Claude D. Pepper Older Americans Independence Center

Stephen Kritchevsky, Ph.D.
Principal Investigator
  336-713-8548   skritche@wakehealth.edu
Dalane Kitzman, MD
Co-Principal Investigator
Kimberly Kennedy, MS, CCRC
Program Administrator
  336-713-8567   kkennedy@wakehealth.edu

The WF OAIC Leadership and Administrative Core (LAC) sets the scientific direction, optimizes administrative and fiscal operations, and ensures the scientific integrity and coherence of the WF OAIC. LAC co-leaders Drs. Kritchevsky and Kitzman will use a proven collaborative leadership model that fosters operational efficiency, high productivity, and innovative translational and multidisciplinary research focused on our theme, “Integrating pathways affecting physical function for new approaches to disability treatment and prevention”.

The Specific Aims of the Leadership and Administrative Core are to:

1.  Provide overall scientific leadership and direction for the WF OAIC. The LAC co-leaders will synthesize information regarding the local and national research environment with input from the OAIC Executive Committee, the OAIC External Advisory Board, the REC Advisory Committee and WF’s senior administrative leadership to guide the direction of the OAIC through:  the mix of Core services; the focus of research development projects; the tailoring of pilot award RFAs; interactions with the OAIC Coordinating Center, other OAICs and other aging-focused research centers; and the selection of early- career faculty for Research Education Component (REC) support. The LAC will integrate WF OAIC Core activities to advance the OAIC’s scientific agenda, improve efficiency, and foster translation between basic and clinical research.

2. Efficiently manage the resources of the WF OAIC in compliance with applicable institutional and NIA/NIH policies. The LAC will: 1) provide administrative and budgetary support to the WF OAIC according to OAIC priorities; 2) seek additional institutional resources to extend the scope of its activities; 3) arrange for the scientific review of pilot and research development projects and candidates seeking REC support; 4) monitor all OAIC activities for timely completion and achievement of targeted goals and milestones, and intervene to remove roadblocks or (if necessary) redirect resources; and 5) assure all OAIC-supported activities follow federal and institutional rules, regulations, and guidelines and promote the responsible conduct of research and participant safety.

3. Increase WF OAIC’s impact by attracting new investigators, capturing new resources, and translating findings beyond traditional research settings. The LAC will attract new researchers and research capabilities to OAIC-supported research by engaging the local and regional academic communities, in coordination with resources from WF’s Sticht Center for Healthy Aging and Alzheimer’s Prevention, the Section of Gerontology and Geriatric Medicine, and other academic and service units.  The LAC will also promote the NIA’s goals for the OAIC program by translating its research to affect the clinical care of older adults and the health and well-being of older adults in the community. 

During the current cycle, the WF OAIC achieved high productivity and innovation, and enhanced its strategic positioning and prominence within Wake Forest and enhanced its local and national impact.  Compared to the previous cycle, publication productivity was increased 5% and OAIC-related extramural funding increased 91%. The outstanding productivity of OAIC investigators occurred despite the challenging funding environment and is attributable (in part) to our innovative strategies to promote efficiency (e.g., thematic alignment, the OAIC Integrated Aging Studies Databank and Repository), and the LAC’s success in leveraging $4.3 million in institutional funds in support of the OAIC mission. 

WF OAIC involvement was critical in securing high-impact awards that enhance the breadth and depth of research resources available to the OAIC, including a new CTSA and a new Alzheimer’s Disease Core Center.  As an Associate Director of the Wake Forest Clinical and Translational Science Institute and director of its KL-2 program, Dr. Kritchevsky aligned CTSI resources with the OAICs for their mutual benefit.  His role as Associate Dean for Research Development provides him with influence over WF’s research priorities.  Locally, the OAIC has successfully expanded our research partnerships to deliver interventions in innovative settings (Meals-on-Wheels, Agricultural Extension Service, YMCA’s and Continuing-Care communities). WF OAIC leaders have been national advocates for the OAIC’s mission and have helped develop multi-centered trials testing hypotheses generated from OAIC work (e.g. LIFE, ENRGISE, PCORI/STRIDE) and pivot large multi-center trials towards OAIC relevant outcomes (e.g., SPRINT, Look AHEAD).  The WF OAIC, under the leadership of Drs. Kritchevsky and Kitzman, will use OAIC support to sustain the LAC’s continual innovation through the 2018-2023 cycle.

To address these objectives our OAIC is composed of seven cores, which currently supports 4 REC Scholars, 17 clinical studies (all which are funded by the NIH), 2 research development projects, and 8 pilot studies.

Leadership and Administrative Core (LAC)
Leader 1:    Stephen Kritchevsky, PhD   skritche@wakehealth.edu
Leader 2:    Dalane Kitzman, MD   dkitzman@wakehealth.edu
The Leadership and Administrative Core is responsible for scientific leadership and direction of the center. It coordinates the functions of the OAIC cores and projects in order to facilitate communication and foster translation between basic and clinical research and ensure access of investigators to core resources. It assures the coordination of OAIC resources and functions with other research and training grants and institutional resources. It is supported by the OAIC Executive Committee, the Joint Scientific Review Panel, and the External Advisory Committee. The core communicates with other OAICs and the NIA and fosters collaborations with other OAICs including UTMB, University of Maryland and Duke. Maintains the OAIC web-based tracking and monitoring system and promotes the use of uniform assessment batteries in all OAIC supported studies. The LAC works with Core leaders to identify, review, and support projects and activities which serve to advance the scientific goals of the OAIC. The LAC and Executive Committee actively identify promising projects and REC candidates through informal networks, review of all new faculty hires at WF, and all new grant awards to WF faculty. WF OAIC overarching resource allocation priorities are based on: 1) scientific merit; 2) theme relevance; 3) REC scholar/junior faculty involvement; 4) Pilot/Exploratory study support; 5) research development projects; and 6) externally supported projects. This priority maintains our thematic coherence and enhances support for projects that may need it.

Research Education Component (REC)
Leader 1:    Stephen Kritchevsky, PhD   skritche@wakehealth.edu
Leader 2:    Denise Houston, PhD   dhouston@wakehealth.edu
Leader 3:    Heidi Klepin, MD   
The Research Education Component (REC) continues to promote the development of future research leaders in the area of focus of this OAIC application, integrating pathways affecting physical function for new approaches to disability treatment and prevention. The core emphasizes development of skills for translating basic findings into clinical research, and clinical findings into basic research. Resources of this core are integrated with other external sources for career support, such as NIH career development and research awards, fellowships, and non-NIH career and research awards. Resources of the REC are also leveraged with assets of the Wake Forest Clinical and Translational Science Institute (CTSI); Dr. Kritchevsky is a Core Faculty member of the CTSI’s KL2 program. The CTSI has a Translational Research Academy, a Mentor Academy, and a K and R Award Writer’s Series, which provide added value to the REC through courses, facilitation of grants, navigating regulations, and evaluating competencies. All REC scholars are encouraged to participate in the Translational Research Academy to help optimize the relative contributions of the CTSI and REC programs. The REC co-leaders are Drs. Kritchevsky and Houston; Dr. Klepin, REC leadership intern, will specifically recruit and advise promising clinical faculty. Dr. Kritchevsky is a national leader in aging research, whose expertise spans the translational spectrum from basic science to policy formulation. Dr. Houston is a national leader in nutrition and aging research with expertise in both epidemiologic studies and clinical trials. Dr. Klepin is a national leader in geriatric oncology with expertise in conducting patient-oriented research, including both pharmacologic and behavioral interventions. Each of the Core Leaders is accomplished in interdisciplinary and team-based research, and well positioned to assure that REC programs and activities are well integrated with other internal and external career development activities. All REC projects continue to utilize Pepper Core support to signify the integration of resources and disciplines. This includes: Ellen Quillen, PhD (Integrative Biology Core) and Atalie Thompson, MD, MPH (Biostatistics and Data Management Core and Clinical Research Core). The REC currently supports five REC scholars which includes two REC scholars that began in the summer/fall of 2021 (Quillen, Thompson) and three new REC scholars (Genesio Karere, PhD; Lindsay Reynolds, PhD; and Jaime Hughes, PhD) that started in April 2022. The three new REC scholars were selected in response to an RFA for REC scholars distributed across the institution in October 2021. Two REC developmental scholars (Chinenyenwa Usoh, MD, and Philip Kramer, PhD) were also selected with the purpose of helping them refine and develop their research ideas and strengthen their research portfolios.

Pilot and Exploratory Studies Core (PESC)
Leader 1:    Dalane Kitzman, MD   dkitzman@wakehealth.edu
Leader 2:    Tom Register, PhD   register@wakehealth.edu
Leader 3:    Jingzhong Ding, MD, PhD   jding@wakehealth.edu
Effective pilot and exploratory studies (PES) play a critical role in the development of successful, externally-funded research proposals, particularly for early stage investigators who often lack other means to obtain preliminary data. The Wake Forest OAIC Pilot and Exploratory Studies Core (WF PESC) proposes to continue our coordinated, multi-faceted group effort to promote PESs, and to further innovate to optimize our processes. Through support from the OAIC grants, Wake Forest University has been very active in efforts to enhance aging related research activities. These activities have focused on the mechanism, treatment and outcomes associated with functional decline and disability and have had a profound impact on the research culture at our institution with greater awareness and interest in addressing these important yet understudied issues of geriatric research.

The overall goal of the WF OAIC PESC is to develop key information needed for the design of definitive, externally funded, translational research studies that promote the WF OAIC mission of advancing our understanding of pathways influencing physical function and developing new approaches to disability prevention and treatment.

This will be achieved by executing the following Specific Aims to:

1) Identify and promote promising key areas of research
2) Identify and recruit talented investigators from complementary fields to focus on OAIC-themed aging research
3) Solicit and facilitate competitive research proposals and conduct peer review to select those with the best science and career development opportunities
4) Coach and mentor investigative teams to maximize the quality of research proposals and projects
5) Team with other WF OAIC cores to facilitate successful completion of the selected pilot projects and mentor junior early career investigators to advance their development as successful translational scientists

Continuously evaluate, refine, and optimize OAIC PESC processes and procedures.

Clinical Research Core (CRC)
Leader 1:    Jack Rejeski, PhD   rejeski@wfu.edu
Leader 2:    Anthony Marsh, PhD   marshap@wfu.edu
Leader 3:    Jeff Williamson, MD, MHS   jwilliam@wakehealth.edu
Leader 4:    Kristen Beavers, PhD   beaverkm@wfu.edu
The Clinical Research Core (CRC) provides institution-wide guidance on the design and conduct of clinical research consistent with the WF OAIC theme (present and past) and involving older adults. The CRC also performs validated, standardized assessments of physical and cognitive function, strength, and disability. Assistance is provided to investigators at all levels of experience and all sizes of research studies with integration of these OAIC measures into their research involving older adults. The Core’s scientific focus is the advancement of physical function based clinical research methods and the design, implementation, and evaluation of interventions designed to measure whether specific interventions developed in this or other cores preserve the independence of older adults. Functional assessment instruments and trial design encompass both community and clinic-based settings. Additionally, members of the core are involved in cross-disciplinary translational research with other cores within the center. The overall hypothesis for this CRC is that the inclusion of efficient, standardized measures of functional assessment will promote translation of the OAIC research into clinical research and care through improved understanding of function as both a risk factor and an outcome (see below). The Core also includes both 1) a recruitment unit and 2) a muscle and adipose tissue biopsy unit for OAIC supported studies. In addition, if including aging-related measures is required as part of specific studies, the Core supported staff will assist investigators by training them or their staff and/or collecting these assessments. Currently the standard assessment battery includes: 1. Anthropometry (Height, Body Mass, Abdominal Circumference) 2. Grip strength (Jamar hand grip dynamometer) 3. Lower extremity muscle power (Keiser knee extension and leg press) 4. The Short Physical Performance Battery (SPPB: three tests of physical function - standing balance, usual pace gait speed over 4 meters, time to rise from a chair and sit down five times) 5. 400 meter walk test (400MWT: study specific protocols for either usual or fast pace gait speed) 6. Pepper Assessment Tool for Disability (PAT-D: self-report instrument) 7. Mobility Assessment Tool – short form (MAT-sf: 10 or 12-item computer based self-report assessment of mobility using animated video clips) 8. Digit Symbol Substitution Test (DSST: validated cognitive assessment that is strongly correlated with walking speed) 9. Montreal Cognitive Assessment© (MoCA: global cognitive assessment that aids in interpreting DSST performance) The core also has the capacity to assess muscle strength of various muscle groups (Biodex isokinetic dynamometer), gait speed and spatiotemporal parameters of gait (GAITRite instrumented mat), and postural sway descriptors (AMTI portable force platform).

Leader 1:    Leon Lenchik, MD   llenchik@wakehealth.edu
Leader 2:    Christina Hugenschmidt, PhD   chugensc@wakehealth.edu
Leader 3:    Ashley Weaver, PhD   asweaver@wakehealth.edu
This core supports independently funded studies, pilot studies, and research development studies in the accurate in vivo measurement of body composition, specifically focusing on skeletal muscle mass and composition, fat mass and distribution, and bone mineral density. This core collaborates with other OAIC cores in the development of new, multidisciplinary, and translation research projects directed at elucidating the etiology, consequences, prevention and treatment of sarcopenia and its sequelae. The BRC has contributed to the success of the WF OAIC by helping to quantify structural and functional tissue-related measures, developing novel bio-imaging techniques, integrating imaging assessments with other OAIC cores, and using imaging technologies for studies of physical function and disability in older persons. The BRC has also provided early-career and experienced investigators access to a broad range of imaging methods relevant to disability and age-related physical decline including dual x-ray absorptiometry (DXA), computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET), and ultrasonography (US) as well as access to expertise and mentoring in bio-imaging including image acquisition, analysis, interpretation, archival, and dissemination. The Bioimaging Resource Core (BRC) has contributed to the success of the WF OAIC by helping to quantify structural and functional tissue-related measures, integrating imaging assessments with other OAIC cores, and using imaging technologies for studies of physical function and disability in older persons. The BRC has also provided early-career and experienced investigators access to a broad range of imaging methods relevant to age-related physical decline including dual x-ray absorptiometry (DXA), computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET), and ultrasonography (US) as well as access to expertise and mentoring in bio-imaging including image acquisition, analysis, interpretation, archival, and dissemination. Over the past year, the BRC has added an emphasis on expanding the imaging infrastructure. The infrastructure initiative has two parts: 1) updating hardware and software and harmonizing archiving with other OAIC and ADRC cores to increase access to data already collected and 2) adding new bone imaging capability to the suite of imaging techniques available to OAIC investigators. The BRC received an administrative supplement (in response to NOT-AG-17-008 and PA-16-287) to develop research on Alzheimer’s disease and Alzheimer’s-related dementias (ADRD). The goal was to harmonize imaging data workflow between the WF OAIC and WF ADRC. In the past year, the BRC made progress on: 1) archiving of past imaging studies using a newly acquired Vendor Neutral Archive (VNA), 2) harmonizing imaging data storage, processing, and archiving between the OAIC and ADRC, and 3) harmonizing imaging data request process between OAIC and ADRC. Such harmonization will allow investigators to ask cutting-edge questions about the brain-body integration including the trajectory of physical decline in people with ADRD and the trajectory of cognitive decline in older adults with mobility disability, obesity, and frailty.

Biostatistical Design and Analysis Core (BIC)
Leader 1:    Iris Leng, PhD   ileng@wakehealth.edu
Leader 2:    Nicholas Pajewski, PhD   npajewsk@wakehealth.edu
Leader 3:    Dan Beavers, PhD   dbeavers@wakehealth.edu
The goal of the Wake Forest OAIC Biostatistics and Research Information Systems Core (BIC) is to build on our outstanding success in biostatistical collaboration and to expand a broad class of statistics/informatics tools tailored to research in aging. The BIC team has highly qualified investigators/staff with expertise in design and management of observational, pilot, and interventional studies; centralized and decentralized data management; forms design and data processing, psychometrics; statistical analysis of data from multiple study designs; and development of novel statistical methods. The BIC team is committed to the WF OAIC’s programmatic aims to: (1) discover new common pathways contributing to age-related declines in physical function and disability; (2) develop, evaluate, and refine strategies for disability treatment and prevention; (3) translate proven strategies beyond traditional research environments; and (4) train the next generation of research leaders focused on disability treatment and prevention. The BIC provides expertise and critical infrastructure essential to the mission of the WF OAIC, and promotes efficiency through centralized data management. BIC members will play a key role in study design, analysis, and interpretation for WF OAIC projects, will be integral members of mentoring teams for REC Scholars and early-stage faculty, and continue their intellectual contributions that strengthen research on aging through the development of novel measurement, statistical, and research informatics tools. During the past year, members of the Biostatistics and Research Information Systems Core (BIC) have continued to provide support for numerous studies performed within the WFU OAIC. Efforts include developing web-based data entry systems for individual studies, harmonizing common measurements taken across multiple studies, performing analyses of pilot/developmental studies and existing data bases, and collaborating on the development of pilot studies and grant submissions resulting from WFU OAIC pilot studies. In addition, faculty in the Core continue to be involved with mentoring committees for REC fellows, collaboration on career development award submissions, reviewing pilot studies and applications of prospective REC fellows. During the past year, members of the BIC collaborated with WFU OAIC investigators in the submission of several R01s, a U24, and a K76 grant. During the past year, members of the BIC collaborated with WFU OAIC investigators in the submission of several R01s, a U24, and a K76 grant. As of October 2021, the BIC has also undergone a planned change in leadership, with Drs. Miller and Ip stepping down from their roles.

