ injury. Second, in a recent trial, targeting MAP to be >lower limit of autoregulation during cardio- pulmonary bypass vs. usual care reduced delirium by 28% and improved memory scores at 1- and 12-months. To date, the majority of research has been conducted in the operating room during cardiopulmonary bypass. However, our preliminary data suggests that the early phase of ICU care may be equally important. In a small pilot study, we found that in the ICU, the extent of MAP outside the limits of autoregulation, as well as impaired autoregulation, were associated with delirium. Importantly, cognitive change was not assessed in this pilot and mechanisms for these findings are unclear. These results motivate the proposed observational study, which will examine whether (a) MAP outside the limits of autoregulation and (b) impaired autoregulation in the ICU are associated with delirium after cardiac surgery (Aim 1) and cognitive change from baseline at 1- and 12- months (Aim 2). In an exploratory mechanistic aim (Aim 3), we will characterize whether perioperative brain injury mediates or baseline neurodegeneration moderates the association of cerebral autoregulation characteristics and delirium and cognitive decline. The results of this study will more precisely characterize the role of cerebral malperfusion in the ICU with delirium and will identify mechanisms through which brain injury occurs. Promising results would also support a trial to target MAP in the ICU based on these methods. Although the cohort is only followed for one year, these results may also provide insight into potential mechanisms for longer-term cognitive decline and ADRD.
  Leader(s): WIRTZ, DENIS
    NIH U01AG060903 / ( 2018 - 2023 )
  AbstractAlterations in the nuclear protein lamin and associated structures in the nucleus have beenidentified as a source of nuclear morphology changes that markedly impact overall cellularfunction. These changes in nuclear morphology are thought to drive molecular changes thatinfluence a wide range of aging-related phenotypes and chronic disease states. Importantly, wehave recently used high-throughput measurements of nuclear morphology to identify outstandingbiomarkers of chronological age. We hypothesize that these age-related changes in nuclearmorphology are highly correlated with chronological age in healthy individuals, and that a specificage-related biological change in lamin underlies this phenomenon. Building on our priordevelopment of these high-throughput and accurate measures of nuclear morphology, we proposehere to further develop this biological discovery and technology as a valid and reliable biomarkerof aging-related biological mechanisms. We hypothesize that changes in nuclear morphology canbe rapidly measured and that age-related alterations correlate with aging-related phenotypes anddisease states independently of chronological age, consistent with a measure of cellular biologicalage. To test these hypotheses and move results toward clinical utility, we have assembled a highlysynergistic, interdisciplinary team propose the following specific aims:Aim 1. Using our validated single-cell technologies, we will develop a mechanistic understandingof how descriptors of nuclear morphology in human dermal fibroblasts and B-lymphocytes arerobust biomarkers of aging in healthy individuals. Aim 2. Establish the accuracy and precisionwith which our proposed biomarkers identify chronological age for individuals with varyingdemographic, behavioral, and health characteristics. Aim 3. We will examine the strength withwhich morphological biomarkers discriminate individuals with adverse phenotypes and outcomesof aging, and at risk for the development of these, from healthy older adults, above and beyondchronological age.
