UNIVERSITY OF CONNECTICUT HEALTH CENTER
Claude D. Pepper Older Americans Independence Center

George A. Kuchel, MD Principal Investigator	860-679-6796	kuchel@uchc.edu
Richard H. Fortinsky, Ph.D. Co-Principal Investigator		fortinsky@uchc.edu
Elizabeth Minor & Laura Masi Center Administrator	860-679-1689 860-679-5465	eminor@uchc.edu

CENTER DESCRIPTION
The mission of the UConn Pepper Center is to establish a thriving interdisciplinary research program to promote health, function and independence in old age. The UConn Pepper Center provides numerous resources to catalyze the growth of multidisciplinary, collaborative aging-related research ranging from basic and preclinical to clinical and community-based to population based research in a sustained fashion. Our theme of Precision Gerontology seeks to leverage an understanding of the growing heterogeneity of aging into interventions rendered more effective by being better targeted. The aims of the UConn Pepper Center are: To develop a strong understanding of the multiple facets of heterogeneity aging. With an extensive understanding, we'll be able to develop targeted, precise and effective interventions to improve care provided to aging adults. To develop and collaborate with researchers from multidisciplinary teams in order to address questions or problems related to aging from the levels of bench to the bedside and institution to out in a community. To foster career development opportunities in an effort to train and collaborate with the next generation of leading geriatric researchers.

CORES

Leadership & Administrative Core (LAC)

Leader 1:	George Kuchel, MD	kuchel@uchc.edu
Leader 2:	Richard H. Fortinsky, PhD	fortinsky@uchc.edu
Leader 3:	Julie Robison, PhD	jrobison@uchc.edu

The Leadership and Administrative Core (LAC) provides the administrative infrastructure and scientific leadership necessary to achieve the overall aims of the UConn Pepper Center. The long-range goal of the LAC is to lead the way in establishing a highly productive research and education program in aging and geriatrics at the University of Connecticut, spanning laboratory, clinical and community, and population-based science collectively guided by the theme of Precision Gerontology.

Research and Education Core (REC)

Leader 1:	David Steffens, MD	steffens@uchc.edu
Leader 2:	George Kuchel, MD	kuchel@uchc.edu

The overarching goal of the Research Education Component (REC) of the UConn Older Americans Independence Center is to cultivate the next generation of investigators and clinician-scientists to become leaders in their career focused on aging with exposure to multidisciplinary translational science, mentorship and expertise in Precision Gerontology. A key component of the Research Education Component (REC) is the Pepper Scholar Program. This program provides financial support, education and training to Pepper Scholars to advance their research careers. Pepper Scholars apply and are chosen as showing particular promise as independent investigators in the field of geriatrics and gerontology. The REC, led by Dr. David Steffens, includes several senior research leaders at UConn who serve as mentors to the Pepper Scholars. The mentors provide each of the scholars with personalized educational opportunities, career development and different networking opportunities in order to facilitate their research interests.

Pilot & Exploratory Studies Core (PESC)

Leader 1:	Lisa Barry, PhD	libarry@uchc.edu
Leader 2:	Rogina Blanka, PhD	rogina@uchc.edu

The UConn Pepper Center Pilot and Exploratory Studies Core (PESC) works to develop and support innovative pilot and exploratory studies that will enhance function and independence in older adults while also advancing knowledge in the field of Precision Gerontology. The PESC provides funding and access to resources offered by each of the UConn Pepper Center research cores, including guidance in research subject recruitment, regulatory and compliance issues, research plan implementation, biostatical considerations, and biomarker analysis. In addition, the PESC provides mentorship and oversight to pilot study investigators to ensure each project is developed and carried out in a timely fashion, and that results are disseminated to optimize scientific impact to the world of aging research.

Biomarkers and Preclinical Research Core (Resource Core 3)

Leader 1:	Laura Haynes, PhD	lhaynes@uchc.edu
Leader 2:	Paul Robson, Ph.D.	paul.robson@jax.org
Leader 3:	Breno S. Diniz, MD, PhD	diniz@uchc.edu

The UConn Pepper Biomarkers and Preclinical Research Core assists investigators with the expertise and various tools needed to integrate biomarkers, drivers of aging and underlying mechanisms of chronic diseases in humans and animal models in order to promote function and independence in the late stages of life. Resource Core 3 is managed by Whitney Wolf (wwolf@uchc.edu).

Data Resource Core (Resource Core 2)

Leader 1:	Richard H. Fortinsky, PhD	fortinsky@uchc.edu
Leader 2:	James Grady Dr.P.H.	jgrady@uchc.edu

The UConn Pepper Center Data Resource Core (RC2) provides help in the selection and interpretation of geriatric health-related outcome measures; database design; and data collection, management and analysis. Content expertise is available to aid in the selection and interpretation of measures evaluating gait, mobility, affect, cognition, behavior, voiding symptoms, incontinence, body composition, bone density, caregiving, and self-reported quality of life. RC2 team members offer advice and guidance in biostatistics, genetic epidemiology, spatial analysis, computational genomics, and microbiome analysis techniques. Resource Core 2 is managed by Nicole Diggens (diggens@uchc.edu).

Recruitment and Community Engagement Core (Resource Core 1)

Leader 1:	Julie Robison, PhD	jrobison@uchc.edu
Leader 2:	Linda Barry, MD	lbarry@uchc.edu

The UConn Pepper Center Recruitment and Community Engagement Core (RC1) provides expertise in the design and development of recruitment plans and implementation of multidisciplinary complex research projects involving older adults. These efforts address recruitment needs for clinical trials, community-based research and studies with a translational clinical to community and health policy emphasis. The Core also partners with the UConn Health Disparities Institute to ensure research includes and asks questions relevant to communities of color and/or communities most vulnerable to adverse health effects, and to strengthen culturally sensitive approaches in all phases. In addition to these recruitment and community outreach efforts, RC1 also provides regulatory services (e.g., IRB application support) and helps investigators with Human Subjects and Clinical Trials Information grant sections and IRB protocol development. RC1 is managed by Lisa Kenyon-Pesce, MPH (Kenyon-pesce@uchc.edu).

CAREER DEVELOPMENT

REC Scholar, Research & Grants Funded During Pepper Supported Time	Years / Publications

Jenna Bartley, PhD Assistant Professor / UConn Center on Aging, UConn School of Medicine The Effect of Metformin on Influenza Vaccine Responses in Aged Mice With aging, T cells undergo a characteristic shift in naïve/memory phenotype, with decreased proliferation, cytotoxicity, and memory responses. Cellular metabolic pathways, such as mammalian target of rapamycin (mTOR) and AMP-activated protein kinase (AMPK), are key regulators of T cell fate and function. Dysregulated metabolism is a hallmark of aging and preliminary studies demonstrate age-related alterations in T cell metabolism, suggesting a link between T cell metabolism and diminished T cell responses with aging. Thus, targeting cellular metabolism may improve overall immune responses and T cell specific responses with aging. Metformin, an FDA approved diabetes drug, modulates mTOR/AMPK to alter metabolism. Further, in young mice, metformin increases CD8 T cell memory formation through AMPK activation and fatty acid oxidation enhancement. In line with the geroscience hypothesis, metformin has been shown to extend lifespan in multiple animal models and reduce all-cause mortality in humans. It is a candidate drug to target the overall biology of aging and the focus of the first large geroscience-guided trial Targeting Aging with Metformin (TAME), making it an ideal intervention to target age-related changes in immune cell metabolism and function. Influenza (flu) is among the leading killers of older adults, yet diminished vaccine responses render them unprotected. Intracellular metabolism modulation has great potential to influence vaccine responses. Inhibition of mTOR with a rapamycin analogue improved flu antibodies and enhanced overall immune function in older adults. Diabetics on metformin have stronger flu vaccine responses than diabetics on other oral hypoglycemics, while incubation with metformin in vitro improved some B cell deficits. More mechanistic studies in murine models would be extremely valuable to inform the design of a larger human clinical trial to investigate the impact of metformin on immune responses in healthy older adults. This study will look to determine the impact of metformin on flu vaccine responses in aged mice, as well as determine the immunometabolic effects of metformin in healthy older adults utilizing cryopreserved peripheral blood mononuclear cells (PBMCs) from a previously completed study (the VEME trial). AFAR Reboot The Effect of Metformin on T Cell Metabolism in Healthy Older Adults. R21 AG071292 Can Senolytics Improve the Aged Response to Viral Infection? R01AR075346 The Mechanistic Effects of a Combined Testosterone Therapy and Exercise Intervention upon Axial Bone and Muscle Post-Hip Fracture R33 AG061456 Translational Geroscience Network R01 AG051647 Combining Testosterone Therapy and Exercise to Improve Function Post Hip Fracture R01 AI173305 Impact of Senolytics on Aged Vaccine Responses	2022-2024 / 10 (total) 0 (1st/Sr)

Cristina Colòn-Semenza, PT, MPT, PhD Assistant Professor / Department of Kinesiology, UConn College of Agriculture, Health & Natural Resources Peer coaching to improve physical activity in older Latinx adults with Parkinson’s disease Conservative projections estimate the number of people living with Parkinson disease (PD) will rise to 1.2 million in the United States and 9.3 million in the most populous nations by 2030. This disease disproportionately affects older adults with incidence and prevalence drastically increasing from the sixth to ninth decades. There is also ethnic variation in the incidence of this progressive neurological disorder, with Hispanics experiencing the highest rates in the US. Physical activity not only reduces risk of this debilitating disease but may also reduce disease progression. Therefore physical activity, specifically in the form of physical therapy, is recognized as a critical component of effective disease management. However, Latinx people living with PD, are less likely to receive physical therapy treatment compared to Caucasians. In fact, older Latinx adults without PD have significantly lower rates of physical activity compared with non-Hispanic whites. Cultural and disease-related barriers compound inactivity and inhibit optimal disease management. The combination of physical therapy and peer support may reduce healthcare disparities for people with PD from under-represented groups. Although little is known about how to increase physical activity in minority populations, older adults from under-represented groups have identified lack of time and motivation, inadequate social support, physical ailments, and chronic health conditions as barriers to physical activity. Facilitators of physical activity noted by older adults from under-represented groups include: receiving positive messages about physical activity from a trustworthy source; making physical activity enjoyable; peer social interaction and support, and competition. Peer support is an obvious facilitator of physical activity. Peers (defined for this study's purposes as Latinx individuals with PD) can address these barriers by sharing knowledge, resources, and friendly competition. Peer interventions for older Latinx adults with PD have not been created to meet the unique needs of this population. This study is a pilot randomized, controlled trial in which 30 Latinx older adults (60 years or older) living with PD will participate in a course of physical therapy via telehealth. Half of the older adults will receive the intervention being that of peer support. If shown to be effective, this intervention could improve disease self-management for those living with progressive neurological conditions from other under-represented groups. University of Connecticut, School of Fine Arts, STEAM Innovation grant Movement and Creativity: Improving Gait and Quality of Life in People with Parkinson Disease through Visually Enhanced Gait Training Effects of a 6-month intervention with targeted amino acid supplement on Parkinson’s disease pathophysiology and symptoms Comparison of whey protein and amino acid supplementation on acute symptoms and L-Dopa pharmacokinetics in people with Parkinson’s disease Peer coaching to improve disease management in older Latinx adults with Parkinson disease: A pilot randomized controlled trial	2022-2024 / 2 (total) 0 (1st/Sr)