Integrative Biology Core
Leader 1:    Barbara Nicklas, PhD   bnicklas@wakehealth.edu
Leader 2:    Osvaldo Delbono, PhD   odelbono@wakehealth.edu
Leader 3:    Jamie Justice, PhD   jjustice@wakehealth.edu
Over the past year, the Integrative Biology Core (IBC) advanced the science of our OAIC by adding biological measures to facilitate translational research for OAIC investigators and by advising and mentoring REC scholars and early-career faculty. We also continued maintenance of our centrally collected and stored Biological Specimen Repository from aging-related studies. The Core provided resources and personnel in support of several externally-funded studies (SOMMA, HALLO-P, U01 Aging Biomarkers, SECRET2, VARIA, INVEST, UPLIFT, B-NET, HOPE and EMPOWER), and externally-funded and OAIC-supported pilots. Core Resource Use and Development of New Services: Repository, Biomarker, and tissue biopsy services—IBC personnel assist study investigators with the proper collection, transfer, and central storage of human biological tissue specimens and facilitate their later use in ancillary studies by other investigators. In the past year the Core supported labeling, tracking and storage of blood samples from participants enrolled in 6 externally-funded studies (INVEST, SOMMA, B-NET, SECRET2, HOPE, and UPLIFT), and assisted with collection, processing, and storage of muscle (SOMMA) and adipose tissue (SOMMA). The Core also expanded its biomarker services through purchase of two instruments for biomarker determination: Ella SimplePlex and Luminex LX200. Ella SimplePlex is a semi-automated device with integrated cartridge system used for targeted biomarkers – which will form the basis for an expanded ‘Pepper Common Battery’ for biomarkers, and Luminex LX200 has advanced multiplexing capability that permits a discovery-based biomarker approach. The two systems work well in tandem, providing industry-standard biomarker multiplexing via Luminex LX200 which can be used to identify specific markers for analysis using Ella SimplePlex. Resources and personnel advanced the science of our OAIC theme by adding measures to externally-funded studies and pilots to facilitate translational research for OAIC investigators, and by advising and mentoring of the REC scholars. In the past year, the Integrative Biology Core (IBC) advanced the science of our OAIC by adding biological measures to facilitate translational research for OAIC investigators, and by advising and mentoring REC scholars and early-career faculty. We also continued maintenance of our centrally collected and stored Biological Specimen Repository from aging-related studies. The Core provided resources and personnel in support of several externally-funded studies (SOMMA, HALLO-P, U01 Aging Biomarkers, SECRET2, VARIA, INVEST, UPLIFT, B-NET, HOPE and EMPOWER), and externally-funded and OAIC-supported pilots.

REC Scholar, Research & Grants Funded During Pepper Supported Time Years /
Lindsay Reynolds, PhD
Assistant Professor / Department of Epidemiology and Prevention
Dietary Patterns and Biological Aging in the Women’s Health Initiative
To examine epigenetic aging measures as a mediator between adherence to healthy dietary patterns and incidence of frailty over ~ 10 years using existing data from the Women’s Health Initiative.
  • (Pending Funding) Title: MARVEL: A Multidisciplinary Assessment of Risks from Vaping during Early Life Project Number: P01CA269048-02 Name of PD/PI: Sutfin/Donny MPIs Source of Support: NCI/NIH Submission date: 5/19/2022 Role: Co-I (co-lead Project 3) Project/Proposal Start and End Date: 04/01/23 - 03/31/28
  • Title: Epigenetics of COPD - SPIROMICS pilot Name of PD/PI: Reynolds, LM Source of Support: Wake Forest Tobacco Control Center of Excellence Year 03/01/2022 - 03/31/2023 1.80 Calendar months
  • Title: Women's Initiative Health (WHI) - Regional Center (RC) Project Number: 75N92021D00005 Name of PD/PI: Vitolins, M. Source of Support: NHLBI Year 10/15/2022 - 10/14/2023 1.8 Calendar months

2022-2024 /
1 (total)
0 (1st/Sr)
Genesio Karere, PhD
Assistant Professor / Department of Internal Medicine, Section on Molecular Medicine
MicroRNA biomarkers and pathways underlying response to exercise intervention in older adults
To identify a panel of circulating miRNA biomarkers and coordinately regulated miRNA-gene networks and pathways indicative of response to exercise in older obese adults from prior WF OAIC supported intervention studies. Specific aims: Using stored samples from the IASDR, 1) Identify a panel of circulating miRNA biomarkers indicative of response to exercise intervention in older adults with obesity; and 2) Identify coordinately regulated miRNA-gene networks and pathways underlying response to exercise intervention in older adults with obesity.
2022-2024 /
1 (total)
0 (1st/Sr)
Jaime Hughes, PhD
Assistant Professor / Department of Implementation Science
Promoting healthy sleep-wake behaviors across a 24-hour cycle in frail older adults
1) describe frail older adults’ sleep-wake behaviors across a 24-hour cycle and explore the association between co-occurring poor sleep and low activity with functional status; 2) explore older adults’ and providers’ attitudes towards a comprehensive sleep-wake intervention, including treatment knowledge and preferences as well as potential intervention and implementation barriers and facilitators; and 3) explore the feasibility and acceptability of daytime intervention components for a comprehensive sleep-wake intervention in frail older adults in a pilot trial.
2022-2024 /
7 (total)
5 (1st/Sr)
Ellen Quillen, PhD
Assistant Professor / Department of Internal Medicine, Section on Molecular Medicine
A multiomic approach to profiling muscle contractility and mobility in healthy adults
  • Wake Forest Pepper Pilot award: Monkeys, muscle, and mobility: a multi-omic approach to understanding the biology of muscle aging (1/22 – 12/22)

2021-2023 /
2 (total)
1 (1st/Sr)
Atalie Thompson, MD, MPH
Assistant Professor / Department of Ophthalmology, Section on Glaucoma
Exploring visual impairment and physical dysfunction in older adults
To determine if age-related differences in both the brain structure and functional brain networks explain age-related differences in visual function and how these differences in visual function relate to differences in physical function.
2021-2023 /
3 (total)
1 (1st/Sr)

Past Scholars
Kathryn Callahan, MD, MS, Gerontology and Geriatric Medicine (2014-2018)
Candace Parker-Autry, MD, Obstetrics-Gynecology (2015-2019)
Rita Bakhru, MD, MS, Pulmonary, Critical Care, Allergy and Immunologic Diseases (2016-2021)
Jamie Justice, PhD, Gerontology and Geriatric Medicine (2017-2018)
Amber Brooks, MD, Anesthesiology (2017-2018)
Sam Lockhart, PhD, Gerontology and Geriatric Medicine (2018-2019)
Hariom Yadav, PhD, Molecular Medicine (2019-2021)
Jason Fanning, PhD, Health and Exercise Science (2019-2021)

1. Project Title: PESC 2020.1 Application of the Novel D3Cr Dilution Method to Better Understand Weight Loss Associated Changes in Muscle Mass and Physical Performance Among Older Adults with Obesity
  Leader: Kristen Beavers, PhD (Health & Exercise Science)
  The number of older adults living with obesity is growing at an unprecedented rate. Intentional weight loss (WL) can reverse obesity but concerns develop as WL decreases muscle mass. Counter-intuitively, despite decreased muscle mass; older adults can significantly improve muscle strength, physical performance, and mobility following intentional WL. We posit these paradoxical observations originate from indirect bioimaging methods commonly used to approximate muscle mass in clinical research. In contrast to these methods, the D3-Creatine (D3Cr) dilution method directly measures whole-body muscle mass. Consequently, D3Cr muscle mass displays stronger associations with physical function (i.e. strength, physical performance, and mobility) than dual energy x-ray absorptiometry (DXA) lean mass. However, given the novelty of this method, D3Cr muscle mass has not been examined in an intentional WL RCT; thus, the effects of intentional WL on changes in D3Cr muscle mass remain unclear. To address this knowledge gap, and as an appropriate next step in this line of research, we propose to add the D3Cr muscle mass measure to the ongoing NIA and Claude D. Pepper Older Americans Independent Center supported RCT (NCT04076618), Incorporating Nutrition, Vest, Education and Strength Training trial (INVEST). This pilot will leverage the current INVEST assessment schedule to add the D3Cr muscle mass measure at baseline and six-months. The primary objective of this pilot is to determine the feasibility of the D3Cr muscle mass measure as part of a clinical WL trial. We hypothesize this method for measuring muscle mass will be feasible among participants enrolled in INVEST. Additionally, our secondary objectives aim to (i) quantify the associations between six-month change in D3Cr muscle mass and change in 1) physical function, and 2) computed tomography (CT) muscle density and cross-sectional area (CSA), and DXA lean mass among 30 INVEST participants and (ii) examine the ability of baseline D3Cr muscle mass, CT muscle density and CSA, and DXA lean mass to predict six-month change in physical function among 90 INVEST participants. Overall, we hypothesize stronger associations will be observed between change in D3Crmuscle mass and physical function, compared to DXA and CT; and that baseline D3Cr muscle mass will predict intervention-related changes in muscle physical function; and, to a greater degree than DXA or CT parameters. These data will provide first of its kind data identifying the feasibility of the D3Cr method in a WL trial, support a prior R01 application (AG070169; 35%; MPIs: Cawthon/K. Beavers), and provide a unique training opportunity for Dr. Miller (T32 AG033534).The number of older adults living with obesity is growing at an unprecedented rate. Intentional weight loss (WL) can reverse obesity but concerns develop as WL decreases muscle mass. Counter-intuitively, despite decreased muscle mass; older adults can significantly improve muscle strength, physical performance, and mobility following intentional WL. We posit these paradoxical observations originate from indirect bioimaging methods commonly used to approximate muscle mass in clinical research. In contrast to these methods, the D3-Creatine (D3Cr) dilution method directly measures whole-body muscle mass. Consequently, D3Cr muscle mass displays stronger associations with physical function (i.e. strength, physical performance, and mobility) than dual energy x-ray absorptiometry (DXA) lean mass. However, given the novelty of this method, D3Cr muscle mass has not been examined in an intentional WL RCT; thus, the effects of intentional WL on changes in D3Cr muscle mass remain unclear. To address this knowledge gap, and as an appropriate next step in this line of research, we propose to add the D3Cr muscle mass measure to the ongoing NIA and Claude D. Pepper Older Americans Independent Center supported RCT (NCT04076618), Incorporating Nutrition, Vest, Education and Strength Training trial (INVEST). This pilot will leverage the current INVEST assessment schedule to add the D3Cr muscle mass measure at baseline and six-months. The primary objective of this pilot is to determine the feasibility of the D3Cr muscle mass measure as part of a clinical WL trial. We hypothesize this method for measuring muscle mass will be feasible among participants enrolled in INVEST. Additionally, our secondary objectives aim to (i) quantify the associations between six-month change in D3Cr muscle mass and change in 1) physical function, and 2) computed tomography (CT) muscle density and cross-sectional area (CSA), and DXA lean mass among 30 INVEST participants and (ii) examine the ability of baseline D3Cr muscle mass, CT muscle density and CSA, and DXA lean mass to predict six-month change in physical function among 90 INVEST participants. Overall, we hypothesize stronger associations will be observed between change in D3Crmuscle mass and physical function, compared to DXA and CT; and that baseline D3Cr muscle mass will predict intervention-related changes in muscle physical function; and, to a greater degree than DXA or CT parameters. In May 2022, baseline and six-month pre-dose/post-dose urine sample collect was completed on our target 24 participants, and samples were sent to Dr. Bill Evan’s group (co-I) for processing. An abstract describing the quantification of total body muscle mass was submitted by Allison Avery (HES graduate student) accepted for presentation at the 2023 Southeastern American College of Sports Medicine (SEACSM) annual meeting (2.24.22; Greenville, SC). A second abstract describing associations between D3Cr muscle mass and DXA lean mass was submitted in December 2022 to the 2023 National American College of Sports Medicine (ACSM) annual meeting by Dr. Daniel Beavers. Collectively, data will serve the basis of Ms. Avery’s thesis and corresponding manuscript (targeting submission to the Journal of Cachexia, Sarcopenia, and Muscle by April 2023).
2. Project Title: PESC.2020.3 Real-world monitoring of limb loading for bone preservation during weight loss
  Leader: Ashley Weaver, PhD, Katherine Hsieh, PhD (Biomedical Engineering)
  Obesity is a serious health concern among older adults that is associated with a loss of physical function and increased disability. Despite known medical complications that accompany obesity, there is reluctance to recommend intentional weight loss for older adults. This hesitation is partly due to reduced bone mineral density (BMD) that is observed with weight loss in this population, which can exacerbate the potential for development of osteoporosis and osteoporotic fracture. Reduced BMD because of weight loss is thought to occur due to less mechanical stress on the bone with reduced body weight. Although resistance training increases mechanical loading and attenuates BMD loss, compliance is challenging among older adults. A novel method to increase mechanical loading and improve BMD is through wearing weighted vests. This mode of increasing external load is currently being evaluated in an active OAIC-investigator led clinical trial (INVEST). However, the INVEST trial does not contain a direct measure of limb loading. The lack of direct limb loading metrics combined with uncertainty as to which loading metrics are associated with improved bone health likely contributes to observed variation in individual levels of preserved BMD with external loading interventions. Therefore, the overarching goal of this study is to evaluate the feasibility of using innovative force-sensing insoles to compare limb-loading response between external loading during intentional weight loss and intentional weight loss alone. Force-sensing insoles are a portable, valid, and reliable wearable technology that measures force at the foot-shoe interface and provides an indicator of overall limb loading. These insoles can be used outside of a research or clinical setting and measures real-world activities for continuous hours. Leveraging the investigator’s ongoing clinical trial, the primary goal of this study is to evaluate the feasibility of measuring daily limb loading using force-sensing insoles in 45 overweight or obese older adults (ages 60-85 years) in an intentional weight loss program combined with weighted vest use (VEST+WL) or resistance training (RT+WL) compared to intentional weight loss alone (WL). We hypothesize we will be able to recruit participants into the study with high adherence and satisfaction when wearing the insoles. We will also compare a) daily loading metrics with the insoles and b) femoral stress and strain between groups using CT imaging and finite element (FE) modeling. Last, we will identify associations and between limb loading metrics, changes in physical function and BMD change. The results of this study will expand the ability for remote home-based assessment and intervention delivery through force-sensing insoles, a necessity during the COVID-19 pandemic. Moreover, these findings will understand how to tailor external loading during weight loss for older adults to maximize their physical function and prevent disability associated with aging. Recent Updates: 44 participants have completed baseline insole assessment: 43 of those have been randomized, 37 participants have competed at-home wear, and 36 have completed follow up assessment. Data collection will be completed by the end of January 2023. Limb loading metrics (cumulative loading, loading rate, peak loading) are being processed and analyzed as data collection is on-going. Baseline data processing is completed, and at-home wear and follow-up data are currently being processed. Subject specific FE models of the dominant leg for randomized subjects have been generated. Simulations have been conducted using a well-validated full human body FE model in the mid-stance stance of the gait cycle to quantify how loads measured at the insole (foot) transfer to loading at the mid-femur level. From this, a translation value was derived to appropriately associate the insole forces to the mid-femur shaft of the isolated femoral FE model. Relationships derived from literature are being used to simulate the mid-femur in the maximal force configuration corresponding to each subject (i.e. heel strike or toe off), which was determined through visual inspection of the force v. time data. Subject-specific FE simulations are in progress, and virtual instrumentation is being developed for the FE models to extract strain metrics from the simulations. As data is being continuously processed, a feasibility paper (Aim 1 of the pilot) is currently drafted and will be submitted in Spring 2023.
3. Project Title: PESC.2020.4 (Ignition Pilot) MicroRNAs biomarkers and miRNA-gene networks associated with exercise-modulated weight loss
  Leader: Genesio Karere, PhD (Internal Medicine)
  The prevalence of overweight and obesity is increasing in the US and the world-wide. Obesity is associated with comorbidities, including cardiovascular disease, diabetes and hypertension. Exercise is a proven approach to weight loss and is accompanied by physiological changes in skeletal muscles. Identification of skeletal muscle miRNAs associated with weight loss and measured in circulating biofluids is important for elucidating molecular indicators of weight loss and exercise-modulated molecular mechanisms underlying the weight loss. MicroRNAs (miRNAs) are post-transcriptional regulators of gene expression that results in alteration of mRNA and protein abundance, impacting diverse biological processes including cell growth, proliferation, differentiation and apoptosis. These processes are fundamental to maintenance of tissue cellular homeostasis. miRNAs expression is responsive to external stimuli, including exercise. Consequently, miRNAs are emerging potential biomarkers because are readily dateable in biofluids, including plasma/serum, saliva and urine, and potential therapeutic targets. Dysregulation of a few specific miRNAs (miR375. 126-3p, 663, 30c-p, 100-5, 27-3p, and 590-5p) has been implicated in weight loss after bariatric surgery (Doyon L et al. 2020). Inhibition of miR-324-5p resulted in reduction of adipose tissue and overall body weight loss in juvenile mice (Li D et al 2019). Other studies have revealed miRNAs dysregulated after exercise. For example, the expression of skeletal muscle-specific miRNAs (miR-1, miR-133a and b, miR-208b and miR-206) measured in plasma increased after chronic exercise (Banzet et al. 2013). In another study, serum circulating levels of miR-486 decreased after chronic versus acute exercise, and the expression was negatively correlated with VO2 max (Aoi et al. 2013). Together these studies separately suggest that miRNAs are responsive to weight loss and exercise. However, a comprehensive study revealing miRNA biomarkers of and molecular mechanisms underlying weight loss due to exercise is lacking. The objective of the proposed pilot study is to evaluate the feasibility of using miRNAs to predict weight loss after exercise and to provide potential mechanistic insights. We hypothesize that miRNAs are potential biomarkers predicative of weight loss after exercise, providing potential insights to molecular mechanisms underlying exercise outcomes.