18. Project Title: Leveraging an ongoing longitudinal study of influenza vaccination to define immune signatures of response and risk of infection in older adults >75
  Leader(s): LENG, SEAN XIAO; BREAM, JAY H.;
    NIH U01AI165826 / ( 2021 - 2026 )
  Project summary Seasonal influenza ( flu ) remains a serious public health threat with the highest burden of severe disease and complications affecting older adults, particularly those over age 75. In addition to vaccine itself, responses to vaccination and vaccine effectiveness in older adults are likely influenced by comorbidity (e.g., frailty), immune senescent remodeling (i.e., immunosenescence and inflammaging), repeated annual vaccination, intra-seasonal immune waning, and virus strain variations both in vaccine formula and in circulation. Since 2014, we have established a study cohort in community-dwelling older adults >75. The cohort has accumulated 815 person-seasons with comprehensive demographic, clinical, functional and laboratory data, as well as banked pre- and post-vaccination serum, plasma, and peripheral blood mononuclear cell (PBMC) samples. We also identified 15 breakthrough flu infection cases with banked post-infection serum, plasma and PBMC samples. Importantly, 20 subjects participated in all 7 seasons, 36 in 6 seasons, 31 in 5 seasons, 16 in 4 seasons, and 165 in 3 seasons or less. Here, we propose to leverage this unique cohort and employ cutting edge immunologic research tools to develop state-of-the-art immune signatures reflecting both general immune status (distribution and function of immune cell subsets through high-dimensional flow analysis and RNA-Seq; cytokine profiling) and influenza-specific immunity (breadth and depth of flu-specific T cell repertoire; distribution/function of homotypic/heterotypic anti-flu T cells through flow analysis and scRNA-Seq; deep serological profiling of strain-specific and cross-reactive flu antibodies). Our objective is to characterize immune signatures and their intra- and inter-seasonal changes over time as determinants of vaccine responses and risk of breakthrough infection in older adults >75. Our specific aims are: 1) Characterize seasonal baseline (pre-existing) immune signatures as determinants of vaccine response and how they change over time. We will not only determine inter-season longitudinal trajectory, but also identify specific baseline immune signatures predict responses to vaccination; 2) Characterize seasonal immune signature responses to vaccination as determinants of risk of breakthrough infection and how they change over time. We will evaluate and compare differences and similarities of immune signature responses elicited by vaccination vs natural infection to explore immune mechanisms of vulnerability; and 3) Characterize intra-seasonal waning of immune signature responses to vaccination and its change across seasons through monthly blood sampling until the end of each flu season across multiple seasons. Upon completion, the proposed studies will advance our understanding of immune signatures as key immunologic mechanisms for vaccine responses and risk of breakthrough infection in a typical geriatric population. Ultimately, these studies will help define correlates of protection and develop more effective immunization strategies including a universal vaccine for this highly vulnerable subset of older adults.
  Leader(s): KLEIN, SABRA L.
    NIH U54AG062333 / ( 2018 - 2023 )
  SEX AND AGE DIFFERENCES IN IMMUNITY TO INFLUENZA (SADII) SUMMARYThe NIH Office of Research on Women s Health (ORWH) should support a Specialized Center of ResearchExcellence (SCORE) on sex differences in influenza immunity because despite having antivirals and vaccines,influenza remains a significant public health threat, causing approximately 100,000 hospitalizations, 30,000deaths, and approximately $7 billion in lost productivity in the United States, alone. Sex and age are emergingas two host variables that significantly impact the pathogenesis of influenza virus infection and responses toinfluenza vaccines. The Sex and Age Differences in Immunity to Influenza (SADII, pronounced sade) SCOREwill leverage the internationally recognized research, resources, and educational opportunities at JohnsHopkins University to transform women s health and impact the development of and policy decisions aboutinfluenza vaccine programs, including universal influenza vaccines. The overarching hypothesis being testedthrough the SADII SCORE Research Projects is that female-biased vaccine-induced immunity to influenzaviruses is age-dependent and reflects both hormonal and genetic differences between the sexes that impactimmune responses (i.e., both effector and memory) to influenza vaccine antigens. SADII will bring togetherinvestigators focused on 1) seasonal influenza vaccination in an existing age and sex stratified humanpopulation; 2) animal models that can test hypotheses and mechanisms of action that are inferred from studiesin human populations; and 3) the contributions of age, frailty, sex, and gender to vaccine outcomes usingquantitative and qualitative statistical models. By using the combined expertise in our research groups, SADIIis uniquely positioned to identify the biological basis behind sex and age differences in immune responses toinfluenza vaccination and disseminate those findings to the broader research, clinical, and public healthcommunities. The overarching mission of the SADII SCORE will be achieved through the following SpecificAims: 1) To provide leadership and oversight of the SADII SCORE and collaboration with other entities atJohns Hopkins and elsewhere to develop a translational research program focused on sex and age differencesin immunology and infectious diseases; 2) To systematically evaluate sex differences in vaccine-inducedimmune responses across the life course using translational approaches involving human studies andmechanistic animal models; and 3) To meet the career enhancement needs of diverse translational scientistsstudying sex differences at Johns Hopkins and beyond. We are prepared to transform women s health, sex,and gender research into a signature initiative at Johns Hopkins and in the fields of microbiology andimmunology.
  1. ?3AR-Dependent Brain-Derived Neurotrophic Factor (BDNF) Generation Limits Chronic Postischemic Heart Failure.
