Claude D. Pepper Older Americans Independence Center

Susan L. Greenspan, M.D.
Principal Investigator
Bari Guzikowski
Program Manager

Gait and balance disorders in older persons are common, disabling and complex. In order to prevent and treat these disorders, a concentrated, multidisciplinary effort to understand causes and consequences, and to develop innovative treatments, is needed. The team of investigators at Pittsburgh offers complementary expertise, outstanding research productivity, and ongoing studies to address this need through a Claude D. Pepper Older Americans Independence Center. This program includes investigators from medicine, bioengineering, rehabilitation, epidemiology/public health, biostatistics, psychology, pharmacology, biology, imaging, informatics, and health services research. Our long range goals are: to address the critical need to improve mobility, balance, and falls risk, both through improved understanding of their causes and through development of preventive and therapeutic interventions.

Our specific aims for the current cycle are to:

  1. Promote multidisciplinary research to elucidate the causes, consequences and management of age-related changes in mobility and balance.
  2. Further extend our work into two high potential areas: a) translational investigations to examine interactions between multiple systems at the level of molecules, signaling systems, cells and their organelles, and tissues, as they impact mobility and balance in living organisms, and b) impact on individual older adults of novel interventions to enhance mobility and balance.
  3. Train young investigators from multiple disciplines to become national leaders in age-related mobility and balance problems in a vibrant, collaborative environment and build a translational sciences workforce through collaborative basic and clinical sciences team mentoring.
  4. Serve as a champion and invaluable resource for investigators, research programs, institutions, OAICs and the public in the area of mobility and balance in older adults.

The Program has 7 Cores:

  • Leadership/Administration Core
  • Pilot Exploratory Studies Core
  • Research Career Development Core
  • Clinical Populations Outcomes Core
  • Integrative Systems Core
  • Data Management, Analysis and Informatics Core
  • Biology of Mobility and Aging Core

Training support is provided directly to Pepper Scholars and also to trainees in related programs.

Research strategies to achieve OAIC goals:

  1. Use Resource Cores to share expertise among projects and investigators.
  2. Use pilot and developmental funds to extend existing studies and develop new studies.
  3. Promote and reward collaborative multidisciplinary teams of investigators with complementary expertise by prioritizing them for funds and support.
  4. Encourage new partnerships with highly productive investigators and programs by offering to partner with our expertise and resources.
  5. Reward development of new methods and techniques.
  6. Facilitate the use of a common set of core measures of mobility, balance and falls in human studies so results can be merged or compared.
  7. Leverage resources by collaborating with other Centers at Pitt, other OAICs, and Centers around the US.
  8. Sponsor seminar series to promote general awareness of expertise and resources, review progress in ongoing projects and facilitate new collaborations.
  9. Support the new OAIC career development program with salary-funded Pepper Scholars in addition to resource support for Novice, Transition to Independence, and Visiting Scholars, with a focus on multidisciplinary teamwork, thematic knowledge, and specific skills.
  10. Promote national discussion through programs at national meetings and other dissemination methods.
  11. Provide administrative infrastructure, intellectual leadership, and oversight.

Leadership and Administrative Core (LAC)
Leader 1:    Susan Greenspan, MD
Leader 2:     Anne Newman, MD MPH
The Leadership Administrative Core (LAC) is responsible for the organizational, communication and regulatory functions of the Pittsburgh Pepper OAIC. The LAC receives valuable input and direction from 5 advisory groups including 1) the External Advisory Board (EAB) (national experts), 2) the Institutional Advisory Board (multidisciplinary group of experts on aging from the University and the UPMC health system), 3) the Community Advisory Board (representatives from local health care agencies, IRB, media, and local leaders), 4) the REC Advisory and the PESC Advisory groups (both internal and external experts). These boards provide advice and insight to the Executive Committee composed of leaders and co-leaders of OAIC cores.

The specific aims of the LAC are to:
  1. Foster communication and multidisciplinary collaboration among OAIC investigators, cores and projects.
  2. Promote awareness and involvement in our work by relevant investigators and research programs in and outside the University of Pittsburgh.
  3. Represent the OAIC to the University through the Institutional and Community Advisory Boards.
  4. Represent the OAIC to other OAICs and the larger academic, NIH, clinical and lay communities.
  5. Through the EAB, maintain independent oversight of OAIC processes, resources and progress.
  6. Establish new independent REC and PESC oversight committees as requested by NIA.
  7. Provide research oversight and safety monitoring for all OAIC human studies and help establish a Data and Safety Monitoring Board as necessary.
  8. Sponsor a Research Seminar series, an Annual Retreat, Workgroups, a publication/communication committee, formal grant reviews, and new partnership initiatives.
  9. Increase basic and translational research partnerships.
  10. Provide administrative support and manage financial records for the OAIC as a whole.
  11. Collaborate outside the Institution on OAIC related themes.

Research Education Component (REC)
Leader 1:    Neil Resnick, MD
Leader 2:    Jen Brach, PhD, PT

The goal of the Research Education Component Core (REC) of the Pittsburgh OAIC is to provide a comprehensive, individualized career development program to prepare future investigators for mobility, balance, and aging research. Our ultimate goal is to develop highly qualified investigators to conduct high quality and high impact research in the field of mobility, balance, and aging and who will become leaders in this field nationally and internationally. We continue to improve our programs with input from our trainees, mentors, Executive Committee, and External Advisory Committee.

Our specific aims of the REC are to:

1. Promote careers in mobility, balance, and aging research among junior investigators at 3 levels:

  • Novices: research mentees at the pre-and post-doctoral level
    Goal: submission and funding of their first research award (F series, Foundation, etc.)
  • Pepper Scholars: junior faculty with initial expertise who receive OAIC salary support
    Goal: submission and funding of a career or R-type award
  • Transition to Independence Investigators: junior faculty with independent career awards
    Goal: submission and funding of an R-type award

2. Foster Trainee success with a comprehensive training program that:

  • Prepares trainees to engage in translational teams across basic, clinical, and health services science
  • Educates in aspects of basic and clinical research via the Clinical and Translational Science Institute (CTSI) and our complimentary sessions that focus on aging, mobility, and balance
  • Creates and monitors individualized teams of experienced mentors
  • Offers multidisciplinary research experiences involving OAIC Cores and investigators, as well as retreats, and a peer-led seminar series that includes sessions for manuscript and grant review, career development, and leadership with CTSI
  • Sponsors a 2-semester intensive grant writing course resulting in a polished grant proposal
  • Uses stipends to protect Scholar time for research and training and provides targeted financial support for initial pilot projects and other opportunities
  • Provides individualized advice, feedback, career guidance, and support to trainees and mentors.

3. Manage all aspects of the training program, including promotion, recruitment, selection, scheduling, monitoring, and evaluation of trainees and the program. The REC helps every Scholar complete a Customized Career Development Plan (CCDP) that is used to plan activities and monitor progress.

4. Collaborate with other cores and units within and outside the institution for OAIC related themes.

5. Enrich Scholar training through participation in the OAIC Coordinating Center’s Visiting Scholar Program.

Pilot and Exploratory Studies Core (PESC)
Leader 1:    Daniel E. Forman, MD
Leader 2:    Fabrisia Ambrosio, PhD, MPT

The goal of the Pilot/Exploratory Studies Core (PESC) of the Pittsburgh OAIC is to promote and fund innovative multidisciplinary pilot research in the topic areas of mobility, balance and aging and their interfaces. The expected outcomes for funded pilot studies are their successful completion in a timely manner, that the findings be presented at a national scientific meeting and submitted for publication in the peer review literature. Moreover, the findings from these pilot studies are expected to support the development of mentored career development awards and independent federally funded grant applications.

The specific aims of the PESC are to:

  1. Promote innovative multidisciplinary research on mobility, balance and aging.
  2. Act as a bridge to foster interactions between the basic geroscience, clinical and community-based research communities.
  3. Encourage supplements to leverage ongoing basic, translational, clinical and community-based studies.
  4. Promote innovative techniques and methods for research on mobility, balance and aging.
  5. Partner with other University of Pittsburgh groups (e.g. Clinical and Translational Science Institute and Aging Institute) that also offer pilot study awards, in addition to the Division of Geriatrics, to increase overall funding for individual pilot projects.
  6. Promote, evaluate, and select for funding Pilot projects ($40,000 per year), small REC Pilots (up to $10,000), and Developmental projects ($70,000 over two years).
  7. Conduct post-award processes (e.g., monitor adherence to ethics, safety, privacy, tracking of subsequent productivity and other related matters) for pilot and developmental projects.

Biology of Mobility and Aging Core (BMAC)
Leader 1:    Toren Finkel, MD, PhD
Leader 2:    Stacey Rizzo, PhD

Problems with mobility and balance with aging are due to changes in multiple systems that develop due to age-related alterations in basic biological processes. Insights accumulated over the last two decades in the basic biology of aging are poised to be rapidly translated into new interventions to promote a longer healthspan, which depends in large part on maintaining mobility and balance. However, significant barriers must be overcome before the approaches and technologies of basic science can be efficiently translated into clinical practice. While the OAIC partnered over the last 10 years with individual basic scientists who study aging, there was not yet a critical mass of activity to justify a distinct Pepper Core. With a major new investment creating an Aging Institute dedicated to using biological sciences to advance aging basic discovery and translation, the OAIC now proposes a Biology of Mobility and Aging Core (BMAC). The goal of this new core is to promote both basic-to-human and human-to-basic translation. The BMAC will provide an engine of discovery and innovation to guide and enhance our clinical and translational efforts. Specific emphasis includes using basic science approaches to uncover novel biomarkers and compounds that might aid in the treatment of age-related alterations in mobility and balance. Moreover, the BMAC will assist in the development and characterization of innovative pre-clinical animal models that can be used to mechanistically explore the fundamental basis of age-related changes in mobility, gait and balance.

The specific aims of the BMAC are to: 

  1. Provide expertise in biomarker development as potential intermediate markers of the aging processes in human studies of aging. This will include the development of novel model systems to accelerate biomarker development.
  2. Provide access and guidance to the design and analysis of high throughput screening (HTS) systems and ‘omic’ technologies for identifying potential molecular targets relevant for mobility, balance and aging.
  3. Provide access to and interpretation of various preclinical model systems. This includes cellular (e.g. muscle stem cells), rodent, zebrafish, and drosophila organisms and establish a preclinical phenotyping platform that faithfully reflects age-related mobility impairment in humans to enable translational studies.
  4. Support the research training mission of the Pepper Center by enhancing the capacity for Team Science and promoting basic-translational-clinical interactions.

Clinical and Population Outcomes Core (CPOC)
Leader 1:    Steven Albert, PhD, MSPH
Leader 2:    Andrea Rosso, PhD, MPH

The Clinical and Population Outcomes Core (CPOC) is dedicated to promoting multidisciplinary research on mobility, balance, and aging through 1) access to human subjects for studies and advice on screening, recruitment, and consent, 2) access to existing data sets from Pitt aging studies for secondary analysis, and 3) resources and space for clinical assessment of mobility and balance. To meet these aims, we provide registries of interested community-dwelling older participants and a Long-Term Care (LTC) Registry of residents from participating institutions, a searchable database on existing Pitt Aging data sets from longitudinal and clinical trial studies, a library of tests and scales with instructions, scoring and advice on implementation, and information on use of our Senior Mobility in Aging Research and Training (SMART) Center space for clinical studies. We successfully launched the Platinum LTC Registry (seniors residing in assisted living and skilled nursing facilities who have consented to research contact).  To date, over 40 facilities signed agreements to participate as recruitment sites, and over 400 residents consented to be contacted.  Our Community Registry, with over 2500 older participants, was a key recruitment source for 60 research studies.  The CPOC SMART Center provided clinical research space for multiple pilot and external projects.  Our Community Advisory Board (CAB) continued to foster community collaboration, stakeholder involvement and feedback on OAIC activities.

Our specific aims of the CPOC are to:

  1. Engage older adults from the community and LTC settings in research by expanding large registries of consented and well-characterized older adults accessible to investigators.
  2. Provide training to investigators on appropriate contact, screening, and consent strategies for research with older populations.
  3. Recruit and maintain a diverse community advisory board of older adults and leaders in aging services to review proposed research and advise the OAIC.
  4. Provide access to ongoing and completed Pitt cohort studies, specimens, clinical trials, and existing databases.
  5. Provide expertise in clinical assessment methodology by providing a standardized set of forms and instructions to promote a common dataset of core assessments for mobility, balance, and falls.
  6. Use noninvasive, portable technology to examine mobility, balance, and physical activity in clinics and in the field through our novel mobile laboratory.
  7. Provide access to space and equipment for OAIC-related studies through our SMART Center.
  8. Promote dissemination of our findings within and outside the Pittsburgh community.

Data Management, Analysis and Informatics Core (DMAIC)
Leader 1:    Subashan Perera, PhD
Leader 2:    Charity Moore Patterson, PhD, MSPH

The overarching goal of the Data Management, Analysis and Informatics Core (DMAIC) is to ensure data and analytic integrity, transparency and reproducibility by continuing to serve as a central source of methodological expertise and a service provider to the researchers of the Pittsburgh Older Americans Independence Center (OAIC).  Methodological expertise is most beneficial when provided by a team such as DMAIC familiar with the balance and mobility in aging theme, specialized measures and methods of the OAIC.

Our specific aims of the DMAIC are to:

  1. Meet data management requirements of Pittsburgh OAIC PESC, REC, developmental and external projects. 
  2. Support quantitative and facilitate qualitative analysis needs of Pittsburgh OAIC projects.
  3. Provide informatics expertise to Pittsburgh OAIC projects.
  4. Support the training mission of the Pittsburgh OAIC with Pepper Scholars and other trainees.
  5. Develop new techniques, as wells as novel application of existing methods to address OAIC-related unmet needs and methodological challenges. 
  6. Collaborate with other cores and units within and outside the institution on OAIC theme-related activities.

Integrative Systems Core (ISC)
Leader 1:    Caterina Rosano, MD, MPH
Leader 2:    Mark Redfern, PhD

Problems of mobility and balance in the aged require multidisciplinary study because they are complex and multifactorial. Advances require integrating expertise and technical resources from biomechanics, physiology, neural control of movement and biology. Thus, the goal of the Integrative Systems Core (ISC) is to provide integrative, multidisciplinary knowledge, skills and techniques that foster an understanding of the biomechanical, structural, functional, physiological and biological influences on age-related mobility and balance. 

Our specific aims of the ISC are to:

  1. Provide cutting-edge resources and expertise to concurrently study both whole-body as well as multiple systems and physiologic mechanisms affecting mobility and balance during aging, both during study planning as well as during implementation and analysis.
  2. Develop and test novel techniques and approaches to address gaps and needs for multi-system evaluation of mobility and balance.
  3. Support the training mission of the OAIC by educating and supporting the work of Pepper trainees through workgroups, seminars, “field trips” and active involvement in trainee research projects.
  4. Collaborate with other cores and Centers in and outside Pitt on OAIC-related activities.
  5. Continuously monitor, evaluate and communicate about Core activities both within and among Core laboratory leaders, as well as with other Pepper Cores, Pepper leadership and NIA.

REC Scholar, Research & Grants Funded During Pepper Supported Time Years /
Nami Safai Haeri, MD
Assistant Professor / University of Pittsburgh School of Medicine
A Novel Method to Examine Muscle Health in Frail Elderly
2022-2024 /
4 (total)
1 (1st/Sr)
Megan M. Marron, PhD
Assistant Professor / University of Pittsburgh School of Public Health
Using –omics to better understand the underlying biology of decline in muscle, liver, and physical functioning with aging
2022-2024 /
24 (total)
10 (1st/Sr)
Marcelo Rocha, MD PhD
Assistant Professor / University of Pittsburgh School of Medicine
Dimethyl-Arginine and Large Vessel Occlusion Stroke in Older Adults
2022-2024 /
28 (total)
7 (1st/Sr)

Past Scholars
Mary Kotlarczyk, PhD, University of Pittsburgh School of Medicine (2017-2020)
Emily Rocha PhD, University of Pittsburgh School of Medicine (2019-2021)
Lena Makaroun MD, MS, University of Pittsburgh/VA Pittsburgh Center for Health (2019-2021)
Samaneh Farsijani, PhD, MSc, University of Pittsburgh School of Medicine (2020-2021)

1. Project Title: Medical Marijuana and Chronic Pain in Older Adults
  Leader: Neelesh NadKarni, MD, PhD, FRCPC; Debra Weiner, MD, FACP

Background: Challenges with conventional treatments for chronic pain have led to many older adults considering medical marijuana (MM) as a treatment option. Older chronic pain sufferers may be  vulnerable to the effects of MM from age-related changes in pharmacokinetic and pharmacodynamic  function, and from changes in the brain that control mobility and cognition. Whether potential benefits from alleviation of chronic pain with MM are counteracted by its adverse effects on mobility in older adults on MM is unknown.

Specific Aims: We will compare adults 60 and over who are pain free (PF) to those with chronic pain  not on MM (CP), and those with chronic pain on MM (CP-MM) on mobility, cognition, gait-cognitive  dual-task measures, mood, anxiety, physical function and quality of life measures. The main hypotheses are that: 1) the CP-MM group will perform the worst on measures of gait speed, physical  function, executive function and dual- task gait and cognitive performance (i.e., the interface between gait and cognitive function), and 2) the CP group will perform the worst on other measures of mood, anxiety and quality of life.

Summary of Methods: This pilot will recruit 20 participants in each group, PF, CP and CP-MM. The CP-MM group will be recruited from Solevo Wellness, a Pittsburgh MM dispensary using targeted  mailings. We will recruit the PF and CP participants from the Pepper Registry and pain clinics. We will assess mobility performance with the short physical performance battery (SPPB) and the Timed-up-Go. We will assess gait parameters with and without dual tasking on the Gait mat II. We will administer standardized tests of executive function, memory, language and visuospatial function. Accuracy and reaction time will be captured on working memory, response inhibition and motor sequencing tasks performed while standing and while walking (dual- tasking). Mood will be assessed with the PHQ-9 anxiety with the GAD-7, physical function with the late life function and disability index, and quality of life with the EuroQoL. We will also capture details of MM type, blood levels of active MM compounds, dosage, administration, and severity of pain on the BPI.

Future use of data: This data will be used to support a prospective cohort study (R01 application) in response to the FOA from NIA/NIDA (PA-17-196) that will address the relative impact of MM as compared with chronic pain itself on mobility, cognitive function, and other geriatric-specific outcomes in older MM users.

Core Collaborations: CPOC, DMAIC

2. Project Title: Investigating Biological Aspects of Aging through Molecular Epidemiology: Linking Genes to Physical Function in Older Adults
  Leader: Adam J. Santanasto, PhD MPH; Joseph M. Zmuda, PhD; Zsolt Urban, PhD; Ryan L. Minster, PhD, MSIS

Specific Aims: To examine the association of RNA expression profiles of the transforming growth factor-beta (TGF-ß) pathway with baseline and 7-10-year change in physical function among older adults.

Brief Background: The TGF-ß signaling pathway is a strong biological candidate pathway that may negatively impact skeletal muscle and physical function with aging. TGF-ß induces pathogenic tissue fibrosis, negatively regulates skeletal muscle differentiation and repair, and contributes to mitochondrial dysfunction. TGF-ß is also implicated in inducing pathogenic fibrosis, muscle wasting and primary myopathies, all of which can impact physical function.

Methods: We propose to assay the expression of genes involved in the TGF-ß signaling pathway, using a custom-designed TGF-ß pathway expression array. We will examine the relationship between mRNA expression and the Short Physical Performance Battery, a comprehensive lower-extremity performance battery that includes gait-speed, balance and timed chair-rise tests.

Future use of Data: The data generated from the Pepper Pilot will be used in future NIH grant proposals to examine tissue-specific (skeletal muscle) expression of genes involved in TGF-ß signaling and their effect on age-related changes to physical function. Further, this dataset will be integrated with data from PI Dr. Santanasto’s K01, which investigates the association of genome-wide genetic markers, circulating TGF-ß, and other biomarkers, to better understanding of biological mechanisms underlying age-related declines in physical function.

Core Collaborations: DMAIC, CPOC

3. Project Title: Cellular senescence, SASP and Metabolites as biomarkers for early aging
  Leader: Aditi U. Gurkar, PhD; Susan Greenspan, MD; Neil M. Resnick, MD; Subashan Perera, PhD

Specific Aims:   The aims of the current proposal are to (1) Design assays for measuring senescence and SASP in whole blood/ serum from the Solve-IT study. (2) Perform global metabolomics on serum to quantitate 600+ metabolites and estimate effects of sex, and physical aging using statistical and bioinformatics methods (3) Perform statistical analysis to identify differentiating biomarkers of interest and their co-occurrence patterns. These biomarkers will be selected from the measured metabolites, senescence and SASP markers.