Roshanak Sharafieh, PhD Assistant Professor / Department of Surgery, UConn School of Medicine Biomarker Development to Promote Geroscience-Guided Approaches to Chronic Wound Management in Older Adults The aging population has the highest rate of developing chronic ulcers with the worst outcomes due to poor wound healing. Chronic wounds/ulcers have been largely overlooked with very little advancements in treatment modalities, although more than 15% of Medicare beneficiaries (8.2 million patients) are affected. Costs of wound care for Medicare beneficiaries range from $28-100 billion dollars depending on outpatient and inpatient hospital stays and surgical interventions. The major types of chronic wounds (ulcers) include venous leg ulcers, diabetic foot ulcers and arterial ulcers. Unfortunately, there is very limited understanding of the underlying pathophysiology of these chronic ulcers and no true biomarkers to aid in the diagnosis, prognosis or treatment of Chronic Ulcers in Aging Adults (CUAA). The goal of this project is to explore an association between older adults with poor wound healing and an accumulation of senescent cells at the wound (ulcer) site. Recently, a new class of biomarkers have been discovered utilizing cell-derived extracellular vesicles (EVs), which are lipid bound vesicles secreted by cells into the extracellular space. These microvesicles/exosomes (MVE) are present in biological fluids, including blood. In addition, using extracellular vesicles, identify blood biomarkers in patients with chronic ulcers, to aid in predicting wound progression and defining more effective treatment plans, which will reduce loss of mobility, thereby leading to a higher quality-of-life for these patients. 5R21AI151840-02 Using Modified Synthetic MicroRNAs to Control Foreign Body Reactions In Vivo 1R43DK123770-01 Development and Validation of Novel Coatings that Extend Glucose Sensor Accuracy and Lifespan in vivo	2022-2024 / 2 (total) 0 (1st/Sr)

Past Scholars

PILOT/EXPLORATORY PROJECTS (3 Pilot Projects Listed)

1.	Project Title:	Re-Engaging Black/African American Older Adults During the COVID-19 era: Developing A Community-Based Intervention
	Leader:	Rupal Parekh, PhD (PL) Christine Tocchi, PhD (co-PL)
	The sudden closure of churches and senior centers caused by the COVID-19 pandemic disproportionately impacted the health and well-being of communities of color, particularly Black/African American (BAA) older adults. Prior to the pandemic, these community centers provided social engagement. However, with the closure of these resources, BAA older adults involuntary “disengaged” from activities at these community centers (either no longer attend or utilize the senior centers/churches less frequently than they did prior to the pandemic). This study seeks to better understand the barriers to and facilitators of re-engagement among BAA older adult members who attend churches and/or senior centers, and to determine if mental and physical function are associated with engagement. Findings will help to develop a psychoeducational intervention to encourage engagement in BAAs. To date, two focus groups with church stakeholders were completed and individual interviews with BAA older adults will be conducted in summer, 2023.

2.	Project Title:	The Heterogeneity of Vulnerabilities in Aging Cohort (HVAC): A new resource for early biomarker discovery and validation
	Leader:	Laura Haynes, PhD (PL) George Kuchel, MD (co-PL) Co-Investigators: Jake Earp, PhD Oh Sung Kwon, PhD Jenna Bartley, PhD Zhichao Fan, PhD Ming Xu, PhD D. Nehar-Belaid, PhD
	Newly discovered and improved biomarkers are needed to improve understanding of shared biological drivers of healthy aging and to develop geroscience-guided interventions to delay frailty onset in older persons (aged 65 and older). Drs. Earp and Kwon are determining the feasibility and potential future utility of specific biomarkers in aging, frailty, and obesity. They have begun recruitment and they will ultimately have biological data from sex-balanced cohorts of 20 healthy/young, 20 healthy/old, 20 old/frail, and 20 old/frail/obese individuals. Samples will be available for additional investigators to conduct pilot studies focused on immunometabolism, autophagy and mitophagy, p21 senescence markers, and single cell genomics.

3.	Project Title:	Apathy: An Early Manifestation of Frailty and Disability in Older Adults with Depression?
	Leader:	Kevin Manning, PhD (PI)
	Dr. Manning’s pilot project is evaluating apathy as an early manifestation of frailty and disability in older adults with depression. This approach, which incorporates the assessment of both behavioral and physical measures, may allow for earlier detection of risk factors for disability, with opportunities for initial insights into the role of inflammation and improved targeting of higher risk population subsets. Dr. Manning has recruited 27 individuals (21 not depressed, 3 depressed and 3 depressed/apathetic individual), has started initial assessments and correlational analysis, and study recruitment is ongoing.

DEVELOPMENT PROJECTS (3 Development Projects Listed)

1.	Project Title:	Gait Velocity Detection Device for Targeted Recruitment in Geriatric Clinic
	Leader:	Lisa Barry, PhD (PL) Song Han, PhD (Co-I) Jatupol Kositsawat, MD (Co-I)
	Core(s):	Recruitment and Community Engagement Core (Resource Core 1)
	Gait speed is often used as an eligibility criterion for and/or a means of stratifying research study participants. The Center on Aging at UConn Health has developed a Radio Frequency Identification (RFID)-based system that offers a feasible and valid means of assessing gait speed in the clinic setting. In addition to being simple, practical, and unobtrusive, this system holds promise as a research recruitment strategy. The objective of this Developmental Project is to use this RFID-based system in the UConn Health geriatrics clinic to expand RC1 recruitment strategies in a novel way. The project will aim to implement a Best Practice Advisory (BPA) in the UConn Health EMR system that indicates if a patient is willing to have contact information added to the Research Volunteer Registry (RVR) so that they may be notified about studies for which they may be eligible. Consequently, following IRB protocol regarding extraction and storage of medical record-extracted data, the medical records of patients who checked “Yes” can be searched to identify individuals who may qualify for a study based on their gait speed. Following implementation of the BPA, the project will evaluate the utility of the RFID-based system as a means of expanding the RVR. We will track the number of patients asked about RVR inclusion and determine the proportion of who opts in/out of joining the RVR through the BPA. This Developmental Project is expected to substantially increase the pool of older individuals who may be willing to participate in research studies.

2.	Project Title:	Developmental Project 2 - Analysis of CITE-seq data from metformin study
	Leader:	Duygu Ucar PhD (co-PL), Jenna Bartley (co-PL)
	Core(s):	Data Resource Core (Resource Core 2)
	This particular project is a collaboration between the UConn OAIC and The Jackson Laboratory for Genomic Medicine (JAX) in Farmington, CT. Human peripheral blood mononuclear cells (PBMCs) were cryopreserved as part of Dr. Bartley’s Vaccination Efficacy with Metformin in Older Adults trial (VEME, PI: Bartley, IND#18974, NCT#03996538, IRB#19-205-2). This clinical trial randomized healthy, nondiabetic/nonprediabetic older adults to metformin or placebo treatment for 20 weeks. To examine the single-cell genomic level changes induced by metformin treatment, CITE-seq was performed on samples prior to and after 20 weeks of metformin treatment. The single cell approach is essential given the remarkable heterogeneity of human blood which increases with aging and, we also believe, with frailty. Such information could help lead to discoveries of risk factors, mechanisms and treatment effects involving metformin. It could also help guide development of interventions targeting shared risk factors, shared mechanisms, or be used in targeting population subsets. The project will explore the role of specific biological hallmarks of aging and determine how metformin treatment, a candidate anti-aging drug, can impact these hallmarks in PBMCs. Sample data will be analyzed from samples generated in the OAIC Developmental Project 3 (DP3) project. PBMC samples will include existing samples from the Vaccination Efficacy with Metformin in Older Adults: A Pilot Study (VEME) (conducted by Jenna Bartley, PhD). Additionally, in future years prospective samples will be obtained and analyzed as part of the Pilot and Exploratory Project entitled "The Heterogeneity of Vulnerabilities in Aging (HVAC) Cohort: A new resource for early biomarker discovery and validation” (PES3).

3.	Project Title:	Developmental Project 3 - Generation of CITE-seq and scRNA-seq data using samples from metformin study & HVAC pilot cohort
	Leader:	Laura Haynes, PhD (PL), Duygu Ucar, PhD (Jax GM; co-PI), Jenna Bartley (Co-PI)
	Core(s):	Biomarkers and Preclinical Research Core (Resource Core 3)
	This particular project is a collaboration between the UConn OAIC and The Jackson Laboratory for Genomic Medicine (JAX) in Farmington, CT. Human peripheral blood mononuclear cells (PBMCs) are routinely obtained and cryopreserved for future use in many different studies at UConn COA. The single cell approach is essential given the remarkable heterogeneity of human blood which increases with aging and we also believe with frailty. In our aging and flu vaccination studies we have observed major robust changes involving only rare PBMC populations. Such information could help lead to discoveries of risk factors, mechanisms and treatment effects involving metformin and/or flu vaccine. It could also help guide development of interventions targeting shared risk factors, shared mechanisms or be used in targeting population subsets. Samples already collected in Dr. Bartley’s Vaccination Efficacy with Metformin in Older Adults study (VEME, PI: Bartley, IND#18974, NCT#03996538, IRB#19-205-2) will be processed for CITE-Seq to interrogate single cell protein level and genomic alterations in nondiabetic older adults due to metformin treatment. Additionally, in future years, PBMCs generated by PESC3, “The Heterogeneity of Vulnerabilities in Aging (HVAC) Cohort: A new resource for early biomarker discovery and validation” will be analyzed via scRNA-seq to interrogate single cell genomic differences due to frailty and obesity in older adults.

RESEARCH (0 Projects Listed)