    Cannavo A, Jun S, Rengo G, Marzano F, Agrimi J, Liccardo D, Elia A, Keceli G, Altobelli GG, Marcucci L, Megighian A, Gao E, Feng N, Kammers K, Ferrara N, Finos L, Koch WJ, Paolocci N
    Circ Res, 2023 Mar 31, 132(7): 867-881 | PMID: 36884028 | PMCID: PMC10281793
    Citations: 62 | AltScore: 61.55
  2. Deletion of quinolinate phosphoribosyltransferase gene accelerates frailty phenotypes and neuromuscular decline with aging in a sex-specific pattern.
    Chung T, Bopp T, Ward C, Notarangelo FM, Schwarcz R, Westbrook R, Xue QL, Walston J, Hoke A
    Aging Cell, 2023 Apr 20 e13849 | PMID: 37078472
    Citations: | AltScore: 3.75
  3. Sarcopenia and Cardiovascular Diseases.
    Damluji AA, Alfaraidhy M, AlHajri N, Rohant NN, Kumar M, Al Malouf C, Bahrainy S, Ji Kwak M, Batchelor WB, Forman DE, Rich MW, Kirkpatrick J, Krishnaswami A, Alexander KP, Gerstenblith G, Cawthon P, deFilippi CR, Goyal P
    Circulation, 2023 May 16, 147(20): 1534-1553 | PMID: 37186680 | PMCID: PMC10180053
    Citations: 239 | AltScore: 393.330000000002
  4. Physical Frailty and Brain White Matter Abnormalities: The Atherosclerosis Risk in Communities Study.
    Ducca EL, Gomez GT, Palta P, Sullivan KJ, Jack CR, Knopman DS, Gottesman RF, Walston J, Windham BG, Walker KA
    J Gerontol A Biol Sci Med Sci, 2023 Feb 24, 78(2): 357-364 | PMID: 35596270 | PMCID: PMC9951053
    Citations: 31 | AltScore: 2.75
  5. Associations of perceived stress, depressive symptoms, and caregiving with inflammation: a longitudinal study.
    Elayoubi J, Haley WE, Roth DL, Cushman M, Sheehan OC, Howard VJ, Hladek MD, Hueluer G
    Int Psychogeriatr, 2023 Feb, 35(2): 95-105 | PMID: 35543307
    Citations: | AltScore: 0.25
  6. Particulate matter composition drives differential molecular and morphological responses in lung epithelial cells.
    Engels SM, Kamat P, Pafilis GS, Li Y, Agrawal A, Haller DJ, Phillip JM, Contreras LM
    bioRxiv, 2023 May 20
    pii: 2023.05.17.541204. | PMID: 37292596 | PMCID: PMC10245696
    Citations: 62 | AltScore: NA
  7. Order of Onset of Physical Frailty and Cognitive Impairment and Risk of Repeated Falls in Community-Dwelling Older Adults.
    Ge ML, Chu NM, Simonsick EM, Kasper JD, Xue QL
    J Am Med Dir Assoc, 2023 Apr, 24(4): 482-488.e4 | PMID: 36852758 | PMCID: PMC10167733
    Citations: 43 | AltScore: 13.35
  8. The Association of Peripheral and Central Olfaction With Frailty in Older Adults.
    Nagururu NV, Bernstein IA, Voegtline K, Olson S, Agrawal Y, Rowan NR
    J Gerontol A Biol Sci Med Sci, 2023 Jul 8, 78(7): 1276-1283 | PMID: 36502375 | PMCID: PMC10329228
    Citations: 47 | AltScore: 456.15
  9. Management of Stable Angina in the Older Adult Population.
    Nanna MG, Wang SY, Damluji AA
    Circ Cardiovasc Interv, 2023 Apr, 16(4): e012438 | PMID: 36916288 | PMCID: PMC10121835
    Citations: 86 | AltScore: NA
  10. Associations between circulating cell-free mitochondrial DNA, inflammatory markers, and cognitive and physical outcomes in community dwelling older adults.