Background:  Aging  comprises  of  a  diverse  array  of  phenotypes  influenced  by  multiple factors  including genetics, epigenetics, environmental influences, diet, exercise and the microbiome. Cellular senescence and senescence associated secretory phenotype (SASP) are known to correlate with age and ablation of such cells drastically improves health span, albeit in model organisms. This hints that cellular senescence can possibly drive aging-related degenerative change. Metabolites are circulating small molecules that are supremely suited to account for biological aging influenced by a number of these factors. This study will simultaneously identify the metabolite profile, and the immune, as well as senescence markers that collectively play an important role in biological aging.

Methods: Cellular senescence and SASP markers will be measured by ELISA and Luminex based assays from whole-blood and serum samples from the Solve-IT study. Metabolomics profiling will be performed from randomly selected 60 participants. Using statistical and bioinformatic approaches we will analyze (a) which metabolites and combination of metabolites best discriminate the cohorts of interest; (b) which senescence markers and combination of markers best discriminate the cohorts of interest; (c) which combinations of metabolites and senescence markers best discriminate the cohorts of interest. By constructing co-occurrence networks we will identify groups of features/phenotypes that co-occur, potentially suggesting the entities that are be involved in a
biological model for aging.

Future Uses: The assays can be applied to other patient cohorts to determine if the unique signature obtained here significantly correlates with falls, mobility, frailty, critical care patient outcome, risk of aging-related degenerative diseases, healthy aging, etc. In particular, this pilot study will provide critical data for a grant application to fund a larger study to understand the relationship of these measures to outcomes of aging. Our approach has the potential to identify metabolic pathways that may drive cellular senescence, immune system and aging, thus providing a mechanistic insight into healthy aging. This will provide an opportunity to develop novel  strategies  to  modulate aging  and  simultaneously  delay  the  onset  of  multiple chronic  degenerative diseases.

Core Collaborations: CPOC, DMAIC, BMAC

4. Project Title: Association of Social Determinants of Health with Functional Status, Mortality, and Healthcare Use in Older Adults Who Survive Critical Illness
  Leader: Leslie Scheunemann, MD, MPH, Eric Roberts, PhD

Rationale: More than half of older critical illness survivors develop new or worsened dysmobility and functional impairments. While suspected to influence critical illness outcomes, there is little evidence about how social determinants of health (e.g., income, education, and environmental characteristics such as housing quality, transportation access, and social support) affect functional outcomes and healthcare utilization in this important and currently highly relevant older population.

Approach: This study uses data from the well-established and locally available Health and Retirement Study, which is linked to Medicare claims. It will identify older critical illness survivors, characterize important baseline individual social determinants of health (SDH), and link to their subsequent survival, pre-and post-illness function (including self-reported walking, stair climbing, falls, and activity level), and use of healthcare resources. Aim 1 will examine the relationship between SDH measured the year prior to critical illness and post-critical illness health outcomes. Aim 2 will assess the relationship between SDH and healthcare utilization.

Relevance to the Pepper theme: Loss of physical function and mobility among older adults after critical illness is highly relevant to the OAIC theme.

Core Collaboration: CPOC (population studies), DMAIC (analysis), includes REC members 

5. Project Title: Mechanisms underlying changes in inflammation in mobility limited older adults
  Leader: Rachel Gottschalk, PhD, Maria Chikina PhD; Co-Is: Drs. Daniel Forman, Anne Newman, Toren Finkel

This pilot examines gene regulatory networks in macrophages from older adults with impaired mobility and elevated IL-6 levels in the Reducing Inflammation for Geriatric Healthspan Therapy (RIGHT) Study, a clinical trial which will test the effects of an IL-inhibitor. 

Significance: Persistent inflammation is associated with aging and the onset and progression of mobility disability and fatigability. Monocytes and macrophages play a pathological role in age-related inflammation and disease,1,2 and there is substantial person-to-person variation in their gene expression and regulation of inflammatory responses, resulting from age, sex, and genetic factors.This variation is key to understanding mechanisms behind healthy vs non-healthy aging, and how therapies may impact inflammation in mobility limited older adults. 

Hypotheses: We expect that 1) inter-person variation in macrophage basal gene expression will predict stimulus-induced macrophage inflammatory responses and 2) these measures will be associated with elevated serum IL-6 and impaired mobility across people. 

Approach: (Aim 1) We will utilize pre-treatment blood collected from the RIGHT trial to assess inter-person variation in inflammatory regulatory networks across 50 elderly subjects with high serum IL-6 (>2.5 pg/ml), an inflammatory cytokine associated poor clinical outcomes,7 and 20 controls (IL-6 <2.5pg/ml). Readouts will include (i) basal serum protein quantification, (ii) macrophage responses to microbial stimuli (inflammatory cytokine output across a range of stimulus concentrations), and (iii) basal and stimulus-induced macrophage gene expression (RNAseq). Using these data and novel computational methods (graphical lasso and causal inference algorithms), we will infer regulatory relationships that govern inflammatory control and identify regulators associated with macrophage responsiveness, elevated serum IL-6, and impaired mobility. (Aim 2) We will analyze a subset of 10 subjects treated with IL-6 inhibitor for 6 months to determine whether serum proteins, macrophage responses, or gene regulatory networks are impacted by therapy. 

Innovation: Our preliminary data suggest that person-to-person variation in inflammatory regulation is most apparent in response to weak stimuli. By using computational and quantitative experimental approaches to elucidate network connectivity and its impact across a broad range of stimulus strengths, this proposal provides a framework for both conceptual and methodological innovation in understanding mechanisms underlying age-associated inflammation. 

Core Collaborations/grants: ISC (Dr. Forman’s Lab), CPOC (Community Registry), DMAIC (statistical analysis). 

Future Proposals: This study will inform a planned R01 grant proposal to further our basic understanding of how gene regulatory networks change with age and impact of IL-6 inhibition.

6. Project Title: A lysosomal-based, small molecule approach to prevent and reverse mobility decline
  Leader: Emily Rocha, PhD, Stacey Rizzo, PhD; Co-Is: Drs. Toren Finkel and Daniel Forman

This Pilot leverages the Pitt/UPMC program in drug development to target critical age-related pathways affecting mobility. A small molecule that activates TFEB will be tested, which can lead to Phase I human testing in 18-24 months. 

Significance: Aging is the main risk factor for neurodegenerative disease and loss of mobility. Aging lysosomes undergo impaired volume and pH regulation, accumulation of indigestible materials, and reduced functional degradative enzymes. Age-related autophagy-lysosomal dysfunction may be responsible for the observed incidental ?-synuclein pathology that occurs at a frequency of 8-22.5% and up to 34.8% in centenarians; thus may play a role in age-related mobility loss. TFEB is a master regulator of autophagy and lysosomal biogenesis and regulates the expression of Coordinated Lysosomal Expression and Regulation (CLEAR)-network proteins, which include many autophagy proteins. Our data indicates that exposure to a novel, small-molecule (BC18630) prolongs nuclear TFEB activation, and can prevent age-related lysosomal dysfunction, ?-synuclein accumulation, neurodegeneration and loss of mobility. 

Hypothesis: Improving lysosomal function using TFEB activator can prevent or delay age-related neuropathology and mobility decline. 

Approach: This pre-clinical study evaluates BC 18630 (a small-molecule that selectively prolongs TFEB activation) to 1) prevent the progression of age-related neuropathologies and mobility decline in healthy aging male and female C57BL/6J mice; and 2) attenuate or reverse neuropathology and mobility decline in advanced aged mice. Following baseline assessments of mobility-related phenotypes, BC18630 will be administered via chow to middle aged (6-8 month) and aged (16-18 month) male and female mice for several months and compared to young ~3-4 month vehicle treated sex- and age-matched controls. Based on data in C57BL/6J mice, the dose will be equivalent to 5 mg/kg/day. A battery of behavior tests before and after treatment will assess aging-related gait and motor coordination in addition to hearing, vision, body mass,and frailty index score. Discrete brain regions will be microdissected from the left hemisphere and used for lysosomal enzymatic activity assays. Right hemisphere regions will be used for histological assessment of autophagy-lysosomal function. 

Innovation: This proposal outlines a unique therapeutic strategy to improve lysosomal function and prevent age-related mobility loss that may prevent accumulation of aggregated proteins and delay the onset of mobility disability.

Core Collaborations/grants: DMAIC (statistical analysis), BMAC (Greenamyre), ISC (Forman), REC (Scholar) 

Future: This pilot will provide data for a NIA R21 or R01 grant.

7. Project Title: The relationship between dietary protein intake, gut microbiome and mobility in older adults
  Leader: Samaneh Farsijani, PhD; Co-Is: Drs. Anne Newman and Subashan Perera

This study builds on the NIA-funded Study of Skeletal Muscle and Mobility in Older Adults (SOMMA), with an add-on study focused on the role of nutrition and the microbiome in influencing muscle health and mobility. 

Significance: The imbalanced composition of gut microbiome(dysbiosis), in aging is associated with gait speed and frailty. Protein intake is an important anabolic stimulus for muscle protein synthesis and may influence the gut microbiome, which can in turn affect muscle function and walking ability. Despite emerging evidence supporting the roles of amount, source and pattern of protein intake in promoting muscle health and mobility, associations with age-related dysbiosis are unclear. This study will determine the relationships between dietary proteins and gut microbiome and help inform development of age-specific dietary recommendations to maintain muscle health and mobility by promoting a healthy gut microbiome. 

Hypothesis: Higher amount and even within-day distribution of protein intake, as well as higher quantity of plant-based proteins are independently associated with increased diversity of the gut microbiome.

Approach: Two 24-h food recalls, a food frequency questionnaire, and fecal samples (for 16S rRNA analysis) will be collected from 200 SOMMA participants (age ? 70-y) residing in Pittsburgh at baseline, for 80% power with ?=0.05 for detection of R2=0.065 between protein intake measures and microbial diversity. 

Innovation: This is the first study to address associations between dietary protein parameters and gut microbiome composition in older adults and will provide preliminary data to test associations with gait speed and mobility in SOMMA. 

Core Collaborations/grants: ISC (Forman and SOMMA), DMAIC (analysis), REC (Scholar). 

Future: Findings will support Dr. Farsijani’s K01 application. 

8. Project Title: Increasing gait automaticity in older adults by exploiting locomotor adaptation
  Leader: Gelsy Torres-Oviedo, PhD; Co-Is: Andrea Weinstein, PhD, Andrea Rosso, MPH, PhD , Douglas Weber, PhD

This study integrates the insights of 4 dynamic investigators with complementary expertise in a pilot study of mechanisms and clinical effects of locomotor adaptability training. 

Significance: Age-related deficits in locomotor adaptation are common and linked to disability and falls. Older adults are slower at adjusting movements when interacting with a new environment and have difficulty switching motor patterns when transitioning across walking conditions. While locomotor training using split-belt walking (SBW), in which legs move at different speeds, has known efficacy, neither the underlying mechanisms nor clinical relevance of improvements are known. 

Hypothesis: SBW-related improvements in locomotor adaptation will translate to increased community mobility activity in older populations by reducing the high cognitive load associated with walking. 

Approach: Locomotor adaptation will is studied with a novel SBW protocol. Initial walking automaticity is assessed with wireless functional near-infrared spectroscopy (fNIRS) during dual-task treadmill walking. Mobility performance is evaluated with instrumented walking surfaces and portable sensors recording body motion and muscle activity. Community mobility is assessed with integrated analysis of accelerometry and global positioning system (GPS)-based measures of walking in-home and in the community. We focus on two measures of adaptability: 1) rate at which individuals adapt to SBW and 2) capacity to switch between context-specific walking patterns. We also determine if improving locomotor adaptability changes the neural and cognitive characteristics post-training. We plan for 30 participants for sufficient power. 

Innovation. SBW targets locomotor adaptability. We characterize the relation between locomotor adaptability and GPS-based measures of community mobility, and functional gait assessment predicting fall risk. 

Future: This will provide needed data for an NIH grant. 

Core Collaborations: ISC (Torres-Oviedo and Redfern labs), DMAIC (analysis). 

9. Project Title: Small Pilot for Pepper Scholar: Function, falls and injuries as risk factors and outcomes of elder abuse in the VA
  Leader: Drs. Lena Makaroun , Debra Weiner, Scott Beach, Ann Marie Rosland

Significance/Approach: Little is known about physical function and falls as risk factors and outcomes for elder abuse (EA).37-43 With VA administrative data, 2 national cohorts of veterans over age 60 will be compared including one that received services for abuse/neglect and one that did not. Logistic regression and mixed modeling will be used to assess candidate variables including demographics, social status, physical/cognitive function, falls and injuries. EA will be the independent variable for outcome analyses, and similar statistical methods will be used to explore the association with outcomes, including change in physical/cognitive function, fall and injuries, health service utilization and placement. 

Innovation: Exam of a vulnerable population. 

Core Collaboration: ISC, PESC, and DMAIC. 

10. Project Title: Continuous Real-world Sensing of Physical Function in Older Cancer Survivors
  Leader: Carissa A. Low, PhD, Grace B. Campbell, PhD, MSW, BSN
  Specific aims: (1) To examine the association between continuous wearable and smartphone sensor data and commonly used clinical measures of physical function in cancer survivors aged 65 and older (2) To develop a preliminary machine learning model using mobile sensor data to differentiate older cancer survivors with impaired physical function, poor performance status, frailty, or history of falls from more physically robust participants. Brief background: Impaired physical function is common among older cancer survivors and is an important predictor of clinical outcomes. Mobile sensors that passively capture continuous objective data provide new opportunities for quantifying physical function in real-world settings during routine daily activities. Summary of methods: We will recruit cancer survivors aged 65 or older (n = 40) to complete a battery of validated performance-based and patient-reported physical function measures. Participants will also collect four weeks of continuous data from wearable devices and personal smartphones that will include physical activity, geographic mobility, sleep, and heart rate. We will evaluate associations between performance-based and patient-reported measures and daily behavioral features and will develop a preliminary model to classify participants into impaired physical function vs. high physical function groups. Future use of data: Data from this project will inform a NIH application assessing physical function longitudinally in a larger sample of older cancer survivors and evaluating the ability of mobile sensing to detect functional decline. This Pepper pilot project will provide important feasibility and effect size data and will help to identify which functional assessments and mobile sensors to use in future work. Core Collaborations: CPOC, DMAIC
11. Project Title: The muscle-brain axis: Exploring the effect of skeletal muscle activity on the connectome and transcriptome of aging animals
  Leader: Amrita Sahu, PhD
  Aims: The overarching goal of these studies is to test the central hypothesis that skeletal muscle contractile activity promotes a more youthful cognitive connectome (Aim 1) and spatially defined transcriptomic profile (Aim 2), ultimately contributing to enhanced cognitive capacity. Background: Physical activity attenuates age-related declines in neurostructual, neurofunctional, and neuromolecular profile of the brain. However, the mechanisms that underlie this beneficial effect of physical activity on aging brains are poorly understood. Individual approaches of cognitive testing, brain architecture analyses, and neuromolecular probing are often used to understand the aging process within the brain. In order to gain a comprehensive mechanistic understanding of aging brain and its response to physical activity, an integrated approach combining behavioral testing (cognition), connectomics (neuroimaging), and spatial –omics (neuromolecular) analyses are warranted. Methods: All animal experiments will be performed with prior approval from the Institutional Animal Care and Use Committee of the University of Pittsburgh. Young and aged male C57BL/6 mice will be used in the studies (Young: 3-6 months, Aged: 21-24 months,). For inducing physical activity in animals, mice will be subjected to a neuromuscular electrical stimulation (NMES) protocol to elicit repetitive skeletal muscle contractions. Mice will receive five stimulation sessions over a period of two weeks, with each session consisting of 20 repetitions. Two days after the last session, animals will be subjected to behavioral testing (spatial memory, short-term memory, and motor activity) or neuroimaging (connectomics). After neuroimaging, the brains will be probed for spatial transcriptomic. Future use of data: We anticipate that using this integrated approach we will be able to identify mechanisms that underlie the benefit of skeletal muscle contractile activity on brain health. Findings from this study will lay the groundwork for developing targeted rehabilitation protocols designed to enhance cognitive functioning in an older population. Preliminary results from this study will also be leveraged to apply for larger funding to determine the effect of NMES on cognitive connectome based on sex. Core Collaborations: BMAC, ISC
12. Project Title: Interplay between Balance, Gait and Sleep in Older Adults with Glaucoma
  Leader: Rakié Cham, PhD, Shachi Tyagi, MD, MS
  Background. Falls are a major health risk for adults with glaucoma. While glaucoma-related changes in vision certainly contribute to falls, other well established risk factors for falls occurring at a greater rate in glaucoma than in older adults need to be considered. Poor sleep, an example of such risk factors, is well documented in glaucoma. In older adults without glaucoma, poor sleep negatively impacts falls risk and postural control, and causes other adverse health outcomes. Yet, we do not know if poor sleep function and disruption in sleep architecture associated with glaucoma, i.e. beyond aging-related symptoms, contribute to the increased prevalence of falls and reduced postural control in this clinical population. The overarching goal of the proposed project is to understand the interplay between sleep and postural control in glaucoma. Specific Aims. Three specific aims will be pursued. In Aim 1, participants with undergo detailed sleep assessments. In Aim 2, the relationship between sleep metrics and postural control function during standing and walking will be examined. In Aim 3, dual-task paradigms will also be used during balance/gait testing to examine attentional influences on postural control. Methods. Adults with advanced glaucoma and controls will participate in the proposed experiments. Our well-established balance/gait assessment protocols including dual-task experiments will be conducted to assess postural control function in various sensory challenging conditions. These protocols probe the ability to integrate multisensory information relevant for mobility through dynamic computerized posturography and gait analyses. In addition, rigorous assessments of sleep will be performed, including validated self-reported measures of sleep function and in-home EEG-based sleep testing. This state-of-the-art sleep assessment technology will provide detailed information related to sleep architecture by recording objective measures of various sleep stages duration. Appropriately constructed mixed linear statistical models will be used to test the hypotheses associated within each aim. The potential mediating effects of sleep on postural control impairments in glaucoma will be of primary interest. Future use of data. The findings can be used to identify specific sleep domains as potentially modifiable risk factors to improve balance/gait and reduce falls-related adverse health outcomes in glaucoma. The data collected in the proposed project may be used to plan larger-scale intervention studies. Core Collaborations: DMAIC, ISC
DEVELOPMENT PROJECTS (4 Development Projects Listed)
1. Project Title: Multi-system measures of mitochondrial dysfunction as early biomarkers of future aging-related mobility impairment
  Leader: Sarah Berman, MD, PhD, J. Timothy Greenamyre, MD, PhD, Daniel E. Forman, MD, Caterina Rosano, MD, MPH
  Core(s): Clinical and Population Outcomes Core (CPOC)
Data Management, Analysis and Informatics Core (DMAIC)

Significance: Mitochondrial dysfunction in both the brain and periphery occurs with aging. This hallmark of aging is multifactorial and affects muscle-skeletal, central nervous, and cardiovascular systems. The multi-system co-occurrence in heart-brain-muscle systems (HBM) likely influences aging-related healthspan outcome measures including the multidimensional syndrome of frailty. Dr. Greenamyre has shown mitochondrial dysfunction in HBM in animal models of Parkinson’s Disease in vitro and in vivo. However, mitochondrial function in humans has been difficult to measure, particularly in brain. Magnetic resonance spectroscopy (MRS) is able to estimate levels of ATP production via monitoring high-energy phosphates, but resolution in brain is poor. Therefore, correlating mitochondrial dysfunction within each independent component of the HBM system with functional outcome measures has not been possible. The ability to predict mobility impairment by non-invasive biomarkers of mitochondrial function may provide a window for intervention prior to the onset of frailty. 

Aims: Our goal is to develop the in-human use of a novel mitochondrial Complex I (Mito-CI) ligand for brain, heart and skeletal muscle using PET imaging to assess mitochondrial function in older adults. Thus, our primary aim is to characterize the pharmacokinetics of 18F-BCPP-EF in human brain, heart and quadriceps and optimize PET data analysis. Our secondary aim is to test the hypothesis that co-occurrence of mitochondrial dysfunction in more than one system plays a synergistic role in the pathogenesis of mobility impairment (e.g. 3>2>1). Conversely, preserved mitochondrial function in any one of these systems may lead to mobility resilience, even in the presence of deficits in the other two. 