PUBLICATIONS

2024

2023

Letter to the Editor: Healthy Eating Patterns: A Stealthy Geroscience-Guided Approach to Enhancing the Human Healthspan.
Al-Naggar IM, Newman JC, Kuchel GA
J Nutr Health Aging, 2023, 27(3): 238-239
https://doi.org/10.1007/s12603-023-1897-1 | PMID: 36973933 | PMCID: PMC10164447
Citations: 1 | AltScore: 2.35
Challenges and opportunities for modeling aging and cancer.
Anczuk?w O, Airhart S, Chuang JH, Coussens LM, Kuchel GA, Korstanje R, Li S, Lucido AL, McAllister SS, Politi K, Polyak K, Ratliff T, Ren G, Trowbridge JJ, Ucar D, Palucka K
Cancer Cell, 2023 Apr 10, 41(4): 641-645
https://doi.org/10.1016/j.ccell.2023.03.006 | PMID: 37001528 | PMCID: PMC10185379
Citations: 1 | AltScore: 78.95
High Risk of Substance Use Disorder-Related Outcomes in Veterans Released from Correctional Facilities in Mid to Late Life.
Barry LC, Steffens DC, Covinsky KE, Conwell Y, Boscardin J, Li Y, Byers AL
J Gen Intern Med, 2023 Apr, 38(5): 1109-1118
https://doi.org/10.1007/s11606-023-08057-y | PMID: 36781577 | PMCID: PMC10110776
Citations: NA | AltScore: 1.25
Antibody-mediated NK cell activation as a correlate of immunity against influenza infection.
Boudreau CM, Burke JS 4th, Yousif AS, Sangesland M, Jastrzebski S, Verschoor C, Kuchel G, Lingwood D, Kleanthous H, De Bruijn I, Landolfi V, Sridhar S, Alter G
Nat Commun, 2023 Aug 24, 14(1): 5170
https://doi.org/10.1038/s41467-023-40699-8 | PMID: 37620306 | PMCID: PMC10449820
Citations: NA | AltScore: 8.6
Impact of Geroscience on Therapeutic Strategies for Older Adults With Cardiovascular Disease: JACC Scientific Statement.
Forman DE, Kuchel GA, Newman JC, Kirkland JL, Volpi E, Taffet GE, Barzilai N, Pandey A, Kitzman DW, Libby P, Ferrucci L
J Am Coll Cardiol, 2023 Aug 15, 82(7): 631-647
https://doi.org/10.1016/j.jacc.2023.05.038 | PMID: 37389519 | PMCID: PMC10414756
Citations: NA | AltScore: 22.75
Altered T cell infiltration and enrichment of leukocyte regulating pathways within aged skeletal muscle are associated impaired muscle function following influenza infection.
Keilich SR, Cadar AN, Ahern DT, Torrance BL, Lorenzo EC, Martin DE, Haynes L, Bartley JM
Geroscience, 2023 Apr, 45(2): 1197-1213
https://doi.org/10.1007/s11357-022-00715-z | PMID: 36580167 | PMCID: PMC9886695
Citations: NA | AltScore: 4.95
Implementing the Care of Persons With Dementia in Their Environments (COPE) Intervention in Community-Based Programs: Acceptability and Perceived Benefit From Care Managers' and Interventionists' Perspectives.
Kellett K, Robison J, McAbee-Sevick H, Gitlin LN, Verrier Piersol C, Fortinsky RH
Gerontologist, 2023 Jan 24, 63(1): 28-39
https://doi.org/10.1093/geront/gnac068 | PMID: 35581164 | PMCID: PMC9872768
Citations: NA | AltScore: NA
Life's Essential 8: Optimizing Health in Older Adults.
Kumar M, Orkaby A, Tighe C, Villareal DT, Billingsley H, Nanna MG, Kwak MJ, Rohant N, Patel S, Goyal P, Hummel S, Al-Malouf C, Kolimas A, Krishnaswami A, Rich MW, Kirkpatrick J, Damluji AA, Kuchel GA, Forman DE, Alexander KP
JACC Adv, 2023 Sep, 2(7):
pii: 100560. https://doi.org/10.1016/j.jacadv.2023.100560 | PMID: 37664644 | PMCID: PMC10470487
Citations: NA | AltScore: 120.45
Association between Residential Exposure to Air Pollution and Incident Coronary Heart Disease Is Not Mediated by Leukocyte Telomere Length: A UK Biobank Study.
Kuo CL, Liu R, Godoy LDC, Pilling LC, Fortinsky RH, Brugge D
Toxics, 2023 May 28, 11(6):
https://doi.org/10.3390/toxics11060489 | PMID: 37368589 | PMCID: PMC10301073
Citations: NA | AltScore: NA
Mid-life leukocyte telomere length and dementia risk: An observational and mendelian randomization study of 435,046 UK Biobank participants.
Liu R, Xiang M, Pilling LC, Melzer D, Wang L, Manning KJ, Steffens DC, Bowden J, Fortinsky RH, Kuchel GA, Rhee TG, Diniz BS, Kuo CL
Aging Cell, 2023 May 30, 22(7): e13808
https://doi.org/10.1111/acel.13808 | PMID: 37254630 | PMCID: PMC10352557
Citations: 1 | AltScore: 26.65
Major depression and the biological hallmarks of aging.
Lorenzo EC, Kuchel GA, Kuo CL, Moffitt TE, Diniz BS
Ageing Res Rev, 2023 Jan, 83: 101805
https://doi.org/10.1016/j.arr.2022.101805 | PMID: 36410621 | PMCID: PMC9772222
Citations: 7 | AltScore: 34.1
Feasibility of a Modified Otago Exercise Program for Older Adults With Cognitive Vulnerability.
Mangione KK, Darreff H, Welsh M, Ni W, Wolff E, Booth JT, Glenney SS, Fortinsky RH
J Appl Gerontol, 2023 Jul, 42(7): 1445-1455
https://doi.org/10.1177/07334648231163050 | PMID: 36919309
Citations: 1 | AltScore: NA
Loss of resilience contributes to detrusor underactivity in advanced age.
Ramasamy R, Baker DS, Lemtiri-Chlieh F, Rosenberg DA, Woon E, Al-Naggar IM, Hardy CC, Levine ES, Kuchel GA, Bartley JM, Smith PP
Biogerontology, 2023 Jan 10, 24(2): 163-181
https://doi.org/10.1007/s10522-022-10005-y | PMID: 36626035 | PMCID: PMC10006334
Citations: NA | AltScore: NA
Effects of Longitudinal Changes in Neuroticism and Stress on Cognitive Decline.
Steffens DC, Manning KJ, Wu R, Grady JJ
Am J Geriatr Psychiatry, 2023 Mar, 31(3): 171-179
https://doi.org/10.1016/j.jagp.2022.10.005 | PMID: 36376230
Citations: 1 | AltScore: 0.25
Does physical activity moderate the association between shorter leukocyte telomere length and incident coronary heart disease? Data from 54,180 UK Biobank participants.
Xiang M, Pilling LC, Melzer D, Kirk B, Duque G, Liu R, Kuchel GA, Wood AR, Metcalf B, Diniz BS, Hillsdon M, Kuo CL
Geroscience, 2023 Aug 7
https://doi.org/10.1007/s11357-023-00890-7 | PMID: 37544968
Citations: NA | AltScore: NA

EXTERNAL ADVISORY BOARD MEMBERS

Barbara Resnick, PhD, RN, CRNP, FAAN, FAANP
University of Maryland, School of Nursing
Serving since 2022 (2 years)

Heather Allore, PhD
Yale University, School of Medicine
Serving since 2022 (2 years)

Jeremy Walston, MD
John Hopkins University, School of Medicine
Serving since 2022 (2 years)

Lona Mody, MD
University of Michigan
Serving since 2022 (2 years)

Roland Thorpe, PhD MS
John Hopkins University, Center on Aging & Health
Serving since 2022 (2 years)

RECOGNITION AND AWARDS (2023-2024)

Cristina Colón-Semenza, PT, MPT, PhD (2023)

2022 National Institute on Aging, Research Centers Collaborative Network, Early Career Investigator Travel Award
2023 University of Connecticut, College of Agriculture, Health & Natural Resources, Justice, Equity, Antiracism, & Inclusion award.
2023 American Physical Therapy Association, Academy of Leadership & Innovation, Social Responsibility award for poster presentation.

Jacob Earp, Ph.D (2023)

2022 Selected for the National Coordinating Center for Older Adults Independence Centers Early Career Visiting Scholar Exchange Program
2023 Selected for the National Institute of Aging’s Butler Williams Scholar Program

Julie Robison, PhD (2023)

Southern Gerontological Society: The Gordon Streib Academic Gerontologist Award.

MINORITY RESEARCH

General Brief Description of Minority Activities:

Project # 1

Rupal Parekh, PhD, Assistant Professor, UConn School of Social Work; Christine Tocchi, PhD, UConn School of Nursing (co-PL)

Re-Engaging Black/African American Older Adults During the COVID-19 era: Developing A Community-Based Intervention

The sudden closure of churches and senior centers caused by the the COVID-19 pandemic has disproportionately impacted the health and well-being of communities of color, particularly Black/African American older adults. Prior to the pandemic these community centers provide social engagement by providing spiritual healing, health-related education, social interaction and activities and political activism. With the closure of these resources, African American older adults involuntary disengaged their involvement. Previous research shows such disengagement is associated with a decrease in quality of life and negative mental and health outcomes.

As churches and senior centers have reopened and resumed their services, African American older adults have either completely become disengaged or utilize the senior centers/churches less frequently than they did prior to the pandemic. This study will develop a psychoeducational intervention to address the needs and concerns of African American older adults as a means of preventing or reducing depressive symptoms and physical disability.

Project # 2

Cristina Colòn-Semenza, Assistant Professor Department of Kinesiology, UConn College of Agriculture, Health & Natural Resource

Peer coaching to improve physical activity in older Latinx adults with Parkinson’s disease

Conservative projections estimate the number of people living with Parkinson disease (PD) will rise to 1.2 million in the United States and 9.3 million in the most populous nations by 2030. This disease disproportionately affects older adults with incidence and prevalence drastically increasing from the sixth to ninth decades. There is also ethnic variation in the incidence of this progressive neurological disorder, with Hispanics experiencing the highest rates in the US.

Physical activity not only reduces risk of this debilitating disease but may also reduce disease progression. Therefore physical activity, specifically in the form of physical therapy, is recognized as a critical component of effective disease management. However, Latinx people living with PD, are less likely to receive physical therapy treatment compared to Caucasians. In fact, older Latinx adults without PD have significantly lower rates of physical activity compared with non-Hispanic whites. Cultural and disease-related barriers compound inactivity and inhibit optimal disease management.

Minority Trainee(s):

Cristina Colòn-Semenza, Assistant Professor Department of Kinesiology, UConn College of Agriculture, Health & Natural Resources
Dr. Colòn-Semenza is a physical therapist whose current research career is focused on improving motivation and engagement with exercise and physical activity in the management of neurological disease and disorders. In January 2022, Dr. Colòn-Semenza was named as a UConn Pepper Scholar. In addition, she recently received a Pre-K Scholar Career Development Award.

Minority Grant(s):

1.	Project Title:	Cardiac Dysfunction in Older Sepsis Survivors
	Leader(s):	MANKOWSKI, ROBERT TOMASZ
		UNIVERSITY OF FLORIDA
		American Heart Association (AHA) 18CDA34080001 / (2018-2021)
	As a result of sepsis, approximately 30% of older Americans (age >65 years) have elevated levels of systemic inflammation at discharge from the intensive care unit (ICU) and die from cardiovascular (CV) events, including congestive heart failure, within 12 months. Although recently improved implementation of evidence-based ICU care has resulted in decreased early hospital mortality in older adults, many survivors become chronically critically ill (CCI) with persistent inflammation and fail to recover. CCI patients are defined as patients who remain in the ICU for more than 14 days with organ failure, in contrast to those who experience rapid recovery (RAP). Due to persistent inflammation, we believe that older CCI patients represent an extremely high-risk new population for cardiac disease and death within 12 months post-sepsis. Cardiac dysfunction after discharge (i.e., impaired cardiac contractility) that may lead to cardiomyopathy and heart failure after sepsis, however, has not been characterized in this high-risk population. Novel measures of myocardial contractility by speckle-tracking echocardiography can detect clinically meaningful dysfunction undetectable by conventional echocardiography (i.e., ejection fraction). Therefore, we propose an observational pilot study to test our central hypothesis that the persistent systemic inflammation that occurs in CCI patients following sepsis is associated with impaired myocardial contractility over 3 months after sepsis onset. We will capitalize on the infrastructure of the NIH-funded project (P50GM11115202) at the University of Florida that is currently successfully enrolling and following sepsis patients for up to 12 months. For the proposed pilot study, we will perform biventricular myocardial contractility analyses and peripheral blood analyses for pro-inflammatory cytokine levels in a subset of older (>65 years) sepsis patients (CCI=40 and RAP=40) enrolled in the parent P50 study at discharge (RAP) or at day 14 in ICU (CCI) and 3 months after sepsis onset. This research project is in close alliance with the mission of the American Heart Association because of the high risk of cardiac events and deaths among older adults after sepsis. A future long-term study may help predict heart failure and help develop anti-inflammatory interventions to lower the CV risk in older sepsis survivors. (AHA Program: Career Development Award)

2.	Project Title:	Role of PFKFB3 in peripheral artery disease
	Leader(s):	RYAN, TERENCE
		UNIVERSITY OF FLORIDA
		American Heart Association (AHA) 18CDA34110044 / (2018-2021)
	Peripheral artery disease (PAD) is a leading cause of atherosclerotic cardiovascular disease death which is estimated to affect more than 20% of individuals older than age 60 (~200 million people worldwide). PAD is defined as a blockage in the peripheral arteries which results in decreased blood flow to the lower legs. Patients with PAD present clinically with symptoms ranging from mild discomfort to unbearable ischemic rest pain and gangrene. Recent clinical work has demonstrated that patients with similar limb blood flow can have markedly different symptoms, suggesting that the patients' response may be dependent on genetic mechanism(s) regulating the limbs response to decreased blood flow. The current treatments for PAD include surgical interventions aimed to improve blood flow to the leg, but mortality rates in PAD remain high (50% within 10 years of diagnosis). The low success rate of PAD therapies indicates that restoration of blood flow alone is not sufficient to rescue the limb, implying that factors other than limb perfusion regulate the limb's response to ischemia. This proposal seeks to address this knowledge gap by advancing the fundamental knowledge on ischemic cell metabolism in both skeletal muscle and endothelial cells, with a long-term goal of developing novel therapies to improve ischemic outcomes in PAD and other ischemic disease. This proposal focuses on the role of glycolytic metabolism in the ischemic limb based on the following discoveries: (i) mice with elevated systemic glycolytic flux display complete protection from ischemic muscle necrosis; (ii) among the genes responsible for elevated glycolytic flux, PFKFB3 is required for ischemic protection; and (iii) PFKFB3 protein expression is decreased in severe PAD patients. Based on these discoveries, we hypothesize that glycolytic metabolism, driven by PFKFB3 expression, regulates muscle cell survival and angiogenesis in ischemia. We will test this hypothesis using the following: Aim 1 will determine if loss of PFKFB3 expression increases ischemic pathology; Aim 2 will determine if overexpression of PFKFB3 is protective against ischemic injury; and Aim 3 will identify novel metabolic targets/pathways regulating ischemic pathology in human PAD samples through metabolomics/proteomics experiments. This work will advance fundamental knowledge on ischemic cell metabolism, develop novel gene therapies, and offer mechanistic insight applicable to multiple diseases and tissues.