We will test the hypothesis using the following specific aims:

1. Identify circulating miRNAs in plasma that correlate with weight loss after exercise. We will use small RNA Seq to assess miRNAs in plasma at baseline and post intervention in two groups: a group that showed weight loss after exercise (n= 5 pairs) and another group that exhibited no change (n= 5 pairs). Outcomes will be identification of miRNAs differentially expressed between baseline and post interventions in each group and miRNAs that are differentially expressed between the groups post intervention.

2. Identify skeletal muscle miRNA-gene regulatory networks associated with weight loss. We use the same study design in Aim 1 and small RNA Seq to identify differentially expressed miRNAs. In addition, we will identify miRNA-gene regulatory networks by integrating miRNA data and existing skeletal muscle transcriptomic data from the same individuals. Outcomes will be identification of skeletal muscle differentially expressed miRNAs and miRNA-gene networks dysregulated in exercise-modulated weight loss, providing potential biomarkers and insights to molecular mechanisms underlying weight loss after exercise.
4. Project Title: PESC.2021.1 Epigenetics of an intensive lifestyle intervention: the Look AHEAD study.
  Leader: Lindsay Reynolds, PhD (Epidemiology and Prevention), Mark Espeland, PhD (Gerontology and Geriatric Medicine), Timothy Howard, PhD (Biochemistry), Carl Langefeld, PhD (Biostatistics)
  Diabetes and obesity increase the risk of age-related health deficits and may accelerate epigenetic aging. Lifestyle interventions promoting weight loss, such as the Action for Health in Diabetes (Look AHEAD) trial intervention, can potentially buffer against decline in age-related health status in overweight or obese adults with type 2 diabetes. However, significant variation exists among who benefits from intensive lifestyle intervention (ILI) programs. Better understanding of the biological impact of ILI could help lay the foundation for personalized medicine approaches to predict individual responses to ILI. Epigenetic aging measures (the difference between a DNA methylation-based measure of biological age vs. chronological age) capture aspects of biological aging, and have potential as biomarkers of impact of ILI. We hypothesize that an ILI is more beneficial for participants with higher baseline measures of epigenetic aging, and that changes in epigenetic aging mediate benefits of ILI on accumulation of health deficits over time. To test our hypothesis, we are proposing to test epigenetic aging measures as predictors and biomarkers of the impact of the Look AHEAD ILI in adults with diabetes and obesity. We will assess baseline epigenetic age acceleration as a predictor of impact of an ILI on frailty in adults with diabetes and obesity. The goal of this pilot study is to generate preliminary data establishing feasibility and estimates for sample size calculations for an R01 application. We will generate epigenomic data and DNA methylation-based estimates of epigenetic aging in samples from a subset (n=32) of participants of the Look AHEAD trial at baseline and ~16 years after baseline. We will generate descriptive statistics for baseline epigenetic aging measures (epigenetic age acceleration and rate of aging) and for the change in epigenetic aging measures from baseline to Year 16 visit. Baseline epigenetic aging and change in epigenetic aging from baseline to Year 16 visit will be compared between intervention arms: ILI (n=16) vs. diabetes support and education (control condition; n=16). We will also compute associations of baseline epigenetic aging measures with change in frailty index from baseline to Year 16 visit (n=32). Our experienced and multi-disciplinary team, led by an Early Career Investigator, is well-positioned to perform the proposed pilot study, and future studies aiming to better understand the biological basis of benefit of an intensive lifestyle intervention for aging adults with diabetes who are overweight or obese. Most recently the pilot study has received the samples, DNA extracted, methylation arrays run, methylation data generated, DNAm GrimAge has been calculated, and data analysis has begun to generate the pilot data to support planned R01 proposal to be submitted in the fall of 2023.
DEVELOPMENT PROJECTS (0 Development Projects Listed)
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RESEARCH (27 Projects Listed)
    NIH K01AG059837 / ( 2018 - 2023 )
  Core(s): - Pilot and Exploratory Studies Core (PESC)
  Project SummaryA key aim of this proposal is to equip the candidate, Dr. Jamie Justice, with the expertise to become anindependent investigator who can advance interventions that extend healthy lifespan to randomized, controlledtrials in older persons. Specifically, cellular senescence is a biologic hallmark of aging that emerging preclinicalevidence indicates could have profound consequences on aging-related disease and function, and removal ofsenescent cells results in robust improvements in healthspan in rodents. Translation of these interventions toclinical trial has been proposed, yet health consequences of cell senescence and therapeutic potential has notbeen evaluated in humans. Dr. Justice's preliminary data in a small number of older women are the first toshow that cells expressing tumor suppressor protein and senescence biomarker p16INK4a are present inadipose tissue from older adults and related to worse physical function, but exercise and weight loss by caloricrestriction may mitigate this burden. The proposed research project represents a critical next step byexamining the effects of caloric restriction (CR) on cell senescence in a prospective randomized controlled trial(RCT). The primary hypothesis is that a CR intervention will reduce senescent cell burden and this reductionwill be related to improvement in functional and metabolic outcomes. This will be accomplished by capitalizingon a recent NIH-funded RCT (VEGGIE, R01DK103531) and the candidate's engaged inter-disciplinaryprimary mentoring team (Drs. Nicklas, Ding, Kritchevsky, Kirkland). VEGGIE will determine the effects of CRdesigned to achieve 10% weight loss vs. health education control in 200 men and women aged 40-65 yearswith obesity (BMI 30-45 kg/m2), to characterize epigenetic and transcriptomic effects of CR in adipocytes andperipheral blood monocytes and T cells, and associations with physical and metabolic function. We propose anancillary investigation in a subset of 90 participants (50-65 years, n=45 per grp) to determine the effects ofCR on senescent cell burden (Aim 1): a) proportion of p16INK4a expressing senescent cells(immunohistochemistry) in subcutaneous abdominal adipose tissue; b) expression of senescence biomarkersin isolated adipocytes and monocytes (RNAseq) and T cells (p16INK4a expression); and c) SASP biomarkers inplasma (cytokine/chemokine panel). We will also examine cross-sectional associations of age and obesity withcell senescence (Aim 2), and relationships between changes in senescence biomarkers and physical functionand metabolic outcomes (Aim 3). The research proposed is aligned with an approved NIA concept todevelop markers of aging-related biologic mechanisms for human studies. Additionally, it will provide essentialtraining for the candidate, who will establish expertise in cell senescence and translational research, anddevelop competencies in leading clinical trials with biological outcomes. This approach provides the idealplatform to advance the candidate's career as an independent investigator, and provide the foundation toestablish the role of cell senescence in human age-related functional decline.
2. Project Title: Effect of protein supplementation during weight loss on older adult bone health
  Leader(s): WEAVER, ASHLEY
    NIH K25AG058804 / ( 2019 - 2023 )
  Project Summary. Dr. Weaver seeks this K25 mentored training award to expand her bioengineering research background in medical imaging and finite element modeling of trauma towards pursuit of an independent research career focused on reducing osteoporosis and fracture in older adults. Weight loss poses an increased risk of bone loss and fracture in older adults. The proposed research will test the overall hypothesis that higher dietary protein intake during and following weight loss will attenuate bone loss in older adults with obesity. Guided by an accomplished multidisciplinary mentoring team with expertise in aging, clinical trials, bone metabolism, nutrition, and radiology, the PI will: (1) Develop knowledge of gerontology and geriatric medicine, (2) Acquire training in the design and execution of clinical trials, 3) Obtain in-depth knowledge on bone metabolism and structure, including the influence of nutrition and weight loss, and 4) Develop expertise in dual-energy computed tomography (CT) acquisition and post-processing to measure volumetric bone mineral density, cortical thickness, and bone marrow adipose tissue. Dr. Weaver's training and research will take place at Wake Forest School of Medicine which has a strong history of clinical research in aging and an exceptional radiology infrastructure. The partnership with her co-mentor at Rutgers within the Department of Nutritional Sciences will provide additional resources and expertise related to the nutritional regulation of bone metabolism. The proposed ancillary study to the ongoing clinical trial, UPLIFT: Utilizing Protein During Weight Loss to Impact Physical Function, will examine bone health over 6 months of active weight loss, followed by 12 months of weight maintenance. Musculoskeletal phenotypes will be compared in older adults with obesity randomized to either: (1) a lower protein diet for weight loss and follow-up, (2) a higher protein diet for weight loss only, or (3) a higher protein diet for weight loss and follow-up. The ancillary study expands the UPLIFT trial by adding dual-energy CT scans of the lumbar spine and proximal femur at baseline, 6 months, and 18 months to compare the influence of a higher versus lower protein intake on: vertebral and femoral trabecular volumetric bone mineral density and cortical thickness (Primary Aim), bone marrow adiposity which may alter the trabecular matrix and affect bone strength (Secondary Aim 1), and bone strength and fracture risk predicted with subject-specific finite element modeling (Secondary Aim 2). The study will test if a higher protein diet improves bone outcomes during active weight loss (evaluated at 6 months), and if maintaining higher protein intake during weight maintenance further preserves bone (evaluated at 18 months). The proposed training and research plan will launch Dr. Weaver's career as an independent investigator focused on applying bioengineering techniques to: 1) develop translational tools for fracture prediction, and 2) assess osteoprotective interventions in clinical trials ultimately leading to improved diagnostics, prognostic tools, clinical recommendations, and therapies for preventing osteoporosis and fracture in older adults.
    NIH K76AG059986 / ( 2018 - 2023 )
  Core(s): - Clinical Research Core (CRC)
  Project SummaryThis Beeson award seeks to equip the candidate, Dr. Kathryn E. Callahan, with the expertise to become anindependent investigator to advance use of aging-related metrics and interventions to promote health, function,and quality of life in frail and at-risk older adults. Frailty is prevalent among older adults, and associated withnegative outcomes, including hospitalizations, mobility disability, admission to skilled nursing facilities, andmortality. Despite efforts to define and quantify frailty, time and resource constraints limit the feasibility of frailtymeasures in clinical practice. Dr. Callahan's preliminary work supports the feasibility of translating anEMR-based Frailty Index, or eFI into the Wake Forest Baptist Health (WFBH) EMR, and demonstrates an initialassociation between eFI score and hospitalizations and mortality. The proposed research project representscritical next steps: (1) to adapt and refine the eFI using ambulatory care data, (2) assess its predictive value forhealthcare outcomes for older adults, and (3) conduct a pilot of implementation in Medicare Shared SavingsProgram/Next Generation Accountable Care Organization primary care practices, to collect critical dataregarding feasibility, acceptability, and effectiveness. The scientific goal is to develop and implement an indexto define a population of frail older adults who would benefit from personalized evidence-based interventions.This work is essential to inform larger-scale implementation trials of interventions to mediate negative andcostly health outcomes for frail older adults. We hypothesize that self-report and functional data from AnnualWellness Visits (AWVs) in the EMR will further refine the predictive value of the eFI; and that implementation ofthe eFI will be feasible and acceptable. This project is supported by engaged mentors (Drs. Williamson andBoustani) and a highly interactive, inter-disciplinary advisory committee (Drs. Foley, Rejeski, and Pajewski)whose expertise and complementary skills are a noteworthy asset to this project. We propose the adaptationand refinement of the eFI within the WFBH EMR, using data from older adults enrolled in the WFBH MSSP/Next Gen ACO (Aim 1): we will integrate AWV data, and refine the predictive value of eFI scores in thispopulation. We will then conduct a pilot study implementing the adapted eFI score in six MSSP/Next Gen ACOprimary care practices, and follow health outcomes. The research proposed aligns with an NIA priority toimprove the health, well-being, and independence of adults as they age. It will also provide essential trainingfor the candidate, who will establish expertise in implementation science, achieve fluency in clinical informatics,and develop competencies in leading implementation trials. This approach provides the ideal platform toadvance the candidate's career as an independent investigator and provides the foundation to establish frailtymetrics in practice, leveraging the learning health system to implement interventions to improve health andfunction.
4. Project Title: Blood Base Bioenergetic Profiling: A Novel Approach for Identifying Alzheimer's Disease Risk and Pathology
    NIH R01AG054523 / ( 2017 - 2024 )
  7. Project Summary/Abstract In Alzheimer's disease (AD), irreversible neurological damage takes place years before the onset of clinical symptoms. Therefore, it is recognized that the development of AD dementia treatment and prevention strategies relies on the early detection of presymptomatic pathology. Previous studies demonstrate that mitochondrial dysfunction plays a key role in the pathophysiology of AD and precedes the formation of plaques and tangles that are hallmarks of this disease. The premise of this study is based on the unique sensitivity of the brain to systemic bioenergetic decline due to its exceptionally high metabolic demand. We hypothesize that bioenergetic capacity is related to early AD pathology and that bioenergetic decline is associated with the long term progression and severity of this disease. Recent work by our group and others demonstrate that blood- based bioenergetic profiling, utilizing cellular respirometry, provides a reliable measure of systemic mitochondrial function. The proposed study will determine whether blood cell bioenergetics is related to AD risk, pathology, cognitive performance, and changes in these parameters over time. Our long term goal is to develop a minimally invasive screening tool that can be used in a clinic/community setting to identify candidates for more intensive diagnostic testing, such as CSF biomarker analysis and brain imaging. This project will be completed in an efficient and cost-effective manner by leveraging resources provided by the NIA-funded Wake Forest Alzheimer' Disease Center Clinical Core (ADCCC). Participants in the ADCCC represent a spectrum of AD risk and disease progression and are being extensively characterized for AD pathologies at baseline and 3 year follow ups. Our preliminary data from ADCCC participants indicate that bioenergetic capacity, measured in blood cells, is lower in participants with mild cognitive impairment. Moreover, our data suggest that bioenergetic deficits are already apparent in cognitively normal participants at high risk for AD. The aims of the proposed study are: 1) To determine bioenergetic profiles most strongly associated with AD risk and reporters of AD pathology (cognitive performance, CSF A 42/tau, hippocampal volume, brain amyloid, and cerebral glucose metabolism); 2) To determine the changes in bioenergetic profiles related to the 3 year progression of cognitive decline and reporters of AD pathology; and, 3) To determine the relationships of mitochondrial content and inflammation with bioenergetic capacity, and reporters of AD pathology at baseline and at follow-up. A central goal of the proposed study is to determine the specific bioenergetic parameters that are most closely associated with AD risk and pathology. Therefore, in addition to convention analytical approaches, we will employ state of the art Machine Learning analyses to identify individual parameters or multivariate signatures that are most closely associated with AD risk and pathology. Completion of this project can impact the detection of presymptomatic AD, provide insights into mechanisms underlying bioenergetic decline associated with AD, and broadly advance translational bioenergetics research.
    NIH R01AG059186 / ( 2019 - 2024 )
  Core(s): - Pilot and Exploratory Studies Core (PESC)
- Clinical Research Core (CRC)
- BioImaging (BioImaging)
  PROJECT SUMMARYOld age and obesity are prevalent risk factors for morbidity and mortality. Weight loss (WL) ameliorates manyclinical consequences of obesity; yet despite its benefits, recommendation of intentional WL in older adultsremains controversial. Reluctance stems, at least in part, from loss of bone mass known to accompany overallWL and the potential for exacerbation of age-related risk of osteoporosis and fracture. Addition of resistanceexercise training (RT) to WL is an effective means to attenuate, but not stop, WL-associated reductions in bonemineral density (BMD); however, conventional RT interventions present barriers to long term feasibility (i.e.,expensive equipment, on-site participation, safety supervision by trained staff, and waning compliance).Alternately, treating the WL-associated decrease in mechanical stress by replacing lost weight externally mayalso preserve bone mass. Pilot data from our institution signal that weighted vest use (designed to mimicweight stability) during WL is both feasible and likely efficacious in reducing WL-associated hip BMD loss whileincreasing biomarkers of bone formation. If confirmed, the greater availability, ease of administration, andreduced cost of weighted vest use to offset WL-associated bone loss, as compared to RT, holds significantpublic health potential as a translatable strategy to maximize the cardiometabolic benefits of WL, whileminimizing negative implications for the musculoskeletal system. The main goal of the proposed R01 study isto compare the effects of WL alone and with weighted vest use or RT on several indicators of bone health andsubsequent fracture risk. We propose a 12 month trial in 192 older (65-79 years) adults with obesity (BMI=30-40 kg/m2) randomized to one of three interventions (n=64/group): WL alone (WL; caloric restriction targeting10% WL and following national obesity treatment guidelines); WL plus weighted vest use (WL+VEST; =6hours/day, weight replacement titrated up to 10% WL); or, WL plus structured RT (WL+RT; 3 days/week, 10exercises, 10-12 repetitions). Our primary study outcome is 12 month change in total hip trabecular volumetricBMD (vBMD) and we hypothesize that despite similar reductions in total body weight: (1) participants in theWL+VEST group will show attenuated losses of total hip trabecular vBMD versus WL, and (2) loss in total hiptrabecular vBMD will be no greater in WL+VEST compared to WL+RT. Led by a talented New Investigator, thisproposal is a natural extension of the work accomplished during the PI s current MRSDA (K01 AG047291), andconfers public health impact by testing a translatable strategy aimed at optimizing intentional WL in older adultswith obesity while elucidating mechanisms governing musculoskeletal response to WL.
    NIH R01AG059416 / ( 2018 - 2023 )
  Core(s): - Clinical Research Core (CRC)
- BioImaging (BioImaging)
- Integrative Biology Core (Integrative Biology Core)