    Nidadavolu LS, Feger D, Chen D, Wu Y, Grodstein F, Gross AL, Bennett DA, Walston JD, Oh ES, Abadir PM
    Immun Ageing, 2023 May 23, 20(1): 24 | PMID: 37221566 | PMCID: PMC10204157
    Citations: 39 | AltScore: NA
  11. Hydropersulfides (RSSH) attenuate doxorubicin-induced cardiotoxicity while boosting its anticancer action.
    Pharoah BM, Zhang C, Khodade VS, Keceli G, McGinity C, Paolocci N, Toscano JP
    Redox Biol, 2023 Apr, 60: 102625 | PMID: 36773545 | PMCID: PMC9929489
    Citations: 94 | AltScore: NA
  12. Context Matters: A Qualitative Synthesis of Adherence Literature for People on Hemodialysis.
    Taylor KS, Umeukeje EM, Santos SR, McNabb KC, Crews DC, Hladek MD
    Kidney360, 2023 Jan 1, 4(1): 41-53 | PMID: 36700903
    Citations: | AltScore: 15.85
  13. The Association of Multiple Sensory Impairment and Telomere Length: The Health ABC Study.
    Vohra V, Cheng MZ, Xue QL, Simonsick EM, Lane AP, Agrawal Y, Rowan NR
    Laryngoscope, 2023 Jun 23 | PMID: 37350340
    Citations: | AltScore: NA
  14. A Study of Physical Resilience and Aging (SPRING): Conceptual framework, rationale, and study design.
    Walston J, Varadhan R, Xue QL, Buta B, Sieber F, Oni J, Imus P, Crews DC, Artz A, Schrack J, Kalyani RR, Abadir P, Carlson M, Hladek M, McAdams-DeMarco M, Jones R, Johnson A, Shafi T, Newman AB, Bandeen-Roche K
    J Am Geriatr Soc, 2023 Jun 30 | PMID: 37386913
    Citations: | AltScore: NA
  15. Patterns of Daily Physical Movement, Chronic Inflammation, and Frailty Incidence.
    Wanigatunga AA, Chiu V, Cai Y, Urbanek JK, Mitchell CM, Miller ER 3rd, Christenson RH, Rebuck H, Michos ED, Juraschek SP, Walston J, Xue QL, Bandeen-Roche K, Appel LJ, Schrack JA
    Med Sci Sports Exerc, 2023 Feb 1, 55(2): 281-288 | PMID: 36170549 | PMCID: PMC9840658
    Citations: 44 | AltScore: 3.25
  16. Wrist-Worn Accelerometry, Aging, and Gait Speed in the Baltimore Longitudinal Study of Aging.
    Wanigatunga AA, Liu F, Urbanek JK, Wang H, Di J, Zipunnikov V, Cai Y, Dougherty RJ, Simonsick EM, Ferrucci L, Schrack JA
    J Aging Phys Act, 2023 Jun 1, 31(3): 408-416 | PMID: 36241170
    Citations: | AltScore: NA
  17. Olfactory Dysfunction and Balance Dysfunction are Associated with Increased Falls in Older Adults.
    Yesantharao LV, Vohra V, Cheng M, Simonsick EM, Agrawal Y, du Lac S, Rowan NR
    Laryngoscope, 2023 May 9, 133(8): 1964-1969 | PMID: 37159236
    Citations: | AltScore: 7.25
  1. Telomere shortening and the transition to family caregiving in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study.
    Armstrong ND, Irvin MR, Haley WE, Blinka MD, Kamin Mukaz D, Patki A, Rutherford Siegel S, Shalev I, Durda P, Mathias RA, Walston JD, Roth DL
    PLoS One, 2022, 17(6): e0268689 | PMID: 35657918 | PMCID: PMC9165822
    Citations: 50 | AltScore: 1
  2. Impact of multimorbidity on long-term outcomes in older adults with non-ST elevation acute coronary syndrome in the North East of England: a multi-centre cohort study of patients undergoing invasive care.
    Beska B, Mills GB, Ratcovich H, Wilkinson C, Damluji AA, Kunadian V
    BMJ Open, 2022 Jul 26, 12(7): e061830 | PMID: 35882457 | PMCID: PMC9330324
    Citations: 28 | AltScore: 13.55
  3. Perioperative Neurofilament Light Plasma Concentrations and Cognition before and after Cardiac Surgery: A Prospective Nested Cohort Study.