Approach: The novel PET imaging ligand, 18F-BCPP-EF is a specific ligand of mito-C1 optimized for brain imaging. 18F-BCPP-EF has been successfully utilized to detect mitochondrial dysfunction in animal PD models and has been safely used in preliminary human studies.19 We have established a collaboration with the developer at Hamamatsu Photonics, and we have synthesized and purified the ligand in preparation for human studies at our center. Benefitting from our combined extensive expertise at the University of Pittsburgh in PET radioligand development, in mitochondrial biology, and in geriatric medicine, we propose to perform the first fully dynamic 18F-BCPP-EF PET imaging and analysis in 20 older adults aged >65 free from neurological diseases. Dr. Berman is currently funded to collect PET brain data of mitochondrial complex I in 10 older adults with mobility disorders and 10 age-matched controls. With this DP, we will expand the sample of control participants to 20 (recruited from the Pepper Registry) and add scan time in the cardiac and skeletal muscles (quadriceps). Measures of mobility will also be obtained. 

Future Studies: This study will provide proof-of-concept of the utility of this PET ligand in aging, and will serve to inform future larger studies to delineate the mechanisms of frailty and possibly early risk of mobility disability. Imaging Complex I in vivo in multiple systems has the potential to 1) provide an early and specific biomarker of mitochondrial dysfunction in multiple systems; and 2) indicate mechanisms underlying the syndrome of physical frailty in aging.

2. Project Title: Joint Modeling of Longitudinal and Survival Data for Dynamic Prediction of Mortality Risk with Gait Speed Serially Collected over Time
  Leader: Robert Boudreau, PhD, Charity Patterson, PhD, MSPH, Subashan Perera, PhD
  Core(s): Clinical and Population Outcomes Core (CPOC)
Data Management, Analysis and Informatics Core (DMAIC)

Significance: One-time physical performance measures are associated with many future outcomes in older adults. It is not clear how to predict future outcomes when serial measures of performance are available, which is a more realistic situation created by subsequent clinic visits. A prediction of an outcome should be updated with any new information about performance. Short term current vs long term trends, the experience of others who have exhibited similar trends, and how to incorporate those, if useful for prediction, need to be considered. Our prior work has shown decline (improvement) in gait speed is associated with worse (better) survival and rate of decline in gait speed over time is related to brain changes. However, they focused on associations and not individual-specific predictions. We are not aware of any other work that has addressed the problem specific to gait speed in a systematic and integrated way. A survival analysis model with time dependent covariates is not appropriate due to the endogenous nature of serial measurements.

Approach: We propose a novel application of the recently developed joint modeling of longitudinal and survival analysis technique to comprehensively address the question. The method makes use of the distribution of trajectories of all the subjects to better estimate individual trajectories, while allowing the latent local, slope and spline-trended mixed model random effects that characterize the trajectories to be potential predictors of survival risk. The joint distribution of the trajectories and survival model are consequently correlated and model fitting is based on optimizing the joint distribution. The survival component acts as a source of informative censoring and addresses the endogenous quandary discussed above. The model can be applied to make individual-specific short and/or long term mortality and gait speed future-trend predictions with confidence/prediction intervals. The predictions can be based on the actual measurements historically collected during a routine clinic visit and currently available along an individual’s trajectory. And predictions are updated over time as new gait speed measurements are obtained. The method has been successfully applied in many other areas of medicine. We will use serial 20m “usual pace” gait speed measures of 3075 older adults in Health ABC (Years 1-6, 8 & 10), and convert them to 4m speeds using a linear or quadratic regression model. Such conversions can be done with a high R2. We will develop the model using Health ABC data and will include 20 years of mortality data, then independently validate it using the CHS (N =5888) cohort who had annual 15’ gait speed assessments and 20 years of mortality data. Briefly, ith participant’s survival component of the joint model is given by  , where  is the true unobserved value of gait speed at time    is the history of such information up to time    are covariates, and  is the baseline hazard function, typically approximated with a piecewise-constant form  where ’s define a partition of the time scale. The longitudinal component for observed gait speeds is, where  and  are design vectors for fixed and random effects. The model can be fit using the R package jm.

Innovation: Apart from scientific innovation, we will enlist a graduate student researcher to train and perform analyses (MS/PhD thesis) adding a new core-specific dimension to the OAIC training mission. With CPOC, we will disseminate to put the resulting risk calculator on the Pitt Pepper website and/or create a smartphone app.

Core Collaboration: CPOC and DMAIC. If successful, mobility-predicted risk could be considered a standard outcome to be used across the OAIC studies.

Future Direction: The STAR trial (Irrgang & Patterson, DoD) has serial measurements of quality of life and time to return to duty/activity/work in a knee surgery population presenting an immediate future application related to balance & mobility.

3. Project Title: Automated Neighborhood Walkability Audits by Machine Learning
  Leader: Andrea Rosso, PhD, MPH, Ervin Sejdik, PhD
  Core(s): Clinical and Population Outcomes Core (CPOC)
Data Management, Analysis and Informatics Core (DMAIC)

Significance: In-person environmental audits provide important information on physical barriers to mobility7 but can be time-consuming. Google Street View now provides access to free, online street-level images. We recently used Google Street View’s historical images to add environmental data retrospectively to the Health ABC cohort (R21 AG054666-01, PI: Rosso). Use of these images for environmental audits has been demonstrated to be valid and reliable for street-level characteristics.14-19 Because Google Street View images are in the public domain and will not be linked to individual data, this research is not considered human subjects research. 

Innovation: No automated methods for environmental features relevant to mobility and falls in older adults currently exist for use in research studies. 

Aims: 1) Identify the environmental components most relevant to falls using existing published literature, and 2) Based on findings in Aim 1, develop computer methods to assess these features in an efficient, reliable, and automated way. 

Approach: We will develop computer-based, automated methods for auditing Google Street View images for environmental features most relevant to mobility and falls in older adults. We first determine the most relevant environmental features through a systematic literature review. We then use machine learning methods to develop automated auditing processes. Since Google Street View images provide visuals of house exteriors, nature, landscaping, and vehicles on the street20, we can use deep learning to identify environmental features by looking for key urban design qualities; walkability: imageability, enclosure, human scale, transparency and complexity.21 Prior studies used several methods to detect and estimate pedestrian volume, visual enclosure, automotive vehicles, and curbsides. Since overlapping images are taken from different perspectives and have different levels of color and illumination, deformable part models (DPM) can be used22-27. Each "deformable part" represents an object model by taking on the appearance properties of the object. The deformations are then linked. Histogram of Oriented Gradient (HOG) is also used to capture the image's region's gradient's intensity and direction23,25,26. Algorithms such as the Aggregated Channel Features (ACF) algorithm can increase computational efficiency by large-scale estimating of HOG and then discarding parts in small-scale images23. Artificial Neural Networks (ANN) can be used to analyze color and texture in Google Street View images27. Feature extraction and segmentation can be performed to isolate regions such as the sky, objects that obstruct the view, and other environmental features of interest22. Extracted features from HOG-ACF or ANN can be used for classification using Support Vector Machine, Decision Trees, Adaboost, or other supervised classification algorithms,23,26,27. Convolutional Neural Networks (CNN) may be able to recognize a wide variety of environmental objects that may affect walkability due to CNN's ability in object classification20. However, CNN is a supervised machine learning method that requires a training set of labeled images. Another method is to use a combination of Region Proposal Networks (RPN) and Fast Region-CNN (RCNN)25. RPN is also a convolutional network that can propose areas or regions in the image, while detection of these regions is done by Fast RCNN. The results of the machine learning audits will be validated against human audits. 

Core Collaborations: CPOC, DMAIC 

Future Uses: These methods would be made available through the CPOC for wide general research use to expand efficient research assessments into community risk factors for any study focused on mobility and falls.

4. Project Title: Targeting age-reprogrammed activity of methionine and tyrosine metabolism to delay frailty, improve motor function, and suppress age-predicting 'epigenetic clock'.
  Leader: Andrey Parkhitko, PhD, Stacey Rizzo, PhD
  Core(s): Biology of Mobility and Aging Core (BMAC)

Metabolic reprogramming represents one of the major driving forces in aging and leads to impaired organismal fitness, an age-dependent increase in susceptibility to diseases, decreased ability to mount a stress response, and increased frailty. Although targeting methionine and tyrosine metabolism has been shown to increase lifespan in different species, at present, no data exist to demonstrate their effects on composite measures of health in general and on muscle health in particular. In addition, MetR in human patients has been only tested in the settings of methionine deprivation from food, which is hardly achievable in clinical settings and results in a moderate decrease in plasma methionine, potentially limiting its efficacy. 

Rationale: Our preliminary data demonstrate that metabolism in general and methionine/tyrosine metabolism particularly are reprogrammed during aging in Drosophila (Parkhitko et al., 2016; Parkhitko et al., 2019) and (Parkhitko et al., eLife under revision). We also identified two novel anti-longevity genes in the methionine metabolism pathway that can improve the age-dependent decline in climbing activity (indicator of neuromuscular function in flies) and extend health- and lifespan (Parkhitko et al., G&D 2016). Similarly, we demonstrated that aging and mitochondrial dysfunction activate the tyrosine degradation pathway and that downregulation of tyrosine aminotransferase, the first and rate-limiting enzyme in the tyrosine degradation pathway, upregulates the production of tyrosine-derived neuromediators and extends lifespan (Parkhitko et al, eLife, under revision). Both methionine and tyrosine metabolism pathways can be targeted with FDA-approved drugs or drugs that are under current development for human applications. For example, we demonstrated that Methioninase, a bacterial enzyme capable of degrading methionine, efficiently depletes methionine and downstream metabolites (Figure 1) and dramatically extends Drosophila lifespan (Parkhitko et al., Aging Cell, under revision). Recombinant Methioninase has been tested in various cancer models in vivo and was safely used in clinical trials in humans (Agrawal et al., 2012; Chaturvedi et al., 2018; Hoffman, 2015). Cancer patients receiving recombinant Methioninase intravenously had a steady decline in serum methionine levels directly proportional to levels of active enzyme with minimal or no toxicity (Tan et al., 1997). This creates a strong rationale for translating these findings to mammalian systems as anti-aging interventions or for the potential treatment of various age-related diseases. 

Approach: We will use either young AD mice or wild-type C57BL/6J mice of different ages: young (4 mo) and old-age (24 mo). We will investigate how manipulations of methionine metabolism via dietary MetR (restricting methionine in mouse food) or enzymatic MetR (feeding mice with Methioninase) or manipulations of the tyrosine metabolism by feeding mice with an FDA-approved drug, nitisinone/orfadin, would affect the frailty index, wheel running, and epigenetic age. To confirm the efficiency of our manipulations and the effect of age, we will measure levels of metabolites from the methionine and tyrosine metabolism pathways in mouse plasma, liver, muscle, and brain. The Frailty Index (FI) is a non-invasive composite measure of health that can assess an effect of treatment on different aspects of healthspan and predict life expectancy and the efficacy of a lifespan-extending interventions up to a year in advance (Sukoff Rizzo et al., 2018), (Schultz, Kane et al., bioRxiv 2019). In addition to the FI, to estimate the potential effects of proposed interventions on lifespan, we will use mouse ‘epigenetic clocks’ to predict the effects of proposed intervention on biological age and lifespan extension. Through this Developmental Pilot, we expect to test how manipulations of methionine and tyrosine metabolism pathways affect the multitude of parameters relevant to aging in mice, with a special focus on the assessments of motor and fine motor function. 

Core Collaborations/ grants: BMAC/ Preclinical Phenotyping Core. 

Future Proposals: This pilot project will provide the necessary data for a National Institute of Aging R01 grant proposal.  Long-term goals include evaluation of recombinant Methioninase and nitisinone/orfadin for lifespan extension in mice and for the effects on the FI in humans.