  Mobility inevitably declines with age, more in some than other people, often leading to mobility disabilitywith dependency, decreased quality of life, and enormous health care costs. The role of age-related biologicalchanges in skeletal muscle on the decline in mobility is poorly understood. We hypothesize that muscle massand the capacity to produce ATP are strong determinants of the mobility disability in older adults. Based onadvances from laboratory studies of muscle aging, we also hypothesize that denervation, oxidative damage,and decreased autophagic flux interact and contribute to declines in fitness, endurance and an increased riskof mobility disability. We will also use transcriptomic profiling by RNAseq to discover patterns of geneexpression that play important roles in the loss of mobility with aging. In the Study of Muscle Mobility and Aging (SOMMA), a prospective, longitudinal study of men andwomen age 70 to 90, our team of experts in clinical and laboratory sciences will use innovative and state-of-the-art technologies with rigorous quality control to test these hypotheses and discover new pathways for theloss of mobility with aging. We will measure quadriceps contractile volume by MRI and total muscle mass byd3 creatine dilution. We will use 31PMRS to assess the capacity of the quadriceps to generate ATP (ATPmax).In tissue form, muscle biopsies quantify denervation and oxidative damage to contractile proteins. SOMMA willbe the first to quantify autophagic flux to assess the role of autophagy in the loss of mobility with aging. We userespirometry on fresh tissue to quantify the contribution of mitochondria to ATPmax and mobility disability.These properties interact: for example, decreased autophagic flux promotes the accumulation of oxidativedamage and denervation, and understanding these relationships will guide the analysis and interpretation ofour results. Furthermore, we will use unbiased RNA-sequencing (RNA-seq) to profile the entire transcriptometo discover new associations between clusters of genes and individual variation in rates of loss of fitness (peakVO2), muscle mass, and risk of mobility disability. Field centers at Wake Forest and Pittsburgh, with exceptional track records for recruiting and retainingolder adults in complex studies, will enroll 875 women and men age 70 89 with a gait speed = 1.0 m/s,providing sufficient power to identify important relationships between individual and combinations of propertiesand the risk of mobility disability. SOMMA may identify and prioritize targets for new therapeutics and tailored exercise regimens. Wealso will create a unique archive of tissue, blood, with longitudinal data about important clinical outcomes thatthe scientific community can use to efficiently test new hypotheses about muscle and loss of mobility withaging.
7. Project Title: Dietary Effects on Imaging and Fluid-based Biomarkers of the Adipose-Brain Axis in Alzheimers Disease
  Leader(s): BRINKLEY, TINA E
    NIH R01AG064014 / ( 2019 - 2024 )
  PROJECT SUMMARY The present proposal, in response to PAR-17-029, seeks to advance our understanding of how crosstalk between adipose tissue (AT) and the brain may contribute to the pathophysiology of Alzheimer's disease (AD). The scientific premise is based on the fact that while body mass index (BMI) is an independent predictor of AD in both mid- and late-life, the association with this crude global measure of obesity is confounded by aging- related changes in AT distribution and function. Although the underlying mechanisms remain to be elucidated, it is clear that BMI is not sufficient to fully understand the obesity-associated risks for AD. Diet influences the risk of both obesity and AD, and investigating dietary interventions that can modulate both AT and the brain may provide critical insight into the overlapping molecular pathways linking these diseases. Our preliminary data suggest that greater amounts of AT in central / visceral (VAT) depots and lower amounts of AT in peripheral / subcutaneous (SAT) depots are associated with a cerebrospinal fluid (CSF) biomarker profile indicative of increased AD pathology. Moreover, minimizing the loss of protective SAT depots following a ketogenic diet may favorably impact AD pathology. To confirm and extend these findings, we propose to conduct an ancillary study to the Brain Energy for Amyloid Transformation in AD (BEAT-AD) trial, a phase 2 randomized clinical trial designed to examine the effects of a 4-month Modified Mediterranean Ketogenic (MMK) diet versus an American Heart Association (AHA) low-fat diet on brain health in 120 adults (age: 55 to 85 years) with amnestic mild cognitive impairment (aMCI) (R01AG055122; PI: Craft). The proposed study will leverage ongoing study procedures, data, and samples to generate new data on AT distribution and function, including their relationship with AD biomarkers and their modulation by diet. Specifically, CT imaging will be leveraged to quantify changes in the cross-sectional area and density of VAT, SAT, and intermuscular AT in the abdomen and thigh, as well as fatty infiltration of liver and skeletal muscle. FDG-PET imaging will also be leveraged to quantify changes in glucose uptake (i.e., metabolic activity) in AT depots of interest. Finally, stored blood and CSF will be used to assess changes in circulating adipokines and AT-derived exosomes. To complement the ongoing collection of CSF, FDG-PET, amyloid PET, and structural/functional MRI, the proposed study will also add 18F-AV-1451 tau PET in a subset of participants (n=60), which will enhance the categorization of participants across the AD spectrum as defined by the NIA-AA Research Framework. This timely, cost-effective, and innovative study will not only expand the scope and impact of the parent trial, but will also address important gaps in the field. Investigating AT distribution and function in the context of the MMK diet may reveal novel targets that are amenable to intervention and new therapeutic agents that can alter the trajectory of AD.
8. Project Title: Investigating the role of adipose tissue in mobility and aging (SOMMA-AT)
    NIH R01AG066474 / ( 2020 - 2025 )
  Project Summary/Abstract Targeted therapies for aging-related mobility disability are urgently needed to preserve quality of life and pre- vent morbidity/mortality in the rapidly expanding aging population. Progressive decline in mobility with aging has been partially attributed to loss of skeletal muscle (SM) mass and function, as well as an increase in the quantity of adipose tissue (AT). The quality of AT and AT-secreted factors are also likely to influence this pro- cess, yet meager evidence exists for this notion. Cellular senescence, a phenomenon by which normal healthy cells cease to divide and therefore become programmed for cellular death, occurs in adipose tissue and is as- sociated with poorer mobility. Furthermore, secreted factors from AT, potentially from senescent or dying cells, induces insulin resistance and atrophy in human skeletal muscle cells. Collectively, these data demonstrate that AT quality (i.e., structure and function) can directly impact skeletal muscle function. This adipose-skeletal muscle crosstalk has been increasingly implicated in poor functional and metabolic outcomes in younger hu- man populations. The unique contributions of AT structure and function and AT-secreted factors to mobility de- cline and skeletal muscle function in the context of human aging have not been addressed. The proposed stud- ies will fill a critical knowledge gap by directly assessing structural and functional components of AT in aging and using their associations with mobility to identify AT-secreted proteins that negatively impact skeletal mus- cle function. The long-term goal of this ancillary study is to leverage and add to the outstanding resources of the parent SOMMA project to understand the contribution of AT quality, AT-secreted factors and AT-skeletal muscle crosstalk to mobility disability and other complications of aging in humans. Our overall objective is to identify key structural and functional components of AT quality - including necrosis, senescence, inflammation, self-renewal and metabolic flexibility - and AT-secreted proteins that influence mobility via direct effects on skeletal muscle. We hypothesize that AT structure and function influences AT-secreted proteins that contribute to aging-related mobility outcomes by directly impacting skeletal muscle function. The stated purpose of Aim 1 is to determine which structural and functional components of AT are associated with slower walking speed. We posit that increased cellular senescence, increased necrosis, increased inflammation, decreased capacity for self-renewal and metabolic inflexibility will be associated with slower walking speed. For Aim 2, we antici- pate that incubation of human muscle cells with known and novel secreted proteins - identified through stand- ard immunoassay panels and unbiased proteomics and shown to be associated with aberrations in AT struc- ture and/or function - will worsen mitochondrial respiration, increase oxidative stress, decrease contractility and muscle cell diameter. This work will have a positive translational impact by improving strategies for prevention and/or treatment of aging-related mobility disability and by promoting knowledge and facilitating future studies to understanding AT-skeletal muscle crosstalk across the lifespan.
9. Project Title: The PREVENTABLE Physical Performance Ancillary Study
    NIH R01AG071807 / ( 2021 - 2027 )
  Project Summary/Abstract Aging is associated with significant declines in muscle mass, strength, and physical performance, which often lead to disability, loss of independence, and adverse clinical outcomes including multimorbidity and mortality. At present, health care providers have no therapeutic options to offer their patients to slow aging-related declines in physical function. Importantly, evidence is emerging that statins could be an effective treatment for preserving physical function by preventing disabling events such as stroke, heart failure, or myocardial infarction. In addition, statins have pleiotropic properties including anti-inflammatory, anti-oxidant, and immuno- modulatory effects, which may slow or prevent aging-related declines in physical function. However, reports of muscle pain and weakness in patients on statins has led to a significant number of patients discontinuing statins. Thus, the proposed study is critical to establish whether statins may help to preserve physical function and independence in older adults, or whether statin-associated muscle symptoms portend a statin-related decline in physical function. The PREVENTABLE trial (U19 AG065188) provides an ideal opportunity to definitively determine the effect of statins as a treatment for aging-related declines in physical function. PREVENTABLE is a placebo-controlled pragmatic clinical trial designed to investigate whether randomization to a statin can prevent dementia and prolong disability-free survival in 20,000 participants aged 75+ years without clinically evident coronary heart disease. While the PREVENTABLE trial will help clarify the effects of statins on self-reported disability, the proposed ancillary study will extend and validate the physical disability data by investigating the effects of statins on changes in physical performance, which are typically observed earlier in the trajectory of functional decline and may be a more sensitive marker for the effects of statin. To determine if statins affect longitudinal change in physical performance, the proposed ancillary will add the Short Physical Performance Battery (SPPB), a validated measure of lower-extremity performance comprised of balance tasks, a 4-m walk, and repeated chair stand test, over 3 years of follow-up in 2,500 PREVENTABLE participants (1,250 per intervention arm). Self-reported information on patient-centered outcomes relevant to physical function including statin-associated muscle symptoms, fatigue, and pain will also be collected. The specific aims of this ancillary study are to: 1) determine whether randomization to statin slows the aging- related decline in usual gait speed; 2) determine whether randomization to statin slows aging-related declines in lower-extremity function (SPPB score) and strength (chair rise time); and 3) explore whether randomization to statin is associated with self-reported statin-associated muscle symptoms, fatigue, and pain. By leveraging the rich resources and infrastructure of PREVENTABLE, this timely and cost-effective study provides a unique opportunity to significantly expand the scope and impact of the parent trial on self-reported physical disability by determining the therapeutic potential of statins to slow aging-related declines in physical performance.
10. Project Title: The relationship between blood based bioenergetics and muscle function, mobility, and aging
    NIH R01AG072734 / ( 2022 - 2026 )
  As people age, they experience declining physical performance, which is associated with diminished quality of life, augmented health care costs, and is a strong predictor of morbidity and mortality. Thus, uncovering mechanisms that underlie age-associated mobility decline and identifying reliable biomarkers to predict this decline is imperative for the development of interventions to maintain physical ability with age. Mitochondria generate chemical energy to support homeostatic function of most cells in the body, and mitochondrial dysfunction is linked to age-associated decline in physical performance. This has been studied predominantly in skeletal muscle mitochondria since muscle function is central to physical ability. However, it is recognized that muscle function is not the sole determinant of mobility, and that input from other organ systems (cardiovascular and central nervous system) is also required. While age associated mitochondrial dysfunction has been observed across all organ systems, the contribution of this systemic bioenergetic dysfunction to age-associated mobility decline has not been assessed. The current study brings together two PIs with expertise in mitochondrial biology who have independently optimized and validated complementary assays (high resolution respirometery and Seahorse extracellular flux analysis) for the measurement of systemic bioenergetic function utilizing blood cells (platelets and peripheral blood mononuclear cells). Preliminary data using these assays show that blood cell mitochondrial function reflects bioenergetics of solid tissues (e.g. skeletal muscle, heart, lung, brain) and correlates with multiple measures of physical ability. However, it is unknown whether blood cell bioenergetics reflect skeletal muscle function or are predictive of mobility decline in older adults. The Study of Muscle, Mobility and Aging (SOMMA) is a multi-site longitudinal study of older adults (=70 years; n=875). SOMMA focuses on the relationship between skeletal muscle mitochondria and mobility decline and will obtain skeletal muscle biopsies to measure mitochondrial function in all participants. Physical performance measures will at baseline and three years follow-up. The current proposal is an ancillary study that synergizes with SOMMA to add blood cell bioenergetic measurements in all SOMMA participants at baseline as well as at the three year follow up visit. Using these data, we will test whether blood cell bioenergetics are 1) reflective of skeletal muscle mass and function, 2) are associated with physical performance measures (400 m walk), and 3) are predictive of physical performance decline in older adults. Completion of this study will elucidate systemic mitochondrial changes that are associated with age-related physical decline, and potentially establish blood cell bioenergetics as a biomarker of systemic mitochondrial function that can be utilized as a surrogate for muscle biopsies, and as a predictor of mobility decline in the aging population.
11. Project Title: Establishing the optimal frequency of dance movement for neurocognitive and physical outcomes in people at risk of Alzheimer's disease
    NIH R01AG076669 / ( 2022 - 2027 )
  PROJECT SUMMARY Dance movement is a form of physical activity that may benefit the brain as much or more than structured aerobic exercise. Despite the potential of dance as an intervention to promote neurocognitive health, gaps in knowledge about essential intervention components are a barrier to definitive trials, specifically:1) a lack of specificity on key prescription parameters including how many times a week dance classes should be taught, 2) need for better estimates of how large an effect dance has on fitness and the brain, and 3) little understanding of the expected time course for change in fitness and the brain in response to dance. The primary aim of this proposal is to test whether weekly dance frequency differentially modifies key outcomes, and from this to test effect sizes to determine sufficient sample sizes for a larger-scale trial. Physical activity promoting interventions tested in older adults have traditionally focused on exercise, i.e., structured physical activity of at least moderate intensity with the express purpose of improving health or fitness. However, in 2003, epidemiological evidence showed that social dance was the only leisure time physical activity associated with lower Alzheimer s disease risk. Since then, multiple smaller studies have shown benefits of dance movement and dance therapy on mobility and neurocognitive health in older adults, including cardiorespiratory fitness, balance, white matter health, and cognition. Dance movement inherently involves simultaneous cognitive stimulation through motor learning and dual-tasking; social interactions; aerobic physical activity that elevates heart rate and improves cardiorespiratory fitness; and improves balance and reduces fall risk. Dance also satisfies key antecedents of lasting behavior change outlined in contemporary behavioral theories including self-efficacy, intrinsic motivation, autonomy, and relatedness. Dance is also culturally relevant and has been practiced spontaneously for thousands of years. This means dance may result in better long-term adherence than more commonly studied forms of aerobic exercise like brisk walking, where data from our group and others shows that adherence drops significantly after intervention ends. This proposal plans to assess outcomes of 1x/weekly, 2x/weekly, and 3x/weekly dance movement classes and 1x/week music appreciation class control at 4 time-points over 6 months to determine the time course of changes in cardiorespiratory fitness, cognition, and key secondary outcomes in 160 adults = 65 years old at risk for Alzheimer s disease due to subjective cognitive decline. 1x/weekly is common for community classes and has been tested in multiple dance studies; 2x/weekly is most common in dance research; and 3x/weekly is most common for aerobic exercise interventions like treadmill walking that target CRF. We aim to determine the optimal frequency of dance movement intervention for a Phase III trial that will effect change in relevant outcomes while maintaining attendance.
12. Project Title: Physical Rehabilitation for Older Patients with Acute HFpEF-The REHAB-HFpEF Trial
  Leader(s): KITZMAN, DALANE W
    NIH R01AG078153 / ( 2022 - 2027 )
  Acute decompensated heart failure (ADHF) is the leading cause of hospitalization in older persons, and is associated with marked physical disability, poor health-related quality of life (HRQOL), frequent rehospitalizations, loss of independence, high mortality, and enormous health care costs. However, most of the trials testing a wide range of medications and strategies in ADHF have been neutral. In our recently completed NIA-funded phase 2 trial (REHAB-HF), an innovative, early, transitional, tailored, and progressive multi-domain physical rehabilitation intervention produced a large improvement in the primary outcome of Short Physical Performance Battery (+1.5 points) in older patients with ADHF. At baseline, the participants (53%) with HF with preserved ejection fraction (HFpEF), had significantly worse impairments in physical function, frailty, HRQOL, and depression than those with HF with reduced EF. They also appeared to derive greater benefit from the intervention, with ~50% larger effect sizes in physical function, frailty, HRQOL, and depression. Patients with HFpEF also appeared to have much greater reductions in rehospitalizations and death and potential for reduced medical resource use. The finding of potentially greater benefit in HFpEF is noteworthy as HFpEF is highly relevant to older persons and has the most urgent need for new treatments since it is: 1) the most common form of HF, nearly unique to older persons, and disproportionately affects older women and Black persons; 2) increasing in prevalence; 3) accepted as a geriatric syndrome; 4) associated with marked impairments in physical function and HRQOL and high rates of frailty; 5) has high morbidity and mortality which are worsening over time; and 6) has limited evidence-based treatments. The phase 3 REHAB- HFpEF trial will focus on this large, growing, vulnerable, underserved population. The 5-year, randomized, attention-controlled, single-blinded trial will enroll 880 older adults age >60 years with ADHF and HFpEF across 20 geographically dispersed clinical centers. We will test the hypothesis that the innovative REHAB-HF intervention will improve the clinically compelling combined primary endpoint of all-cause rehospitalizations and mortality during 6-month follow-up, the most vulnerable time period following ADHF hospitalization (Aim 1) and the secondary endpoint of prevalence of major mobility disability, a clinically meaningful outcome in trials of older adults, at 6-months (Aim 2). We will also assess the intervention s impact on HRQOL, frailty, depression, physical activity, and health care costs. Our diverse, cohesive, multi-disciplinary team and experience from the phase 2 trial will ensure efficient and effective execution and dissemination. REHAB-HFpEF directly addresses the key recommendations of several recent NIA and NHLBI sponsored workshops. Its results could improve key outcomes that are meaningful to patients, caregivers, health systems, and payers. The trial has strong potential to change clinical guidelines, reduce health care costs, and influence national coverage decisions for the large, growing, underserved, high-risk population of older patients with acute HFpEF.
13. Project Title: ASPIRE: A Study Promoting Critical Illness Recovery in the Elderly
    NIH R03AG060076 / ( 2019 - 2023 )