3.	Project Title:	Calf Muscle Mitochondrial Dysfunction and Impaired Autophagy in Peripheral Artery Disease
	Leader(s):	LEEUWENBURGH, CHRISTIAAN
		UNIVERSITY OF FLORIDA
		American Heart Association (AHA) 18SFRN33900136 / (2018-2022)
	Lower-extremity peripheral artery disease (PAD) results in ischemia-reperfusion-induced oxidative stress in calf skeletal muscle and reduced skeletal muscle metabolic activity, but the specific mitochondrial defects and their association with functional impairment and decline in people with PAD are not established. In this basic-science research study of Northwestern Universitys Strategically Focused Research Network (SFRN), we will delineate the specific mitochondrial abnormalities in calf muscle of people with PAD. In Aim 1, we will analyze calf-muscle biopsy specimens stored at Northwestern from 75 well-characterized people with and without PAD. Aim 1A will test the hypothesis that mitochondrial (mt)DNA regions that encode the electron transport chain (ETC) proteins have greater damage, resulting in poorer ETC function in PAD compared to those without PAD. In Aim 1B, we will investigate the D-loop region of mtDNA involved in regulating mtDNA replication, to determine if the increased mtDNA abundance in PAD is due to oxidative stress. Aim 1C will investigate whether autophagy, the process that removes damaged mitochondria is incomplete in PAD. In Aim 2, we will analyze calf-muscle biopsies collected in the SFRNs population/epidemiology study (PI Greenland). This project will recruit 50 participants with PAD and 50 without PAD and follow them longitudinally with baseline and 2-year follow-up biopsies. Of those with PAD, 30 will have an Ankle-Brachial Index (ABI) of >0.20 between their legs. We will determine whether: a) the leg with lower ABI (more ischemia) has greater mitochondrial abnormalities than the leg with higher ABI (less ischemia); b) mitochondrial abnormalities are associated with greater functional impairment and faster functional decline in PAD participants; and c) PAD participants have more adverse changes in their muscle at 2-year follow-up than non-PAD participants. In Aim 3, we will analyze calf-muscle biopsies from the NICE trial (PI McDermott) to determine whether the NICE Trial interventions significantly increase activity of pathways involved in mitochondrial biogenesis and metabolic health, compared to placebo. This projects overall goal is to identify specific mitochondrial defects associated with skeletal muscle pathophysiologic changes in PAD. Results are expected to identify new potential targets for interventions that may improve functional performance and prevent functional decline in PAD. (AHA Program: Strategically Focused Research Network)

4.	Project Title:	Longitudinal Modeling and Sequential Monitoring of Image Data Streams
	Leader(s):	QIU, PEIHUA
		UNIVERSITY OF FLORIDA
		National Science Foundation 1914639 / (2019-2022)
	In imaging applications related to earth and environmental monitoring, manufacturing industries, medical studies and many others, collected image data are often in the form of data streams in the sense that new images are acquired sequentially over time. In such applications, one fundamental task is to monitor the image sequence to see whether the underlying longitudinal process of the observed images changes significantly over time. This project aims to develop novel and effective statistical methods for answering this question. Because of the wide applications of image sequence monitoring, this project will have broader impacts on society through its applications in different disciplines and areas. Open source R packages will be developed and distributed freely for convenient use by practitioners. A web portal will also be developed for individual researchers to try the proposed methods. The PI plans to integrate the research results into educational activities, including the development of new curriculum modules, the mentoring of Ph.D. students, and outreach to local high schools students for after-school activities to raise their interests in data modeling and scientific research, and contribute to the workforce development in Science, Technology, Engineering and Mathematics. This project aims to develop a flexible longitudinal modeling approach and an effective sequential monitoring scheme for analyzing image data streams, and study their statistical properties. The proposed longitudinal model for describing observed images in a given time interval is flexible, and its estimation procedure has the edge-preservation property while removing noise. It can accommodate both geometric misalignments among observed images and spatio-temporal data correlation in the observed image data. The proposed image monitoring approach can account for dynamic longitudinal patterns of the observed image data streams. To this end, image pre-processing, including image denoising and image registration, will be performed properly before image monitoring. The proposed methods will consider both cases where the observation times are equally or unequally spaced.

5.	Project Title:	FLUAD? vs. Fluzone? High-Dose Study
	Leader(s):	SCHMADER, KENNETH
		DUKE UNIVERSITY
		Centers for Disease Control and Prevention 200-2012-53663 / (2016-2021)
	The objective of this randomized controlled clinical trial is to compare the reactogenicity, safety, and effect on functional status and quality of life in older adults of the high dose influenza vaccine (Fluzone?) versus the MF-59 adjuvanted influenza vaccine (FLUAD?). In this randomized safety trial of 757 older adults (adjuvanted inactivated influenza vaccine, trivalent [aIIV3], 378; high dose inactivated influenza vaccine [HD-IIV3], 379), the proportion of participants with moderate-to-severe injection-site pain (primary outcome) was not higher after aIIV3 than HD-IIV3. No vaccine-related serious adverse events occurred. Post-vaccination HRQOL impact was similar between aIIV3 and IIV3-HD groups. From a safety standpoint, aIIV3 or HD-IIV3 is an acceptable option to prevent influenza in older adults.

6.	Project Title:	Mitochondrial Function in Postmortem Muscle
	Leader(s):	SCHEFFLER, TRACY
		UNIVERSITY OF FLORIDA
		United States Department of Agriculture 2017-67017-26468 / (2017-2021)
	Our goal is to understand how mitochondria influence postmortem metabolism and tenderization, in order to optimize meat quality and value. Living muscle relies primarily on mitochondria and aerobic metabolism for energy; ATP is necessary for muscle contraction and relaxation, and to fuel active transport and maintain ion gradients. In fact, mitochondrial density varies in muscle cells and is a key factor influencing energy producing capacity. At slaughter, exsanguination eliminates the blood supply to muscle cells, and oxygen is no longer delivered to mitochondria for oxidative phosphorylation. Anaerobic glycolysis predominates in the postmortem period; breakdown of glycogen generates lactate and H+, which accumulate in postmortem muscle and result in pH declining to a final or ultimate pH (pHu) near 5.6. At this point, ATP is exhausted and no longer generated, and rigor is complete and additional ATP is not generated by metabolism. The rate and extent of metabolic processes postmortem significantly impact water holding capacity, color, and protease-mediated tenderization of meat. Because the oxygen supply to muscle is removed at harvest, the contribution of mitochondria to postmortem metabolism and meat quality has been largely disregarded. However, the role of mitochondria in cellular function and homeostasis is multifaceted and extends beyond ATP production. Our overall objective is to define how postmortem conditions and inherent muscle metabolic and contractile properties influence mitochondria function and integrity. Our objectives are to evaluate changes in mitochondrial function in oxidative and glycolytic muscles during the first 24h postmortem determine mitochondrial function in oxidative and glycolytic muscles under pH and oxygen tension conditions that simulate postmortem muscle assess mitochondrial respiration and postmortem metabolism in longissimus muscles with varying mitochondrial content.

7.	Project Title:	Identifying Genes That Regulate Mitochondrial Positioning at the Synapse During Aging
	Leader(s):	HAN, SUNG MIN
		UNIVERSITY OF FLORIDA
		American Federation for Aging Research (AFAR) AGR00015406 / (2019-2021)
	A decline in the functions of the nervous system is a hallmark of aging, and can lead to many age-related changes in balance, mobility, hearing, vision, smell, and taste. The function of the nervous system depends on the maintenance of synapses-the special contact area where neurons communicate with other neurons. Many lines of?evidence suggest that the function and structure of synapses change with aging. At the synapse, mitochondria remain tightly packed to supply adequate energy and maintain calcium homeostasis. These mitochondrial functions are required to support synaptic function. Despite clear evidence supporting the important role of mitochondria at synapses, and the effect aging has on synaptic function, the molecular mechanism(s) that mediate mitochondrial positioning at synapses and how aging affects this regulation remain unclear. Our goal is to uncover the underlying mechanisms that regulate mitochondrial positioning and function at the synapse during the aging process. My proposed aims are based on my hypothesis that mitochondrial localization at the synapse is actively regulated by currently unknown molecules in response to local demand for mitochondrial support and function. We will apply our expertise in cell biology and our novel imaging approaches to discover short- and long-term changes in mitochondrial behavior at synapses in a wide range of genetic backgrounds in response to aging and acute mitochondrial stressors. To reveal new mechanisms that mediate mitochondrial localization at the synapse, we have established an innovative visual genetic screen for assessing mitochondrial distribution in the AIY interneuron of Caenorhabditis elegans. We anticipate that these screens will identify novel molecules that regulate mitochondrial targeting or anchoring at the synapse. As evidence supporting the strength and feasibility of this approach, our unsaturated pilot screens have already identified several mutants with abnormal mitochondrial targeting to the synapse. Successful completion of the proposed research will substantially increase the knowledge base of how synaptic mitochondria respond to aging. We expect this research to have widespread implications in the neurobiology of aging, particularly in understanding the maintenance of synaptic function in aging and other neuronal diseases associated with abnormal mitochondrial positioning and function.

8.	Project Title:	The Impact of Reactogenicity of the Recombinant Zoster Vaccine on the Physical Functioning and Quality of Life of Older Adults
	Leader(s):	SCHMADER, KENNETH
		DUKE UNIVERSITY
		Glaxo Smith Kline GSK Zoster 063 / (2017-2019)
	Herpes zoster and its related complications are associated with significant medical burden, which negatively affects quality of life and daily functioning of older patients. The recently licensed recombinant zoster vaccine (RZV) offers high efficacy but is associated with local and systemic reactions. This study assessed the impact of RZV on the quality of life and daily functioning of 400 older participants. Grade 3 reactogenicity occurred in 9.5% of participants and was associated with a transient clinically important decrease in SF-36 Physical Functioning score (affecting activities such as walking, carrying groceries, climbing stairs) and the EQ-5D-5L on Days 1 and 2 post-first vaccination. No clinically meaningful reductions in mean SF-36 Physical Functioning scale scores from pre- to post-RZV dose-1 were observed over a 7 day period post-vaccination.

9.	Project Title:	CEREBRAL NETWORKS OF LOCOMOTOR LEARNING AND RETENTION IN OLDER ADULTS
	Leader(s):	CLARK, DAVID J
		VETERANS HEALTH ADMINISTRATION
		VA I01RX003115 / (2019-2023)
	Aging often leads to substantial declines in walking function, especially for walking tasks that are more complex such as obstacle crossing. This is due in part to a lack of continued practice of complex walking (sedentary lifestyle) combined with age-related deficits of brain structure and the integrity of brain networks. Neurorehabilitation can contribute to recovery of lost walking function in older adults, but major and persistent improvements are elusive. A cornerstone of neurorehabilitation is motor learning, defined as an enduring change in the ability to perform a motor task due to practice or experience. Unfortunately, in most clinical settings, the time and cost demands of delivering a sufficiently intensive motor learning intervention is not feasible. There is a need for research to develop strategies for enhancing motor learning of walking (?locomotor learning?) in order to improve the effectiveness of neurorehabilitation. The objective of this study is to use non-invasive brain stimulation to augment locomotor learning and to investigate brain networks that are responsible for locomotor learning in mobility-compromised older adults. We have shown that frontal brain regions, particularly prefrontal cortex, are crucial to control of complex walking tasks. Our neuroimaging and neuromodulation studies also show that prefrontal cortex structure and network connectivity are important for acquisition and consolidation of new motor skills. However, a major gap exists regarding learning of walking tasks. The proposed study is designed to address this gap. Our pilot data from older adults shows that prefrontal transcranial direct current stimulation (tDCS) administered during learning of a complex obstacle walking task contributes to multi-day retention of task performance. In the proposed study we will build upon this pilot work by conducting a full scale trial that also investigates mechanisms related to brain structure, functional activity, and network connectivity. We will address the following specific aims: Specific Aim 1: Determine the extent to which prefrontal tDCS augments the effect of task practice for retention of performance on a complex obstacle walking task. Specific Aim 2: Determine the extent to which retention of performance is associated with individual differences in baseline and practice-induced changes in brain measures (working memory, gray matter volume, task- based prefrontal activity, and brain network segregation). Specific Aim 3: Investigate the extent to which tDCS modifies resting state network segregation. We anticipate that prefrontal tDCS will augment retention of locomotor learning, and that our data will provide the first evidence of specific brain mechanisms responsible for locomotor learning/retention in older adults with mobility deficits. This new knowledge will provide a clinically feasible intervention approach as well as reveal mechanistic targets for future interventions to enhance locomotor learning and rehabilitation.