    Brown CH, Lewis A, Probert J, Parish M, Tian J, Mandal K, Everett A, Colantuoni E, Kamath V, Hogue C, Moghekar A
    Anesthesiology, 2022 Sep 1, 137(3): 303-314 | PMID: 35984933
    Citations: | AltScore: 9.7
  4. The combined effects of physical frailty and cognitive impairment on emergency department- versus direct-admission hospitalizations.
    Buta B, Friedman AB, Chung SE, Sheehan OC, Blinka MD, Gearhart SL, Xue QL
    BMC Geriatr, 2022 Aug 31, 22(1): 718 | PMID: 36042414 | PMCID: PMC9429704
    Citations: 40 | AltScore: 4.85
  5. Agreement between standard and self-reported assessments of physical frailty syndrome and its components in a registry of community-dwelling older adults.
    Buta B, Zheng S, Langdon J, Adeosun B, Bandeen-Roche K, Walston J, Xue QL
    BMC Geriatr, 2022 Aug 25, 22(1): 705 | PMID: 36008767 | PMCID: PMC9403951
    Citations: 37 | AltScore: 2.35
  6. The effects of vitamin D supplementation on frailty in older adults at risk for falls.
    Cai Y, Wanigatunga AA, Mitchell CM, Urbanek JK, Miller ER 3rd, Juraschek SP, Michos ED, Kalyani RR, Roth DL, Appel LJ, Schrack JA
    BMC Geriatr, 2022 Apr 10, 22(1): 312 | PMID: 35399053 | PMCID: PMC8994906
    Citations: 37 | AltScore: 32.15
  7. Moving toward clinical implementation of the physical frailty phenotype in kidney transplantation.
    Chen X, Shafaat O, Liu Y, King EA, Weiss CR, Xue QL, Walston JD, Segev DL, DeMarco MA
    Am J Transplant, 2022 Apr 29, 22(9): 2277-2278 | PMID: 35486021 | PMCID: PMC9427715
    Citations: 5 | AltScore: NA
  8. Revision of frailty assessment in kidney transplant recipients: Replacing unintentional weight loss with CT-assessed sarcopenia in the physical frailty phenotype.
    Chen X, Shafaat O, Liu Y, King EA, Weiss CR, Xue QL, Walston JD, Segev DL, McAdams-DeMarco MA
    Am J Transplant, 2022 Apr, 22(4): 1145-1157 | PMID: 34953170 | PMCID: PMC8983565
    Citations: 39 | AltScore: 11.65
  9. Long-term Trajectories of Frailty and its Components after Kidney Transplantation.
    Chu NM, Ruck J, Chen X, Xue QL, Norman SP, Segev DL, McAdams-DeMarco MA
    J Gerontol A Biol Sci Med Sci, 2022 Feb 20, 77(12): 2474-2481
    pii: glac051. | PMID: 35184167 | PMCID: PMC9799205
    Citations: 49 | AltScore: 1
  10. New horizons in evidence-based care for older people: individual participant data meta-analysis.
    Clegg A, Bandeen-Roche K, Farrin A, Forster A, Gill TM, Gladman J, Kerse N, Lindley R, McManus RJ, Melis R, Mujica-Mota R, Raina P, Rockwood K, Teh R, van der Windt D, Witham M
    Age Ageing, 2022 Apr 1, 51(4):
    pii: afac090. | PMID: 35460409 | PMCID: PMC9034697
    Citations: 52 | AltScore: 49.93
  11. Angiotensin receptor blocker use is associated with upregulation of the memory-protective angiotensin type 4 receptor (AT(4)R) in the postmortem brains of individuals without cognitive impairment.
    Cosarderelioglu C, Nidadavolu LS, George CJ, Marx-Rattner R, Powell L, Xue QL, Tian J, Oh ES, Ferrucci L, Dincer P, Bennett DA, Walston JD, Abadir PM
    Geroscience, 2022 Aug 15, 45(1): 371-384 | PMID: 35969296 | PMCID: PMC9886717
    Citations: 72 | AltScore: 0.75
  12. Higher Angiotensin II Type 1 Receptor Levels and Activity in the Postmortem Brains of Older Persons with Alzheimer's Dementia.