RESEARCH (31 Projects Listed)
1. Project Title: Establishing a Distribution Approach for the On the Move Group Exercise Program
  Leader(s): BRACH, JENNIFER
    PCORI EADI-19784 / ( 2021 - 2022 )
  Mobility is a critical component of independence for older adults. Through a PCORI-funded trial, the project team demonstrated that the On the Move (OTM) group exercise program both improved mobility in older adults and was more effective than a standard exercise program for improving mobility. Though the project team and others have demonstrated the benefits of improving mobility through exercise, the programs are seldom used outside of the research setting. A fundamental obstacle to successful dissemination and implementation of evidence-based exercise programs is the lack of a systematic approach for marketing and distribution.
2. Project Title: Leveraging a natural experiment to identify the effects of VA community care programs on health care quality, equity, and Veteran experiences
    VA I01HX003457 / ( 2022 - 2026 )
  Background: The Veterans Choice Program and MISSION Act have transformed how VA delivers care by expanding Veterans eligibility to receive VA-funded care from community providers. The effects of this change on the quality and equity of care are unknown. Understanding these effects is critical, given the importance of these programs to VA and the complexity of managing care for Veterans across different health systems. To address this evidence gap, we will use a quasi-experimental regression discontinuity (RD) design and examine outcomes in medically and socially vulnerable subgroups to determine the impact of Choice and MISSION on quality and equity of Veterans health care. To further examine impacts on vulnerable groups, we will analyze disparities in ratings of community care from VA s Survey of Healthcare Experiences of Patients (SHEP). Significance: This proposal addresses cross-cutting HSR&D research priorities, including evaluating the quality and equity of care for Veterans in the context of a key legislative priority for VA: the MISSION Act. We will examine how the effects of receiving community care, and patient experiences with community care, differ in vulnerable populations, addressing VA priorities related to equity. The project constitutes an advancement in the rigor of research while directly informing ongoing and high priority clinical initiatives within VA. Innovation and Impact: Our project is innovative because it uses an RD design to provide causal evidence about the effects of community care on the quality and equity of outpatient care and prescribing. The project is also innovative and impactful in its attention to subpopulations of socially and medically vulnerable Veterans, including analyses of disparities in community care patient experiences from national survey data. By working closely with operational partners and a Veterans Advisory Board, we will impact VA policy by translating findings into actionable recommendations to improve community care, particularly for vulnerable groups. Specific Aims: (1) Identify the effects of receiving outpatient community care through Choice and MISSION on quality and equity. (2) Identify the effects of community care on the quality and equity of prescribing. (3) Compare Veterans experiences with community care in vulnerable and other Veteran populations. Methodology: We will use an RD design and analyses of both administrative and VA survey data to assess the effects of Choice (all program years) and MISSION (2019-2022) on the quality and equity of Veterans health care. Aims 1-2 will use a quasi-experimental RD design that compares Veterans just above vs. below distance and travel time eligibility thresholds for VA community care in Choice and MISSION. We will study effects of community care use on quality overall and, to evaluate implications for equity, in vulnerable subpopulations defined by the presence of serious mental illness or substance use disorders, complex chronic conditions, low income, and racial/ethnic minority status. Outcome variables in Aim 1 focus on outpatient processes of care (e.g., continuity of care) and outcomes linked to care coordination (e.g., admissions for ambulatory care-sensitive conditions). Outcome variables in Aim 2 focus on prescribing safety and quality (e.g., drug-drug interactions), therapeutic duplication, and refill non-adherence. These analyses use VA Corporate Data Warehouse, Planning Systems Support Group, Medicare, and Program Integrity Tool data. In Aim 3, we will analyze national data from the VA SHEP Community Care survey (conducted among community care recipients) to compare patient-reported experiences with community care among Veterans in vulnerable populations vs. other Veterans. Outcome variables in Aim 3 include 5 domains of Veterans experiences with care coordination, provider communication, and timely access in VA community care. Next Steps/Implementation: Through close partnerships with the Office of Community Care, Pharmacy Benefits Management, Office of Health Equity, and a Veterans Advisory Board, we will rapidly disseminate our findings and translate them into actionable recommendations to improve quality and equity in community care.
3. Project Title: Identifying Risk and Improving Care for Elder Abuse among Veterans
  Leader(s): MAKAROUN, LENA
    VA IK2HX003330 / ( 2022 - 2027 )
  Background. Elder abuse (EA) is the physical, sexual or psychological abuse, financial exploitation or neglect of an adult age =60 years. One in 10 older adults experience EA annually in the US, with many experiencing multiple types. Veterans are at particularly high risk due to the high prevalence of EA risk factors in this population. Experiencing EA is linked to depression, injury, increased healthcare use and mortality, but despite its prevalence and morbidity, fewer than 5% of cases are detected, limiting opportunities for intervention. While screening is a common approach to improving detection of similar conditions, screening tools for EA have not been well validated or widely studied. Furthermore, EA screening may miss important high-risk populations, such as those with dementia, necessitating the development of additional detection strategies that complement screening. This research aims to improve EA risk detection in VA by both evaluating and optimizing current EA screening approaches and by leveraging VA healthcare data to identify Veterans with clinical suspicion of EA who may benefit from further assessment. Significance/Impact. With the growing population of older adults in the US and over 10 million US Veterans age =60 years, improving detection of and interventions for EA is a national and VA public health priority. By improving detection of EA via both better-informed screening and novel data-driven tools, this research aligns with VA HSR&D s priority to improve care for our nation s aging Veterans and their caregivers. Innovation. This research integrates elder abuse and implementation science conceptual frameworks to develop new approaches to improving EA detection. This study will evaluate the test characteristics of the first-ever data marker for EA suspicion using unique VA data elements and will employ innovative data informatics approaches, such as natural language processing (NLP), to address a complex social problem with large health impacts. Specific Aims. Aim 1 is a national assessment of the current landscape of EA screening practices in VA medical centers (VAMCs) and a quantitative evaluation of facility level factors associated with screening. Aim 2 is a quantitative study that will identify the best performing EA administrative marker (AM) in VA data. Aim 3 is a qualitative study that will elucidate opportunities for, facilitators of and barriers to implementation of healthcare-based EA detection programs in VA. Methodology. In close partnership with the VA Office of Care Management and Social Work, Aim 1 will conduct a national survey of VAMCs to assess current practices around EA screening and detection; VA facility-level data will be used to assess structural characteristics associated with screening. Aim 2 will examine three potential EA suspicion AMs and select the best performing via comparison to a multi-component reference standard consisting of: a) simplified rule-based NLP of progress note content, and b) evaluation of discordance between AMs and NLP through targeted medical record review. In Aim 3, early-, recent-, and non-EA screener sites identified in Aim 1 varying in EA case volume according to the AM selected in Aim 2 will be recruited for in- depth qualitative interviews to elucidate opportunities for, facilitators of, and barriers to EA detection programs in VA. Implementation/Next steps. Findings from this research will be used to derive and validate a novel EA Suspicion Tool (EAST) in VA, then develop and implement a detection approach that improves efficiency and impact by combining improved EA screening with comprehensive EA assessments targeted towards those at highest risk. Candidate. Dr. Lena Makaroun is a geriatrician and Core Investigator at the VA Center for Health Equity Research and Promotion. The goal of this CDA is to gain training and research experience in improving EA detection among older Veterans through in-depth training in: (1) real-world EA evaluation and intervention programs; (2) implementation science; (3) framework-guided qualitative methods; and (4) prediction analytics. This CDA will support Dr. Makaroun s long-term career goal of becoming an independent VA health services researcher focused on improving care delivery, intervention and, ultimately, prevention of EA in older adults.
    NIH K01AG057726 / ( 2018 - 2023 )
  Core(s): - Clinical and Population Outcomes Core (CPOC)
- Data Management, Analysis and Informatics Core (DMAIC)
  Age-related declines in physical function are common and lead to increased health care costs, institutionalization andmortality. As a traditional epidemiologist with unique expertise in skeletal muscle aging and physical function, I haveresearched lifestyle interventions (weight loss, aerobic and resistance training) to prevent age-related declines in physicalfunction. However, lifestyle changes are difficult to adopt, especially for those at the highest risk for functional decline. Toextend the benefits of these interventions, it is imperative to understand biological processes underlying changes in functionwith aging and following intervention. As such, the current proposal will provide the candidate with advanced training inmolecular epidemiology and biology of aging, yield novel insight on the genetic and biological basis of physical functionamong older adults and lay the foundation for future research. Specially, Aim 1 will identify genes and genetic variants forphysical function and changes in physical function with aging. Aim 2 will examine blood RNA expression for componentsof the transforming growth factor beta (TGF- ) pathway, which is implicated in muscle dysfunction and pathogenic fibrosis,with physical function and its change with aging. Aim 3 will test if serum levels of TGF- and procollagen type 3 N-terminal propeptide (P3NP - a biomarker of pathogenic fibrosis) are related physical function among older adults. I willleverage robustly collected physical function measures, biological samples, and an ultra-high-density genome-widepolymorphism map from the NIA-funded Long Life Family Study (LLFS), a multi-center study of exceptional aging andlongevity in families and fromThe Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE)Consortium. The proposed research and training is very innovative. First, despite being implicated in several age-relatedconditions there have been no human studies that have examined the relationship between TGF- or P3NP and physicalfunction. Further, LLFS has a large number of oldest old , who are understudied and at the highest risk for functionaldecline. There has also been limited research on the genetics of physical function. The proposed career development awardwill provide the applicant with essential new mentorship, knowledge and skills in human genetics and molecularepidemiology including but not limited to blood RNA expression and protein biomarker development (Aim 2 and 3),genome wide association (GWA) and linkage analyses (Aim 1), meta-analysis(Aim 1) and bioinformatics (Aim 1)approaches to follow-up association and linkage analyses. Finally, this award will be critical for facilitating my transitionto an independent research career in aging and molecular epidemiology with a focus on physical function. As anepidemiologist with expertise in both traditional and molecular methods,I will be well-positioned to contribute to theadvancement of the evolving field of GeroScience.
5. Project Title: The relationship between protein intake, gut microbiome, inflammaging and loss of mobility in older adults
    NIH K01AG071855 / ( 2022 - 2026 )
  This K01 application is for Dr. Samaneh Farsijani to establish a research career in Nutritional Epidemiology and acquire skills to integrate omics (gut microbiome) and non-omics (dietary intake) data towards her long-term goal in Precision Nutrition to develop age-specific dietary recommendations, replacing the current one-size-fits-all approach, to promote healthy aging. The proposal is derived from the candidate s extensive training in nutrition and interdisciplinary research background in biology and epidemiology. The proposed training goals are directed to advance candidate s skills in 1) aging & nutritional epidemiology; 2) advanced biostatistics; 3) gut microbiome; and 4) career development. Acquired skills will be applied toward the proposed scientific goal to determine the relationships between protein intake, gut microbiome, inflammation, and mobility loss in older adults. Aging is associated with inefficient utilization of dietary proteins, due to anabolic resistance, which potentially leads to functional losses. Also, up to 50% of US older adults fail to meet the Recommended Dietary Allowance (RDA) for protein (0.8 g/kg body weight/d). Therefore, a higher protein intake, above the RDA (1.0-1.2 g/kg/d), has been suggested to compensate for changes in protein metabolism and to maintain muscle health in aging. However, this strategy has not been incorporated into dietary guidelines due to inconclusive evidence from small and short- term studies, which were unable to show the underlying mechanisms and causal relationships between protein intake and mobility function in older adults. Gut dysbiosis (i.e., changes in gut microbiome) and inflammaging (i.e., low-grade chronic inflammation in aging) have been linked to frailty in older adults. Since diet plays a key role in shaping the gut microbiome and inflammation, it may be speculated that the effects of protein intake on mobility function are mediated through alterations of dysbiosis and inflammaging. Our central hypotheses are: i) high protein intake reduces the risk of mobility limitation by ameliorating inflammaging; ii) different protein intake metrics are independently associated with gut microbiome and inflammaging; and iii) gut dysbiosis is associated with mobility impairment in older adults. This proposal will leverage data from Health, Aging & Body Composition (Health ABC), and Study of Muscle, Mobility & Aging (SOMMA) cohorts to address three Aims: Aim 1: To simulate a pragmatic clinical trial using the Health ABC cohort to determine i) the effect of protein intake on the risk of mobility limitation, and ii) its causal mediation by amelioration of inflammaging. Aim 2: a) To characterize the associations between different metrics of protein intake (i.e., quantity, source and within-day distribution pattern), gut microbiome composition, and fecal metabolites; and b) to determine the association between gut dysbiosis and inflammaging in SOMMA. Aim 3: To determine the cross-sectional associations between gut microbial composition and fecal metabolites with mobility (i.e., gait speed) in older adults from SOMMA. This project will broaden our insights into the influence of protein intake, as a modifiable factor, on gut microbiome, inflammaging, and muscle health in aging with the ultimate goal to drive age-specific dietary advice.
  Leader(s): ROBERTS, ERIC T
    AHRQ K01HS026727 / ( 2019 - 2023 )
  Core(s): - Clinical and Population Outcomes Core (CPOC)
- Data Management, Analysis and Informatics Core (DMAIC)
  PROJECT SUMMARY / ABSTRACT This AHRQ Mentored Research Scientist Career Development Award (K01) for Dr. Eric T. Roberts, anassistant professor of health policy and management at the University of Pittsburgh Graduate School of PublicHealth, will establish Dr. Roberts as a health economist with expertise in health insurance and health carepolicy for aging and low-income populations. Research proposed for this K01 award will harness natural experiments created by eligibility thresholdsand policy variation within Medicare subsidy programs to rigorously evaluate how these programs affectpatients' use of care, access to providers, and health. This project will focus on two subsidy programs forlow-income Medicare beneficiaries: the Medicare Savings Programs (MSPs), which are partial Medicaidbenefits that defray out-of-pocket costs for physician services and inpatient care, and the Part D Low-IncomeSubsidy (LIS), which helps to pay for prescription drugs. Using the Health and Retirement Study linked toMedicare and Medicaid claims, Dr. Roberts will examine how discontinuities in subsidy eligibility affectpatients' use of care including medication adherence, physician visits, and hospitalizations and healthstatus. Dr. Roberts will also examine the relationship between state Medicaid policies specifically, providerpayment rates and rules for recertifying program eligibility with MSP enrollment and patients' access tocare. Evidence generated from this research can guide reforms to increase the benefits of the MSPs and LISto low-income Medicare beneficiaries and to the Medicare program. This project draws on Dr. Roberts' quantitative training, knowledge of Medicare and Medicaid policy, andprior research on health disparities. This work will extend Dr. Roberts' scholarship into the field of aging whileincorporating methods in pharmaceutical health services research. Therefore, for this K01 award, Dr. Robertswill engage in training and career development activities that focus on acquiring expertise in aging andpharmaceutical health services research. Through mentorship from health services researchers and clinicalexperts, Dr. Roberts will also focus on applying training in these content areas to health policy research. Thistraining plan complements the proposed research and will equip Dr. Roberts to establish an independentresearch program examining policy innovations to improve care for low-income Medicare beneficiaries,quantifying the clinical and economic impacts of policy reforms for patients, payers, and health systems.
7. Project Title: Human Factors of Aging Program
  Leader(s): REDFERN, MARK S
    NIH K07AG061256 / ( 2021 - 2025 )
  Abstract: The candidate, Mark S Redfern, PhD, is a professor at the University of Pittsburgh with a primary appointment in the Department of Bioengineering, Swanson School of Engineering, and secondary appointments in Otolaryngology, School of Medicine, and Physical Therapy, School of Health and Rehabilitation Science. He is applying for a K07 to establish a new program in Human Factors of Aging to educate and support researchers, clinicians and students focused on improving the lives of older adults. A unique aspect of the curriculum is including design for cognitive decline and Alzheimer s disease through a partnership with Pitt s Alzheimer s Disease Research Center (ADRC). Research often leads to ideas and findings that can have direct application to improve the lives of people of all ages. One limiting step in the translation of these new ideas is the incorporation of human factors in the design. Incorporating the human factors of aging is a critical component of any medical device design for an older population. There are physical (e.g. mobility, dexterity, anthropometry, strength, range of motion), sensory (e.g. vision, hearing, vestibular, proprioception) and cognitive considerations (e.g. memory, executive function, cognitive speed). Translation of ideas for older adults with cognitive decrements and Alzheimer s disease is particularly difficult. The interactions of cognitive decrements with the physical and sensory changes associated with aging require special attention during design that to-date is not addressed. To address this need, Dr. Redfern, in collaboration with the ADRC, will establish a new and novel educational program with a curriculum to bring the necessary knowledge of Human Factors of Aging to the research community. This curriculum will address not only physical and sensory considerations, but also the unique requirements for adults with cognitive decline, and how they interact with other age-related issues. The long-term goal is to improve the development of new medical devices and interventions that are targeted to be used by/with older adults taking into consideration cognitive decline. The specific aims are to: 1) partner with the ADRC to educate clinicians, researchers, and engineers in the human factors of aging to improve the translation of their ideas into effective interventions 2) support investigators with collaborative advising and consultation on special issues in aging-related applications and availability of the Human Factors in Medical Device Laboratory for development and evaluation of medical devices/interventions targeting for older populations; and 3) develop a multidisciplinary community of investigators with interests and expertise in human factors of aging; including experts from the ADRC. Dr. Redfern s background as a senior NIH/NIA researcher, longtime educator in Human Factors/Ergonomics, and positions in academic leadership make him the ideal person to create a sustainable and effective program. The proposed partnership with the ADRC will bring together a unique strength found nowhere else.
    AHRQ K08HS027210 / ( 2019 - 2024 )
  Core(s): - Clinical and Population Outcomes Core (CPOC)
- Data Management, Analysis and Informatics Core (DMAIC)
  ABSTRACTAccess to high-quality post-intensive care unit (ICU) recovery services is a major problem for thousands ofolder Americans living in rural communities who survive critical illness each year. They and their families oftenexperience uncoordinated care, poor health, reduced independence and quality of life, and high ongoinghealthcare utilization. Any scalable solution will require the flexibility to address multimorbidity, physical, cogni-tive, and psychological dysfunction, caregiver stress, and end-of-life transitions, all of which are common. Toaddress this problem: (1) The principal investigator will acquire new skills that position her as an independentimplementation physician scientist specializing in improving the quality of geriatric critical care in the post-ICUperiod. She will complete a career development plan including didactic courses, experiential research, and in-tensive transdisciplinary mentoring with her team from geriatric psychiatry, occupational therapy, critical care,and biostatistics. It will equip her with expertise in stakeholder engagement, transitional care, rehabilitation,telehealth, and implementation science; (2) The proposed research will develop and pilot test a scalable,stakeholder-informed, evidence-based ICU recovery intervention called TeleRecovery. In TeleRecovery, anurse practitioner and occupational therapist will deliver transitional care, family training and support, andskills-based rehabilitation to rural-dwelling older adults, starting at ICU transfer. From discharge until gradua-tion back to primary care, they will partner with home health providers via telehealth to implement the careplan. Instead of developing TeleRecovery de novo, we will use stakeholder engagement to adapt transitionalcare (Transitional Care Model) and skills-based rehabilitation (Patient-Driven Skills Training) interventions.These interventions have proven success among clinical populations with key similarities to ICU survivors;combining them will comprehensively address rural-dwelling, older ICU survivors complex needs. The firststep in developing TeleRecovery will be semi-structured interviews and focus groups with a full range of stake-holders patients, families, hospital- and community-based providers, and healthcare administrators includingpayers to identify priorities, barriers, and facilitators in delivering ICU recovery care for older ICU survivors.We will integrate results into a model of care delivery that is patient-centered and improves health-system qual-ity, affordability, and access. Second, we will conduct stakeholder workshops, telehealth software modification,interventionist training, and user testing to apply the model from Aim 1 to develop TeleRecovery for rural, olderICU survivors. Finally, we will conduct a pilot study to evaluate its feasibility and acceptability among rural,older ICU survivors. This research will generate: (1) partnerships among institutional leaders in critical care,home health, healthcare administration and finance, rehabilitation, and telehealth to facilitate further research;(2) a pilot tested TeleRecovery intervention that is ready for testing in a clinical trial; (3) an independent imple-mentation physician scientist capable of seeing TeleRecovery through implementation and dissemination.
9. Project Title: Activity and Participation in Vestibulopathy
  Leader(s): KLATT, BROOKE
    NIH K23DC020215 / ( 2022 - 2027 )
  Current vestibular rehabilitation intervenes upon vestibular impairments (balance, gaze stability, and dizziness). Activity and participation are reduced in people with vestibulopathy, but are not addressed in vestibular rehabilitation protocols. Approximately 40% of people with vestibulopathy do not fully recover and transition to a state of chronic disability, which often results from reductions in activity and participation, and. Evidence from rehabilitation science within other populations suggest that return to full activity and participation is related to functional mobility status, and also several behavioral, personal, and environmental factors. Similarly, we suspect that cognitive, mood, and personal (confidence, coping, and fear avoidance) factors that are modifiable, may impact activity and participation in people with vestibulopathy. It is also unknown whether improvements in activity and participation are related to remediation of impairments following vestibular rehabilitation. Activity and participation represent important domains to target to optimize outcomes and reduce chronic disability. This career development award will establish Dr. Brooke Klatt as a clinical scientist with expertise in 3 primary domains: (1) cohort design and analysis; (2) qualitative methodology, and (3) complex rehabilitation intervention development and behavioral clinical trial methodology. Dr. Klatt has assembled a multi-disciplinary team of experts in rehabilitation intervention development and implementation (Jennifer Brach, PhD, PT and Elizabeth Skidmore, PhD, OTR/L), activity and participation assessment and epidemiological methods (Andrea Rosso, PhD, MPH), behavioral impacts on vestibular recovery (Jeffrey Staab, MD), and clinical trial methodology (Megan Hamm, PhD and Charity Patterson, PhD, MSPH). Dr. Klatt will conduct a series of studies to develop an enhanced vestibular intervention that will augment current vestibular rehabilitation targeted to improve activity and participation. She will investigate whether impairments (balance, gait, gaze stability, dizziness, cognition, and mood) as well as personal factors (confidence, coping skills, and fear avoidance) are related to activity and participation in people with vestibulopathy (Aim 1), and she will determine if reductions in vestibular impairment is related to improvements in activity and participation (Aim 2). She will use stakeholder input from clinicians and patients to determine the delivery features that show the greatest promise for improving activity and participation in people with vestibulopathy (Aim 3). Dr. Klatt s is plan to develop effective interventions to enhance current vestibular rehabilitation addresses the NCMRR research priorities to mitigate acquisition of secondary conditions by using a multimodal approach to promote vestibular plasticity and sensorimotor function. The proposed training will be the foundation for a future R01 application examining the efficacy of the enhanced vestibular intervention to improve activity and participation and the quality of life for individuals with vestibulopathy.
  Leader(s): BRACH, JENNIFER S
    NIH K24AG057728 / ( 2017 - 2022 )
  Core(s): - Clinical and Population Outcomes Core (CPOC)
- Integrative Systems Core (ISC)