  ASPIRE: A Study Promoting critical Illness Recovery in the Elderly Project Abstract: Older people have a higher risk of developing a critical illness requiring invasive mechanical ventilation than younger people. Additionally, muscle wasting, which occurs quickly and progresses rapidly in all patients who are critically ill and on mechanical ventilation, is more severe in older adults. This results in long-term physical impairments, particularly in older survivors of critical illness. ICU rehabilitation, when administered early, has been shown to be effective at attenuating the degree of physical function impairment in survivors. However, there are barriers to the provision of early ICU rehabilitation, including delirium and coma. Additionally, older patients have been routinely excluded from critical care trials even though they make up the majority of the critically ill population. We recently performed a pilot feasibility trial of a novel, early ICU rehabilitation protocol in older adults utilizing an in-bed cycle ergometer. The in-bed cycle ergometer allowed for ICU rehabilitation to start at a particularly early point in the ICU course when muscle wasting begins, and allowed delivery of rehabilitation even when patients were comatose or delirious. We hypothesize that the novel, early ICU rehabilitation protocol using an in-bed cycle ergometer will improve functional outcomes in older survivors of critical illness. As such, the specific aims of the proposal are to evaluate the effect of the early ICU rehabilitation intervention on 1) physical function (as measured by the SPPB at ICU discharge), 2) muscle mass (as measured by ultrasound at ICU discharge), and 3) quality of life (measured with the SF-36 at 6 months post-discharge). This will be the first randomized controlled trial to test this novel early ICU rehabilitation intervention in older patients. This project and period of training with the GEMSSTAR award will be critical in my transition to becoming a clinical trialist with a focus on improving older adults' physical function following critical illness.
14. Project Title: Novel Computed Tomography (CT) Imaging Biomarkers in Older Adults for Predicting Adverse Geriatric Health Outcomes
    NIH R21AG070804 / ( 2021 - 2024 )
  Blood-based biomarkers have been widely used in studying various metabolic pathways contributing to aging, including energy metabolism, chronic inflammation, cellular senescence, and endothelial function. Like blood- derived biomarkers, imaging-based biomarkers can be evaluated as potential predictors of aging outcomes. For study of non-neurologic aging, biomarkers derived from computed tomography (CT) offer great promise. Recent advances in scanner technology and image processing mean that most CT examinations can be obtained in less than one minute, lowering participant burden. In addition, radiation doses have been lowered and the intra- and inter-scanner variability has improved. In parallel, machine learning tools allow for automated image processing and segmentation, increasing efficiency of image analysis, and reducing bias. For these reasons, CT is increasingly being used to study skeletal muscle and adipose tissue. On CT, muscle quantity is typically measured by cross-sectional area (CSA). Muscle quality is traditionally quantified by skeletal muscle density (SMD) and intermuscular adipose tissue (IMAT) cross-sectional area. In addition to being a measure of muscle quality, IMAT may be considered as a measure of fat quantity. We recently developed and validated an automated machine learning tool to determine traditional CT measures of muscle and adipose tissue quantity and quality. To better characterize tissue quality, we have also applied radiomic texture analysis to muscle tissue on CT images. Texture analysis refers to the quantification of image voxel inter-relationships and provides a measure of tissue heterogeneity. To our knowledge, this technique has never been applied to CT images from community-based epidemiological studies. We propose to relate these CT-based assessments of muscle and adipose tissues to important geriatric outcomes, focusing on hip and other fractures as well as falls, physical performance, and strength. We will complete these analyses on archived CT images in MrOS (a prospective cohort study of healthy aging in older men, with a particular focus on osteoporosis) and Health ABC (a prospective cohort study of non-disabled Black and White older adults). Abdominal CT images were collected at the baseline exam for MrOS men in the United States (N~3700 in 2000-2), MrOS men in Hong Kong (N~400 in 2001-3), and Health ABC (N~3000 in 1997-8). Health ABC also collected CT images at the mid-thigh. In Health ABC, mid-thigh and abdominal CT images were repeated in a subset five years later (N~600 in 2000-3). We will add three aims: 1) test the hypothesis that that greater muscle and fat tissue heterogeneity features at the abdomen and mid-thigh are associated with increased risk of hip and other fractures, 2) test the hypothesis greater muscle and fat tissue heterogeneity features at the abdomen and mid-thigh are associated with lower strength and poor physical performance (walking speed and chair stands); their decline over time; and risk of falls, and 3) characterize changes in muscle and fat tissue heterogeneity features at the mid-thigh over 6 years.
15. Project Title: Geroscience Education and Training (GET) Network
    NIH R25AG073119 / ( 2021 - 2024 )
  Summary In developing educational materials and meeting with our GET Network advisory committees we often discuss where the educational boundaries of the GET Network may dovetail with existing or upcoming training programs in aging (both basic and clinical) and geroscience. For example, the NIA's Division of Aging Biology recently published an approved concept informed by the Trans-NIH GeroScience Interest Group (GSIG) to create short-term educational programs with a primary focus on courses that enhance and expand Geroscience skills and development at all levels of professional career development. This concept is aligned with the mission of the GET Network, yet independent. Similarly, other NIA-supported R25's (eg, R25AG071488) are also creating educational content or delivery methods highly relevant to other groups. We hope to share resources, update on our progress, and get input from a wider group of people working on similar concepts, as we all have much to learn for long-standing educational programs in aging. An opportunity presented itself when we were approached by the CEO of GSA, James Appleby, about disseminating GET Network content and scope at the society's 2022 meeting. During our discussions, we realized that more than just presenting work completed within the GET Network, there is a real advantage to engaging with investigators and educators beyond the GET Network. We are therefore requesting an administrative supplement to support a preconference workshop at the 2023 GSA meeting to allow us to harmonize with other educational programs, introduce key concepts for teaching and training programs in geroscience, and disseminate our work. This is directly aligned with the goals of the GET Network, but represents additional work beyond what was proposed in the parent award. We will invite 50 interdisciplinary participants to attend and contribute as speakers and discussants, including students, early career contributors and key stakeholders. Additionally, we plan to hold meetings for our Content and Dissemination committee members on the same day. Finally, three junior faculty or postdocs will be selected to record the discussions and participate in a separate whitepaper writing retreat to develop a manuscript of the meeting proceedings for submission to a GSA-affiliated journal.
16. Project Title: AIDS and Aging Research Platform (AARP)
    NIH R33AG067069 / ( 2020 - 2025 )
  ABSTRACT Effective antiretroviral therapy (ART) for people living with HIV (PLWH) has dramatically reduced mortality resulting in many surviving into middle and old age. Despite this success, PLWH experience high rates of comorbidities, multimorbidity (>1 major chronic illness), and functional decline at ages 10-15 years younger than uninfected controls. Geriatric syndromes, such as frailty and falls, are becoming more prevalent in PLWH. Thus, there is an urgent need to focus on the healthspan of PLWH rather than just mortality. Healthspan, in contrast to lifespan, is defined as the time someone is healthy not just alive. The Claude D. Pepper Older American Independence Centers (OAlCs) were established to help define aging phenotypes and advance research into the causes, prevention and treatment of functional decline with age. OAlCs have developed and validated functional assessments in aging, but lack depth and breadth of HIV expertise. In contrast, Centers for AIDS Research (CFARs) have unparalleled expertise in HIV-related basic, clinical and social/behavioral research, but lack robust resources and expertise in aging biology, geriatric clinical phenotypes and functional assessments. Our R24 project, Developing Research At The Interface Of HIV And Aging was in response to PA-12-064 Network and Infrastructure Support for Development of Interdisciplinary Aging Research. Through this R24 we successfully linked CFARs and OAICs to support pilot projects in high-priority focus areas and mentor researchers at the interface of HIV and Aging. Our vision for this proposal is to build on this success deepening the ongoing linkage of CFARs and OAICs and expanding the network to include Nathan Shock Centers of Excellence in the Basic Biology of Aging (NSCs) and the McKnight Brain Institutes (MBIs). By bringing together OAICs expertise on functional decline in aging, with NSC expertise in aging biology and the mechanisms underlying function decline, with MBI expertise on age-related cognitive decline, and CFAR expertise on HIV, we create an integrated approach to advancing and accelerating investigation at the interface of HIV and aging via the following Aims: Aim 1. Provide specific training models and a brief inventory of tools to efficiently collect data to improve HIV clinical care and outcomes research. Aim 2. Using a geroscience approach, provide a platform for pilot studies to determine the links between molecular hallmarks of aging with functional decline, and the development of common comorbidities among aging PLWH. Aim 3. Develop infrastructure for evaluating interventional approaches and their application to HIV care. Aim 4. Provide educational support, implementation advice and mentoring for emerging investigators to establish/advance research programs in HIV and aging. These synergistic aims leverage and expand the infrastructure and close ties built in the R24 of HIV expertise from CFARs with the gerontology and functional assessment expertise within the OAlCs and expand them with inclusion of NSCs and MBIs to enhance and accelerate investigation at the interface of HIV and aging.
17. Project Title: Effects of Western and Mediterranean Diets on Metabolic and Neuropathologic Risk Factors for Alzheimer's Disease in Nonhuman Primates
    NIH RF1AG058829 / ( 2018 - 2023 )
  Summary This study examines the effects of diet on peripheral metabolism and central nervous system (CNS) phenotypes and pathways implicated in early-stage Alzheimer's disease (AD) pathology in nonhuman primates (NHPs). The premise for the study is based on evidence that dietary patterns are powerful modulators of brain aging. Habitual consumption of simple sugars and saturated fat, characteristic of a Western diet, is associated with chronic diseases and increased risk of AD and vascular cognitive impairment. Conversely, high intake of dietary fruits and vegetables, fish, and healthy fats, characteristic of a Mediterranean diet, is associated with reduced risk of chronic diseases, AD, and vascular cognitive impairment. Evidence supporting these associations comes from population-based studies that may be affected by confounders, or from rodent studies with limited translational relevance. Identification of specific mechanisms underlying dietary effects has been challenging to date. However, in our 1-month randomized trial in older adults comparing Western and prudent diet, we observed changes in AD and pathologic aging markers (e.g. cerebrospinal fluid A 42, lipoproteins, insulin, and oxidative stress markers), suggesting that Western diet composition may alter the brain in ways that promote AD-related neuropathologies. Nonhuman primates offer unique opportunities to model complex human diseases, and we and others have shown that they develop AD pathology and diet- related metabolic and vascular disorders with aging. The proposed study leverages a NIH-funded investigation in which adult female cynomolgus monkeys were randomized to consume a Western or Mediterranean-like diet for 30 months. Metabolic, vascular, and behavioral phenotyping, MR imaging, and serial collections of cerebrospinal fluid occurred in the Baseline and Treatment phases. At necropsy, multiple peripheral and vascular tissues were obtained and the brains collected using a protocol adapted from human AD guidelines. We now propose to use these archived tissue, images, and data to determine the effects of Western vs. Mediterranean diet on structural and functional CNS characteristics relevant to AD risk. Our overarching hypothesis is that, compared to a Western diet, consuming a Mediterranean diet protects against neuropathologic, vascular, inflammatory, oxidative, and other phenotypes associated with increased risk of AD. Our Specific Aims are to determine effects of Western and Mediterranean diets on: AD neuropathology, neurovascular pathophysiology, neuroinflammation, oxidative stress, and gene expression to identify the peripheral mediators of diet effects on the CNS, and novel pathways and mechanisms which may be involved in diet/AD interactions.
18. Project Title: Translational Training in Aging and Alzheimer?s Disease Related Disorders
    NIH T32AG033534 / ( 2009 - 2027 )
  Translational Training in Aging and Alzheimer s Disease Related Disorders This renewal application seeks to sustain our T32-supported Training Program to continue training postdoctoral fellows in the conduct of translational research focused on optimizing cognitive and physical function with aging and Alzheimer s disease-related disorders (ADRD). This T32 has been continuously funded since 2009; in November, 2019, its scope and number of trainees increased from 3 to 5 fellows to include specific training in research related to ADRD, in alignment with the newly funded P30 Alzheimer s Disease Research Center. Of the 19 trainees appointed or who are pending appointment since the T32 began in 2009, 10 have an ADRD focus (53%). Of the 9 trainees appointed or who are pending appointment since the T32 was revised to include an ADRD focus in 2019, 6 have an ADRD focus (66.7%).Nationwide, there is a dearth of competent investigators trained in the appropriate skills to conduct research on prevention and treatment of mobility disability, ADRD, and other conditions that lead to loss of independence with aging. Thus, the research of our T32-supported trainees has been, and will continue to be, instrumental in advancing knowledge regarding the prevention of cognitive and functional disability and the best health care for older adults. The overall goal of our T32 Training Program is to help develop a new generation of researchers by providing an integrated career development path centered on training PhD/MD fellows in the skills and competencies needed to conduct translational research with a focus on the prevention of physical and cognitive disability. Importantly, the unique and seamless integration of both aging and ADRD research within the Wake Forest School of Medicine (WFSM) Section on Gerontology and Geriatric Medicine, and the supporting ADRC and Pepper Older Adult Independence Center, provides the ideal environment to facilitate trainees knowledge of the biological contributions and risk factors for aging- and ADRD-related changes in physical and cognitive function, and their inter-connectedness. Our scholars acquire 1) scientific knowledge in the fields of aging and brain biology, geroscience, and ADRD; 2) competencies needed to successfully and ethically conduct preclinical experiments, clinical trials, and/or longitudinal cohort studies of relevance to aging and ADRD; 3) experience and expertise in the measurement of cognitive and/or physical disability outcomes; and 4) specific technical or methodological skills in line with their individual interests. This training will place them in a position to successfully transition to an early-stage faculty position and to be highly competitive for new funding to continue their path towards independence. With a current research portfolio of funded grants totaling $73.96 million in direct costs ($55.7 million from NIA) awarded to our T32 Program Faculty, we have the scientific expertise, resources, and research opportunities available for training the next generation of investigators for success in aging and ADRD research.
19. Project Title: Aging Biomarkers: Integrating Omic Profiles with Mechanistic Measures
    NIH U01AG060897 / ( 2018 - 2023 )
  Project Summary The objective of this study is to develop and validate biomarkers that reflect mechanisms of biological aging. At least five pharmacologic compounds approved for human use extend health span and life span in rodent models. Parallel approaches in humans would require studies lasting 40+ years and are infeasible. Rather, the field needs reliable human biomarkers that indicate beneficial (or adverse) effects of an intervention on aging-related pathways over shorter time periods. Epigenomics and resultant transcriptomic changes may unite mechanisms of biological aging implicated in animal studies and unravel novel pathways. In a genome- wide analysis of monocyte samples in 1,200 persons (aged 55-94 years) from the Multi-Ethnic Study of Atherosclerosis (MESA), we identified 1,794 age-associated methylation sites and 2,704 age-associated transcripts, which over-represented several networks, including mitochondrial bioenergetics and autophagy. We further demonstrated associations of these gene networks with aging-related diseases independent of age. In addition to omic profiles, functional phenotyping may provide further advantages as biomarkers of the aging process. For example, our studies in older adults indicate the bioenergetic capacity of peripheral blood mononuclear cells is positively associated with physical function measures even when controlling for age. We predict that these epigenetic, transcriptomic, and functional markers will be associated with the development of aging-related comorbidities and are responsive to caloric restriction. We propose to utilize existing longitudinal assessments of monocyte epigenetic/transcriptomic profiles and age-related health outcomes from 1,800 middle-aged and older adults (55-94 years) in the MESA study. Leveraging an ongoing randomized clinical trial (VEGGIE) of caloric restriction in 200 adults (40-70 years), we also propose to add skeletal muscle biopsy (N=80). The specific aims are: 1) to determine whether aging-related monocyte transcriptomic/epigenomic pathways individually or in combination predict changes in aging-related diseases over an 8-year follow up (N=1,800); and 2) To determine whether caloric restriction shifts aging-related monocyte transcriptomic/epigenomic pathways (N=200) and bioenergetic measures in circulating cells and skeletal muscle (N=80) towards a younger pattern and whether these changes individually or in combination correlate with changes in aging-related metabolic, physical and cognitive health outcomes. The proposed study will generate a panel of biomarkers reflecting a comprehensive battery of aging pathways by integrating transcriptomic and epigenomic profiles with bioenergetics in circulation and skeletal muscle, from an existing longitudinal cohort study and an ongoing clinical trial of caloric restriction, to efficiently and cost-effectively validate potential biomarkers through multiple convergent strategies.
20. Project Title: Health Aging & Later-Life Outcomes Planning (HALLO-P)
    NIH U01AG073240 / ( 2021 - 2024 )
  Core(s): - Clinical Research Core (CRC)
- BioImaging (BioImaging)
- Biostatistical Design and Analysis Core (BIC)
- Integrative Biology Core (Integrative Biology Core)