    Cosarderelioglu C, Nidadavolu LS, George CJ, Marx-Rattner R, Powell L, Xue QL, Tian J, Salib J, Oh ES, Ferrucci L, Dincer P, Bennett DA, Walston JD, Abadir PM
    J Gerontol A Biol Sci Med Sci, 2022 Apr 1, 77(4): 664-672 | PMID: 34914835 | PMCID: PMC8974324
    Citations: 66 | AltScore: 15.55
  13. The Influence of Frailty on Cardiovascular Disease: The Time for a \Frailty Academic Research Consortium\ Is Now!
    Damluji AA, Cohen MG
    Circ Cardiovasc Interv, 2022 Jan, 15(1): e011669 | PMID: 35041458 | PMCID: PMC8852245
    Citations: 10 | AltScore: 16.75
  14. Position Statement on Vascular Access Safety for Percutaneous Devices in AMI?Complicated by Cardiogenic Shock.
    Damluji AA, Tehrani B, Sinha SS, Samsky MD, Henry TD, Thiele H, West NEJ, Senatore FF, Truesdell AG, Dangas GD, Smilowitz NR, Amin AP, deVore AD, Moazami N, Cigarroa JE, Rao SV, Krucoff MW, Morrow DA, Gilchrist IC
    JACC Cardiovasc Interv, 2022 Oct 24, 15(20): 2003-2019 | PMID: 36265932 | PMCID: PMC10312149
    Citations: 86 | AltScore: 47.55
  15. At the Crossroad Between Skeletal and Cardiac Muscle Cells.
    deFilippi CR, Damluji AA
    Circulation, 2022 Jun 14, 145(24): 1780-1783 | PMID: 35696457 | PMCID: PMC9202001
    Citations: 13 | AltScore: 13
  16. Exploring the Experiences of Co-morbid Pain and Depression in Older African American Women and Their Preferred Management Strategies.
    Drazich BF, Jenkins E, Nkimbeng M, Abshire Saylor M, Szanton SL, Wright R, Beach MC, Taylor JL
    Front Pain Res (Lausanne), 2022, 3: 845513 | PMID: 35295801 | PMCID: PMC8915555
    Citations: 55 | AltScore: NA
  17. Genome-Wide Analysis in Drosophila Reveals the Genetic Basis of Variation in Age-Specific Physical Performance and Response to ACE Inhibition.
    Gabrawy MM, Khosravian N, Morcos GS, Morozova TV, Jezek M, Walston JD, Huang W, Abadir PM, Leips J
    Genes (Basel), 2022 Jan 14, 13(1):
    pii: 143. | PMID: 35052483 | PMCID: PMC8775566
    Citations: 57 | AltScore: 11.75
  18. Domains of Frailty Predict Loss of Independence in Older Adults after Non-Cardiac Surgery.
    Goeddel L, Murphy Z, Owodunni O, Esfandiary T, Campbell D, Shay J, Tang O, Bandeen-Roche K, Gearhart S, Brown CH
    Ann Surg, 2022 Sep 20, 278(2): e226-e233 | PMID: 36124773 | PMCID: PMC10025167
    Citations: 28 | AltScore: 0.25
  19. Frailty in Patients Undergoing Surgery for Brain Tumors: A Systematic Review of the Literature.
    Huq S, Liu J, Romano R, Seal S, Khalafallah AM, Walston JD, Mukherjee D
    World Neurosurg, 2022 Jul 14, 166: 268-278.e8
    pii: S1878-8750(22)00986-X. | PMID: 35843574
    Citations: | AltScore: 5.8
  20. Interventions for Frailty Among Older Adults With Cardiovascular Disease: JACC?State-of-the-Art Review.
    Ijaz N, Buta B, Xue QL, Mohess DT, Bushan A, Tran H, Batchelor W, deFilippi CR, Walston JD, Bandeen-Roche K, Forman DE, Resar JR, O'Connor CM, Gerstenblith G, Damluji AA
    J Am Coll Cardiol, 2022 Feb 8, 79(5): 482-503 | PMID: 35115105 | PMCID: PMC8852369