  Midcareer Investigator Award in Translational Patient-Oriented Research in AgingThis application is for a K24 Midcareer Investigator Award in Patient-Oriented Research to promote mentoringand career development in dissemination and implementation research that improves mobility and preventsdisability in community-dwelling older adults. Dr. Jennifer Brach, PI of the proposed award, is a physicaltherapist, epidemiologist and scientist committed to mentoring health professional trainees and junior facultyand working to improve the mobility and quality of life of older adults. For over 15 years, she has conductedpatient-oriented research studies focused on increasing successful aging among vulnerable older adults andshe has built a strong multi-disciplinary network of research collaborators who are available to co-mentortrainees and junior faculty. Her long-term goal is to bridge the gap between clinical research, public health, andeveryday practice by transferring the findings from clinical trials to practice settings and communities, wherethe findings will improve mobility and prevent disability in older adults and to train health professionals andjunior faculty for a successful career in academic investigation. Dr. Brach seeks support from a NIA K24 careeraward to: 1) establish a research training and mentoring program that will prepare beginning scholars tobecome successful, independent patient-oriented researchers in disability prevention in aging, 2) obtainadditional training and participate in practical experiences in dissemination and implementation science thatwill enhance her translational research skills, and 3) extend her currently funded work to bridge the gapbetween clinical research and practice settings and the community. Dr. Brach has a substantial and growingtrack record of mentorship of trainees from a variety of disciplines; the requested K24 support would allow herto curtail teaching and administrative responsibilities so that she can focus the majority of her time on researchand mentoring.
    MICHAEL J FOX FOUNDATION MJFF-008849 / ( 2021 - 2023 )
  Core(s): - Biology of Mobility and Aging Core (BMAC)
  Dopamine neurons are highly vulnerable to age-dependent increases in mitochondrial dysfunction, oxidative stress, and protein accumulation due to their high metabolic activity, low antioxidant capacity and post-mitotic nature. Failure to remove these damaged mitochondria will likely lead to a bioenergetic crisis that ultimately contributes to the onset and/or progression of Parkinson s disease. The deubiquitinating enzyme, ubiquitin specific protease 30 (USP30) blocks mitochondrial degradation. In Parkinson s disease, USP30 is increased in dopamine neurons, therefore, blocking USP30 may be neuroprotective by allowing damaged / dysfunctional mitochondria to be degraded. We hypothesize that using targeted genetic technology to block USP30 will allow damaged mitochondria to be removed, and the overall pool of healthy mitochondria to increase. This will enhance dopamine neuron bioenergetics, reduce oxidative stress and promote neuronal survival.
  Leader(s): GIANAROS, PETER J
    NIH P01HL040962 / ( 1997 - 2023 )
  Core(s): - Integrative Systems Core (ISC)
  ABSTRACTBiobehavioral Studies of Cardiovascular Disease (PO1-HL040962)This Program Project (P01) continuation application focuses on the human brain substrates of behavioral andsocio-environmental influences on cardiovascular disease (CVD) risk in midlife adults. Proposed are 3 Projectsthat are conceptually cross-linked and supported by 3 Core Units. Collaborative investigators representmultiple disciplines, including psychology, neuroscience, biophysics, medicine, psychoneuroimmunology,epidemiology, machine learning, bioinformatics, and statistics. Project 1 aims to elucidate functional andstructural brain phenotypes that predict the multiyear progression of preclinical vascular disease anddysfunction, with a focus on neural circuitries for visceral control that coordinate autonomic, neuroendocrine,hemodynamic, and immune physiology with stress- and emotion-related behavioral processes. Project 2 aimsto establish whether functional characteristics of these visceral control circuits moderate the influences ofstress-related environmental exposures on the progression of preclinical vascular disease and dysfunction,tracking individuals' behavior and cardiovascular physiology in daily life to test a novel neuro-diathesis modelof CVD risk. Project 2 also tests for the first time whether daily life physical activity associates with daily lifestress physiology through its effects neural circuits for visceral control. Project 3 aims extend those of the otherProjects by elucidating the neural and peripheral processes linking physical activity with physiological andpsychophysiological markers of CVD risk (including daily life affect and stress physiology) using anexperimental intervention methodology. These P01 aims are unique in cardiovascular behavioral medicine, andthey will be pursued in the context of multi-component data collection efforts that satisfy all project-specificaims. As a result, the P01 will create new opportunities for integrative and translational science on the humanneurobiology of CVD risk that cuts across multiple methods and levels of analysis. Helping to advance itsparent field, the P01 will generate and disseminate original and expansive public-domain resources and tools tothe broader scientific and clinical communities through comprehensive data and software sharing andeducational objectives. Enabling a precise focus on early CVD etiology, the study cohorts comprise nearly 900midlife adults without clinically apparent CVD, and study methods will include novel combinations ofneuroimaging, ecological momentary assessments of experienced environments, ambulatory hemodynamicmonitoring, autonomic, neuroendocrine, immune, and vascular assessments, laboratory clinical evaluations,hetero-method health behavior assessments, and arterial imaging. The 3 Core Units of this P01 provide forsynergy and inter-project coordination by administrative, data management and participant accrual services;measurement and instrumentation support; and direction in cutting-edge bio-statistical and data-intensive(machine learning) analyses. The present application thus represents a thematic continuation and next-generation extension of translational neurobiological research on CVD by this P01, which was initiated in 1988.
  Leader(s): ROSSO, ANDREA L
    NIH R01AG057671 / ( 2018 - 2022 )
  Core(s): - Clinical and Population Outcomes Core (CPOC)
- Data Management, Analysis and Informatics Core (DMAIC)
  Project Summary/AbstractAs many as 30 million older adults in the US have walking limitations which could impact community mobility.Restriction in community mobility contribute to disability, institutionalization, and poor quality of life. Comparedto walking in clinical settings, community mobility requires rapid negotiation of complex, multi-sensorial, andoften variable and unpredictable environments. Successful community mobility requires rapid integration ofinformation both external (e.g. surface quality, distances) and internal (e.g. fatigue, pain) to the individual.Integration of these inputs primarily occurs at the level of the central nervous system. Under normal conditions,this integration favors automatic motor control with few demands on attention-related networks, primarilylocated in the prefrontal cortex (PFC). As automatic motor control diminishes in older adults, activation of thePFC during walking tasks increases. Age-related impairments in body systems (e.g. musculoskeletal,cardiopulmonary) increase the demands of walking while concurrent impairments in the brain can reducecapacity for motor control. The mismatch in demands and capacity can be magnified when walking occurs inthe context of complex community environments (e.g. uneven surfaces, attentional demands); therefore,automatic motor control is likely a critical component of community mobility. Motor skill training (MST) is anintegrated intervention approach developed to improve walking. The goal of MST is restoration of automaticmotor control and behavioral flexibility during walking, which are needed for addressing environmentalchallenges during community mobility. The MST approach may restore automatic motor control and provideolder individuals with the capacity to address environmental challenges and maintain community mobility. Wepropose to test the effects of MST on community mobility and motor control. Community mobility will bequantified by state of the art, objective measures from global position system (GPS) tracking, including activityspace (the area travelled by an individual in daily activities) and time away from home. Central motor controlwill be assessed by wireless functional near-infrared spectroscopy (fNIRS) at the PFC during dual-taskwalking. Further, we will assess the influence of individuals cognitive function and neighborhood environmentsby neighborhood socioeconomic status and walkability audits on changes in community mobility. We willleverage an ongoing randomized, 12-week efficacy trial of standard therapy compared to standard plus MST(R01 AG045252; PI: Jennifer Brach) that is enrolling individuals aged 65 years and older with gait speeds 0.6-1.2 m/s (n=248). The primary outcome of the parent trial is gait speed; our proposal will extend the outcomefrom clinic-based measures to real world community mobility at baseline and 12, 24, and 36 week follow-upvisits. Results will provide evidence for intervention approaches to improve community mobility of older adults.
  Leader(s): ERICKSON, KIRK I
    NIH R01AG060741 / ( 2018 - 2023 )
  Core(s): - Integrative Systems Core (ISC)
  Abstract African Americans are almost two times more likely than whites (i.e., Caucasians) to experience Alzheimer'sdisease or other dementias. For those over the age of 65, the prevalence of cognitive impairment is 8.8% in whitesand 23.9% in African Americans. Even in the age range of 55-64, African Americans are 4 times more likely toexperience cognitive impairment than their age-matched white counterparts. Increased risk of dementia amongAfrican Americans may be attributed to lower levels and quality of education, lower socioeconomic status (SES),and higher prevalence of vascular diseases, Type II diabetes, hypertension, and obesity, all of which arerecognized as risk factors for dementia. A critical public health question emerges from these statistics that weintend to address in this proposal: Is there an effective method for reducing or eliminating the race disparitiesin cognitive and brain health Fortunately, physical activity (PA) interventions may be effective at improvingneurocognitive function and reducing risk for dementia. Despite these promising results, prior PA interventionshave had few African Americans making it difficult to stratify results by race to determine whether AfricanAmericans respond to PA in a similar manner and magnitude as whites. In addition, the terms `physical activity'and `exercise' are often considered unpleasant, painful, and fatiguing, which can negatively influence interest,enrollment, and long-term adherence. Methods that increase PA without using the term PA (e.g., dancing) couldbe effective at improving health outcomes while simultaneously having a wider impact on translation and long-term adherence. Here we propose an innovative and culturally sensitive method of increasing PA in older (60-80 yrs) African Americans. We propose a randomized intervention where 180 older African Americans areassigned to either a moderate intensity African Dance group 3 days per week (N=90) or to an AfricanEducation group 3 days per week (N=90) for 6-months. Both before and at the completion of the intervention,we will collect a comprehensive neuropsychological battery and MRI metrics of brain health and function toidentify biological pathways by which PA influences neurocognitive health in an African American population.This proposal has the potential to utilize community-based activities to improve health of older AfricanAmericans. In addition, it could establish a platform (i.e., dance) to implement future interventions targetingminority populations to reduce health disparities. We have three primary aims: Aim 1. Examine whether a 6-month African Dance intervention improves cognitive performance compared to an educational control group.Aim 2. Examine whether African Dance influences brain morphology, task-evoked neural responses, cerebralblood flow, and resting state connectivity. Aim 3. Explore potential physiological and socioemotionalmechanisms of the dance intervention. We will collect measures of physical and psychosocial health such as waistcircumference, blood pressure, blood glucose and lipid levels, mood, anxiety, depression, and loneliness andexamine whether intervention-related changes to these measures mediate improvements in cognitiveperformance.
    NIH R01AG061005 / ( 2019 - 2024 )
  Core(s): - Biology of Mobility and Aging Core (BMAC)
  ABSTRACT Skeletal muscle trauma resulting from an injury or surgery often results in significant functional declinesin older adults. These declines are at least partially attributed to failed muscle healing. Muscle regeneration ispredominantly dictated by the action of muscle stem, or satellite , cells (MuSCs), a reserve cell population thattypically demonstrates considerable dysfunction with increasing age. According to the stem cell niche concept, stem cell responses are largely determined by biophysical and biochemical cues that emanate fromthe surrounding microenvironment. Indeed, expanding recognition of the influence of the microenvironment onstem cell behavior has led to a recent surge in the development of bioinspired and engineered extracellularmatrix (ECM) approaches for the treatment of skeletal muscle injuries. Still lacking, however, is an in-depthknowledge of whether and how pathogenic instructional characteristics of the native ECM disrupt MuSCfunction and skeletal muscle regeneration. While it is evident that MuSC activation, self-renewal, proliferationand differentiation are influenced by physical and dynamic niche interactions, a mechanistic understanding ofthe direct impact of age-related ECM alterations on skeletal muscle regenerative capacity is unknown. The over-arching goal of this project is to test our central hypothesis that age-related biophysicalalterations in the skeletal muscle ECM promotes a fibrogenic conversion in MuSCs, ultimately drivingimpaired skeletal muscle regeneration. Further, we hypothesize that these pathogenic biophysicalchanges may be reverted, at least partially, by mechanical stimulation. To achieve this goal, we willemploy an integrated approach that encompasses cutting-edge super-resolution imaging and 3-D tissueengineering methods to address two specific aims. Aim 1 studies will measure, manipulate, and mimic thebiophysical properties of young and aged skeletal muscle ECM in order to dissect the effect of age-relatedarchitectural and elastic ECM modifications on MuSC fate. Aim 2 studies will identify mechanisms by whichmechanical stimulation modulates biophysical properties of the aged ECM to promote MuSC myogenicity andmuscle regeneration. Successful achievement of these aims will further our understanding of 1) theinstructional capabilities of the native ECM on MuSC lineage specification, 2) how these instructionalcapabilities change over time, and 3) the molecular mechanisms controlling age-related declines in skeletalmuscle regenerative potential. Taken together, successful completion of these studies may provide afoundation for the identification of novel ECM targets in the treatment of skeletal muscle injuries for a geriatricpopulation. More broadly, an improved insight into how age-associated alterations in biomechanical,architectural and dynamic ECM properties direct MuSC function will expand our fundamental understanding ofaging and stem cell biology.
16. Project Title: Comprehensive functional genomic analysis of the multi-disease associated CDKN2A/B locus
  Leader(s): LI, GANG ; FINKEL, TOREN ;
    NIH R01AG065229 / ( 2021 - 2026 )
  ABSTRACT The incidence of cardiovascular disease (CVD), Type 2 diabetes (T2D) and cancers all dramatically increase as a function of age. The underlying mechanisms of these diseases, which vary, are incompletely understood. Genome-wide association studies (GWAS) have identified many SNPs that are associated with these conditions. One of the strongest associations comes from the CDKN2A/B locus on chromosome 9p21.3 which has been associated with multiple age-related diseases, as well as overall human lifespan. Within this 200 kb locus, there are three encoded proteins, p16INK4a, p14ARF and p15INK4b, and one antisense non-coding RNA, the inhibitor of CDK4 (INK4) locus (AS/ANRIL). To date, it has not been firmly established which, if any, of these genes are the risk genes for the associated diseases. There are ~193 disease-associated, noncoding SNPs in linkage disequilibrium (LDs) across this 200 kb region, represented by 18 lead SNPs used for GWAS analysis. While the mechanisms underlying the contribution of these SNPs to specific diseases are not fully understood, a single genetic region associated with multiple different age-related diseases suggests that this locus may modulate these conditions by promoting aging itself, perhaps via induction of cellular senescence as a common mechanism. In this application, we propose to apply an experimental approach using high throughput techniques we have recently developed including Reel-seq and FREP/SDCP-MS, to systematically dissect this locus. We will first identify the disease-associated functional SNPs (fSNPs), as well as the regulatory elements across the 58 kb core region primarily associated with cardiovascular diseases using Reel-seq. Next, we will identify the regulatory proteins that specifically bind to all the fSNPs, as well as the regulatory elements, using FREP/SDCP- MS. A range of relevant cell types related to atherosclerosis will be used to generate the nuclear extract required for our screens. We will demonstrate the role of these regulatory proteins by confirming their direct effects on p16INK4a, p14ARF, p15INK4b and AS/ANRIL expression, and subsequently on cell cycle regulation and cellular senescence. A range of complementary techniques such as RNAi, CRISPR/cas9 gene editing, will be employed. Such analysis will provide the first in-depth understanding of this critical genomic region, as well as a unique strategy to uncover unifying biochemical pathways that simultaneously regulate atherosclerosis, as well as potentially multiple other age-related diseases.
  Leader(s): RESNICK, NEIL M.
    NIH R01AG065288 / ( 2020 - 2025 )
  Core(s): - Clinical and Population Outcomes Core (CPOC)
- Data Management, Analysis and Informatics Core (DMAIC)
- Integrative Systems Core (ISC)
  PROJECT SUMMARY Prevalent, morbid, and costly ($66 billion/year in 2007), incontinence is a major problem, especially for older adults, in whom the most common type is urgency incontinence (UUI). Generally ascribed to bladder spasms, UUI's actual causes are unknown, and therapy remains inadequate. Recent data suggest that one cause is poor bladder control by the brain. In our recent R01 we used biofeedback (BFB) as a probe to explore this. The exciting findings suggest that one `phenotype' of UUI in older adults seems to be caused by a breakdown in brain control, which can be restored by successful behavioral therapy, while another is refractory. Our proposed new study will explore this further by attempting to differentiate the mechanisms associated with disease and aging. The goal is to identify which brain mechanisms should be suppressed because they are contributing to or causing UUI, which should be enhanced because they are helping to compensate for UUI, and which should be ignored because they are incidental to aging and not related to UUI. Current data suggest that bladder control comprises 3 cerebral circuits that maintain continence by suppressing the voiding reflex in the midbrain. In our UUI phenotype that responded to BFB, the mechanism involved enhancing deactivation of the first brain circuit (medial prefrontal cortex, mPFC) which resulted in less activation of the second circuit (which includes the midcingulate cortex). In the phenotype that was resistant to BFB, no brain changes were seen. Yet, although we have an emerging picture of the brain's role in UUI, we have only rudimentary understanding of what is `normal', i.e. how the brain normally controls the bladder. More relevant, we do not know whether this control mechanism is the same across the lifespan, or if it changes owing to the impact of aging. Thus, our overall aim is to characterize continence control in both young and old people, and examine how changes due to bladder control failure differ in each age group. Our specific aims are to characterize normal voiding in the continent old and young in order to better understand and verify the working model and to use the comparison to older adults with UUI to understand the mechanism of brain failure in these individuals. To address these aims, we will conduct a detailed clinical and neuroimaging study to study 80 asymptomatic women and 80 UUI women, each group divided equally into young (18-45) and old (65+ years). The study will enable us to evaluate the changes in brain structure and function and to identify brain mechanisms involved in continence control, changes due to aging (both benign and contributory to UUI), and changes due to disease. The study will provide the comprehensive data on brain mechanisms involved in the normal continence mechanism in order to better corroborate our working model, understand the aging process, and assess targets for therapy. It will thereby enable scientists to develop novel and more effective new therapies based on the revolution in neuroscience and more hope for UUI sufferers.
    NIH R01AG066825 / ( 2020 - 2025 )
  Core(s): - Clinical and Population Outcomes Core (CPOC)
- Data Management, Analysis and Informatics Core (DMAIC)
  Although close to 85% of residents in long-term care facilities (LTC) have osteoporosis and the risk of osteoporotic fractures is nearly 10 times that of community dwelling elderly, few are treated and studies are scarce. The large pivotal osteoporosis trials in postmenopausal women exclude those who are sedentary, frail or functionally impaired even though this is the group at highest fracture risk. Before a fracture reduction study can be justified in this cohort, an investigation demonstrating efficacy and predictability is a necessary first step. We have previously demonstrated that zoledronic acid (ZOL) can maintain bone mineral density (BMD) and is safe in frail elderly. However a dual action anabolic antiresorptive agent has a distinct advantage to build bone rapidly. The newly approved once monthly dual action romosozumab (ROMO), provides significant improvements in BMD and fracture reduction in 1 year. If ROMO were given prior to a potent antiresorptive medication such as ZOL, this combination (rapid boost over a year with ROMO and maintain integrity 2nd year with ZOL) could provide a novel treatment paradigm in this high risk population. The concern for ROMO is the potential increase risk of cardiovascular events demonstrated in one pivotal study. Before a large fracture reduction trial can be justified in this frail population, a study demonstrating BMD efficacy and safety is imperative. We will test the hypotheses that in frail institutionalized women, one year of ROMO prior to one year of ZOL will 1) be more efficacious compared to one year of calcium plus vitamin D prior to a year of ZOL as demonstrated by improvements in conventional bone density measurements, 2) improve novel measures of bone trabecular microstructure and bone turnover markers, and 3) provide characteristics associated with responders and non-responders. To address these hypotheses, we propose to conduct a 2-year, randomized, double-blind controlled trial to test the efficacy and safety of ROMO (year 1) and ZOL (year 2) compared to calcium+vitamin D (year 1) and ZOL( year 2), in 200 institutionalized frail women age 65+ in LTC. Safety will be carefully monitored. Serious adverse events (SAE's) will be obtained by a novel electronic alert system that provides real time notifications including ROMO associated cardiovascular SAE's. This study includes innovative features: 1) focus on the neglected LTC population of frail residents in whom we have a track record of successful enrollment, 2) inclusion of a newly approved potent dual action agent feasible in LTC, 3) assessments of bone structure, 4) point of care vertebral fracture images, 5) mobile lab allowing onsite participation, and 6) electronic alerts for real time adverse events. Despite the call by national consensus groups for the past 2 decades to address osteoporosis in frail elderly, trials and treatments are sparse. This study will challenge the current paradigm of avoiding anti-osteoporosis therapy and provide an innovative approach for geriatric osteoporosis, and help target robust responders.
  Leader(s): RIZZO, STACEY J
    NIH R01AG067289 / ( 2020 - 2025 )
  Core(s): - Biology of Mobility and Aging Core (BMAC)
  Project Summary/Abstract Our long-term goal is to identify therapeutic agents that can prevent the pathogenesis of Alzheimer s disease (AD). The number of AD cases is rising dramatically worldwide, and there is an urgent need to develop new therapies that are more efficacious than the four currently approved drugs for AD which provide only modest symptomatic relief. Every clinical trial to date has failed to demonstrate disease-modifying efficacy for AD, which may in part be due to our limited understanding of the mechanisms that precede the pathogenesis of AD, and that are distinct from normal healthy aging. The overall aims of our proposal are to further understand the mechanisms underlying dysregulation of the autophagy-inflammation network that becomes progressively dysregulated with age, and accelerated by pathological conditions. Systemic inflammation is a biomarker of this dysregulation, as exemplified by its prevalence in many aging-related disorders including cardiovascular disease, diabetes, cancers, and neuroinflammation in neurodegenerative disorders such Alzheimer s disease (AD). We hypothesize that mechanisms which drive systemic inflammation are common to both the biology of aging and AD and propose that interventions which target the shared feature of systemic inflammation, via regulation of the autophagy-inflammation network, may have potential as therapeutic agents for the prevention of conversion to disease pathogenesis in AD, as well as improve healthspan and longevity in aging populations. For this proposal we will use a combination of genetic and pharmacological tools to understand which brain specific cell types may be involved in the regulation of the autophagy-inflammation network via both mTOR dependent and mTOR-independent mechanisms that modulate inflammation. Findings from our studies will provide mechanistic insights at a cellular level and innovative therapeutic strategies for further research. Specifically, we will investigate the individual cell types that contribute to the neuroprotective effects of mTOR inhibition in progressive AD, and confirm and extend the data on the beneficial effects of lifespan and healthspan in sporadic AD with prophylactic treatment of rapamycin. Critically, since age and genetics are the leading risk factors for AD, we will evaluate interventions in preclinical model systems that incorporate both aging and genetic risk factors for AD. We will therefore test the role of direct manipulation of AMPK on modulation of lifespan and healthspan in normal aging and in AD susceptible models, and the beneficial role of MAG lipase inhibition in normal healthy aging and in the pathogenesis of AD in comparison to the effects of rapamycin in a mouse model of late onset AD.
20. Project Title: Preeclampsia and the Brain: Small vessel disease and cognitive function in early midlife
    NIH R01AG072646 / ( 2022 - 2026 )
  Cerebral small vessel disease (cSVD) predisposes to vascular cognitive impairment and dementia, including Alzheimer s Disease. Preeclampsia (PE), a pregnancy-specific disorder with acute hypertension and placental SVD, is emerging as a sex-specific risk factor for dementia later in life. How PE is implicated in the etiology of dementia is not known. Women with PE have SVD also in other vascular beds, including the brain, after pregnancy and worsening with older age, suggesting this process evolves over time. However, studies on SVD in midlife are sparse. Midlife is an ideal time to assess this risk as PE-differences in cognition are already detectable, and yet there is time to mitigate progression to dementia. Cerebral SVD (cSVD) in midlife may hold the key to understand how PE is implicated in cognitive impairment. Placental SVD, known as maternal vascular malperfusion (MVM) predicts worse short-term pregnancy outcomes. We find MVM and PE combined predict long-term worse maternal vascular health in cardiac, sublingual, and cerebral beds. In our pilot study (n=24) MVM and PE combined predicted lower cerebrovascular reactivity (CVR, an early stage of cSVD), especially in fronto-parietal areas; in turn, lower CVR in these regions was associated with, and appeared to explain, PE-related worse cognition. Importantly, these findings were independent of hypertension, suggesting PE has direct and lasting vascular effects . PE and MVM may be early indicators of a future cerebrovascular phenotype, manifesting in midlife as lower CVR, and may explain how PE affects cognition. We propose to study midlife women with and without prior PE to: 1) Characterize the neural basis of PE-related poorer cognitive performance, 2) Assess whether placental SVD (MVM) predicts cSVD and cognition, and 3) Explore whether sublingual SVD and circulating markers of SVD are markers of cSVD and cognition. We propose a neurocognitive study to capture early stages of cSVD and cognitive status in a racially diverse cohort of 450 women (1:1 PE and non PE) from our ongoing WINDOWS study, mean age=45, 15 years post- pregnancy, 30% black, with existing data on PE, MVM, and sublingual SVD 10 years after pregnancy. We will use our advanced multimodal neuroimaging protocols to quantify cSVD (including CVR, blood flow, connectivity), standardized validated protocols to measure cognition, and non-invasive markers of SVD (sublingual SVD, and circulating biomarker profiles) . Our project is uniquely positioned to identify a previously occult high-risk group that can be identified at delivery by placental pathology, and who may benefit from risk- stratification for dementia, to mitigate or delay disease progression.