  The Health, Aging and Later-Life Outcomes Planning Grant (HALLO-P) is submitted in response to RFA-AG-21-016. Collectively, HALLO-P affiliated investigators have led 17 clinical trials of caloric restriction (CR; 3 ongoing), enrolling 2,773 adults (ages 55-91) with BMIs = 27 kg/m2, showing multiple beneficial physiologic changes associated with lower disease and disability risk. Whether this translates to actual reductions in disease and disability is unclear. A large multi-year trial with definitive clinical outcomes is needed to fill this evidence gap. Time restricted feeding (TRF) could be an attractive alternative to CR if it produced similar health benefits, was more easily sustained, and mitigated CR s undesirable loss of muscle and bone. The overall goal of this 3-year HALLO planning grant is to develop a protocol for a rigorous, multi-site, randomized clinical trial (RCT) comparing clinically-relevant health outcomes in older persons randomized to daily CR, a TRF regimen, or a non-dietary attention control group employing innovative mHealth tools to promote adherence. We will complete a 12-month pilot study enrolling 120 older adults (age =60 years; 50% women; =23% minority) to provide critical information on feasibility, intervention delivery, and data informing effect size determination. HALLO-P s Objectives are to: 1. Establish a scientific advisory board and other structures to guide planning activities and the design of a full- scale RCT that engage a wide range of stakeholders and build a national constituency for the project. 2. Refine our mHealth behavior-change and adherence tracking platform the HALLO-P Companion App to optimize delivery of both the CR and TRF interventions. 3. Conduct focus groups and a 12-month pilot RCT of: 1) 20% CR delivered in-person; 2) 20% CR delivered remotely via video conferencing; and 3) TRF (8-10 hours) with ad libitum caloric intake. Pilot data will help refine recruitment criteria, estimate recruitment yields, and refine intervention approaches. We will use doubly- labeled water to measure achieved CR and continuous glucose monitoring to assess adherence to TRF. 4. Model aging biomarker changes for differing CR doses using WF OAIC repositories and the HALLO-P pilot. Existing epidemiological databases will be used to estimate the anticipated effect of these biomarker changes on clinical outcomes and to derive key design metrics related to inclusion/exclusion criteria, and event rates related to multi-morbidity, health deficit accumulation, and functional decline/disability; and 5. Integrate new data, the scientific literature .and expert advice to prepare a protocol, and develop informed consent forms, manuals of operation, study forms, and related systems to permit the rapid launch of the larger trial upon completion of the pilot activities in coordination with the other U01 project funded by this mechanism.
21. Project Title: The Wake Forest Nonhuman Primate Radiation Survivor Cohort
  Leader(s): CLINE, J. MARK
    NIH U01AI150578 / ( 2020 - 2027 )
  Abstract/Summary Acute effects of radiation exposures are the focus of emergency medical responses and mitigation efforts, but the major burden of radiation injury lies in delayed effects. These late and usually long-term effects of exposure on normal healthy tissues include cellular, molecular, and metabolic changes leading to organ dysfunction and failure; fibrosis; and neoplasia. The Radiation Survivor Cohort (RSC) is a unique and irreplaceable population of nonhuman primate (NHP) radiation survivors, which serves the nation s need to identify and understand the late effects of radiation exposure; provides long-term outcome validation of acute biomarker measurements; and provides critical data regarding tissue damage and recovery. RSC investigators at Wake Forest have assessed adverse effects of single-dose whole-body exposures of 1-8.5 Gy in over 140 rhesus monkeys observed for up to 15 years after irradiation, with 38 controls. The cohort includes juvenile and adult exposures, males and females, and subsets of animals that did or did not receive mitigating treatments such as hematopoietic growth factors or antibiotics. Observations have included an annual cycle of clinical examinations, imaging (ultrasound, CT and MRI), clinical pathology, and ultimately necropsy examinations. Major diseases identified to date include (1) metabolic disease and type II diabetes mellitus; (2) myocardial diastolic dysfunction with fibrosis; (3) neurologic disorders with MRI-detected brain lesions; (4) chronic renal disease with fibrosis; (5) gastrointestinal disease resulting in chronic diarrhea; (6) immune compromise with impaired response repertoire; (7) neoplasms, primarily including sarcomas, hematopoietic, epithelial, and neuroendocrine types. Other stereotypical radiation effects are seen, such as cataracts and gonadal atrophy at higher doses. Multiple disorders in the same animal were common, up to 8 in high-dose animals, with diabetes being the most common co-morbid condition. The overarching goal for the proposed new funding period is to identify and study relevant patterns of post-irradiation morbidity and mortality in this unique, controlled, well- defined NHP population, by collaborating and sharing data with NIH-funded and other federally-funded investigators. Sharing will include samples (blood, tissue, body fluids, microbiome) and data (clinical, imaging, pathology, gene sequence, gene expression, immunophenotyping and other data types) with an active investigator community currently consisting of 62 investigators across 18 institutions, including outreach to new investigative teams. The specific aims of this program are to (1) identify and share patterns of post-irradiation morbidity; (2) identify genomic and biomarker characteristics of animals with differing radiation-induced disorders; (3) assess late effects of prior mitigator treatment; and (4) refine the cohort to balance age, sex, dose, and mitigator type, in order to maximize the scope of inference of data derived from the cohort.
22. Project Title: Bisphosphonate Use to Mitigate Bone Loss Secondary to Bariatric Surgery
    NIH U01AR080969 / ( 2022 - 2027 )
  PROJECT SUMMARY Despite well recognized improvements in obesity-related comorbidities, mounting evidence implicates sleeve gastrectomy (SG) in the onset of skeletal fragility. Bisphosphonate therapy reduces osteoporotic fracture risk and may also be effective in minimizing bone loss associated with SG. Once-monthly oral risedronate is a commonly prescribed bisphosphonate with a favorable gastrointestinal profile that acts by inhibiting the activity of osteoclast cells, thereby decreasing the rate of bone resorption. Because SG is associated with a significant increase in bone resorption, we hypothesize that risedronate use will counter bone loss in this clinical scenario, ultimately reducing long-term fracture risk. Indeed, pilot data from our group signal that six months of risedronate use is both feasible and likely effective at reducing bone resorption and bone mineral density (BMD) loss post- SG as compared to placebo. Intriguingly, we also observe a signal for appendicular lean mass preservation with risedronate use. This novel finding aligns with data from animal models of clinical pathology and limited observational data in humans, suggestive of a bisphosphonate-induced lean-mass sparing effect. If true, confirmatory data from a definitively designed trial is poised to influence clinical management of the SG patient, while also providing a platform upon which to interrogate mechanisms of bone-muscle crosstalk. To fill these knowledge gaps, the main objective of the proposed study is to definitively test whether risedronate use can effectively counter SG associated bone loss. To do this, we propose to randomize 120 middle-aged and older (=40 years) SG patients to six months of risedronate or placebo treatment, with bone and muscle outcomes assessed at baseline, six, and 12 months. Due to its robust change following SG and clinical utility in predicting fracture, our primary outcome is change in total hip areal (a)BMD measured by dual energy x-ray absorptiometry (DXA). This will be complemented by DXA-acquired aBMD assessment at other skeletal sites and appendicular lean mass, as well as quantitative computed tomography (QCT) derived changes in bone (volumetric BMD, cortical thickness, and strength) and muscle (cross sectional area, fat infiltration) at the hip and spine allowing for novel assessment of intervention effectiveness on several state of the art bioimaging metrics as well as select physical function tasks. Biomarkers of bone turnover and bone-muscle crosstalk will also be assessed in a tertiary aim, providing mechanistic insight into intervention-related changes to the bone-muscle unit. Definitive data has the potential to shift current clinical practice while also offering insight into underlying biologic mechanisms.
23. Project Title: Wake Forest Atrium HeartShare Clinical Center
  Leader(s): KITZMAN, DALANE W
    NIH U01HL160272 / ( 2021 - 2026 )
  Project Summary Heart Failure with Preserved Ejection Fraction (HFpEF) is the most common form of HF in the US and is associated with high morbidity and mortality. However, its pathophysiology is incompletely understood, and most trials have been neutral such that few evidence-based treatments exist. In response, NIH convened 2 workshops co-led by Dr. Kitzman (PI). The highest priority research recommendation was a coordinated effort to create a large cohort of HFpEF patients and controls and perform comprehensive, deep phenotyping. This became the basis for HeartShare, whose ultimate goals are to discover novel HFpEF mechanisms, subtypes, and therapeutic targets. Our Wake Forest - Atrium HFpEF team is highly qualified to serve as a Clinical Center and make robust, over-arching contributions to HeartShare. Dr. Kitzman is internationally recognized as a thought-leader in HFpEF with a sustained track record of developing novel concepts regarding HFpEF pathogenesis, mechanisms, and outcomes and designing and conducting innovative studies to test them. His team has extensive experience in all key aspects of the HeartShare program, particularly in recruiting, retaining, and phenotyping diverse populations of HFpEF patients and controls, often significantly exceeding goals for racial and gender diversity. Our institutions have ~15,000 HFpEF clinical visits annually. In all, our team has led or helped lead recruitment and phenotyping for 69 studies, mostly NIH-sponsored, with 15,354 participants, demonstrating our ability to fulfill HeartShare recruitment and phenotyping goals. Data from these studies will be contributed to the Cohort phase of HeartShare. We will make robust contributions to HeartShare by achieving 4 Specific Aims: Aim 1) Provide thought leadership in collaboration with the HeartShare Steering Committee; Aim 2) Contribute data, images, and stored specimens cohort phase of HeartShare from our numerous studies of HFpEF and controls, and identify and phenotype HFpEF patients and controls from the electronic health record using robust bioinformatics tools; Aim 3) Recruit, consent, enroll and follow at least 250 HFpEF patients plus controls (type and number to be determined by consensus); Aim 4) Conduct state-of- the-art deep phenotyping exams using a collaboratively determined protocol. Our phenotyping proposal is highly innovative, with advanced echo-Doppler and cardiac magnetic resonance imaging, CPET, physical activity monitoring, remote and artificial intelligence electrocardiography, sampling of skeletal muscle, adipose, blood, and microbiome, and mitochondrial energetics, and brain structure/function. Our diverse, cross- disciplinary team has the full range of complementary expertise and access to the robust resources of two large, closely affiliated health systems to ensure fulfillment of all HeartShare s goals. We will help accelerate and optimize the program s success with our insight, creativity, and sustained track record of collaboration, innovation, and dissemination.
    NIH U19AG065188 / ( 2019 - 2026 )
  Core(s): - Clinical Research Core (CRC)
  There is an urgent need for evidence to guide clinical care of older adults due to demographic shifts, includinglonger life expectancy and a recent doubling of the older adult population. Statins reduce recurrent CVD eventsand prevent initial events in patients younger than 75 years. However, clinical research has often excludedpersons older than 75 years due to a higher prevalence of comorbidity and frailty so little to no evidence isavailable to guide care in this population. For older adults living longer, the promise of preventing cognitiveimpairment is as compelling as preventing a CVD event, but some evidence suggests statins maycontribute to memory difficulty or muscle symptoms. There is equipoise regarding the usefulness of statinsfor primary CVD, dementia, and disability prevention in adults older than 75 years, especially in the settingof multiple chronic conditions, advanced age, or frailty. Evidence to improve cognitive and functionaloutcomes in older populations with diverse race/ethnicity and health status will require new clinical trialapproaches with sustainable methodology and infrastructure. We propose PREVENTABLE (PRagmaticEValuation of evENTs And Benefits of Lipid-lowering in oldEr adults), the first statin trial with a non-CVDprimary outcome survival free of dementia or persisting disability. Using a placebo-controlled pragmaticclinical trial (PCT) design across PCORnet and VA network, the trial will be under the leadership of Dr. KarenAlexander at DCRI, Dr. Jeff Williamson at WFSM, Dr. Adrian Hernandez at DCRI, and Dr. Walter Ambrosius atWFSM. This team has established experience and track-record of accomplishment in the design and conductof PCTs, trial expertise in ascertaining cognitive and disability outcomes in older adults, and is supported by arobust administrative infrastructure for coordinating these shared responsibilities for success. The overarchinggoal of PREVENTABLE is to generate knowledge about the role of statins in older adults, a population in whichrisk/benefit for primary prevention has been under studied. The hypothesis is that a large trial conducted in anolder adult population will demonstrate the benefit of statins for reducing dementia, disability, and CV events.We further hypothesize that extensive genomic, biochemical and imaging ancillary studies will offer uniqueinsights into these key outcomes. PREVENTABLE has the following specific aims: AIM 1: Determine the roleof a moderate-intensity statin in preventing dementia and prolonging disability-free survival in patients 75 yearsand older without clinically evident coronary heart disease, including those with frailty, impaired physicalfunction, mild cognitive impairment, polypharmacy, and multi-morbidity. AIM 2: Determine the role of moderate-intensity statin in preventing hospitalization for myocardial infarction/acute coronary syndrome, stroke, heartfailure, revascularization or cardiovascular-related death, and preventing either mild cognitive impairment ordementia. AIM 3: Test the safety and tolerability of statins in older adults and collect 17,000 bio-specimens toadvance precision health.
25. Project Title: Research Centers Collaborative Network Renewal
    NIH U24AG058556 / ( 2018 - 2026 )
  The problems of an aging society transcend the boundaries of any specific discipline and play out across multiple biologic and societal domains. The six National Institute on Aging center programs address these problems but typically from a specific disciplinary perspective. To provide a mechanism to foster cross-disciplinary collaborations the Research Centers Collaborative Network (RCCN) was established in 2008. It is led by the American Federation for Aging Research and the Wake Forest School of Medicine. The RCCN addresses the challenge of building multidisciplinary collaborations by employing 5 complementary strategies: 1) identifying intellectual opportunities that are best advanced by inter-center collaboration; 2) stimulating the development of cross-center collaborations; 3) providing new opportunities for early career researchers to expand their multidisciplinary collaborative network; and 4) leveraging RCCN activities to bring additional resources to multidisciplinary aging research. Its first two years were highly successful. In a highly praised workshop series, it brought together key thought leaders from each of the 6 NIA center programs, offered didactic programs for early career researchers, established a Webinar series, worked with NIA center coordinating centers to coordinate activities and promote dissemination, and worked with the CTSA s Inclusion of Older Adults workgroup to increase recruitment of older adults to clinical research among other achievements. Its goals going forward build on these achievements and introduce important innovations and refinements. The RCCN s specific aims for the next cycle are to: 1. Stimulate cross-center collaboration through: a) Workshops focused on cross-cutting scientific themes each relevant to 4 or more center programs; and b) Pilot grants supporting the initiation of cross-center collaborations. 2. Provide educational opportunities for early career investigators to build competencies in multidisciplinary and cross-institutional research. 3. Work with NIA Center program coordinating centers and other NIA supported research networks to: a) disseminate cutting edge multidisciplinary science; b) foster connections between the 6 NIA center programs and other NIA-supported research networks; and c) develop tools, standards and guidelines to promote multi-disciplinary and multi-institutional research. 4. Expand its impact through fostering applications to foundations, the CTSA program and other potential sponsors whose interests align with NIA Center programs. The RCCN employs multiple evaluation strategies designed to strengthen and adapt its programs and to gauge its impact in fostering multidisciplinary approaches to solving the problems facing older adults.
26. Project Title: MoTrPAC Consortium Coordinating Center
    NIH U24AR071113 / ( 2016 - 2023 )
  Summary Physical inactivity is a major public health challenge underlying a broad range of health problems at all ages. While physical activity (PA) has shown to produce relevant health benefits, the underlying molecular mechanisms are poorly known. The coordinated effort of clinical and animal studies supported by bioinformatics and chemical analyses will achieve the Molecular Transducers of Physical Activity Consortium (MoTrPAC) goals of assessing the molecular changes that occur in response to PA. The Consortium Coordinating Center (CCC) for the MoTrPAC will provide support for the organization, administration, planning, standardization, documentation, monitoring and reporting activities relating to the MoTrPAC. The CCC will play a pivotal role in ensuring the cohesion of the MoTrPAC by enhancing communication and integration across all study components, including the Clinical Sites, the Preclinical Animal Study Sites, the Bioinformatics Center, the Chemical Analysis Sites, and the various study committees. The CCC will develop strategies and strategic planning processes by integrating activities of the MoTrPAC investigators with the input provided by the Data Safety Monitoring Board, the External Scientific Advisors, outside experts, and the NIH. The CCC will facilitate interactions and communications with junior and senior investigators outside the consortium to maximize the use of the MoTrPAC resources toward achieving the overall research goals. To accomplish these goals and maximize the progress and productivity of the MoTrPAC, the CCC will promote team science, team leadership, and innovative leadership approaches across all study components. Strategic planning that follows the principles of the dynamic theory of strategy will be fostered to evaluate alternative approaches, maintain the cutting-edge scientific focus, leverage state-of-the-art coordination technologies, anticipate challenges, and maximize future opportunities to ensure the success of the consortium. The CCC will comprise four integrated components led by four highly qualified PIs who have a long-lasting track record of successfully working in synergy. The four CCC components comprise the Administrative Coordinating Center (PI Dr. Pahor), the Data Management, Analysis, and Quality Control Center (PI Dr. Miller), the Biospecimens Repository (PI Dr. Tracy), and the Exercise Intervention Core (PI Dr. Rejeski). The CCC will employ innovative project management tools and web-based tracking of exercise adherence and diet, and will capitalize on the outstanding track record and expertise of its investigators in: (a) working together; (b) successfully coordinating, managing, and leading large long-term multicenter clinical trials involving PA and other interventions; (c) implementing rigor and transparency in research, (d) acquiring, managing, storing and analyzing biological samples; (e) conducting animal exercise studies; (f) sharing resources; (g) publishing results; and (h) leading multidisciplinary teams. The CCC will ensure and promote the continued success of the MoTrPAC in advancing knowledge about the molecular changes that occur in response to PA, and relating these changes to the health benefits of PA.
27. Project Title: Mapping and validating senescent cells in human muscle, ovary and breast
  Leader(s): MELOV, SIMON
    NIH U54AG075932 / ( 2021 - 2026 )