10.	Project Title:	EXPLORING THE EFFECTS OF EXERCISE TRAINING ON PTSD SYMPTOMS AND PHYSICAL HEALTH IN OLDER VETERANS WITH PTSD
	Leader(s):	HALL, KATHERINE SHEPARD
		DURHAM VA MEDICAL CENTER
		VA I01RX003120 / (2020-2024)
	Posttraumatic stress disorder (PTSD) is prevalent among military Veterans, and affects over 30% of older, Vietnam-era Veterans. These servicemembers have endured nearly 40 years with these symptoms, and as a result, have significantly poorer health, higher rates of chronic disease and obesity, and an excess mortality rate 3 times higher than the general population. Clearly PTSD is more than just a psychological disorder. There is evidence to suggest that the pathway from PTSD to poor health is mediated by behavioral risk factors, such as exercise. Structured exercise is a highly effective, pluripotent strategy for the prevention, treatment, and management of chronic physical and psychological health conditions in older adults. To date, only a few pilot studies of exercise and PTSD have been published, and all suffer a major limitation: a singular focus on outcomes ?above the neck.? These studies do not report the impact of exercise on physical health- and mobility-related outcomes that contribute to long-term impairment and disability in Veterans with PTSD. There have been no studies of exercise and PTSD done in older adults, representing a significant research gap. This research examines a wellness-based approach to promoting health in older Veterans with PTSD, targeting exercise, a major modifiable risk factor. The objective of this study is to compare the impact of a supervised exercise program on PTSD symptoms and related health outcomes versus a healthy aging attention control group (HA-ATC). This study will be a randomized controlled trial of a 6-month, supervised exercise program among 188 Veterans ?60 years of age with PTSD at the Durham VAHCS. Participants will be randomly assigned to Supervised Exercise or HA-ATC. The exercise arm will include 3 weekly exercise sessions, each one lasting approximately 60 minutes, led by an exercise specialist. The HA-ATC will receive a health education program and materials modeled on the 10 KeysTM to Healthy Aging curriculum and the National Council on Agings Aging Mastery Program. The HA-ATC will include an 8-week face-to-face group program followed by 4 monthly sessions, the latter of which will be further supplemented with mailed informational packets, email newsletters, webinars, and group video telehealth sessions. Participants in the Exercise intervention arm will receive an individualized exercise prescription based on the individual?s exercise history, current exercise capacity, personal preferences, and current health status. This will be a multicomponent program that includes a selection of 8 to 12 strengthening, balance, and flexibility exercises targeting the major muscle groups as well as primary joints. Participants will also be instructed in endurance exercise, including treadmill walking or recumbent bicycle. The exercise protocol will consist of a 5-10 minute warm-up, followed by a series of progressive aerobic and strengthening exercises, and will end with a 5 minute cool-down. The primary outcome for this study will be PTSD symptoms assessed with the CAPS-5. Physical function, another outcome of primary interest will be measured objectively with a Physical Performance Battery. This test battery assesses aspects of daily function including balance (single leg stance), gait speed (4 meter walk), and chair stands (# in 30 seconds). Aerobic endurance, the investigators primary functional outcome, will be assessed with the 6-minute walk test (6MWT). Secondary outcomes include depression, sleep, and cognitive function. Outcomes will be assessed at baseline, 3 months, and 6 months. Assessments will be repeated 12 weeks post-intervention (9 months) to examine whether any observed exercise intervention effects are maintained. Mixed linear models will be used to compare outcomes for the two study arms.

11.	Project Title:	AEROBIC EXERCISE AND COGNITIVE TRAINING IN OLDER ADULTS
	Leader(s):	NOCERA, JOE ROBERT
		VETERANS HEALTH ADMINISTRATION
		VA IK2RX000744 / (2012-2018)
	DESCRIPTION This proposal, 'Aerobic Exercise and Cognitive Training in Older Adults', is resubmission for a Career Development Award- Level 2 with Dr. Joe R. Nocera as the Principal Investigator and a mentoring team of Drs. Bruce Crosson, Ron Shorr, Marco Pahor and Michael Marsiske. Dr. Nocera received his undergraduate degree (B.A., 2001) from the University of California, Los Angeles. He completed his graduate degrees in Kinesiology from the University of Nevada, Las Vegas (M.S., 2004) and the University of Georgia (Ph.D., 2007). Following completion of his terminal degree, Dr. Nocera earned a post- doctoral fellowship under a National Institute of Health T32 training grant within the Department of Neurology at the University of Florida. Dr. Nocera then received a CDA-1 aimed at studying the effects aerobic exercise on executive language function in older adults. It was hypothesized, and demonstrated in the preliminary CDA-1 work, that the robust documented benefits of aerobic exercise on cognition could carry over to more specific executive language functions. Concurrently, the CDA-1 was designed to increase Dr. Nocera's understands of cognitive neuroscience thus bridges the gap between cognitive functions and Dr. Nocera's previous education emphasis of physical function in older adults. The general purpose of the career development in this CDA-2 application is to further and more substantially develop Dr. Nocera's understanding of cognitive neuroscience for the purpose of designing interventions aimed at improving function and quality of life in older veterans. Specific training components in the proposal include; skills in cognitive neuroscience with specific training in cognitive aging, measurement, neuroanatomy, and basic imaging approaches. Additionally, the proposal is designed to develop Dr. Nocera's skills in clinical/translational research necessary for high-quality clinical trials research. The purpose ofthe CDA-2 study will build on the CDA-1, which demonstrating an improvement in cognitive function via aerobic exercise, by adding a cognitive training component that will be done immediately following the aerobic exercise. It is hypothesized that the aerobic exercise will potentiate and increase the generalizability of the cognitive training. Importantly, this study wil focus on older veterans at-risk for mobility disability. This area is of particular importance for he VA system, considering a large percentage of veterans are entering old age and therefore likely to suffer from age-related cognitive decline and mobility disability. To address our research question 60 older veterans (age 65-89) will be randomized to one of two 12-week intervention groups: 1) Cognitive Training alone (CT) or 2) Aerobic Exercise + Cognitive Training (AE+CT). The aerobic exercise arm of the study will follow the same format shown to improve a broad range of executive functions in older adults in previous research as well as our CDA-1 pilot work. The cognitive training arm will consists of a popular commercially-available brain fitness program that has demonstrated specific cognitive improvements and high adherence. Ultimately, this investigation will substantially advance the development of treatments for cognitive impairment because these goals explore an intervention that may potentially have pervasive effects on patient quality of life from a cognitive as well as a physical standpoint. Concurrently, this proposal will provide Dr. Nocera with the skill necessary to grow into a successful, independent VA Research.

12.	Project Title:	ROLE OF MICRORNAS ON AGE AND CONTRACTION-INDUCED SKELETAL MUSCLE GROWTH
	Leader(s):	RIVAS, DONATO A
		TUFTS UNIVERSITY BOSTON
		NIH K01AG047247 / (2015-2020)
	DESCRIPTION (provided by applicant): The age-associated loss of skeletal muscle mass and function (sarcopenia) is associated with substantial social and economic costs. The plasticity and adaptability of skeletal muscle to contraction (i.e. resistance-exercise) is a fundamental physiological event leading to larger and more robust skeletal muscle. However, muscle growth in response to resistance exercise (RE), like other anabolic stimuli, is attenuated in older adults The cause of aberrant muscle adaptation with aging is complex. Recent work has revealed a novel role for small non-coding RNAs, called microRNAs (miRNA) in the regulation of gene expression. Using an integrated bioinformatics analysis of protein-coding gene and miRNA array data from young and older men, I identified ten specific miRNAs as important regulators of muscle plasticity (Plasticity Related miRs [PR-miRs]) leading to the transcriptional response to exercise and lean mass in young and older men. However, the precise mechanisms underlying the expression of PR-miRs on age-related changes in muscle anabolism and sarcopenia are currently unknown. Thus, the overall objective of this K01 application will be to determine the mechanistic role(s) of these PR-miRs in skeletal muscle adaptation to anabolic stimulation in 1) healthy young, 2) sarcopenic older and 3) age- and functionally-matched non-sarcopenic older males and females. This will be accomplished by determine the differences in expression of PR-miRs with aging and sarcopenia in response to anabolic stimulation (AIM 1). Mechanistically determine the extent to which manipulation of PR-miR levels in vitro, in human primary myocytes, can reverse anabolic resistance observed with age and sarcopenia (AIM 2) and the effect of altering PR-miRs levels on skeletal muscle growth and development (AIM 3). This project will improve our understanding of the molecular mechanisms that contribute to the loss of skeletal muscle and eventually leading to the development of drug therapies for the treatment of sarcopenia in the ever growing aging population. The mentorship team includes, Dr. Roger Fielding, a leader in aging research and muscle biology, Dr. Kenneth Walsh, a cardiovascular researcher and leading molecular biologist, Dr. Laurence Parnell a computational biologist and authority in gene and miRNA expression analysis, Dr. Thomas Gustafsson a physician-scientist and clinical researcher and Dr. Thomas Travison an expert in biostatistics. The mentorship team has a variety of know-how in every facet of this project including, conducting human clinical trials and skeletal muscle biology, computational biology and genomics and molecular biology and mechanisms. The proposed career development plan includes research-oriented and didactic training at Tufts University, Boston University and the Karolinska Institute in Stockholm,Sweden. The pursuit of the specific aims of the research project, the multidisciplinary mentorship team and the career development plan will facilitate a transition to an independent research career.

13.	Project Title:	PHARMACOLOGICAL MANAGEMENT OF PAIN IN ALZHEIMER'S DISEASE AND RELATED DEMENTIA
	Leader(s):	WEI, YU-JUNG
		UNIVERSITY OF FLORIDA
		NIH K01AG054764 / (2017-2022)
	Summary: My career goal is to become an independent geriatric pharmacoepidemiologist with expertise inpharmacotherapy quality measurement and outcomes evaluation in the fields of pain and aging. The clinicalfocus of my research has centered on the management of multi-morbidity in older adults and particularly, theinterplay of mental and physical disease and its treatment. One example of combination of health problems iselderly patients who live with Alzheimer's disease and related dementia (ADRD) and also suffer from chronicpain. To date, data on quality of pain medication prescribing and the sequelae of poor pain control in patientswith ADRD are scarce. Studies investigating these associations are limited by small sample size, and none hasattempted to establish the effect of adequate pain control on preventing mental health (MH) disorders. Thegoal of my K01 proposed research is to provide preliminary data that improve our understanding of currentpain medication prescribing and potential discrepancies between practices and pain guidelines, and toformulate hypotheses for future research regarding the role of pain control in reducing MH problems in ADRD.We propose a longitudinal design using 4 years (2011-2014) of Medicare 5% sample whose billing records arelinked to nursing home resident assessment data (Minimum Data Set, MDS, 3.0). Because it is unclearwhether MDS 3.0 can accurately detect patients with pain and MH disorders, we first conduct a feasibility studyof validating MDS-based pain, depression, and behavioral symptoms against medical records at two nursinghomes (Aim 1). With the nationally representative Medicare-MDS data, we explore the quality ofpharmacological pain management and its determinants among ADRD and non-ADRD residents with non-cancer pain (Aim 2). The quality will be examined based on five common clinical standards--pain medicationselection, pain medication scheduling, pharmacological prevention of drug adverse event, contraindicatedmedication use, and overall pain control. We then explore the extent to which pain control is associated with adecreased risk for select MH disorders, including depression, behavioral symptoms, anxiety, and sleepdisorders in ADRD (Aim 3). This project is well tailored for me to apply the knowledge and skills that will beobtained from training activities with my Primary Mentor, Dr. Almut Winterstein (pharmacoepidemioloy, qualitymeasurement and outcome assessment) and Co-Mentors: Drs. Roger Fillingim (pain), Marco Pahor (aging),Babette Brumback (advanced methods for longitudinal data), and Laurence Solberg (clinical geriatric care andassessment). For further guidance, I enlist the expertise of Dr. Siegfried Schmidt in the field of pain medicineand Dr. Steven DeKosky in ADRD. This K01 award will provide protected time for me to receive trainingneeded to prepare an R01 grant application to examine pain medication practices and their impact on healthoutcomes in ADRD. The results from this line of research are expected to lead to better pharmacological painmanagement and improved pain and health outcomes in older adults with cognitive impairments.