21. Project Title: Longitudinal Examination of Neighborhood Disadvantage, Cognitive Aging, and Alzheimer's Disease Risk in Disinvested, African American Neighborhoods
    NIH R01AG072652 / ( 2022 - 2027 )
  Project Summary African Americans (AAs) have disproportionately higher rates and earlier onset of Alzheimer s disease and related dementias (ADRD) relative to White Americans. Although prior research has made significant contributions to our understanding of racial disparities in ADRD, we still lack a comprehensive understanding of how the individual lived experience of being AA, including cumulative exposure to structural racism, contributes to elevated ADRD risk and the potential mechanisms underlying those risks. Building on the existing, community-based research infrastructure developed by our team s previously funded studies, we will follow a cohort of residents (n=1133) living in two historically disinvested, predominantly AA communities to understand how dynamic neighborhood socioeconomic conditions across the lifecourse contribute to cognitive outcomes in mid- and late-life adults. This proposal rests on the premise that neighborhood segregation and subsequent disinvestment contributes to poor cognitive outcomes for AAs via factors including a) lower access to educational opportunities and b) higher exposure to race- and socioeconomically-relevant stressors, including discrimination, trauma, and adverse childhood events. In turn, these cumulative exposures foster psychological vigilance in residents, leading to cardiometabolic dysregulation and sleep disruption, which may mediate associations between neighborhood disadvantage and ADRD risk. We also will examine potential protective factors that may promote cognitive health, including neighborhood social cohesion, safety, and satisfaction. The proposed study will leverage our existing longitudinal data on risk and protective factors, biobehavioral mediators, and baseline cognitive assessments, and will include: 1) three waves of cognitive assessments in the full cohort of participants who are 50 years+ (participants who are aged 35-49 years will have two assessments) and clinical adjudication of ADRD in participants who are 50+ (n=906), 2) additional assessments of blood pressure and objective sleep, 3) a comprehensive assessment of life and residential history using the questionnaire from the Health and Retirement Study (HRS); and 4) in-depth qualitative interviews to reveal lifecourse opportunities and barriers experienced by AAs in achieving optimal cognitive health in late life. Understanding how structural racism has influenced the lived experience of AAs including dynamic changes in neighborhood conditions over time is critical to inform multi-level intervention and policy efforts to reduce pervasive racial and socioeconomic disparities in ADRD.
    NIH R01HD074819 / ( 2013 - 2023 )
  Core(s): - Clinical and Population Outcomes Core (CPOC)
- Data Management, Analysis and Informatics Core (DMAIC)
  ABSTRACTImpaired swallowing (oropharyngeal dysphagia or OPD) causes nearly 150,000 annual hospitalizations andover 220,000 additional hospital days, and prolongs hospital lengths of stay by 40%. OPD risk is typicallyidentified through subjective standard institutional screening (SIS) protocols and those identified throughscreening undergo gold standard imaging testing such as videofluoroscopy (VF). However, SIS methods over-or underestimate risk, and completely fail to identify patients with silent OPD who silently aspirate food intotheir lungs, raising their risk of pneumonia and other adverse events. Pre-emptive detection of silent or near-silent aspiration is essential. Our long-term goal is to develop an instrumental dysphagia screening approachbased on high-resolution cervical auscultation (HRCA) to accurately predict OPD-related adverse events, andinitiate more timely intervention measures to mitigate them. The overall objective here is to develop accurate,advanced data analysis approaches to translate HRCA signals to swallowing events observed in VF images.Our strong preliminary data has led us to our central hypothesis: HRCA coupled with advanced data analyticstools are powerful approaches to automate and improve existing dysphagia screening protocols. The rationaleis that a reliable, robust early-warning instrumental OPD screening approach will reduce adverse events inpatients with silent aspiration/dysphagia, shorten length of stay, reduce cost, and improve patient health.Guided by strong preliminary data, we will pursue the following three specific aims: (1) define HRCA signalsignatures that characterize the entire continuum swallowing safety from unimpaired to severely impaired; (2)translate HRCA swallow signal signatures and equate them to validated measures of swallowing impairment;and (3) prospectively assess the effectiveness of our HRCA system in predicting clinically significant OPD andaspiration in a randomized, controlled trial. Under the first aim, we will collect HRCA swallow signatures fromunimpaired people, and combine and analyze them along with our large database of swallows of people withOPD to characterize the entire range of swallowing function from unimpaired through severe OPD. Under thesecond aim, we will develop HRCA OPD severity cutoffs and match them to gold standard derived OPDimpairment cutoffs to establish HRCA s ability as a diagnostic surrogate that differentiates clinically significantOPD and aspiration from benign swallowing impairments. Under the third aim, we will test HRCA in a clinicalsetting by deploying HRCA with consenting patients, and comparing the accuracy of independent HRCA,independent SIS, and HRCA+SIS to VF data from all participants. The approach is innovative, as it willcombine technology with clinical judgment to shift the OPD screening paradigm and fundamentally improveefforts to reduce morbidity and mortality caused by OPD. Our work is significant, because it will translate to anearly-warning HRCA screening tool that will elevate the current standard of patient care by ensuring thatpatients with OPD are correctly identified before adverse events can occur.
    NIH R01HL134809 / ( 2017 - 2022 )
  Core(s): - Clinical and Population Outcomes Core (CPOC)
- Integrative Systems Core (ISC)
  PROJECT ABSTRACTElevated blood pressure (BP), including hypertension (HTN) and preHTN, affects 2 in 3 American adults and isa major contributor to cardiovascular disease (CVD) morbidity, mortality, and healthcare costs. Despitewidespread use of pharmacotherapy, only about half of HTN is controlled, highlighting a need for innovativestrategies to decrease the burden of elevated BP. Though regular exercise in the form of moderate-to-vigorousphysical activity (MVPA) occurring in bouts of at least 10 minutes is recommended to decrease BP, we proposethat reducing time spent sitting or `sedentary behavior' (SED) is a distinct, novel strategy that could lower BP inindividuals with preHTN and HTN. Recent occupational and leisure changes (e.g., computers, video streaming)have resulted in more than half of the American day being spent in SED. At the same time, many observationalstudies have linked excessive SED with adverse outcomes, including HTN and CVD. Moreover, same daylaboratory studies suggest that reducing or interrupting SED decreases BP acutely and our preliminary datasuggest that systolic BP (SBP) is reduced by 4-6 mmHg after a 12-week SED intervention. Yet, there have beenno robust, randomized trials of sufficient size and duration to demonstrate that reducing SED has sustainedbenefits on BP. Before clinical or public health SED recommendations can be made, such experimental evidenceis imperative. Thus, the goal of this application is to demonstrate the efficacy of SED reduction to decrease BPin a 3-month randomized, clinical trial (intervention vs. control) in 300 adults (150 per group) with pre-to-Stage IHTN who have structured, prolonged SED as desk workers. We will use our proven approach that intervenes onmultiple levels (individual, environmental modification with a sit-stand desk attachment) and utilizes behavioralstrategies (individual counseling, self-monitoring, external prompting with a wrist-worn monitor light-intensityphysical activity (LPA) (standing, light movement) and short spurts (<10 min) of activity (sporadic MVPA) asreplacement behaviors. We will comprehensively study the effects of our intervention on vascular health byassessing resting BP, ambulatory BP, and carotid-femoral pulse wave velocity (cfPWV) (Aim 1) and key potentialmechanisms (plasma renin activity, aldosterone) (Aim 2). We will use objective activity monitoring to evaluatedose-response relationships between amount of achieved SED reduction (and resulting increases in LPA andsporadic MVPA) with changes in outcomes (Aim 3). We will also study adiposity, fitness, and insulin sensitivityas exploratory outcomes that could change with our intervention, and if so, might relate to BP. Results from thisstudy will determine whether decreasing SED can improve BP and vascular health and inform the necessarydose of SED reduction for clinically meaningful benefits. Also, evaluation of our novel intervention approach willinform future interventions for SED research and for designing translatable, population-level programs. If SEDreduction improves BP, it could provide an important additional tool in the fight against elevated BP and CVD.and text messaging). These strategies will facilitate a targeted 2-4 hr/day SED reduction by increasing
  Leader(s): FINKEL, TOREN
    NIH R01HL142589 / ( 2019 - 2023 )
  Core(s): - Biology of Mobility and Aging Core (BMAC)
  The entry of calcium into the mitochondria is fundamentally important in regulating bioenergeticcapacity and modulating cell death thresholds. For nearly fifty years, mitochondria were knownto have a selective calcium-selective pore in the inner mitochondrial membrane. Entry ofcalcium through this pore, often termed the calcium uniporter, was believed to be essential inboosting ATP production by augmenting the activity of multiple calcium-sensitive mitochondrialmatrix enzymes. This increase in mitochondrial calcium therefore allowed for a rapid butregulated increase in mitochondrial ATP under conditions of increased energetic demand. Whileunder these conditions, the entry of calcium appears beneficial, additional evidence suggestedthat excessive calcium entry triggers a mitochondrial cell death program characterized byopening of the mitochondrial permeability transition pore (mPTP). Such situations appear to beparticularly relevant to tissue injury occurring in the setting of ischemia-reperfusion injury. Whileconsiderable electrophysiological, biophysical and physiological data existed on themitochondrial inner membrane calcium pore, its molecular identity remained elusive for over fiftyyears. That situation has demonstrably changed in the last five years with the rapididentification of the components of the inner mitochondrial calcium uniporter complex (MCUC)now known to be composed of at least four proteins. These components include the pore-forming protein MCU, its apparent membrane scaffold EMRE and two calcium-sensitiveregulators MICU1 and MICU2. The molecular identity of the MCUC paved the way for thecreation of mouse models in which one or more component of the complex has been deleted.This, in turn, allows for a more detailed and precise analysis of the physiological role ofmitochondrial calcium in regulating both bioenergetics and cell death. Here, we propose toanalyze the role of the MCUC in basal and stress-induced cardiovascular physiology. Ourparticular emphasis will be on the role of the MCUC in ischemia/reperfusion injury, metabolismand aging. This analysis, we believe, will increase our fundamental understanding of bothmitochondrial biology and cardiac physiology and potentially pave the way for new treatmentstrategies targeting a diverse array of conditions ranging from reperfusion injury to the age-dependent decline in cardiac function.
25. Project Title: Mapping the cell specific DNA damage-induced molecular and bioelectrical responses in the 3D cardiac unit
    NIH R01HL161106 / ( 2021 - 2026 )
  PROJECT SUMMARY This project will test the hypothesis that DNA damage in cardiomyocytes activates p53 leading to mitochondrial alterations and secretion of paracrine factors that drive heart failure. The premise for this has been established from our preliminary data and from the work of others. First, DNA damage and activated DNA damage response (DDR) have been observed in cardiovascular disease (CVD) in humans. Second, studies also show evidence that multiple cell types in the cardiac unit, including cardiomyocytes (CM) and cardiac fibroblasts (CF) display markers of DNA damage and cellular senescence in several disease pathologies. Third, we have recently identified that nuclear DNA damage drives dilated cardiomyopathy. Specifically, cardiomyocyte-depletion of the DNA repair endonuclease, ERCC1-XPF in mice, upregulates the DNA damage response gene, p53, and leads to irregular mitochondrial cristae, accumulation of lipids and increased oxidative stress. Additionally, there is an increase in several cardiac failure and senescence associated markers. However, the exact molecular underpinnings and cell-specificity of these DNA damage-induced changes is poorly understood. One barrier to addressing this question in vivo has been lack of appropriate tools, where DNA damage can be introduced in only one cell type (e.g., CM) and its effect on CF and cardiac function can be investigated. Additionally, 2D cell culture and co-culture systems fall short, as they cannot reproduce tissue dynamics present in a cardiac unit. Herein, we have developed several tools enable the study of cell-cell communication of 3D multicellular system. Specific Aim 1 will map the molecular, functional, and architectural changes upon loss of ERCC1 in CM. In this aim, we will test the mechanistic role of p53 and reactive oxygen species on a number of cellular and mitochondrial parameters, as well as cardiomyocyte electrophysiology. Specific Aim 2 will test whether stochastic, spontaneous DNA damage in the CM or CF drives cardiac electromechanical dysfunction in a cell- autonomous or cell non-autonomous manner through a paracrine effect on neighboring cells. Here, we will analyze the pathological secretome upon genotoxic stress, as well as test the role of eliminating senescent cells on cardiac health. This work is technically innovative as it uses a number of unique tools including concomitant optical and bioelectrical measurements in 3D cardiac organoids. These contributions will be significant because DNA damage is unavoidable and intimately linked to cardiac health and disease. Our team is uniquely qualified to perform this work, with expertise in DNA damage/ repair, cellular senescence, nanofabrication, human iPSC- derived cardiac tissue engineering, and data science. This analysis, we believe, will increase our fundamental understanding of the connection between DNA damage and heart disease and potentially pave the way for new treatment strategies.
26. Project Title: Reducing slip-and-fall accidents in the workplace: Role of small-scale roughness of floor surfaces to improve friction
    Centers for Disease Control and Prevention R21OH012126 / ( 2021 - 2023 )
  Project Summary Fall-related injuries burden over 140,000 workers annually, causing significant human suffering and an economic cost of $10 billion in Workers' Compensation. Approximately half of occupational falls are caused by slipping. An under-explored pathway to preventing these slip-and-fall events is to design flooring for workplaces with high friction performance. High-friction flooring prevents the slip events that lead to a fall. Unfortunately, current methods to characterize floor-surface topography are unable to predict friction performance, limiting innovation in this area. In order to catalyze innovation in high-friction flooring, there is a need for improved scientific understanding of the flooring factors that contribute to friction. Our preliminary studies and existing literature suggest that small-scale topography (features at the 1-nm to 1- m scale) is critical for predicting floor performance, but is not measurable using conventional characterization techniques. The purpose of this R21 project is to measure these small-scales of floor-surface topography, and to use them to develop a mechanics-based predictive model for friction. This research is innovative because it will employ novel experimental methods and analysis techniques that have never been applied to flooring surfaces, and because it will develop a mechanics-based model to predict the relationship between floor structure and friction performance, where prior research has relied solely on empirical correlations. The proposed research will be accomplished through two Aims: Aim 1: Quantify the dependence of shoe-floor friction performance on small-scale topography. This Aim will investigate the ability of small-scale topography to explain variations in shoe-floor friction performance that cannot be explained using current measurement techniques. Then we will test the first hypothesis: Hypothesis 1: Roughness parameters that consider the full range of scales will improve our ability to predict COF values compared with those using just stylus profilometry. Aim 2: Establish a predictive mechanics-based model for shoe-floor friction based on multiscale surface topography. In this Aim, we will develop and validate a multiscale finite element model that captures viscoelastic contributions to friction across all length scales. We will test the second hypothesis: Hypothesis 2: A mechanics-based model using multiscale topography will more accurately predict shoe-floor friction compared with conventional approaches, i.e., statistical models based on stylus profilometry. This research is expected to lead to foundational knowledge and a modeling tool for optimizing high-friction flooring in workplaces. Working with an industry trade group, the Tile Council of North America (TCNA), this research will achieve impact by guiding the evidence-based development of high-friction flooring for workplaces. Thus, the proposed research is expected to achieve impact in improving workplace safety.
27. Project Title: Physical Activity and Dementia: Mechanisms of Action
  Leader(s): ERICKSON, KIRK I
    NIH R35AG072307 / ( 2021 - 2026 )
  Abstract Exercise is one of the most promising methods for positively influencing neurocognitive function in late adulthood. Yet, despite this recognition, several major knowledge gaps preclude the ability to broadly prescribe exercise to prevent or treat cognitive impairment. This R35 proposal includes a series of innovative and potentially groundbreaking studies that will contribute to major advancements in the field of exercise and brain health. The studies that we describe in this proposal would be led by several highly promising junior scientists with the support of an experienced and dedicated mentorship team. The conceptual and scientific framework for the hypotheses described in this proposal orbit around three major challenges facing the field of exercise and cognitive aging: (1) We have a poor understanding of the mechanisms by which exercise influences cognitive function in late adulthood, (2) We have a poor understanding of the factors that moderate, or explain individual variation in, the response to exercise, and (3) We do not understand the factors that predict long- term adoption of exercise behavior and how to reduce barriers and enhance incentives for individuals who find it challenging to continue to exercise. Despite the clear benefits of an active lifestyle, most people fail to meet public health recommendations for exercise. The more we know about the factors that predict and enhance long-term adoption of exercise, the more we will know about whether exercise influences incidence of Alzheimer s Disease and best practices for prescribing and maintaining exercise for the prevention and treatment of cognitive impairment. We propose to conduct secondary analysis of banked data from two rigorous and well-controlled supervised exercise randomized clinical trials (RCTs) and to conduct a 3-year follow-up of >570 participants from both of these RCTs of exercise to assess cognitive, cardiorespiratory fitness, and physical activity levels. In particular, we propose to examine whether exercise-induced changes in cardiometabolic and sleep measures mediate exercise-derived benefits to cognitive and brain outcomes. We will also target moderators of exercise including APOE genotype and racial disparities to better characterize which individual difference variables influence the magnitude of effects of exercise on brain health. Finally, we propose a discovery aim that would leverage our rich measurement of participants at the genetic, physiological, brain, cognitive, and socioemotional levels to perform predictive modeling to forecast long-term adoption of exercise (or barriers prohibiting long-term adoption). In short, this research proposal describes a broad and ambitious line of work that will produce groundbreaking and innovative studies to address significant gaps in our understanding of exercise and brain health in late adulthood. The aims target several major AD/ADRD milestones identified by NIH and will position junior scientists in leadership roles to advance the field forward in significant and pioneering ways.
    NIH T32AG055381 / ( 2018 - 2023 )
  Core(s): - Clinical and Population Outcomes Core (CPOC)
- Integrative Systems Core (ISC)
  Training Grant in Population Neuroscience of Aging & Alzheimer s Disease (PNA) The objective of this new pre- and post-doctoral training program is to train highly talented individuals to pursuesuccessful independent research in the etiology of Alzheimer s Disease and other age-related dementia (ADRD). Eligibleapplicants are PhD graduates or candidates in Epidemiology, Neuroscience, Information Science, Biostatistics,Biomedical informatics and MD/DO graduates with training in Neurology, Psychiatry, Geriatric medicine, and relateddisciplines. We request support for 3 pre-doctoral and 2 post-doctoral positions annually, with a period of training of up to3 years for post-docs and 4 years for pre-docs (up to 5 in some cases). The field of brain aging has profoundly changed because of the collision of two phenomena: worldwide increase ofour aging population, and rapid technological advancements in health measurements in general and in brain science inparticular. Our successes in extending lifespan, with marginal improvements in healthspan, have not only increased thenumber of adults reaching very old ages, but they have also increased the heterogeneity of age-related neurocognitivephenotypes. For these new older adults, there is a very high burden of chronic conditions affecting the central nervoussystem either directly (e.g. stroke) or indirectly (heart conditions, diabetes). Cumulative exposure to chronic conditions,biological ageing, chronological aging and possibly to other life-long environmental factors, interact with each other invery complex ways and are all strong drivers of increased risks of developing dementia. While it is reasonable to expectbrain integrity to decline and dementia rates to increase over time, we cannot assume that chronological years and yearsspent with a disease would have linearly additive effects on brain integrity. Understanding these complex pathways is fundamentally important to conduct rigorous etiological research intocauses and determinants of brain degeneration and dementia. Unfortunately, training and research in the field to date havefocused on dementia as an individual condition, and have mostly considered older age as an homogenous population,while relegating multiple chronic conditions and other health issues as collateral problems , or as completely separateproblems. However, it is clear that to understand these complex issues and improve the brain health of the growingpopulation of elderly living with chronic diseases for a long time, it is necessary to have expertise in diseases of both thebrain/central nervous system and also other organ systems. We are also living through a time of great technologicaladvances in non-invasive and automated methods to measure brain abnormalities, the application of which is providingever more precise phenotypes but also very large and complex datasets. Such data require careful sampling designs andanalytical approaches infused with an understanding of the condition being studied to effectively produce new knowledgeto move research to treatment and prevention. We propose that the successful clinical neuroepidemiological investigatorsof the future must be able to link comorbidities, environmental exposures, lifestyles, genomics, e.g. host susceptibility,with knowledge of modern technology of neurosciences and measurement of brain disease and data science. Our proposed T32 in Population Neuroscience of Aging & Alzheimer s Disease (PNA) merges this gap and aims tocross-train researchers in these inter-related fields. Co-directors Drs. Rosano (Epidemiology) and Ganguli (Psychiatry)have designed a new training formula that benefits from the extensive resources and faculty affiliated with the Schools ofPublic Health (Biostatistics), Medicine (Neurology, Biomedical Informatics), Arts and Science (Neuroscience,Psychology), and Information Science, as well as several University Centers and Institutes: the Alzheimer DiseaseResearch Center, the Center for the Neural Basis of Cognition, the Brain Institute, the Center for Aging, Population andHealth, the Claude Pepper, the Aging Institute. Our curriculum responds to the changing landscape of career pathways, by including: a) foundationalknowledge in data science; b) availability of multi-center and international databases; c) enhanced training incutting-edge multimodal methodologies to measure brain changes with age, including neuroimaging and post-mortemassessments; d) hands-on experiences with internet-based designs for recruitment and data collection. Training in theresponsible conduct of research and efforts to increase diversity are important objectives of the program.
    NIH U01AG061393 / ( 2018 - 2023 )
  Core(s): - Clinical and Population Outcomes Core (CPOC)
- Integrative Systems Core (ISC)
  ABSTRACT In older age, walking becomes slower and less automated, requiring more attention and prefrontal resources.Common causes of age-related walking impairments are cerebral small vessel disease (cSVD) and changes inperipheral systems. We have recently discovered that ~20% of older adults maintain fast gait speed even in thepresence of common locomotor risk factors, thus appearing resilient. Our work suggests that the nigrostriataldopamine (DA) system may be a source of this resilience. We hypothesize that higher nigrostriatal DAneurotransmission drives resilience to locomotor risk factors via higher connectivity with sensorimotornetworks, thus reducing prefrontal-mediated motor control and restoring automated control of walking. Resilience due to the nigrostriatal DA system is a novel and highly promising area of inquiry. Unlike vascularlesions and brain structural impairments, DA neurotransmission is potentially modifiable, thereby offering novelapproaches to reduce age-related walking impairments. Although of substantial potential value to wellbeing inaging, there is a critical gap in knowledge of age-related mobility with simultaneous measures of nigrostriatalDA system, cSVD and peripheral system impairments. Our aims are: AIM 1: Quantify the DA-related contribution to mobility resilience, cross-sectionally and longitudinally.We hypothesize that nigrostriatal DA neurotransmission predicts walking performance, during usual and dualtask conditions and reduces the negative effects of cSVD and peripheral system impairment on walkingperformance. AIM 2: Assess DA-related automated control of walking, cross-sectionally and longitudinally. Wehypothesize nigrostriatal DA neurotransmission acts synergistically with connectivity of sensorimotor networksto predict higher walking performance and lower prefrontal activation while walking. As a first translational step in testing the effects of DA on resilience, we propose to collect pilot data for amechanistic target-engagement study in slow-walking older adults with cSVD and pronounced age-associatedstriatal DA loss. Exploratory AIM 3: To assess the effects of 1 week of L-DOPA administration on connectivityand gait speed as a function of molecular markers of striatal DA release in non-resilient elderly withpronounced age-associated striatal DA losses. This research is innovative in that it goes beyond explaining impairments, to revealing resilience factors andtheir mechanisms as the basis for novel interventions. It has high impact because recent findings suggest thatpharmacological and behavioral interventions can improve DA signaling. Our team has unique expertise in theuse of novel technologies and represents decades as thought leaders in the study of aging, brain and mobility.
30. Project Title: Defining the impact of stromal aging on ovarian cancer initiation
    NIH U01AG077923 / ( 2021 - 2026 )