    Citations: 2 | AltScore: 104.33
  21. Mitochondrial Creatine Kinase Attenuates Pathologic Remodeling in Heart Failure.
    Keceli G, Gupta A, Sourdon J, Gabr R, Sch?r M, Dey S, Tocchetti CG, Stuber A, Agrimi J, Zhang Y, Leppo M, Steenbergen C, Lai S, Yanek LR, O'Rourke B, Gerstenblith G, Bottomley PA, Wang Y, Paolocci N, Weiss RG
    Circ Res, 2022 Mar 4, 130(5): 741-759 | PMID: 35109669 | PMCID: PMC8897235
    Citations: 81 | AltScore: 3.85
  22. Association between walking energy utilisation and longitudinal cognitive performance in older adults.
    Kuo PL, An Y, Gross AL, Tian Q, Zipunnikov V, Spira AP, Wanigatunga AA, Simonsick EM, Ferrucci L, Resnick SM, Schrack JA
    Age Ageing, 2022 Dec 5, 51(12): | PMID: 36571773 | PMCID: PMC9792087
    Citations: 52 | AltScore: 5.35
  23. Serum concentrations of losartan metabolites correlate with improved physical function in a pilot study of prefrail older adults.
    Lee JL, Zhang C, Westbrook R, Gabrawy MM, Nidadavolu L, Yang H, Marx R, Wu Y, Anders NM, Ma L, Bichara MD, Kwak MJ, Buta B, Khadeer M, Yenokyan G, Tian J, Xue QL, Siragy HM, Carey RM, de Cabo R, Ferrucci L, Moaddel R, Rudek MA, Le A, Walston JD, Abadir PM
    J Gerontol A Biol Sci Med Sci, 2022 May 3, 77(12): 2356-2366
    pii: glac102. | PMID: 35511890 | PMCID: PMC9799219
    Citations: 57 | AltScore: 31.25
  24. Improvements of Disability Outcomes in CAPABLE Older Adults Differ by Financial Strain Status.
    Liu M, Xue QL, Samuel L, Gitlin LN, Guralnik J, Leff B, Szanton SL
    J Appl Gerontol, 2022 Feb, 41(2): 471-477 | PMID: 33267710 | PMCID: PMC8169719
    Citations: 23 | AltScore: 0.75
  25. Valsartan and sacubitril combination treatment enhances collagen production in older adult human skin cells.
    Marin S, Godet I, Nidadavolu LS, Tian J, Dickinson LE, Walston JD, Gilkes DM, Abadir PM
    Exp Gerontol, 2022 Aug, 165: 111835 | PMID: 35598697
    Citations: | AltScore: 8.25
  26. Circulating Cell-Free Genomic DNA Is Associated with an Increased Risk of Dementia and with Change in Cognitive and Physical Function.
    Nidadavolu LS, Feger D, Wu Y, Grodstein F, Gross AL, Bennett DA, Walston JD, Oh ES, Abadir PM
    J Alzheimers Dis, 2022, 89(4): 1233-1240 | PMID: 36031893 | PMCID: PMC9969834
    Citations: 43 | AltScore: 133.91
  27. The influence of heart failure on clinical and economic outcomes among older adults =75 years of age with acute myocardial infarction.
    Pasala S, Cooper LB, Psotka MA, Sinha SS, deFilippi CR, Tran H, Tehrani B, Sherwood M, Epps K, Batchelor W, Damluji AA
    Am Heart J, 2022 Apr, 246: 65-73 | PMID: 34922928 | PMCID: PMC8917998
    Citations: 16 | AltScore: 9.45
  28. Transitions to Family Caregiving and Latent Variables of Systemic Inflammation Over Time.
    Roth DL, Bentley JP, Mukaz DK, Haley WE, Walston JD, Bandeen-Roche K
    Res Aging, 2022 Apr 15, 45(2): 173-184 | PMID: 35422166
    Citations: | AltScore: 5.2
  29. Losartan Mitigates Oxidative Stress in the Brains of Aged and Inflamed IL-10-/- Mice.
    Saleh N, Cosarderelioglu C, Vajapey R, Walston J, Abadir PM
    J Gerontol A Biol Sci Med Sci, 2022 Sep 1, 77(9): 1784-1788 | PMID: 35486382 | PMCID: PMC9434460
    Citations: 51 | AltScore: 3.2
  30. Early identification of frailty: Developing an international delphi consensus on pre-frailty.
    Sezgin D, O'Donovan M, Woo J, Bandeen-Roche K, Liotta G, Fairhall N, Rodr?guez-Laso A, Ap?stolo J, Clarnette R, Holland C, Roller-Wirnsberger R, Illario M, Ma?as LR, Vollenbroek-Hutten M, Dogu BB, Balci C, Pernas FO, Paul C, Ahern E, Romero-Ortuno R, Molloy W, Cooney MT, O'Shea D, Cooke J, Lang D, Hendry A, Kennelly S, Rockwood K, Clegg A, Liew A, O'Caoimh R
    Arch Gerontol Geriatr, 2022 Mar-Apr, 99: 104586 | PMID: 34896797
    Citations: 3 | AltScore: 12.75
  31. Cardiogenic Shock From Heart Failure Versus Acute Myocardial Infarction: Clinical Characteristics, Hospital Course, and 1-Year Outcomes.