14.	Project Title:	THE AMPK/ULK1/P27KIP1 AXIS REGULATES AUTOPHAGY AND CELL SURVIVAL IN AGED SATELLITE CELLS
	Leader(s):	WHITE, JAMES P.
		DUKE UNIVERSITY
		NIH K01AG056664 / (2017-2022)
	a. Project summary/abstract:Sarcopenia is the age-related loss in skeletal muscle mass and strength; it leads to a host of co-morbiditiesincluding loss of physical function and overall resilience. One such perturbation in persons with sarcopenia isthe diminished ability to regenerate muscle after injury. Muscle stem cells, referred to as satellite cells, arerequired to activate, proliferate and differentiate to regenerate muscle and restore physical function. Agedsatellite cells are slower to activate upon injury; susceptible to apoptosis; and less efficient in repairing injuredmuscle. The AMPK/ULK1/p27Kip1 pathway appears critical for successful transition from quiescence to entryinto the cell cycle. Our preliminary data identify perturbations in the AMPK/ULK1/p27Kip1 pathway withadvanced age. This award period will investigate the role of the AMPK/ULK1/p27Kip1 pathway in thephenotype of satellite cell aging in both human and mouse models. In Aim1, we will test the hypothesis thatactivation of AMPK and its downstream targets ULK1 and p27Kip1 regulate the autophagy/apoptosis decisionin aged satellite cells. We will use molecular assays to rescue the functional loss of this pathway in aged cellsand return proliferative capacity. In Aim 2, we will test the hypothesis that exercise, a physiological inducer ofAMPK and autophagy, stimulates the AMPK/ULK1/p27Kip1 pathway, thereby enhancing proliferation andmetabolic function in aging murine and human satellite cells. Aim 3 will test the hypothesis thatAMPK/ULK1/p27Kip1 signaling will regulate the beneficial effects of caloric restriction on aged satellite cells.Together, the experiments in this proposal will test the hypothesis that the AMPK/ULK1/p27Kip1 pathway isimpaired in aging satellite cells resulting in a reduction in autophagy and susceptibility to apoptosis. Keyaspects of Dr. White's career enhancement will be: to learn how to coordinate clinical exercise trials; to trainin methods of satellite cell isolation and metabolic analysis, especially in the context of the aging organism.The training program will entail dedicated internal and external scientific presentations; pertinent coursework/workshops in stem cell biology and aging; and intensive career mentorship to ensure progress towardindependence. The research and career development plan detailed in this proposal will be conducted with ateam of outstanding mentors. Dr. William E. Kraus, a professor at the Duke Medical School is an establishedexpert in clinical exercise studies and muscle/satellite cell biology; he will serve as the primary mentor. Drs.Kenneth Schmader, Deborah Muoio (Duke) and Amy Wagers (Harvard) will serve as co-mentors; they willfacilitate training in aging biology, cell metabolism and aging stem cell biology, respectively. The environmentat the Duke School of Medicine is ideal for the research and training activities outlined in this proposal. Thisaward will provide Dr. White with optimal training to ensure an outstanding start to his career as anindependent investigator.

15.	Project Title:	DEPRESCRIBING CENTRAL NERVOUS SYSTEM MEDICATIONS IN HOSPITALIZED OLDER ADULTS
	Leader(s):	PAVON, JULIESSA M
		DUKE UNIVERSITY
		NIH K23AG058788 / (2019-2024)
	This K23 Career Development Award in Aging focuses on the development of Dr. Juliessa Pavon, a hospital-based geriatrician, and on reducing central nervous system (CNS) medication use in hospitalized older adults.Dr. Pavon?s long-term goal is to improve the resilience of older adults against the acute stressors ofhospitalization. She has built her research program on investigating hazards of hospitalization, and a majorthreat is high-risk medication exposure. Sub-optimal CNS medication use during hospitalization is a keymodifiable risk factor for poor health outcomes; common classes include opioids, anxiolytics, anti-depressants,antipsychotics, and hypnotics. Our preliminary data suggests that nearly 40% of hospitalized older adults areexposed to anxiolytics and 60% to opioids during their hospital stay. De-prescribing is a systematic process oftapering or reducing medications. Interventions to facilitate de-prescribing that target specific medicationclasses, like CNS medications, or specific populations, like those with existing cognitive impairment, have notbeen well-studied in the inpatient setting. This gap represents a key opportunity to reduce potentiallyinappropriate CNS medications and their debilitating side effects in vulnerable patients--in line with the NationalInstitute of Aging?s priorities to improve medication use in older adults. Dr. Pavon?s K23 award proposes todevelop and pilot test a de-prescribing intervention that is informed by a theoretical model of behavioralchange. Aim 1 results will inform the epidemiology of the problem and identify target populations forrecruitment. Aim 2 will use qualitative methods to examine barriers and facilitators of hospital de-prescribing.Results will inform the intervention delivery strategies best suited to facilitate CNS medication de-prescribing ina well-tolerated, feasible manner. Aim 3 will develop and pilot test a multi-component hospital-based de-prescribing intervention that uses health informatics for content delivery, and provider behavior change andpatient activation strategies. This work will advance understanding of 1) which patients and CNS medicationclasses to target for de-prescribing interventions, 2) whether there are unique barriers to de-prescribing in thehospital setting, and 3) the optimal delivery strategy for safely de-prescribing. During this K23 grant period, Dr.Pavon will also complete additional training in Markov modeling statistical techniques, interventiondevelopment, health informatics, and leadership. Dr. Pavon?s mentor team will provide scientific support withexpertise in aging, pharmacology, hospital medicine, and research methodology. This career developmentplan will give Dr. Pavon the skills in conducting intervention development studies within the hospital setting.This training and resulting data will establish Dr. Pavon as a strong candidate for an R01 intervention designedto facilitate de-prescribing of CNS medications for the nearly 1 in 2 older adults that will experience exposure toa CNS medication during hospitalization.

16.	Project Title:	METABOLOMIC & RADIOGRAPHIC MARKERS OF FRACTURE RISK AMONG OLDER ADULTS WITH DIABETES
	Leader(s):	LEE, RICHARD H.
		DUKE UNIVERSITY
		NIH K23AG058797 / (2018-2023)
	ABSTRACTAmong its medical complications, type 2 diabetes mellitus in older adults is associated with atwo-fold increase in the risk of hip and other low-trauma bone fractures. Paradoxically, thisincreased risk occurs despite a higher average bone mineral density. This increased fracturerisk is likely multifactorial, stemming from metabolic dysfunction that results in both increasedfalls risk and decreased bone strength. However, fracture risk stratification currently is limitedlargely to bone density testing and clinical risk tools that do not perform adequately for adultswith diabetes. Because bone is both a metabolic and structural tissue, metabolomics andbiomechanical analyses would be particularly useful for developing and assessing newmeasures of fracture risk. The objective of this application is to develop and evaluateradiographic and laboratory biomarkers of fracture risk among older adults with diabetes,utilizing biomechanical and translational measures. The proposed research has the followingaims: 1) Determine the association between metabolomic profiles and incident clinical fractureamong older adults with diabetes; 2) Compare geometric and biomechanical measures at thefemoral neck and intertrochanteric region among older adults with diabetes, with and without hipfracture. This application builds upon the prior published work and clinical expertise of thePrinciple Investigator, Dr. Richard Lee, and provides him additional research skills to assist withhis career development goal of understanding the interaction of chronic medical conditions onthe bone health of older adults, focusing on diabetes. Dr. Lee is a dual-trained Geriatrician andEndocrinologist with expertise in metabolic bone disease. The primary training goals of thisproposal include the following: 1) Develop laboratory and analytical skills in translational sciencethat will be used in the development and evaluation of clinical biomarkers, including ?omicstechnologies; 2) Acquire principles and skills in biomechanical engineering and materialsscience to integrate with clinical and epidemiological analyses. By integrating biomechanicalengineering and metabolomics approaches with epidemiologic research to identify new markersof fracture risk, this application addresses a significant source of morbidity and mortality amongan increasing proportion of older adults.

17.	Project Title:	INVESTIGATIONS OF BOTANICALS ON FOOD INTAKE, SATIETY, WEIGHT LOSS, AND OXIDATIVE
	Leader(s):	ANTON, STEPHEN D
		UNIVERSITY OF FLORIDA
		NIH K23AT004251 / (2009-2014)
	DESCRIPTION (provided by applicant): My training to date has provided me with a solid understanding of the behavioral, psychosocial, and environmental factors that contribute to eating behavior and weight management; however, my understanding of physiology and the biological mechanisms regulating eating behavior and body weight remains to be improved. Therefore, I seek to increase my knowledge of the physiological aspects of age- related metabolic conditions, and the potential role botanical extracts may have in affecting physiology, eating behavior, body weight, and oxidative stress levels. This knowledge, coupled with my previous training, will provide an ideal foundation from which I can build a unique and independent line of research investigating alternative and adjunctive treatments involving botanicals for age-related metabolic conditions (obesity, type 2 diabetes). My immediate career goals are to 1) obtain a R01 grant to further examine the potential effects of different doses of the selected botanical compounds on food intake, body weight, and oxidative stress levels and 2) increase my understanding of the effects that botanicals have on physiological processes related to food intake. My long-term career goal is to become an independent investigator focused on developing safe and effective alternative or adjunctive interventions involving natural compounds for the treatment of obesity and other metabolic conditions. The proposed line of research will explore the role that botanical compounds have in affecting food intake, neuroendocrine signals, satiety, weight loss, and oxidative stress levels. Study 1 will investigate the effects of two promising botanicals (garcinia cambogia derived hydroxycitric acid, and glucomannan) on food intake, satiety, and weight loss using a double-blind, placebo controlled design. Based on the findings from study 1, the botanical with the most significant effects on food intake will be used in a 24-week, placebo controlled calorie restricted weight loss trial. In addition to body weight, this trial will examine the effects of the selected compound on: 1) food intake, 2) self-reported satiety, 3) postprandial neuroendocrine signals (i.e., CCK, GLP-1, insulin, and leptin), and 4) oxidative stress levels (i.e., DNA and RNA oxidation). PUBLIC HEALTH RELEVANCE: Botanicals represent important sources of potential new adjunctive therapies for obese and insulin resistant individuals and may enhance the health benefits of weight loss interventions by reducing systemic oxidative stress levels.