  BIOLOGICAL ANALYSIS CORE - PROJECT SUMMARY This Buck Institute Tissue Mapping Center (TMC) proposes to map senescent cells in three human somatic and reproductive tissues; ovaries, breast tissue and skeletal muscle. A major gap in the field has been to define specific cellular senescence markers for distinct cells and tissue types. We propose to fill this gap by defining markers of cellular senescence in the context of aging in human tissues. The capabilities of this core include a deep knowledge of multiple aspects of senescence encompassing the SASP, novel senolytics, and preliminary data defining senescent cells in human muscle tissue. Tissues received in the Biospecimen Core will be conveyed to the Biological Analysis Core and subjected to multiple procedures designed to identify senescent cell signatures (either protein or mRNA) in nuclei or biofluids, and confirmed in tissue sections. The results from the Biological Analysis Core will be conveyed to the Data Analysis Core, and coordinated through the Administrative Core. The Biological Analysis Core will spatially map and determine the signatures of cellular senescence in healthy human ovaries, breast, and muscle in both sexes across an aging continuum through four specific aims. 1) Determine the unique transcriptional signature of large senescent cells. We will determine the transcriptional signatures of large senescent cells, which are lost during conventional single cell workflows and use this data to determine the prevalence of such signatures in the breast, ovary, and muscle. 2) Determine senescent protein signatures of the breast, ovary, and skeletal muscle. We will comprehensively analyze secreted senescence-associated secretory phenotype (SASP) proteins from bio fluids, and cell culture systems from muscle, breast, and ovaries using different senescence inducers and senolytics. 3) Determine senescent transcriptional signatures of the breast, ovary, and skeletal muscle. We will use a bootstrapping strategy on key cell types from the tissues in this aim, to determine unique single cell senescent signatures derived from a range of senescent inducers on prototypical cell cultures from each tissue. We will use these data to map similar signatures back to complex fully profiled data sets derived from intact tissues using snRNA-seq, cell assignment, and expression analysis. 4) Determine spatial relationship and frequencies of senescent cells in tissue sections. We will take advantage of emerging technologies from Nanostring (Digital Spatial Profiling), and 10X technologies (Visium) to build on our knowledge discovered in the first three aims to better understand frequency and subtypes of senescent cells within tissue sections from tissue sections. In conjunction with other cores we expect to create a comprehensive spatial map and signatures of senescence in reproductive tissues (breast and ovary) and also the sex-specific and longitudinal differences in muscle, a somatic tissue, with age.
  1. Targeting Obesity to Optimize Weight Loss in Cardiac Rehabilitation: A PILOT STUDY.
    Brinkley TE, Hsu FC, Bowman BM, Addison T, Kitzman DW, Houston DK
    J Cardiopulm Rehabil Prev, 2023 Jan 1, 43(1): 39-48
    https://doi.org/10.1097/HCR.0000000000000750 | PMID: 36441136 | PMCID: PMC9797431
    Citations: 34 | AltScore: 0.25
  2. A Randomized, Controlled Trial of Resistance Training Added to Caloric Restriction Plus Aerobic Exercise Training in Obese Heart Failure With Preserved Ejection Fraction.
    Brubaker PH, Nicklas BJ, Houston DK, Hundley WG, Chen H, Molina AJA, Lyles WM, Nelson B, Upadhya B, Newland R, Kitzman DW
    Circ Heart Fail, 2023 Feb, 16(2): e010161
    https://doi.org/10.1161/CIRCHEARTFAILURE.122.010161 | PMID: 36314122 | PMCID: PMC9974606
    Citations: 50 | AltScore: 45.4
  3. Is an MRI-derived anatomical measure of dementia risk also a measure of brain aging?
    Casanova R, Anderson AM, Barnard RT, Justice JN, Kucharska-Newton A, Windham BG, Palta P, Gottesman RF, Mosley TH, Hughes TM, Wagenknecht LE, Kritchevsky SB
    Geroscience, 2023 Feb, 45(1): 439-450
    https://doi.org/10.1007/s11357-022-00650-z | PMID: 36050589 | PMCID: PMC9886771
    Citations: 55 | AltScore: 13.2
  4. Risedronate use may blunt appendicular lean mass loss secondary to sleeve gastrectomy: Results from a pilot randomized controlled trial.
    Flores LE, Beavers KM, Beavers DP, Greene KA, Madrid DA, Miller RM, Ard JD, Bilek LD, Weaver AA
    JCSM Rapid Commun, 2023 Jan-Jun, 6(1): 18-25
    https://doi.org/10.1002/rco2.72 | PMID: 37273449 | PMCID: PMC10236921
    Citations: 37 | AltScore: NA
  5. Serum factors mediate changes in mitochondrial bioenergetics associated with diet and exercise interventions.
    Gonzalez-Armenta JL, Bergstrom J, Lee J, Furdui CM, Nicklas BJ, Molina AJA
    Geroscience, 2023 Jun 27
    https://doi.org/10.1007/s11357-023-00855-w | PMID: 37368157
    Citations: | AltScore: 9.7
  6. Vitamin D Supplementation and Muscle Power, Strength and Physical Performance in Older Adults: A Randomized Controlled Trial.
    Houston DK, Marsh AP, Neiberg RH, Demons JL, Campos CL, Kritchevsky SB, Delbono O, Tooze JA
    Am J Clin Nutr, 2023 Jun, 117(6): 1086-1095
    https://doi.org/10.1016/j.ajcnut.2023.04.021 | PMID: 37084814
    Citations: | AltScore: 25.75
  7. Effect of Baseline BMI and IL-6 Subgroup Membership on Gait Speed Response to Caloric Restriction in Older Adults with Obesity.
    Hsieh KL, Neiberg RH, Beavers KM, Rejeski WJ, Messier SP, Nicklas BJ, Beavers DP
    J Nutr Health Aging, 2023, 27(4): 285-290
    https://doi.org/10.1007/s12603-023-1909-1 | PMID: 37170436
    Citations: | AltScore: 1.6
  8. Factors associated with falls in older adults: A secondary analysis of a 12-month randomized controlled trial.
    Hsieh KL, Speiser JL, Neiberg RH, Marsh AP, Tooze JA, Houston DK
    Arch Gerontol Geriatr, 2023 May, 108: 104940
    https://doi.org/10.1016/j.archger.2023.104940 | PMID: 36709562 | PMCID: PMC10068618
    Citations: 50 | AltScore: 2
  9. Rate-Adaptive Pacing for Heart Failure With Preserved Ejection Fraction.
    Kitzman DW, Upadhya B, Pandey A
    JAMA, 2023 Mar 14, 329(10): 797-799
    https://doi.org/10.1001/jama.2023.1053 | PMID: 36871286 | PMCID: PMC10265352
    Citations: 17 | AltScore: NA
  10. Associations of physical function and body mass index with functional brain networks in community-dwelling older adults.
    Laurienti PJ, Miller ME, Lyday RG, Boyd MC, Tanase AD, Burdette JH, Hugenschmidt CE, Rejeski WJ, Simpson SL, Baker LD, Tomlinson CE, Kritchevsky SB
    Neurobiol Aging, 2023 Jul, 127: 43-53
    https://doi.org/10.1016/j.neurobiolaging.2023.03.008 | PMID: 37054493 | PMCID: PMC10227726
    Citations: 49 | AltScore: NA
  11. Associations of interleukin-6 with functional trajectories in older adults with cancer: Findings from the Health, Aging, and Body Composition Study.
    Loh KP, Consagra W, Magnuson A, Baran A, Gilmore N, Giri S, LoCastro M, Isom S, Sohn MB, Williams GR, Houston DK, Nicklas B, Kritchevsky S, Klepin HD
    Exp Gerontol, 2023 Jun 15, 177: 112185
    https://doi.org/10.1016/j.exger.2023.112185 | PMID: 37119835 | PMCID: PMC10205678
    Citations: 35 | AltScore: NA
  12. Effect of exercise modality and weight loss on changes in muscle and bone quality in older adults with obesity.
    Madrid DA, Beavers KM, Walkup MP, Ambrosius WT, Rejeski WJ, Marsh AP, Weaver AA
    Exp Gerontol, 2023 Apr, 174: 112126
    https://doi.org/10.1016/j.exger.2023.112126 | PMID: 36796657 | PMCID: PMC10033433
    Citations: 72 | AltScore: 27.5
  13. A Liquid Biopsy-Based Approach to Isolate and Characterize Adipose Tissue-Derived Extracellular Vesicles from Blood.
    Mishra S, Kumar A, Kim S, Su Y, Singh S, Sharma M, Almousa S, Rather HA, Jain H, Lee J, Furdui CM, Ahmad S, Ferrario CM, Punzi HA, Chuang CC, Wabitsch M, Kritchevsky SB, Register TC, Deep G
    ACS Nano, 2023 Jun 13, 17(11): 10252-10268
    https://doi.org/10.1021/acsnano.3c00422 | PMID: 37224410
    Citations: | AltScore: 1.5
  14. Physical activity and relationship to physical function, quality of life, and cognitive function in older patients with acute decompensated heart failure.
    Nelson MB, Shiroma EJ, Kitzman DW, Duncan PW, Reeves GR, Whellan DJ, Mentz RJ, Chen H, Pastva AM
    Am Heart J, 2023 Feb, 256: 85-94
    https://doi.org/10.1016/j.ahj.2022.11.002 | PMID: 36372251 | PMCID: PMC9840656
    Citations: 54 | AltScore: 21.3
  15. Role of a Novel Self-Reported Questionnaire for Frailty Assessment in HFpEF.
    Pandey A, Kitzman DW
    JACC Heart Fail, 2023 Apr, 11(4): 404-406
    https://doi.org/10.1016/j.jchf.2023.01.026 | PMID: 37019556 | PMCID: PMC10283081
    Citations: 15 | AltScore: 10
  16. Frailty and Effects of a Multidomain Physical Rehabilitation Intervention Among Older Patients Hospitalized for Acute Heart Failure: A Secondary Analysis of a Randomized Clinical Trial.
    Pandey A, Kitzman DW, Nelson MB, Pastva AM, Duncan P, Whellan DJ, Mentz RJ, Chen H, Upadhya B, Reeves GR
    JAMA Cardiol, 2023 Feb 1, 8(2): 167-176
    https://doi.org/10.1001/jamacardio.2022.4903 | PMID: 36598761 | PMCID: PMC9857661
    Citations: 35 | AltScore: 89.1
  17. An Examination of Whether Diabetes Control and Treatments Are Associated With Change in Frailty Index Across 8 Years: An Ancillary Exploratory Study From the Action for Health in Diabetes (Look AHEAD) Trial.
    Simpson FR, Justice JN, Pilla SJ, Kritchevsky SB, Boyko EJ, Munshi MN, Ferris CK, Espeland MA, Look AHEAD Research Group
    Diabetes Care, 2023 Mar 1, 46(3): 519-525
    https://doi.org/10.2337/dc22-1728 | PMID: 36542537 | PMCID: PMC10020016
    Citations: 39 | AltScore: NA
  1. Designing Actionable Solutions and Curriculum for Pain Disparities Education.
    Adams MCB, Denizard-Thompson NM, DiGiacobbe G, Williams BL, Brooks AK
    Pain Med, 2022 Feb 1, 23(2): 288-294
    https://doi.org/10.1093/pm/pnab289 | PMID: 34601612 | PMCID: PMC9020483
    Citations: 23 | AltScore: 12.4
  2. Body composition from single versus multi-slice abdominal computed tomography: Concordance and associations with colorectal cancer survival.
    Anyene I, Caan B, Williams GR, Popuri K, Lenchik L, Giri S, Chow V, Beg MF, Cespedes Feliciano EM
    J Cachexia Sarcopenia Muscle, 2022 Dec, 13(6): 2974-2984
    https://doi.org/10.1002/jcsm.13080 | PMID: 36052755 | PMCID: PMC9745558
    Citations: 35 | AltScore: 8.8
  3. Effects of muscle quantity and bone mineral density on injury and outcomes in older adult motor vehicle crash occupants.
    Armstrong W, Costa C, Poveda L, Miller AN, Ambrosini A, Hsu FC, Kiani B, Martin RS, Stitzel JD, Weaver AA
    Traffic Inj Prev, 2022, 23(sup1): S86-S91
    https://doi.org/10.1080/15389588.2022.2124864 | PMID: 36190765 | PMCID: PMC9839521
    Citations: 25 | AltScore: 3.95
  4. Daily Low-Dose Aspirin and Risk of Serious Falls and Fractures in Healthy Older People: A Substudy of the ASPREE Randomized Clinical Trial.
    Barker AL, Morello R, Thao LTP, Seeman E, Ward SA, Sanders KM, Cumming RG, Pasco JA, Ebeling PR, Woods RL, Wolfe R, Khosla S, Hussain SM, Ronaldson K, Newman AB, Williamson JD, McNeil JJ
    JAMA Intern Med, 2022 Dec 1, 182(12): 1289-1297
    https://doi.org/10.1001/jamainternmed.2022.5028 | PMID: 36342703 | PMCID: PMC9641595
    Citations: 29 | AltScore: 204.086
  5. Longitudinal relationship of baseline functional brain networks with intentional weight loss in older adults.
    Burdette JH, Bahrami M, Laurienti PJ, Simpson SL, Nicklas BJ, Fanning J, Rejeski WJ
    Obesity (Silver Spring), 2022 Apr, 30(4): 902-910
    https://doi.org/10.1002/oby.23396 | PMID: 35333443 | PMCID: PMC8969753
    Citations: 39 | AltScore: 163.08
  6. Economic Outcomes of Rehabilitation Therapy in Older Patients With Acute Heart Failure in the REHAB-HF Trial: A Secondary Analysis of a Randomized Clinical Trial.
    Chew DS, Li Y, Zeitouni M, Whellan DJ, Kitzman D, Mentz RJ, Duncan P, Pastva AM, Reeves GR, Nelson MB, Chen H, Reed SD
    JAMA Cardiol, 2022 Feb 1, 7(2): 140-148
    https://doi.org/10.1001/jamacardio.2021.4836 | PMID: 34817542 | PMCID: PMC8613698
    Citations: 34 | AltScore: 33
  7. The impact of Dietary Weight loss, Aerobic Exercise, and Daylong Movement on Social Cognitive Mediators of Long-term Weight loss.
    Fanning J, Nicklas B, Furlipa J, Rejeski WJ
    J Behav Med, 2022 Oct 10, 46(3): 499-508
    https://doi.org/10.1007/s10865-022-00359-6 | PMID: 36215000 | PMCID: PMC9548422
    Citations: 46 | AltScore: NA
  8. Intervening on exercise and daylong movement for weight loss maintenance in older adults: A randomized, clinical trial.
    Fanning J, Rejeski WJ, Leng I, Barnett C, Lovato JF, Lyles MF, Nicklas BJ
    Obesity (Silver Spring), 2022 Jan, 30(1): 85-95
    https://doi.org/10.1002/oby.23318 | PMID: 34932885 | PMCID: PMC8711609
    Citations: 45 | AltScore: 149.55
  9. Risedronate or Exercise for Lean Mass Preservation During Menopause: Secondary Analysis of a Randomized Controlled Trial.
    Flores LE, Kupzyk K, Waltman N, Beavers KM, Bilek L
    JCSM Rapid Commun, 2022 Jul-Dec, 5(2): 154-161
    https://doi.org/10.1002/rco2.59 | PMID: 36186606 | PMCID: PMC9517955
    Citations: 39 | AltScore: NA
  10. Geriatric Domains in Patients with Heart Failure with Preserved Ejection Fraction.
    Goyal P, Zainul O BS, MD, Marshall D, Kitzman DW
    Cardiol Clin, 2022 Nov, 40(4): 517-532
    https://doi.org/10.1016/j.ccl.2022.06.006 | PMID: 36210135 | PMCID: PMC10282897
    Citations: 141 | AltScore: NA
  11. Gradient and Acceleration of Decline in Physical and Cognitive Functions in Older Adults: A Disparity Analysis.
    Ip EH, Chen SH, Rejeski WJ, Bandeen-Roche K, Hayden KM, Hugenschmidt CE, Pierce J, Miller ME, Speiser JL, Kritchevsky SB, Houston DK, Newton RL, Rapp SR, Kitzman DW
    J Gerontol A Biol Sci Med Sci, 2022 Aug 12, 77(8): 1603-1611
    https://doi.org/10.1093/gerona/glac109 | PMID: 35562076 | PMCID: PMC9373944
    Citations: 50 | AltScore: 4
  12. Evaluation of a blood-based geroscience biomarker index in a randomized trial of caloric restriction and exercise in older adults with heart failure with preserved ejection fraction.
    Justice JN, Pajewski NM, Espeland MA, Brubaker P, Houston DK, Marcovina S, Nicklas BJ, Kritchevsky SB, Kitzman DW
    Geroscience, 2022 Jan 10, 44(2): 983-995
    https://doi.org/10.1007/s11357-021-00509-9 | PMID: 35013909 | PMCID: PMC9135899
    Citations: 57 | AltScore: 0.5
  13. Tailoring a physical activity intervention to older adults receiving intensive chemotherapy for acute myeloid leukemia (AML): One size does not fit all.
    Klepin HD, Tooze JA, Rejeski J, Mihalko S, Pardee TS, Demark-Wahnefried W, Powell BL, Geiger AM, Kritchevsky S
    J Geriatr Oncol, 2022 May, 13(4): 511-515
    https://doi.org/10.1016/j.jgo.2021.11.017 | PMID: 35487616 | PMCID: PMC9060358
    Citations: 30 | AltScore: 13.85
  14. Quantifying Cardiothoracic Variation with Posture and Respiration to Inform Cardiac Device Design.
    Kondaveeti GA, Bhatia VA, Lahm RP, Harris ML, Gaewsky JP, Gayzik FS, Greenhalgh JF, Hamilton CA, Stacey RB, Weaver AA
    Cardiovasc Eng Technol, 2022 May 26, 14(1): 13-24
    https://doi.org/10.1007/s13239-022-00631-5 | PMID: 35618869 | PMCID: PMC9699900
    Citations: 18 | AltScore: 2.85
  15. Age-based differences in the disability of spine injuries in pediatric and adult motor vehicle crash occupants.
    Lynch SD, Weaver AA, Barnard RT, Kiani B, Stitzel JD, Zonfrillo MR
    Traffic Inj Prev, 2022, 23(6): 358-363
    https://doi.org/10.1080/15389588.2022.2086980 | PMID: 35709315 | PMCID: PMC9756938
    Citations: 21 | AltScore: 5.05
  16. Physical Rehabilitation in Older Patients Hospitalized with Acute Heart Failure and Diabetes: Insights from REHAB-HF.
    Murray EM, Whellan DJ, Chen H, Bertoni AG, Duncan P, Pastva AM, Kitzman DW, Mentz RJ
    Am J Med, 2022 Jan, 135(1): 82-90
    https://doi.org/10.1016/j.amjmed.2021.08.001 | PMID: 34516959 | PMCID: PMC8688185
    Citations: 41 | AltScore: 7.85
  17. Transcriptional profiles in olfactory pathway-associated brain regions of African green monkeys: Associations with age and Alzheimer's disease neuropathology.
    Negrey JD, Dobbins DL, Howard TD, Borgmann-Winter KE, Hahn CG, Kalinin S, Feinstein DL, Craft S, Shively CA, Register TC
    Alzheimers Dement (N Y), 2022, 8(1): e12358
    https://doi.org/10.1002/trc2.12358 | PMID: 36313967 | PMCID: PMC9609452
    Citations: 57 | AltScore: 13
  18. Intervention Adherence in REHAB-HF: Predictors and Relationship With Physical Function, Quality of Life, and Clinical Events.
    Nelson MB, Gilbert ON, Duncan PW, Kitzman DW, Reeves GR, Whellan DJ, Mentz RJ, Chen H, Hewston LA, Taylor KM, Pastva AM
    J Am Heart Assoc, 2022 Jun 7, 11(11): e024246
    https://doi.org/10.1161/JAHA.121.024246 | PMID: 35656973 | PMCID: PMC9238741
    Citations: 29 | AltScore: 2
  19. Frailty Status Modifies the Efficacy of Exercise Training Among Patients With Chronic Heart Failure and Reduced Ejection Fraction: An Analysis From the HF-ACTION Trial.
    Pandey A, Segar MW, Singh S, Reeves GR, O'Connor C, Pi?a I, Whellan D, Kraus WE, Mentz RJ, Kitzman DW
    Circulation, 2022 Jul 12, 146(2): 80-90
    https://doi.org/10.1161/CIRCULATIONAHA.122.059983 | PMID: 35616018 | PMCID: PMC10273304
    Citations: 43 | AltScore: 31.05
  20. Examining the Role of Nonsurgical Therapy in the Treatment of Geriatric Urinary Incontinence.
    Parker-Autry C, Neiberg R, Leng XI, Matthews CA, Dumoulin C, Kuchel G, Kritchevsky SB
    Obstet Gynecol, 2022 Aug 1, 140(2): 243-251
    https://doi.org/10.1097/AOG.0000000000004852 | PMID: 35852275 | PMCID: PMC9502119
    Citations: 31 | AltScore: 1.25
  21. Obesity Status and Physical Rehabilitation in Older Patients Hospitalized With Acute HF: Insights From REHAB-HF.
    Peters AE, Kitzman DW, Chen H, Nelson MB, Pastva AM, Duncan PW, Reeves GR, Upadhya B, Whellan DJ, Mentz RJ
    JACC Heart Fail, 2022 Dec, 10(12): 918-927
    https://doi.org/10.1016/j.jchf.2022.07.008 | PMID: 36164731 | PMCID: PMC10234458
    Citations: 34 | AltScore: 22.95
  22. Aging and Neural Vulnerabilities in Overeating: A Conceptual Overview and Model to Guide Treatment.
    Rejeski WJ, Laurienti PJ, Bahrami M, Fanning J, Simpson SL, Burdette JH
    PCN Rep, 2022 Sep, 1(3):
    pii: e39. https://doi.org/10.1002/pcn5.39 | PMID: 36589860 | PMCID: PMC9797202
    Citations: 72 | AltScore: 0.25
  23. Geriatric assessment for older adults receiving less-intensive therapy for acute myeloid leukemia: report of CALGB 361101.
    Ritchie EK, Klepin HD, Storrick E, Major B, Le-Rademacher J, Wadleigh M, Walker A, Larson RA, Roboz GJ
    Blood Adv, 2022 Jun 28, 6(12): 3812-3820
    https://doi.org/10.1182/bloodadvances.2021006872 | PMID: 35420672 | PMCID: PMC9631575
    Citations: 38 | AltScore: 5.1
  24. Psychosocial stress increases risk for type 2 diabetes in female cynomolgus macaques consuming a western diet.
    Silverstein-Metzler MG, Frye BM, Justice JN, Clarkson TB, Appt SE, Jeffrey Carr J, Register TC, Albu-Shamah M, Shaltout HA, Shively CA
    Psychoneuroendocrinology, 2022 May, 139: 105706
    https://doi.org/10.1016/j.psyneuen.2022.105706 | PMID: 35259592 | PMCID: PMC8977247
    Citations: 72 | AltScore: 8.1
  25. Predicting Future Mobility Limitation in Older Adults: A Machine Learning Analysis of Health ABC Study Data.
    Speiser JL, Callahan KE, Ip EH, Miller ME, Tooze JA, Kritchevsky SB, Houston DK
    J Gerontol A Biol Sci Med Sci, 2022 May 5, 77(5): 1072-1078
    https://doi.org/10.1093/gerona/glab269 | PMID: 34529794 | PMCID: PMC9071470
    Citations: 30 | AltScore: 2.5
  26. Relationship of self-reported and performance-based visual function with performance-based measures of physical function: the Health ABC study.
    Thompson AC, Miller ME, Webb C, Williamson JD, Kritchevsky SB
    J Gerontol A Biol Sci Med Sci, 2022 Nov 8
    pii: glac225. https://doi.org/10.1093/gerona/glac225 | PMID: 36346340
    Citations: | AltScore: NA
  27. Improvisational Movement to Improve Quality of Life in Older Adults With Early-Stage Dementia: A Pilot Study.
    Thumuluri D, Lyday R, Babcock P, Ip EH, Kraft RA, Laurienti PJ, Barnstaple R, Soriano CT, Hugenschmidt CE
    Front Sports Act Living, 2021, 3: 796101
    https://doi.org/10.3389/fspor.2021.796101 | PMID: 35098120 | PMCID: PMC8795741
    Citations: 69 | AltScore: 4.7
  28. The geriatrics research instrument library: A resource for guiding instrument selection for researchers studying older adults with multiple chronic conditions.
    Tisminetzky M, Delude C, Allore HG, Anzuoni K, Bloomstone S, Charpentier P, Hepler JP, Kitzman DW, McAvay GJ, Miller M, Pajewski NM, Gurwitz J
    J Multimorb Comorb, 2022, 12: 26335565221081200
    https://doi.org/10.1177/26335565221081200 | PMID: 35586036 | PMCID: PMC9106318
    Citations: 16 | AltScore: 3
  29. Predictors of Clinically Meaningful Gait Speed Response to Caloric Restriction Among Older Adults Participating in Weight Loss Interventions.
    Tse K, Neiberg RH, Beavers DP, Kritchevsky SB, Nicklas BJ, Kitzman DW, Rejeski WJ, Messier SP, Beavers KM
    J Gerontol A Biol Sci Med Sci, 2022 Oct 6, 77(10): 2110-2115
    https://doi.org/10.1093/gerona/glab324 | PMID: 34694401 | PMCID: PMC9536440
    Citations: 26 | AltScore: 3.25
  30. Defining the Specific Skeletal Muscle Adaptations Responsible for Exercise Training Improvements in Heart Failure With Preserved Ejection Fraction.
    Tucker WJ, Kitzman DW
    Circ Heart Fail, 2022 Oct, 15(10): e010003
    https://doi.org/10.1161/CIRCHEARTFAILURE.122.010003 | PMID: 36200441 | PMCID: PMC9757148
    Citations: 15 | AltScore: NA
  31. Skeletal muscle sympathetic denervation disrupts the neuromuscular junction postterminal organization: A single-cell quantitative approach.
    Wang ZM, Messi ML, Rodrigues ACZ, Delbono O
    Mol Cell Neurosci, 2022 May, 120: 103730
    https://doi.org/10.1016/j.mcn.2022.103730 | PMID: 35489637 | PMCID: PMC9793435
    Citations: 36 | AltScore: 2.35
  32. Older Patients With Acute Decompensated Heart Failure Who Live Alone: An Analysis From the REHAB-HF Trial.
    Warraich HJ, Kitzman DW, Nelson MB, Mentz RJ, Rosenberg PB, Lev Y, Whellan DJ
    J Card Fail, 2022 Jan, 28(1): 161-163
    https://doi.org/10.1016/j.cardfail.2021.06.005 | PMID: 34147611 | PMCID: PMC8734952
    Citations: 5 | AltScore: 5.1
  33. Severity of functional impairments by race and sex in older patients hospitalized with acute decompensated heart failure.
    Ye F, Nelson MB, Bertoni AG, Ditzenberger GL, Duncan P, Mentz RJ, Reeves G, Whellan D, Chen H, Upadhya B, Kitzman DW, Pastva AM
    J Am Geriatr Soc, 2022 Dec, 70(12): 3447-3457
    https://doi.org/10.1111/jgs.18006 | PMID: 36527410 | PMCID: PMC9759671
    Citations: 52 | AltScore: 1.5
  34. Cardiac troponin T and autoimmunity in skeletal muscle aging.
    Zhang T, Feng X, Dong J, Xu Z, Feng B, Haas KM, Cawthon PM, Beavers KM, Nicklas B, Kritchevsky S
    Geroscience, 2022 Aug, 44(4): 2025-2045
    https://doi.org/10.1007/s11357-022-00513-7 | PMID: 35034279 | PMCID: PMC9616986
    Citations: 131 | AltScore: 3.8