  Age is a major risk factor for high grade serous ovarian cancer (HGSOC) with an average age at diagnosis of 63. Ovulation and aging induce inflammatory changes in the fallopian tube microenvironment, the origin of most HGSOC. Over time, cells become senescent and secrete regulatory factors known as the senescence associated secretory phenotype (SASP). SASP-induced changes in the local microenvironment have been implicated in cancer promotion. However, the role of the aging microenvironment in ovarian cancer initiation is unknown creating a major barrier to effective early detection and prevention strategies for this deadly disease. The goal of this proposal is to define the impact of aging on interactions between stromal cells and cancer initiating cells (CIC) that drive ovarian cancer formation. Mesenchymal stromal/stem cell (MSC) are multipotent stromal progenitor cells critical to tissue homeostasis across the lifespan. In cancer, MSCs undergo epigenomic reprogramming to become pro-tumorigenic cancer associated MSCs (CA-MSCs). The pro-tumorigenic CA-MSC phenotype is driven by the activation of the Wilms tumor 1 (WT1) transcription factor. WT1 induces the secretion of CA-MSC derived BMP4 which increases the pool of ovarian CICs. Preliminary data demonstrate that with increasing age, MSCs can express WT1 and adopt a cancer promoting phenotype even before cancer starts. We have termed these cells high risk MSCs (hrMSCs). Preliminary data indicate that hrMSCs (i) recapitulate the CA-MSC phenotype and are enriched in the stroma of pre-malignant epithelial cells, (ii) secrete SASP-like proteins which both induce epithelial cell DNA damage and support the survival of DNA damaged epithelial cells and (iii) support established cancer cell growth. AMP-activated protein kinase (AMPK) may be critical to CA- MSC/hrMSC formation. In a clinical trial Metformin, which increases AMPK, reversed the CA-MSC phenotype in some patients correlating with improved survival. Preliminary data shows a more potent, novel AMPK activator, BC1618, alters the hrMSC secretome. We hypothesize that aging induces epigenetic changes which convert MSCs to hrMSCs and that hrMSCs create a pro-tumorigenic microenvironment that supports the growth of ovarian CICs. Our collaborative team with expertise in aging, stromal stem cells and CICs propose to: 1) Determine the impact of aging on the fallopian tube MSC phenotype and spatial relationship to CICs. We hypothesize that aged MSCs obtain a high risk phenotype through altered DNA methylation and support adjacent CIC formation. 2) Determine the impact of aged hrMSCs on CIC formation and ovarian cancer progression. We hypothesize that aged hrMSCs promote CIC formation and progression via WT1-mediated BMP4 and SASP secretion. 3) Target aging hrMSCs to limit ovarian cancer formation. We hypothesize that the AMPK activator, BC1618, through altering age-related MSC epigenetic changes, will decrease hrMSC formation and ovarian cancer initiation. This work will broaden our understanding of ovarian cancer initiation by defining the critical role of aging stroma in CIC formation and offer new avenues for early detection and prevention strategies.
31. Project Title: Biospecimen-Core
  Leader(s): ROJAS, MAURICIO
    NIH U54AG075931 / ( 2021 - 2026 )
  ABSTRACT Biospecimen Core: Lung and heart function and aging are major determinants of human health and lifespan, respectively. Combined, lung and heart diseases are the leading cause of morbidity and mortality world-wide (WHO s Global Health Estimates 2020). The Biospecimen Core (BC) will generate high-quality, clinically annotated, and pathologically evaluated specimens from normal human lung and heart (and corresponding vessels and lymph nodes) to provide the fundamental basis for the creation of high-resolution, multi-modal, and multi-dimensional senescence maps. The BC investigators will use their expertise in collecting, processing, annotating, classifying, and distributing tissue samples and primary cells lines for lung and heart senescence mapping. The core will excel in providing already catalogued tissues with as little ischemia-induced artifacts as possible, and meet all legal and ethical standards including broad donor consent. The BC follows NIH/NCI Best Practices for Biorepositories, with standard operating procedures (SOPs) in place to ensure the highest biospecimen and clinical information quality to meet all legal and ethical standards. The biorepository efforts are approved through OSU, Pitt, and URMC IRB protocols that cover the procurement, processing, and distribution of human biospecimens. The BC will collect whole tissue from humans across the lifespan and will provide whole tissue, precision cut tissue slices (PCTS), and purified cells to the TriState SenNet TMC. Together with the Data Analysis Core (DAC), the BC will use established metadata collection protocols to collect metadata in a consistent and interoperable format.
  1. Dissemination and Implementation of Evidence-Based Falls Prevention Programs: Reach and Effectiveness.
    Brach JS, Juarez G, Perera S, Cameron K, Vincenzo JL, Tripken J
    J Gerontol A Biol Sci Med Sci, 2022 Jan 7, 77(1): 164-171 | PMID: 34244780 | PMCID: PMC8751789
    Citations: | AltScore: NA
  2. Effect of Timing and Coordination Training on Mobility and Physical Activity Among Community-Dwelling Older Adults: A Randomized Clinical Trial.
    Brach JS, Perera S, Shuman V, Gil AB, Kriska A, Nadkarni NK, Rockette-Wagner B, Cham R, VanSwearingen JM
    JAMA Netw Open, 2022 May 2, 5(5): e2212921 | PMID: 35604689 | PMCID: PMC9127558
    Citations: | AltScore: 1
  3. Predicting falls within 3 months of emergency department discharge among community-dwelling older adults using self-report tools versus a brief functional assessment.
    Dasgupta P, Frisch A, Huber J, Sejdic E, Suffoletto B
    Am J Emerg Med, 2022 Mar, 53: 245-249 | PMID: 35085878 | PMCID: PMC9231635
    Citations: | AltScore: 4.35
  4. Perceived Physical Fatigability Predicts All-Cause Mortality in Older Adults.
    Glynn NW, Gmelin T, Renner SW, Qiao YS, Boudreau RM, Feitosa MF, Wojczynski MK, Cosentino S, Andersen SL, Christensen K, Newman AB
    J Gerontol A Biol Sci Med Sci, 2022 Apr 1, 77(4): 837-841 | PMID: 34908118 | PMCID: PMC8974332
    Citations: | AltScore: 243.43
  5. Impact of strength and balance on Functional Gait Assessment performance in older adults.
    Karabin MJ, Sparto PJ, Rosano C, Redfern MS
    Gait Posture, 2022 Jan, 91: 306-311 | PMID: 34800923 | PMCID: PMC8671379
    Citations: 1 | AltScore: NA
  6. Validation of the Traditional Chinese Version of the Pittsburgh Fatigability Scale for Older Adults.
    Lin C, Glynn NW, Gmelin T, Wei YC, Chen YL, Huang CM, Shyu YC, Chen CK
    Clin Gerontol, 2022 May-Jun, 45(3): 606-618 | PMID: 33934690
    Citations: | AltScore: NA
  7. Effectiveness of a behavioral lifestyle intervention on weight management and mobility improvement in older informal caregivers: a secondary data analysis.
    Liu X, King J, Boak B, Danielson ME, Boudreau RM, Newman AB, Venditti EM, Albert SM
    BMC Geriatr, 2022 Jul 28, 22(1): 626 | PMID: 35902809 | PMCID: PMC9336094
    Citations: | AltScore: 0.25
  8. Cardiac rehabilitation in older adults: Apropos yet significantly underutilized.
    Lutz AH, Forman DE
    Prog Cardiovasc Dis, 2022 Jan-Feb, 70: 94-101 | PMID: 35016915 | PMCID: PMC8930627
    Citations: 1 | AltScore: 4
  9. Perceived physical fatigability improves after an exercise intervention among breast cancer survivors: a randomized clinical trial.
    Qiao Y, van Londen GJ, Brufsky JW, Poppenberg JT, Cohen RW, Boudreau RM, Glynn NW
    Breast Cancer, 2022 Jan, 29(1): 30-37 | PMID: 34328623
    Citations: 1 | AltScore: 17.75
  10. \Getting There\: Transportation as a Barrier to Research Participation Among Older Adults.
    Rigatti M, DeGurian AA, Albert SM
    J Appl Gerontol, 2022 May, 41(5): 1321-1328 | PMID: 35196908 | PMCID: PMC9035082
    Citations: | AltScore: 2.5
  11. LRRK2 and idiopathic Parkinson's disease.
    Rocha EM, Keeney MT, Di Maio R, De Miranda BR, Greenamyre JT
    Trends Neurosci, 2022 Mar, 45(3): 224-236 | PMID: 34991886 | PMCID: PMC8854345
    Citations: 4 | AltScore: 21.35
  12. Barriers and facilitators to resuming meaningful daily activities among critical illness survivors in the UK: a qualitative content analysis.
    Scheunemann L, White JS, Prinjha S, Eaton TL, Hamm M, Girard TD, Reynolds C, Leland N, Skidmore ER
    BMJ Open, 2022 Apr 26, 12(4): e050592 | PMID: 35473739 | PMCID: PMC9045053
    Citations: | AltScore: 8.15
  13. Physical Therapists and Physical Therapist Assistants' Knowledge and Use of the STEADI for Falls Risk Screening of Older Adults in Physical Therapy Practice in the United States.
    Vincenzo JL, Schrodt LA, Hergott C, Perera S, Tripken J, Shubert TE, Brach JS
    Int J Environ Res Public Health, 2022 Jan 26, 19(3):
    pii: 1354. | PMID: 35162377 | PMCID: PMC8834951
    Citations: | AltScore: NA
  1. Relationship Between Personality Measures and Perceived Mental Fatigability.
    Allen HL, Gmelin T, Moored KD, Boudreau RM, Smagula SF, Cohen RW, Katz R, Stone K, Cauley JA, Glynn NW
    J Aging Health, 2021 Nov 25 8982643211055032 | PMID: 34821521 | PMCID: PMC9130341
    Citations: | AltScore: 8.08
  2. Digital Technology Differentiates Graphomotor and Information Processing Speed Patterns of Behavior.
    Andersen SL, Sweigart B, Glynn NW, Wojczynski MK, Thyagarajan B, Mengel-From J, Thielke S, Perls TT, Libon DJ, Au R, Cosentino S, Sebastiani P, Long Life Family Study.
    J Alzheimers Dis, 2021, 82(1): 17-32 | PMID: 34219735 | PMCID: PMC8328075
    Citations: 1 | AltScore: 45
  3. Elevated IL-6 and CRP Levels Are Associated With Incident Self-Reported Major Mobility Disability: A Pooled Analysis of Older Adults With Slow Gait Speed.
    Beavers DP, Kritchevsky SB, Gill TM, Ambrosius WT, Anton SD, Fielding RA, King AC, Rejeski WJ, Lovato L, McDermott MM, Newman AB, Pahor M, Walkup MP, Tracy RP, Manini TM
    J Gerontol A Biol Sci Med Sci, 2021 Nov 15, 76(12): 2293-2299 | PMID: 33822946 | PMCID: PMC8598983
    Citations: | AltScore: 4.5
  4. In Search of an Optimal Subset of ECG Features to Augment the Diagnosis of Acute Coronary Syndrome at the Emergency Department.
    Bouzid Z, Faramand Z, Gregg RE, Frisch SO, Martin-Gill C, Saba S, Callaway C, Sejdic E, Al-Zaiti S
    J Am Heart Assoc, 2021 Feb 2, 10(3): e017871 | PMID: 33459029 | PMCID: PMC7955430
    Citations: 3 | AltScore: 4.35
  5. Estrogen, brain structure, and cognition in postmenopausal women.
    Boyle CP, Raji CA, Erickson KI, Lopez OL, Becker JT, Gach HM, Kuller LH, Longstreth W Jr, Carmichael OT, Riedel BC, Thompson PM
    Hum Brain Mapp, 2021 Jan, 42(1): 24-35 | PMID: 32910516 | PMCID: PMC7721237
    Citations: 4 | AltScore: 4.55
  6. Cardiac Rehabilitation for Patients With?Heart?Failure: JACC Expert Panel.
    Bozkurt B, Fonarow GC, Goldberg LR, Guglin M, Josephson RA, Forman DE, Lin G, Lindenfeld J, O'Connor C, Panjrath G, Pi?a IL, Shah T, Sinha SS, Wolfel E, ACC?s Heart Failure and Transplant Section and Leadership Council.
    J Am Coll Cardiol, 2021 Mar 23, 77(11): 1454-1469 | PMID: 33736829
    Citations: 9 | AltScore: 253.949999999999
  7. High-intensity exercise and cognitive function in cognitively normal older adults: a pilot randomised clinical trial.
    Brown BM, Frost N, Rainey-Smith SR, Doecke J, Markovic S, Gordon N, Weinborn M, Sohrabi HR, Laws SM, Martins RN, Erickson KI, Peiffer JJ
    Alzheimers Res Ther, 2021 Feb 1, 13(1): 33 | PMID: 33522961 | PMCID: PMC7849126
    Citations: 3 | AltScore: 24.03
  8. Differences in Comorbid Conditions Among Older Adult Participants in Cardiac Rehabilitation.
    Cahill BJ, Allsup K, Delligatti A, Althouse AD, Forman DE
    J Cardiopulm Rehabil Prev, 2021 Mar 1, 41(2): 109-112 | PMID: 32947323
    Citations: 1 | AltScore: 6.3
  9. Ratings of Perceived Exertion During Walking: Predicting Major Mobility Disability and Effect of Structured Physical Activity in Mobility-Limited Older Adults.
    Cenko E, Chen H, Gill TM, Glynn NW, Henderson RM, King AC, Pahor M, Qiu P, Rego A, Reid KF, Tudor-Locke C, Valiani V, You L, Manini TM
    J Gerontol A Biol Sci Med Sci, 2021 Sep 13, 76(10): e264-e271 | PMID: 33585918 | PMCID: PMC8436976
    Citations: | AltScore: 3.25
  10. A high-throughput screen for TMPRSS2 expression identifies FDA-approved compounds that can limit SARS-CoV-2 entry.
    Chen Y, Lear TB, Evankovich JW, Larsen MB, Lin B, Alfaras I, Kennerdell JR, Salminen L, Camarco DP, Lockwood KC, Tuncer F, Liu J, Myerburg MM, McDyer JF, Liu Y, Finkel T, Chen BB
    Nat Commun, 2021 Jun 23, 12(1): 3907 | PMID: 34162861 | PMCID: PMC8222394
    Citations: 7 | AltScore: 10.65
  11. Older Workers with Physically Demanding Jobs and their Cognitive Functioning.
    Choi E, Kim SG, Zahodne LB, Albert SM
    Ageing Int, 2021 Jan 8, 47(1): 55-71 | PMID: 33437106 | PMCID: PMC7791149
    Citations: | AltScore: 4.2
  12. Zoledronic acid and bone health in older adults with cognitive impairment.
    Churilla BM, Perera S, Greenspan SL, Resnick NM, Kotlarczyk MP
    Osteoporos Int, 2021 Aug 2, 33(1): 293-298 | PMID: 34341833 | PMCID: PMC8758516
    Citations: | AltScore: NA
  13. Testing a new, intensified infusion-withdrawal protocol for urinary urgency provocation in brain-bladder studies.
    Clarkson BD, Karim HT, Griffiths DJ, Resnick NM
    Neurourol Urodyn, 2021 Jan, 40(1): 131-136 | PMID: 33118637 | PMCID: PMC7902294
    Citations: | AltScore: NA
  14. Prevalence and severity of perceived mental fatigability in older adults: The Long Life Family Study.
    Cohen RW, Meinhardt AJ, Gmelin T, Qiao YS, Moored KD, Katz RD, Renner SW, Glynn NW, LLFS Research Group.
    J Am Geriatr Soc, 2021 Mar 5, 69(5): 1401-1403 | PMID: 33675035 | PMCID: PMC8142668
    Citations: 2 | AltScore: 1
  15. Physical Frailty Phenotype and the Development of Geriatric Syndromes in Older Adults with Coronary Heart Disease.
    Damluji AA, Chung SE, Xue QL, Hasan RK, Walston JD, Forman DE, Bandeen-Roche K, Moscucci M, Batchelor W, Resar JR, Gerstenblith G
    Am J Med, 2021 May, 134(5): 662-671.e1 | PMID: 33242482 | PMCID: PMC8107119
    Citations: 6 | AltScore: 8.3
  16. Is Human Walking a Network Medicine Problem? An Analysis Using Symbolic Regression Models with Genetic Programming.
    Dasgupta P, Hughes JA, Daley M, Sejdic E
    Comput Methods Programs Biomed, 2021 Jul, 206: 106104 | PMID: 33951562 | PMCID: PMC8205964
    Citations: | AltScore: 1
  17. Acceleration Gait Measures as Proxies for Motor Skill of Walking: A Narrative Review.
    Dasgupta P, VanSwearingen J, Godfrey A, Redfern M, Montero-Odasso M, Sejdic E
    IEEE Trans Neural Syst Rehabil Eng, 2021, 29: 249-261 | PMID: 33315570 | PMCID: PMC7995554
    Citations: 2 | AltScore: NA
  18. The Association between Poor Diet Quality, Physical Fatigability and Physical Function in the Oldest-Old from the Geisinger Rural Aging Study.
    Davis B, Liu YH, Stampley J, Wood GC, Mitchell DC, Jensen GL, Gao X, Glynn NW, Still CD, Irving BA
    Geriatrics (Basel), 2021 Apr 15, 6(2):
    pii: 41. | PMID: 33920900 | PMCID: PMC8167721
    Citations: 2 | AltScore: NA
  19. The industrial solvent trichloroethylene induces LRRK2 kinase activity and dopaminergic neurodegeneration in a rat model of Parkinson's disease.
    De Miranda BR, Castro SL, Rocha EM, Bodle CR, Johnson KE, Greenamyre JT
    Neurobiol Dis, 2021 Jun, 153: 105312 | PMID: 33636387 | PMCID: PMC8026730
    Citations: 7 | AltScore: 59.45
  20. Home-Based Cardiac Rehabilitation: EXPERIENCE FROM THE VETERANS AFFAIRS.
    Drwal KR, Wakefield BJ, Forman DE, Wu WC, Haraldsson B, El Accaoui RN
    J Cardiopulm Rehabil Prev, 2021 Mar 1, 41(2): 93-99 | PMID: 33647921
    Citations: 3 | AltScore: 3.6
  21. Exercise interventions for older adults with Alzheimer's disease: a systematic review and meta-analysis protocol.
    Faieta JM, Devos H, Vaduvathiriyan P, York MK, Erickson KI, Hirsch MA, Downer BG, van Wegen EEH, Wong DC, Philippou E, Negm A, Ahmadnezhad P, Krishnan S, Kahya M, Sood P, Heyn PC
    Syst Rev, 2021 Jan 4, 10(1): 6 | PMID: 33397453 | PMCID: PMC7779651
    Citations: 2 | AltScore: 13.5
  22. The Relationship Between Intermuscular Fat and Physical Performance Is Moderated by Muscle Area in Older Adults.
    Farsijani S, Santanasto AJ, Miljkovic I, Boudreau RM, Goodpaster BH, Kritchevsky SB, Newman AB
    J Gerontol A Biol Sci Med Sci, 2021 Jan 1, 76(1): 115-122 | PMID: 32614950 | PMCID: PMC7756684
    Citations: 4 | AltScore: 10.85
  23. Body Composition by Computed Tomography vs Dual-Energy X-ray Absorptiometry: Long-Term Prediction of All-Cause Mortality in the Health ABC Cohort.
    Farsijani S, Xue L, Boudreau RM, Santanasto AJ, Kritchevsky SB, Newman AB
    J Gerontol A Biol Sci Med Sci, 2021 Nov 15, 76(12): 2256-2264 | PMID: 33835154 | PMCID: PMC8599045
    Citations: | AltScore: 6.8
  24. How has COVID-19 affected the treatment of osteoporosis? An IOF-NOF-ESCEO global survey.
    Fuggle NR, Singer A, Gill C, Patel A, Medeiros A, Mlotek AS, Pierroz DD, Halbout P, Harvey NC, Reginster JY, Cooper C, Greenspan SL
    Osteoporos Int, 2021 Apr, 32(4): 611-617 | PMID: 33558957 | PMCID: PMC7869913
    Citations: 9 | AltScore: 149.45
  25. The role of mitochondria in cellular senescence.
    Ghosh-Choudhary SK, Liu J, Finkel T
    FASEB J, 2021 Dec, 35(12): e21991 | PMID: 34758157 | PMCID: PMC8720272
    Citations: 2 | AltScore: 36.8
  26. An Optimal Self-Report Physical Activity Measure for Older Adults: Does Physical Function Matter?
    Glynn NW, Meinhardt AJ, LaSorda KR, Graves JL, Gmelin T, Gerger AM, Caserotti P, Boudreau RM
    J Aging Phys Act, 2021 Apr 1, 29(2): 193-199 | PMID: 32788419 | PMCID: PMC9034731
    Citations: 2 | AltScore: NA
  27. Response to \Comment on: Fatigability: A Prognostic Indicator of Phenotypic Aging\.
    Glynn NW, Qiao YS, Simonsick EM, Schrack JA
    J Gerontol A Biol Sci Med Sci, 2021 Jul 13, 76(8): e161-e162 | PMID: 33649762 | PMCID: PMC8277087
    Citations: | AltScore: NA
  28. Combining advanced computational and imaging techniques as a quantitative tool to estimate patellofemoral joint stress during downhill gait: A feasibility study.
    Gustafson JA, Elias JJ, Fitzgerald GK, Tashman S, Debski RE, Farrokhi S
    Gait Posture, 2021 Feb, 84: 31-37 | PMID: 33264730 | PMCID: PMC7902369
    Citations: 1 | AltScore: NA
  29. Validation of perceived physical fatigability using the simplified-Chinese version of the Pittsburgh Fatigability Scale.
    Hu Y, Zhang H, Xu W, Zhao M, Liu J, Wu L, Zou L, Zuo J, Liu Y, Fan L, Bair WN, Qiao YS, Glynn NW
    BMC Geriatr, 2021 May 26, 21(1): 336 | PMID: 34039260 | PMCID: PMC8157666
    Citations: | AltScore: NA
  30. Fall Risk-Increasing Drugs, Polypharmacy, and Falls Among Low-Income Community-Dwelling Older Adults.
    Ie K, Chou E, Boyce RD, Albert SM
    Innov Aging, 2021, 5(1): igab001 | PMID: 33644415 | PMCID: PMC7899132
    Citations: 2 | AltScore: 0.5
  31. Transforming the Medication Regimen Review Process Using Telemedicine to Prevent Adverse Events.
    Kane-Gill SL, Wong A, Culley CM, Perera S, Reynolds MD, Handler SM, Kellum JA, Aspinall MB, Pellett ME, Long KE, Nace DA, Boyce RD
    J Am Geriatr Soc, 2021 Feb, 69(2): 530-538 | PMID: 33233016
    Citations: 3 | AltScore: 13
  32. The feasibility and acceptability of a web-based physical activity for the heart (PATH) intervention designed to reduce the risk of heart disease among inactive African Americans: Protocol for a pilot randomized controlled trial.
    Kariuki JK, Gibbs BB, Erickson KI, Kriska A, Sereika S, Ogutu D, Milton H, Wagner L, Rao N, Peralta R, Bobb J, Bermudez A, Hirshfield S, Goetze T, Burke LE
    Contemp Clin Trials, 2021 May, 104: 106380 | PMID: 33798731 | PMCID: PMC8180502
    Citations: 2 | AltScore: NA
  33. Cardiac Rehabilitation Knowledge and Attitudes of Cardiology Fellows.
    Kellar G, Hickey GW, Goss F, Fertman C, Forman DE
    J Cardiopulm Rehabil Prev, 2021 Jan 1, 41(1): 30-34 | PMID: 33031134
    Citations: 1 | AltScore: 11.5
  34. Lactoferrin for the treatment of age-associated inflammation - A pilot study.
    Laskow T, Langdon J, Abadir P, Xue QL, Walston J
    Physiol Int, 2021 Apr 9 | PMID: 33844642 | PMCID: PMC9211386
    Citations: | AltScore: NA
  35. Triggers and alleviating factors for fatigue in Parkinson's disease.
    Lin I, Edison B, Mantri S, Albert S, Daeschler M, Kopil C, Marras C, Chahine LM
    PLoS One, 2021, 16(2): e0245285 | PMID: 33540422 | PMCID: PMC7861907
    Citations: 2 | AltScore: 2.25
  36. The secretome mouse provides a genetic platform to delineate tissue-specific in vivo secretion.
    Liu J, Jang JY, Pirooznia M, Liu S, Finkel T
    Proc Natl Acad Sci U S A, 2021 Jan 19, 118(3):
    pii: e2005134118. | PMID: 33431665 | PMCID: PMC7826384
    Citations: 9 | AltScore: 14.75
  37. Modulation of lysosomal function as a therapeutic approach for coronaviral infections.
    Liu Y, Lear T, Larsen M, Lin B, Cao Q, Alfaras I, Kennerdell J, Salminen L, Camarco D, Lockwood K, Ma J, Liu J, Tan J, Myerburg M, Chen Y, Croix CS, Sekine Y, Evankovich J, Finkel T, Chen B
    Res Sq, 2021 Apr 23
    pii: | PMID: 34013250 | PMCID: PMC8132244
    Citations: | AltScore: 2.35
  38. Cardiac Rehabilitation and Survival for Ischemic Heart Disease.
    Lolley R, Forman DE
    Curr Cardiol Rep, 2021 Nov 6, 23(12): 184 | PMID: 34741670 | PMCID: PMC8571661
    Citations: | AltScore: NA
  39. Catechol-O-Methyltransferase Genotype, Frailty, and Gait Speed in a Biracial Cohort of Older Adults.
    Mance S, Rosso A, Bis J, Studenski S, Bohnen N, Rosano C
    J Am Geriatr Soc, 2021 Feb, 69(2): 357-364 | PMID: 33043988 | PMCID: PMC7902408
    Citations: | AltScore: 53.75
  40. A Metabolite Composite Score Attenuated a Substantial Portion of the Higher Mortality Risk Associated With Frailty Among Community-Dwelling Older Adults.
    Marron MM, Harris TB, Boudreau RM, Clish CB, Moore SC, Murphy RA, Murthy VL, Sanders JL, Shah RV, Tseng GC, Wendell SG, Zmuda JM, Newman AB
    J Gerontol A Biol Sci Med Sci, 2021 Jan 18, 76(2): 378-384 | PMID: 32361748 | PMCID: PMC7812434
    Citations: 5 | AltScore: 1.75
  41. Remote Research and Clinical Trial Integrity During and After the Coronavirus Pandemic.
    McDermott MM, Newman AB
    JAMA, 2021 May 18, 325(19): 1935-1936 | PMID: 33885728
    Citations: 8 | AltScore: 45.85
  42. Load-dependent relationships between frontal fNIRS activity and performance: A data-driven PLS approach.
    Meidenbauer KL, Choe KW, Cardenas-Iniguez C, Huppert TJ, Berman MG
    Neuroimage, 2021 Apr 15, 230: 117795 | PMID: 33503483 | PMCID: PMC8145788
    Citations: 4 | AltScore: 5.7
  43. Estimating cardiorespiratory fitness in older adults using a usual-paced 400-m long-distance corridor walk.
    Moffit RE, Qiao YS, Moored KD, Santanasto AJ, Lange-Maia BS, Cawthon PM, Goodpaster BH, Strotmeyer ES, Newman AB, Glynn NW
    J Am Geriatr Soc, 2021 Nov, 69(11): 3328-3330 | PMID: 34269423 | PMCID: PMC8595496
    Citations: 1 | AltScore: 12.05
  44. Rapamycin Treatment of Tendon Stem/Progenitor Cells Reduces Cellular Senescence by Upregulating Autophagy.
    Nie D, Zhang J, Zhou Y, Sun J, Wang W, Wang JH
    Stem Cells Int, 2021, 2021: 6638249 | PMID: 33603790 | PMCID: PMC7870298
    Citations: 5 | AltScore: 17.208
  45. Cardiovascular care of older adults.
    O'Neill DE, Forman DE
    BMJ, 2021 Aug 31, 374: n1593 | PMID: 34465575
    Citations: 4 | AltScore: 199.99
  46. Exercise Intolerance in Older Adults With?Heart?Failure With Preserved Ejection?Fraction: JACC State-of-the-Art Review.
    Pandey A, Shah SJ, Butler J, Kellogg DL Jr, Lewis GD, Forman DE, Mentz RJ, Borlaug BA, Simon MA, Chirinos JA, Fielding RA, Volpi E, Molina AJA, Haykowsky MJ, Sam F, Goodpaster BH, Bertoni AG, Justice JN, White JP, Ding J, Hummel SL, LeBrasseur NK, Taffet GE, Pipinos II, Kitzman D
    J Am Coll Cardiol, 2021 Sep 14, 78(11): 1166-1187 | PMID: 34503685 | PMCID: PMC8525886
    Citations: 9 | AltScore: 19.3
  47. Evaluation of the Bidirectional Relations of Perceived Physical Fatigability and Physical Activity on Slower Gait Speed.
    Qiao YS, Gmelin T, Renner SW, Boudreau RM, Martin S, Wojczynski MK, Christensen K, Andersen SL, Cosentino S, Santanasto AJ, Glynn NW
    J Gerontol A Biol Sci Med Sci, 2021 Sep 13, 76(10): e237-e244 | PMID: 33170216 | PMCID: PMC8436994
    Citations: 2 | AltScore: 1.5
  48. Validation of Perceived Mental Fatigability Using the Pittsburgh Fatigability Scale.
    Renner SW, Bear TM, Brown PJ, Andersen SL, Cosentino S, Gmelin T, Boudreau RM, Cauley JA, Qiao YS, Simonsick EM, Glynn NW
    J Am Geriatr Soc, 2021 May, 69(5): 1343-1348 | PMID: 33469914 | PMCID: PMC8127403
    Citations: 5 | AltScore: 1
  49. Does Medicaid coverage of Medicare cost sharing affect physician care for dual-eligible Medicare beneficiaries?
    Roberts ET, Desai SM
    Health Serv Res, 2021 Mar 28, 56(3): 528-539 | PMID: 33778957 | PMCID: PMC8143678
    Citations: 1 | AltScore: 4.35
  50. Medicaid Coverage 'Cliff' Increases Expenses And Decreases Care For Near-Poor Medicare Beneficiaries.
    Roberts ET, Glynn A, Cornelio N, Donohue JM, Gellad WF, McWilliams JM, Sabik LM
    Health Aff (Millwood), 2021 Apr, 40(4): 552-561 | PMID: 33819086 | PMCID: PMC8068502
    Citations: 5 | AltScore: 100.1
  51. Anticholinergic Medication Use, Dopaminergic Genotype, and Recurrent Falls.
    Rosso AL, Marcum ZA, Zhu X, Bohnen N, Rosano C
    J Gerontol A Biol Sci Med Sci, 2021 Aug 31, 77(5): 1042-1047
    pii: glab258. | PMID: 34463739 | PMCID: PMC9071487
    Citations: | AltScore: NA
  52. Total carotenoid intake is associated with reduced loss of grip strength and gait speed over time in adults: The Framingham Offspring Study.
    Sahni S, Dufour AB, Fielding RA, Newman AB, Kiel DP, Hannan MT, Jacques PF
    Am J Clin Nutr, 2021 Feb 2, 113(2): 437-445 | PMID: 33181830 | PMCID: PMC7851823
    Citations: 5 | AltScore: 19.95
  53. Association of Protein and Genetic Biomarkers With Response to Lumbar Epidural Steroid Injections in Subjects With Axial Low Back Pain.
    Schaaf S, Huang W, Perera S, Conley Y, Belfer I, Jayabalan P, Tremont K, Coelho P, Ernst S, Cortazzo M, Weiner D, Vo N, Kang J, Sowa G
    Am J Phys Med Rehabil, 2021 Jan 1, 100(1): 48-56 | PMID: 32576742 | PMCID: PMC8128510
    Citations: 1 | AltScore: 2.85
  54. Older adults' social network and support and its association with physical activity.
    Schlenk EA, Sereika SM, Martire LM, Shi X
    Geriatr Nurs, 2021 Mar-Apr, 42(2): 517-523 | PMID: 33039202 | PMCID: PMC8716010
    Citations: | AltScore: NA
  55. Clinical-Community Connections: Incorporating Evidence-Based Programs for Improved Patient Outcomes.
    Schrodt LA, Sledge RA, Hergott C, Rohrer B, Sidelinker J, Brach JS, Vincenzo J, Shirley KD, Shubert TE
    Top Geriatr Rehabil, 2021 Jul-Sep, 37(3): 163-167 | PMID: 34366559 | PMCID: PMC8336763
    Citations: | AltScore: NA
  56. Prefrailty, impairment in physical function, and risk of incident heart failure among older adults.
    Segar MW, Singh S, Goyal P, Hummel SL, Maurer MS, Forman DE, Butler J, Pandey A
    J Am Geriatr Soc, 2021 May 29, 69(9): 2486-2497 | PMID: 34050919
    Citations: 3 | AltScore: 25.83
  57. Enhancing the potential of aged human articular chondrocytes for high-quality cartilage regeneration.
    Shen H, He Y, Wang N, Fritch MR, Li X, Lin H, Tuan RS
    FASEB J, 2021 Mar, 35(3): e21410 | PMID: 33617078 | PMCID: PMC8041516
    Citations: 2 | AltScore: NA
  58. COVID-19 and effects on osteoporosis management: the patient perspective from a National Osteoporosis Foundation survey.
    Singer AJ, Fuggle NR, Gill CB, Patel AR, Medeiros AP, Greenspan SL
    Osteoporos Int, 2021 Apr, 32(4): 619-622 | PMID: 33558958 | PMCID: PMC7869916
    Citations: 2 | AltScore: NA
  59. Cognitive and Motor Perseveration Are Associated in Older Adults.
    Sombric CJ, Torres-Oviedo G
    Front Aging Neurosci, 2021, 13: 610359 | PMID: 33986654 | PMCID: PMC8110726
    Citations: 4 | AltScore: NA
  60. Subjective Sleep Quality and Trajectories of Interleukin-6 in Older Adults.
    Stahl ST, Smagula SF, Rodakowski J, Dew MA, Karp JF, Albert SM, Butters M, Gildengers A, Reynolds CF 3rd
    Am J Geriatr Psychiatry, 2021 Feb, 29(2): 204-208 | PMID: 32680764 | PMCID: PMC7759575
    Citations: | AltScore: 0.25
  61. Risk Factors Associated With Transition From Acute to Chronic Low Back Pain in US Patients Seeking Primary Care.
    Stevans JM, Delitto A, Khoja SS, Patterson CG, Smith CN, Schneider MJ, Freburger JK, Greco CM, Freel JA, Sowa GA, Wasan AD, Brennan GP, Hunter SJ, Minick KI, Wegener ST, Ephraim PL, Friedman M, Beneciuk JM, George SZ, Saper RB
    JAMA Netw Open, 2021 Feb 1, 4(2): e2037371 | PMID: 33591367 | PMCID: PMC7887659
    Citations: 7 | AltScore: 238.056
  62. The TOPAZ study: a home-based trial of zoledronic acid to prevent fractures in neurodegenerative parkinsonism.
    Tanner CM, Cummings SR, Schwarzschild MA, Brown EG, Dorsey ER, Espay AJ, Galifianakis NB, Goldman SM, Litvan I, Luthra N, McFarland NR, Mitchell KT, Standaert DG, Bauer DC, Greenspan SL, Beck JC, Lyles KW
    NPJ Parkinsons Dis, 2021 Mar 1, 7(1): 16 | PMID: 33649343 | PMCID: PMC7921548
    Citations: 1 | AltScore: 21.95
  63. Group Lifestyle Phone Maintenance for Weight, Health, and Physical Function in Adults Aged 65-80 Years: A Randomized Clinical Trial.
    Venditti EM, Marcus MD, Miller RG, Arena VC, Greenspan SL, Rockette-Wagner B
    J Gerontol A Biol Sci Med Sci, 2021 Jan 18, 76(2): 352-360 | PMID: 32918078 | PMCID: PMC7812425
    Citations: 1 | AltScore: NA
  64. Physical Therapists as Partners for Community Fall Risk Screenings and Referrals to Community Programs.
    Vincenzo JL, Hergott C, Schrodt L, Perera S, Tripken J, Shubert TE, Brach JS
    Front Public Health, 2021, 9: 672366 | PMID: 34249840 | PMCID: PMC8267879
    Citations: 1 | AltScore: NA
  65. Capitalizing on Virtual Delivery of Community Programs to Support Health and Well-Being of Older Adults.
    Vincenzo JL, Hergott C, Schrodt L, Rohrer B, Brach J, Tripken J, Shirley KD, Sidelinker JC, Shubert TE
    Phys Ther, 2021 Apr 4, 101(4):
    pii: pzab001. | PMID: 33439254 | PMCID: PMC8023634
    Citations: 3 | AltScore: 68.45
  66. Jump power, leg press power, leg strength and grip strength differentially associated with physical performance: The Developmental Epidemiologic Cohort Study (DECOS).
    Winger ME, Caserotti P, Ward RE, Boudreau RM, Hvid LG, Cauley JA, Piva SR, Harris TB, Glynn NW, Strotmeyer ES
    Exp Gerontol, 2021 Mar, 145: 111172 | PMID: 33245997 | PMCID: PMC7855418
    Citations: 2 | AltScore: NA