18.	Project Title:	NEURO-INFLAMMATION IN POSTOPERATIVE COGNITIVE DYSFUNCTION: CSF AND FMRI STUDIES
	Leader(s):	BERGER, MILES
		DUKE UNIVERSITY
		NIH K76AG057022 / (2017-2022)
	This is a K76 Beeson career development award for Dr. Miles Berger, a geriatric neuro-anesthesiologist with a focus on postoperative cognitive disorders. Each year >16 million olderAmericans undergo anesthesia and surgery, and up to 40% of these patients developpostoperative cognitive dysfunction (POCD), a syndrome of postoperative thinking and memorydeficits. Although distinct from delirium, POCD (like delirium) is associated with decreased qualityof life, long term cognitive decline, early retirement, increased mortality, and a possible increasedrisk for developing dementia such as Alzheimer?s disease. We need strategies to prevent POCD,but first, we need to understand what causes it. A dominant theory holds that brain inflammationcauses POCD, but little work has directly tested this theory in humans. Our preliminary datastrongly suggest that there is significant postoperative neuro-inflammation in older adults whodevelop POCD. In this K76 award, we will prospectively obtain pre- and post-operative cognitivetesting, fMRI imaging and CSF samples in 200 surgical patients over age 65. This will allow us toevaluate the role of specific neuro-inflammatory processes in POCD, its underlying brainconnectivity changes, and postoperative changes in cerebrospinal fluid (CSF) Alzheimer?sdisease (AD) biomarkers, such as the microtubule-associated protein tau. This project willadvance understanding of neuro-inflammatory processes in POCD and clarify the potential link(s)between these processes and postoperative changes in AD pathology, in line with the NationalInstitute of Aging?s mission to understand aging and fight cognitive decline due to AD. During thisK76 grant period, Dr. Berger will also complete an individually tailored MS degree in TranslationalResearch that will include training in immunology methods, fMRI imaging, cognitive neuroscience,geroscience, and physician leadership. This career development plan will give Dr. Berger thetransdisciplinary skills to pursue his longer term goal of improving postoperative cognitive functionfor the more than 16 million older Americans who have anesthesia and surgery each year.

19.	Project Title:	NORTH CAROLINA DIABETES RESEARCH CENTER
	Leader(s):	NEWGARD, CHRISTOPHER B
		WAKE FOREST UNIVERSITY HEALTH SCIENCES
		NIH P30DK124723 / (2020-2021)
	PROJECT SUMMARY/ABSTRACT ? METABOLOMICS CORE Comprehensive metabolic analysis, or ?metabolomics?, is a technology that defines the chemical phenotype of living systems. Given that metabolic fluxes and metabolite levels are downstream of genomic, transcriptomic, and proteomic variability, metabolomics provides a highly integrated profile of biological status. As such, it has unique potential for discovery of biomarkers that predict disease incidence, severity, and progression, and for casting new light on underlying mechanistic abnormalities. Metabolomic analyses are challenging, however, due to the complexity inherent in measuring large numbers of intermediary metabolites with diverse chemical properties in a quantitatively rigorous and reproducible fashion. The DMPI Metabolomics Core Lab has a long history of collaborative research and has established a strong and reliable infrastructure for conducting measurements for investigators at Duke and at outside institutions. Thus, it is well poised to become the NCDRC Metabolomics Core. While Duke has world-renowned facilities for metabolomics, its use by diabetes investigators outside of Duke (such as WF and UNC researchers) has been limited by bottlenecks, particularly in the analysis and interpretation of data, which the NCDRC seeks to address by establishing the NCDRC Metabolomics Core with support from Research Navigators.

20.	Project Title:	PICS: A NEW HORIZON FOR SURGICAL CRITICAL CARE
	Leader(s):	MOORE, FREDERICK A
		UNIVERSITY OF FLORIDA
		NIH P50GM111152 / (2014-2019)
	DESCRIPTION (provided by applicant): Despite 30 years of intensive research, morbidity and mortality of sepsis in surgical intensive care unit (ICU) patients remain unacceptably high. Although recent advances in early ICU care have reduced in-hospital mortality, with the aging population a new epidemic of chronic critical illness (CCI) has emerged and its progression into what we call the persistent inflammation, immunosuppression and catabolism syndrome (PICS) has unacceptable morbid long-term consequences. Our overarching hypothesis is that PICS is now a predominant clinical trajectory in the surgical ICU patients after sepsis, and is the greatest, near-term clinical challenge in surgical ICUs. We further hypothesize that PICS is caused, at least in part, by dysregulated myelopoiesis and expansion of myeloid-derived suppressor cells (MDSCs), aggravated by aging and largely driven by acute kidney injury (AKI), resulting in imbalance of angiogenic and anti-angiogenic factors. This Sepsis and Critical Illness Research Center (SCIRC) application comprises four projects and five cores drawn from two colleges (Medicine and Public Health and Health Professions) and eight University of Florida Health departments (Surgery, Medicine, Anesthesiology, Biostatistics, Molecular Genetics and Microbiology, Aging and Geriatric Research, and Physical Therapy) and will address the following questions in four projects: #1a) What is the incidence and early risk factors for CCI in septic surgical ICU patients and what are the long-term cognitive and functional consequences? #1b) Can novel biomarkers predict, early, which patients will develop CCI, and, later, which CCI patients will have morbid long-term outcomes (i.e., PICS)? #2) Is PICS inherently driven by dysregulation in myelopoiesis and inappropriate MDSC expansion, promoting persistent inflammation, immunosuppression and catabolism?; #3) Does AKI, through dysregulation of anti-angiogenic and angiogenic cytokines, drive the expansion of MDSCs, inflammation, and anti-angiogenesis?; and #4) Does CCI contribute significantly to muscle atrophy, especially in mechanically ventilated patients' diaphragms and extremities, and will resistance exercise improve muscle strength, reduce inflammation, and alter the trajectory of CCI away from the PICS phenotype? We will study 400 surgical ICU patients who develop sepsis for at least one year, and use murine models of chronic polymicrobial sepsis for mechanistic studies and interventional methods. We recognize that no single therapeutic intervention will prevent PICS, but the SCIRC's overall goal is to understand the prevalence and pathogenesis of this new syndrome at a mechanistic level. Only through multi-disciplinary translational research by basic and clinical scientists with diverse expertise in critical care medicine, physical therapy, immunology, molecular biology, and understanding of muscle, kidney, and aging physiology, can CCI progression into PICS be understood and novel therapies developed.

21.	Project Title:	ADAPTABILITY AND RESILIENCE IN AGING ADULTS (ARIAA)
	Leader(s):	BARTLEY, EMILY J.
		UNIVERSITY OF FLORIDA
		NIH R00AG052642 / (2016-2021)
	Growing evidence supports the presence of dysregulated pain modulation in older adults, an effect which may heighten age-associated risk for chronic pain. While persistent pain is common in older adults, chronic low back pain is the leading cause of disability in this population and results in significant impairments in psychosocial and physical functioning. Given reports of suboptimal treatment of pain in older adults, improvements in pain management in this cohort are of critical importance. Resilience is characterized as a dynamic process resulting in positive adjustment and adaptation after exposure to adversity. The benefits of resilience in health-related functioning are manifold, and recent evidence suggests that resilience plays an important role in fostering adaptive physiological and affective responses to pain. Given this, capitalizing on positive resources is a promising target for enhancing pain adaptation, and is especially salient to older adults given the burden of high-impact pain in this group. Therefore, the overall goal for this mentored career development application (K99/R00) is to fill this knowledge gap and characterize resilience mechanisms associated with adaptive pain modulatory capacity in older adults with chronic low back pain. Primary training goals for the current application are to: 1) develop a comprehensive knowledge base in biopsychosocial processes of aging and enhance training in the assessment and treatment of older adults; 2) increase knowledge in the understanding and assessment of psychosocial and biological (i.e., inflammatory, neuroendocrine) markers associated with pain and resilience; and 3) augment training in the design, implementation, and analysis of randomized clinical trials. The proposed study is delineated into two phases. Study 1 (K99 Phase) will examine associations among measures of resilience, biological markers of inflammation and neuroendocrine activity, and pain modulatory capacity in older adults with chronic low back pain. Increased knowledge and understanding of the resilience pathways that promote adaptability to pain will allow for the development of a targeted resilience intervention during Study 2 (R00 Phase). This phase will provide the opportunity for examining intervention effects on pain modulatory function and patterns of pain- evoked recovery in physiological and affective systems, and will establish whether a resilience-oriented intervention confers benefits in psychosocial and physical functioning in older adults with chronic low back pain. The proposed career development plan extends from the PI's prior work on affective regulation and mechanisms of vulnerability in chronic pain, and will forge a path towards understanding and investigating psychological therapies of resilience that improve pain and disability in older adults.

22.	Project Title:	AGING IN 1000 HEALTHY YOUNG ADULTS: THE DUNEDIN STUDY
	Leader(s):	MOFFITT, TERRIE E ; CASPI, AVSHALOM ;
		DUKE UNIVERSITY
		NIH R01AG032282 / (2009-2020)
	DESCRIPTION (provided by applicant): Declining fertility rates, aging of the baby-boomers, and increasing life expectancy are leading to population aging. As the population ages, this increases the public-health burden of age-related conditions, such as cardiovascular disease, type 2 diabetes, and dementia. Treating un-prevented diseases in late life has proven costly and ineffective. It is now known that potentially preventable risk exposures and physiological causes of age-related disease emerge in childhood. This recognition lends new scientific significance to studies that have followed cohorts from childhood. It is also now known that the pathogenesis of age-related diseases involves gradually accumulating decline in organ systems, beginning in the first half of the life course. Consequently, new interventions aiming to prevent age-related diseases will have to be applied to individuals while they are yet young, before they reach midlife. Translation of basic-science geronotology discoveries into interventions for young humans is lacking because virtually nothing is known about the process of biological aging during the first half of the life course. This prompts our proposal to study the pace of biologicalaging from the twenties forward. We will use the Dunedin Multidisciplinary Health & Development Study, a longitudinal study of a birth cohort now entering its fifth decade. This study combines methods of demographic/economic surveys, clinical- quality health assessments, biobanking, and linkage to nationwide administrative records (health, welfare, finances). We propose to administer a full-day data-collection protocol to the 1004 living members of the birth cohort. To assess each cohort member's pace of biological aging we will: (a) measure biomarkers across multiple organ systems, and (b) statistically model correlated change in these biomarkers assessed at ages 26, 32, 38, and 45 years. We will describe individual variation in the pace of aging, plus its developmental origins, genomic signatures, functional consequences, and economic costs. We will identify attributes that set apart individuals whose bodies are months or years younger than their chronological age. The proposed work will improve knowledge by generating findings to support future interventions to slow aging, prevent age-related disease, and improve the quality of longer lives.

23.	Project Title:	ESTROGEN AND COGNITION OVER THE LIFESPAN
	Leader(s):	FOSTER, THOMAS C ; KUMAR, ASHOK ;
		UNIVERSITY OF FLORIDA
		NIH R01AG037984 / (2010-2023)
	AbstractSex differences are evident in vulnerability to age-related cognitive decline and diseases of aging. Estradiol(E2) is protective against neurodegenerative diseases, including Alzheimer?s disease, implicating sexhormone effects on sex differences in vulnerability. However, obstacles to sex steroid treatments includeclosing of the therapeutic window observed as decreased effectiveness of E2 treatment with advanced age.The goal of the proposed research is to provide an understanding of the mechanisms for E2 effects onmemory and the closing of the therapeutic window. Closing of the therapeutic window is marked by a decreasein E2-responseive transcription and an inability of E2 treatment to enhance N-methyl-D-aspartate receptor(NMDAR)-mediated synaptic transmission examined several days after treatment. Aim 1 will test thehypothesis that E2 treatment, several days prior to testing, specifically influences NMDAR-dependentepisodic memory, such that it can rescue an age-related decline in episodic memory examined on the watermaze and novel object recognition tasks. Aim 2 will test the hypothesis that E2 effects on memory andNMDAR function are mediated by reversal of NMDAR hypofunction, mediated by redox regulation ofphosphatase/kinase activity, similar to that previously described in aging males. Thus, it is predicted that priorto closing of the therapeutic window (i.e. in animals in which E2 treatment improves cognition and increasesNMDAR function), E2 treatment will promote antioxidant enzyme activity, reduce oxidative stress, andminimize redox-mediated decrease in CaMKII activity and NMDAR function. Further, following closing of thetherapeutic window (i.e. for animals in which E2 does not rescue cognition and NMDAR function), E2treatment will not promote antioxidant enzyme activity or reduce oxidative stress, and the NMDAR responseand CaMKII activity will be decreased due to an oxidized redox state. Aim 3 will test the hypothesis that age-related changes in transcriptional responsiveness to E2 are due, at least in part, to epigenetic regulationthrough DNA methylation. It is predicted that decreased responsiveness of E2-sensitive genes will beassociated with DNA hypermethylation, particularly in gene body regions (introns), and specific to CpG,relative to non-CpG methylation sites. The proposed studies will employ a powerful combination of behavioraltests that are sensitive to NMDAR function, patch-clamp recording of NMDAR synaptic responses, measuresof oxidative stress and enzyme activity, transcription, and DNA methylation.