Nir Barzilai
Albert Einstein College of Medicine
Serving since 2012 (11 years)

Heather Whitson
Duke University
Serving since 2018 (5 years)

Kirk Erickson
University of Pittsburgh
Serving since 2018 (5 years)

Nathan LaBrasseur
Mayo Clinic
Serving since 2018 (5 years)

Ashley Weaver (2022)
  • Research Excellence Awards, WFUSM
Atalie Thompson (2022)
  • Translational Research Academy Scholar, WFUSM
  • Translational Science Leadership Academy, WFUSM
Gagan Deep (2022)
  • Research Excellence Award, Wake Forest University School of Medicine
Jaime Speiser (2022)
  • Top 8 Cited Paper in the Past 3 Years, Expert Systems with Applications Journal (Publication 1c, Speiser et al.)
Jaime Speiser, PhD (2022)
  • Top 8 Cited Paper in the Past 3 Years, Expert Systems with Applications Journal (Publication #5, Speiser et al.)
Jamie Justice, PhD (2022)
  • AFAR Vincent Cristofalo Rising Star in Aging Research Award
  • Travel Awardee, NIA / AFAR Research Centers Collaborative Network (RCCN), Measuring Biologic Age Workshop
  • Jarrahi Research Scholars Fund in Geroscience Innovation
  • Early Career Investigator in Basic/Translational Science Award, Wake Forest University School of Medicine
Stephen Kritchevsky, PhD (2022)
  • Special Achievement Award, Wake Forest School of Medicine Faculty Award
Tina Brinkley, PhD (2022)
  • WFUSM Department of Internal Medicine – Top Papers Published in 2021


General Brief Description of Minority Activities:
The Maya Angelou Research Center for Health Equality (MA-RCHE) has been established by the WFUSM to address issues related to racial and ethnic health disparities. Its overarching goal is to enhance wellness, improve quality of life, and reduce the burden of disease in underrepresented minorities through a comprehensive program in four core areas: health education, career/leadership development, research, and dissemination/application of new research findings for more effective and efficient health care approaches.

A key feature of the MA-RCHE is its model campus/community partnership involving WFUSM, the Reynolda Campus of Wake Forest University, Winston-Salem State University (a historically Black college/university) and the Forsyth County community at-large. This partnership brings the vast experiences, knowledge base and resources of each partner to bear on health problems of underrepresented minorities.

Minority Trainee(s):
  • Gagan Deep, PhD, Associate Professor, Cancer Biology
    PESC Pilot 2019.1 Isolation and molecular characterization of exosomes secreted by visceral adipose tissue
  • Genesio Karere, PhD, Assistant Professor, Department of Internal Medicine, Section on Molecular Medicine
    Current REC scholar Project title: MicroRNA biomarkers and pathways underlying response to exercise intervention in older adults
  • Raghunatha Yammani, PhD, Associate Professor, Internal Medicine, Molecular Medicine
    PESC 2019.2 Is Restoring Protein Homeostasis A Viable Therapy For Age-Related Osteoarthritis?

Minority Grant(s):
  Leader(s): FOY, CAPRI G
    NIH R21AG027413 / (2008-2011)
  DESCRIPTION (provided by applicant): Regular physical activity has been shown to enhance physical function and health-related quality of life and reduce morbidity and mortality among older adults. Unfortunately, compliance rates to physical activity programs are distressingly low, even among asymptomatic populations. Many traditional exercise interventions do not provide the self-regulatory skills necessary for long-term behavioral change. These issues become more prominent as the population of older Americans continues to increase. Although only a small percentage of older adults engage in habitual physical activity, there are episodic charity events involving moderate physical activity that attract large numbers of participants of all age ranges. These actions are a form of prosocial behavior, defined as voluntary, intentional behavior that results in benefits for another. The opportunity to help others seems to be a motive to inspire these individuals to at least engage in acute moderate physical activity. In previous pilot work (Section 4.1.a), we found that participants randomized into a prosocial behavior physical activity group demonstrated increased physical activity at 3 months compared to those in a standard exercise group. Our current research question contemplates whether prosocial behavior may be implemented as a viable behavioral incentive for long-term physical activity. Therefore, the primary aim of this investigation is to determine the feasibility of conducting a 9-month prosocial behavior intervention to increase physical activity among 80 underactive older adults. To our knowledge, the use of prosocial behavior as a motivational tool for physical activity has not been investigated, and represents a novel approach. The PBPA program will allow participants to earn boxes of food for donation to the Second Harvest Food Bank of Northwest North Carolina based upon their weekly physical activity. Other specific aims include determining the ability to successfully recruit participants into the study, the ability of participants to adhere to the PBPA program, and the ability to retain participants throughout the study. If successful, preliminary data from this study will be used to seek R01 funding to conduct a fully powered, longitudinal trial.
    NIH R21AG058249 / (2017-2020)
  PROJECT SUMMARY Chronic pain has emerged as an urgent age-related health issue that significantly compromises physicalfunctioning and quality of life, with the adverse effects amplified by both obesity and sedentary behavior. The annualcost of pain in the United States is nearly 30% higher than the combined costs of cancer and diabetes. In 2016, the NIHcalled for a National Pain Strategy to: 1) expand non-pharmacological treatment options in older adults, who areparticularly susceptible to the side effects of opioid and other pain medications; 2) develop accessible treatments that aretailored to individuals; and 3) increase the development of self-management programs for chronic pain. The purpose ofthis R-21 is to develop and test the feasibility and acceptability of a novel, patient-centered intervention to reducechronic pain and improve physical functioning in older adults, leveraging the combination of telecoaching andindividually-adaptive mHealth tools to decrease both body mass and sedentary behavior. The proposal consists oftwo phases. The first phase will use an iterative user-centered design process to develop the mHealth application, to adaptthe weight loss and sedentary behavior components of the intervention to a telecoaching model, and to evaluate theusability and feasibility of the intervention for obese, older adults with chronic pain. In the second phase we will conducta pilot randomized controlled trial to provide initial evidence for effect sizes (pain and physical function) associated withthe proposed intervention, and to estimate the sample size needed for a full scale randomized controlled trial design thatcompare the effects of the intervention versus usual care on pain ratings and physical function in overweight/obese olderadults with chronic pain.
3. Project Title: THE ENRGISE STUDY
    NIH U01AG050499 / (2015-2019)
  DESCRIPTION (provided by applicant): Growing evidence from our group and others shows that low-grade chronic inflammation, characterized by elevations in plasma C-reactive protein, tumor necrosis factor alpha, and particularly Interleukin-6 (IL-6), is an independent risk factor o disability, impaired mobility, and lower walking speed. Low-grade chronic inflammation is a modifiable risk factor. However, it is unknown whether interventions that reduce the levels of inflammatory markers per se improve mobility, or avert decline in mobility in older persons. To address this gap in evidence we propose the randomized clinical trial ENRGISE (ENabling Reduction of low-Grade Inflammation in SEniors) to test the ability of anti-inflammatory interventions for preventing major mobility disability by improving or preserving walking ability. We have maximized the public health impact of our proposed interventions by selecting interventions that are safe, tolerable, acceptable, and affordable for vulnerable older persons. Based on an extensive literature review, we propose to test the efficacy vs. placebo of the angiotensin receptor blocker losartan and omega-3 polyunsaturated fatty acids in the form of fish oil, alone and in combination. Both angiotensin receptor blockers and omega-3 polyunsaturated fatty acids have shown to reduce IL-6 in clinical trials and preliminary data suggest that they may improve physical function. We plan to recruit older persons who are at risk for, or with, mobility impairment, as measured by slow gait speed and self-reported mobility difficulty, and who have elevated levels of IL-6, the marker most consistently associated with mobility limitations. Preliminary data regarding feasibility need to be gathered before such a tria can be effectively designed and implemented. We propose to conduct a feasibility phase that includes performing meta-analyses of existing trials and cohorts, and conducting a pilot trial to assess the effects of the interventions on several inflammatory markers and walking speed. This will allow us to refine the design, recruitment yields, target population, adherence, retention, tolerability, sample-size, and cost for the main ENRGISE trial. We will assemble the multicenter research infrastructure needed for the ENRGISE pilot and main trials, including the biorepository, and we will develop the materials needed for implementing the trials, including the protocol, manual of operations, data and safety monitoring plan, forms, quality control and quality assurance plan, and recruitment and retention materials.