Luigi Ferrucci, MD, PhD
National Institutes of Aging
Serving since 2004 (18 years)

Nicolaas Bohnen, MD, PhD
University of Michigan
Serving since 2004 (18 years)

Pamela Duncan
Wake Forest
Serving since 2004 (18 years)

Ken Covinsky MD, MPH
University of California San Francisco
Serving since 2021 (1 years)

Rozalyn Anderson, PhD
University of Wisconsin, Veterans Administration Hospital
Serving since 2021 (1 years)

C. Elizabeth Shaaban, PhD, MPH (2021)
  • 2021. Admission to Advanced Psychometric Methods in Cognitive Aging Research 2021 Workgroup Sessions. (Competitive admission).
  • 2021-Present. University of Pittsburgh Alzheimer Disease Research Center (ADRC) Research Education Component (REC) Scholar
  • 2020-2021. University of Pittsburgh ADRC Optimizing Scientific Careers in AD Research (OSCAR) Scholar. Leadership apprenticeship.
Daniel Forman, MD (2022)
  • Michael L. Pollock Established Investigator, American Assoc of CV and Pulmonary Rehabilitation
Fabrisia Ambrosio, PhD, MPT (2022)
  • elected to the American Institute for Medical and Biological Engineering (AIMBE) College of Fellows, in recognition of their distinguished and continuing achievements in medical and biological engineering
Lena Makaroun MD, MS (2021)
  • 2019 - Presidential Poster Award, American Geriatrics Society Annual Meeting
  • 2019 - Science and Innovation Walking Tour Selectee, American Geriatrics Society Annual Meeting
  • 2021 - VA Pittsburgh Healthcare System Early Career Investigator Contest Poster Winner (HSR&D category)
Nami Safai Haeri, MD (2021)
  • Helmsley Charitable Trust Abstract Award from The Endocrine Society
Neil Resnick, MD (2022)
  • 2022 Joseph T. Freeman Award - a lectureship in geriatrics awarded to a prominent clinician in the field of aging, both in research and practice.
Steven M. Albert, PhD, MS, FGSA, FAAN (2022)
  • 2021-22 Fulbright Lecturer/Research Award: "A comparative study of community prevention of disability in older adults: Japan and the U.S."
Susan Greenspan, MD (2022)
  • 2022 UPMC Grand Champion for the 14th Annual UPMC Celebrating Senior Champions


General Brief Description of Minority Activities:
Not defined.

Minority Trainee(s):
  • Diana Alvarez-Davidek MD, Novice REC Member
    Age-related mitochondrial decline in lung function
  • Gardenia Juarez, Pepper Novice Trainee
    Reducing Fear of Falling and Preventing Falls
  • Gelsy Torres-Oviedo, PhD, Pepper REC Transitioned to Independence Trainee
    Increasing gait automaticity in older adults by exploiting locomotor adaptation
  • Keisha Ward, MD, Pepper Novice Trainee
    Alzheimers in minorities
  • Mary Ackenbom, MD, Pepper Novice Trainee
    Physical and cognitive impairment in older women after urogynecological surgery

Minority Grant(s):