    Sinha SS, Rosner CM, Tehrani BN, Maini A, Truesdell AG, Lee SB, Bagchi P, Cameron J, Damluji AA, Desai M, Desai SS, Epps KC, deFilippi C, Flanagan MC, Genovese L, Moukhachen H, Park JJ, Psotka MA, Raja A, Shah P, Sherwood MW, Singh R, Tang D, Young KD, Welch T, O'Connor CM, Batchelor WB
    Circ Heart Fail, 2022 Jun, 15(6): e009279 | PMID: 35510546 | PMCID: PMC9286066
    Citations: 28 | AltScore: 32.2
  32. Acute Myocardial Infarction and Cardiogenic Shock Interventional Approach to Management in the Cardiac Catheterization Laboratories.
    Tehrani BN, Damluji AA, Batchelor WB
    Curr Cardiol Rev, 2022, 18(2): 15-30 | PMID: 34823461 | PMCID: PMC9413732
    Citations: 150 | AltScore: 3
  33. Association of Frailty Status and Dietary Patterns in a Nationally Representative Sample of United States Adults with Olfactory Dysfunction.
    Vohra V, Leland EM, Schlosser RJ, Kamath V, Rowan NR
    Nutrients, 2022 Mar 15, 14(6):
    pii: 1238. | PMID: 35334897 | PMCID: PMC8954153
    Citations: 44 | AltScore: 3.7
  34. Metabolomics Captures the Biological Signatures of Aging and Health Span and Identifies Pathway Targets for Intervention.
    Westbrook R, Abadir PM
    J Gerontol A Biol Sci Med Sci, 2022 Dec 29, 77(12): 2343-2345 | PMID: 36041017 | PMCID: PMC9799213
    Citations: 6 | AltScore: 9.55
  35. Metabolomics-Based Identification of Metabolic Dysfunction in Frailty.
    Westbrook R, Zhang C, Yang H, Tian J, Guo S, Xue QL, Walston J, Le A, Abadir PM
    J Gerontol A Biol Sci Med Sci, 2022 Dec 29, 77(12): 2367-2372 | PMID: 36580380 | PMCID: PMC9799179
    Citations: 25 | AltScore: NA


Harvey J. Cohen, M.D.
Walter Kempner Professor of Medicine, Director Emeritus, Center for the Study of Aging and Human Development, Chair Emeritus, Department of Medicine, Duke University Medical Center
Serving since 2003 (20 years)

Luigi Ferrucci, M.D., Ph.D.
Scientific Director, Senior Investigator, Longitudinal Studies Section, National Institute on Aging, National Institutes of Health
Serving since 2003 (20 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 (15 years)

Gerald Beck, Ph.D.
Section Head, Clinical Trials; Design and Analysis, Department of Quantitative Health Sciences, Cleveland Clinic Foundation
Serving since 2013 (10 years)

Howard Bergman, M.D.
Assistant Dean, International Affairs, Faculty of Medicine and Health Sciences, Professor of Family Medicine, Medicine and Oncology and the Institute for Health and Social Policy, McGill University 
Serving since 2013 (10 years)

Nicholas Rowan (2023)
  • Johns Hopkins University Center for AIDS Research (JHU CFAR), Developmental Core Award.
Qinchuan Wang (2023)
  • Glenn and AFAR Junior Faculty Award, CaMKII as a Cause of Age-Related Sarcopenia.


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.
  • Melissa Hladek, Assistant Professor
    Using Human-Centered Design to Adapt CAPABLE as a Prehabilitation Intervention for Adults with Frailty Awaiting Kidney Transplant.
  • 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

No minority grant information specified.