24.	Project Title:	NEURAL SIGNATURES OF HEALTHY AND UNHEALTHY AGING
	Leader(s):	HARIRI, AHMAD R ; MOFFITT, TERRIE E ;
		DUKE UNIVERSITY
		NIH R01AG049789 / (2015-2020)
	DESCRIPTION (provided by applicant): Declining fertility rates, aging of the baby-boomers, and increasing life expectancy are leading to population aging. As the population ages, this increases the public-health impact of age-related conditions, such as cardiovascular disease, type 2 diabetes, and dementia. Treating un-prevented diseases in late life has proven costly and ineffective. Consequently, effective strategies are needed in midlife to prevent age-related diseases and to improve the quality of longer lives. It is now known that potentially preventable risk exposures and physiological causes of age-related disease emerge in childhood. This recognition lends new scientific significance to studies that have followed cohorts from childhood. It is also now known that the pathogenesis of age-related diseases involves gradually accumulating damage to organ systems, beginning in the first half of the life course. Of these organ systems, the central nervous system is integral, prompting our proposal to add neuroimaging to the Dunedin Multidisciplinary Health & Development Study, a longitudinal study of both problematic and positive processes of adult development and aging, in a birth cohort now entering its fifth decade. This study combines methods of demographic/economic surveys, clinical-quality health assessments, biobanking, and linkage to nationwide administrative records (health, welfare, finances). We propose to administer a multimodal MRI protocol to the 1004 living members of the birth cohort. Our proposed neuroimaging protocol will measure individual variation in brain function, structure, and connectivity. We focus on the hubs of four neural circuits and the core behavioral capacities each supports: (1) the amygdala and emotion/threat, (2) the ventral striatum and motivation/reward, (3) the hippocampus and memory, and (4) the dorsolateral prefrontal cortex and executive control. With the resulting midlife neural measures, we propose three primary aims that will generate findings about problematic and successful aging: Aim 1 tests whether prospectively ascertained early- life adversity is linked to midlife neural measures. Aim 2 tests whether neural measures are linked to real-world behaviors (e.g., saving behavior) necessary to prepare for successful aging. Aim 3 tests if neural measures are related to the accelerated pace of biological aging. The proposed work will improve knowledge by generating findings about the neural correlates of age-related diseases and successful healthy aging. These findings are expected to support preventing disease and enhancing preparedness for wellbeing in late life. Beyond the proposed 5-year project, follow-up neuroimaging is envisaged. This project thus brings neuroimaging into three timely and vigorous areas of aging science: the study of early-life programming of lifelong health, the study of midlife preparation for successful aging, and mind-body research linking brain function to physical health.

25.	Project Title:	EPIGENETIC MECHANISMS PROMOTING LONGEVITY
	Leader(s):	KRAUS, VIRGINIA
		DUKE UNIVERSITY
		NIH R01AG054840 / (2018-2023)
	AbstractCirculating small regulatory RNAs (sRNAs) are short non-coding RNAs (typically ~19-25nt in size). They mediatea broad spectrum of biological processes through regulation of gene expression. Our experimental evidenceindicates that serum levels of miRNAs (one form of sRNA) change considerably, the vast majority increasingwith age. The ability of circulating sRNAs to travel among tissues enables them to transmit signals and regulatea broad spectrum of biological functions. sRNAs exist in a variety of RNase-insensitive ribonucleoprotein or lipidcomplexes, or are encapsulated inside different types of extracellular vesicles. Consequently, in contrast tomessenger RNA, sRNAs are protected from extracellular RNases and are measurable and stable in samplesstored for decades. Despite numerous recent developments, we are far from understanding the role of sRNAsin aging. An understanding of their role in aging mammals, and in humans in particular, is still very limited dueto the increased complexity and longer life-spans of mammals compared with invertebrates. This projectleverages existing human sample resources from three completed NIH-funded studies (EPESE, STRRIDE andCALERIE), to discover and validate longevity-associated miRNAs in humans. Our preliminary analysis of 175circulating microRNA--in the NIA-funded Duke Established Populations for Epidemiologic Studies of the Elderly(Duke EPESE) community-based cohort of elders--identified 32 differentially expressed circulating miRNAs(p<0.05) associated with longevity; in all cases, their concentrations at baseline were higher in long-termsurvivors (>10 years) compared with age, sex and race matched but short-term survivors (<2 years); a subsetof these miRNAs predicted longevity independent of age, gender, race and functional status. The Duke EPESEcohort was aged 71 and older at the time of blood sampling and now has 25 years of longitudinal mortality data(through 2016) with which to address key questions about sRNAs and longevity in humans. sRNA discoveriesin Duke EPESE will be validated in plasma and muscle samples from completed human clinical trials of relevanceto longevity that investigated the health-promoting effects of exercise (STRRIDE cohort) and caloric restriction(CALERIE cohort). A human three-dimensional muscle tissue organ system will be used to understand theirmechanisms of action (with and without simulated exercise and caloric restriction), by testing sRNA mimics andinhibitors. Our preliminary analyses of 7 of our top longevity-related miRNA in this model system demonstratedproduction and secretion of all of them by muscle and statistically significantly increased secretion of two of themwith simulated muscle exercise. Together our approach will permit us to determine if sRNAs associated withlongevity are favorably modulated in tissue and blood in humans by exercise and/or caloric restriction, and ifthey appear to mediate any of the observed health benefits of these interventions. The totality of the data(generated in vivo and in vitro), will be systematically examined to identify pathways of sRNA action in humansand profiles of sRNA that could serve as biomarkers to predict longevity status.

26.	Project Title:	SENESCENCE AND GROWTH DIFFERENTIATION FACTORS AS MODIFIERS OF AGING
	Leader(s):	LEBRASSEUR, NATHAN K
		MAYO CLINIC
		NIH R01AG055529 / (2018-2023)
	PROJECT SUMMARY/ABSTRACTAging is the primary risk factor for the majority of chronic diseases. Studies in mice have implicated specificgrowth and differentiation factors (GDFs) and proteins secreted by senescent cells as potential modifiers ofaging. The objective of this proposal is to establish the rationale and provide robust clinical evidence for GDF8,GDF11, and senescence-related proteins eotaxin (CCL11), intracellular adhesion molecule 1 (ICAM1), activinA (AA), and plasminogen activator inhibitor 2 (PAI2), as indicators of biological age and age-related conditionsin humans. The central hypothesis is that circulating concentrations of GDFs and senescence-related proteinsare associated with, and predictive of, clinically important health outcomes and can be altered by physicalactivity. Samples from the Lifestyle Interventions and Independence for Elders (LIFE) Study; the largest andlongest randomized trial of a physical activity intervention in older adults, will be used to test this hypothesis,and samples from the Health, Aging, and Body Composition (HABC) Study will be used to validate studyfindings. A novel multiplexed liquid chromatography-tandem mass spectrometry assay will be leveraged toaccurately quantify GDFs, and an advanced multiplexing platform will be used to measure senescence-relatedproteins in LIFE and HABC biospecimens. In Specific Aim 1, a multidisciplinary team will first determine theextent to which baseline concentrations of GDF8, GDF11, CCL11, ICAM1, AA and PAI2 are associated withbaseline measures of physical (i.e., gait speed, Short Physical Performance Battery (SPPB) score),cardiopulmonary (i.e., blood pressure, forced expiratory volume), and cognitive (i.e., processing speed,memory) function, inflammation, and prevalence of multimorbidity (based on the ICD-9 codes for 20 chronicconditions). In Specific Aim 2, the degree to which baseline concentrations of GDFs and senescence-relatedproteins predict longitudinal changes in a) gait speed and SPPB score, b) major mobility disability (i.e., theinability to walk 400m), c) combined cardiovascular events (e.g., myocardial infarction, heart failure, stroke); d)adjudicated falls and injurious falls, e) cognitive function (as Aim 1), and f) the number of chronic conditions (asin Aim 1), at 1 and 2 years in LIFE and at 2 and 4 years in HABC will be determined. Finally, Specific Aim 3 willaddress whether a structured physical activity intervention impacts longitudinal changes in GDF8, GDF11,CCL11, ICAM1, AA, and PAI2, compared to a health education control intervention, and the degree to whichchange in the concentrations of these proteins parallel change in the health outcomes described in Aim 2. Thesuccessful completion of the proposed research will fill an important translational gap in our understanding ofhow GDFs and senescence-related proteins predict and, therefore, potentially mediate aging related disabilityand disease in older women and men. Ultimately, these proteins may be viable targets for innovative therapiesto extend human healthspan.

27.	Project Title:	INTERMITTENT PNEUMATIC COMPRESSION FOR DISABILITY REVERSAL IN PAD: THE INTERCEDE TRIAL
	Leader(s):	MCDERMOTT, MARY MCGRAE
		NORTHWESTERN UNIVERSITY AT CHICAGO
		NIH R01AG057693 / (2018-2023)
	PROJECT SUMMARY Our work and that of others has established that people with lower extremity peripheral artery disease(PAD) have greater functional impairment and faster rates of functional decline than people without PAD.However, few therapies improve functioning or prevent functional decline in people with PAD. Intermittent pneumatic compression (IPC) is a non-invasive intervention, consisting of an air pumpinside inflatable cuffs that are wrapped around the feet, ankles, and calves and worn for two hours daily. Every20 second, the cuffs rapidly inflate, followed by rapid deflation. During deflation, arterial blood return into thearteriovenous pressure gradient generates shear stress and stimulates nitric oxide production. Preliminaryevidence suggests that IPC improves lower extremity blood flow and walking endurance in people with PADand that benefits persist for up to 12 months after intervention completion. However, evidence is limited bysmall sample sizes, high loss to follow-up, lack of blinding, and lack of sham controls. Clinical practiceguidelines do not mention IPC as a therapeutic option in PAD. A definitive randomized trial is needed. Walking exercise is first-line therapy for PAD. However, many PAD patients are unable or unwilling toexercise. Therefore, in people with PAD, we will determine whether IPC augments the benefits of exercise onwalking endurance and whether IPC alone improves walking endurance compared to sham control. We willconduct a randomized trial (2 x 2 factorial design) of 230 PAD participants randomized to one of four groups:Group A: IPC + exercise; Group B: IPC + ?no exercise? control; Group C: sham control + exercise; and GroupD: sham control + ?no exercise? control. The IPC and sham interventions will be delivered for six months. Inour primary specific aims, we will determine whether IPC combined with exercise improves the 6-minute walkat 6-month follow-up compared to exercise alone and whether IPC alone improves the 6-minute walk at 6-month follow-up, compared to sham control. In secondary aims, we will determine whether benefits of IPCpersist by re-measuring study outcomes at twelve-month follow-up, six months after the IPC intervention iscompleted. We will also delineate mechanisms by which IPC affects walking performance, by measuringchanges in MRI-measured calf muscle perfusion, physical activity (measured with ActiGraph), and calf musclebiopsy measures of angiogenesis, muscle regeneration, mitochondrial biogenesis, mitochondrial activity, andautophagy. Based on preclinical evidence that IPC increases nitric oxide abundance and promotesvasodilation in skeletal muscle distant from the lower extremities, we will determine whether IPC improvessystemic endothelial function, by measuring changes in brachial artery flow-mediated dilation. If the IPC intervention with and without exercise improves functional performance and preventsfunctional decline in PAD, this non-invasive and well tolerated intervention will have a major impact onpreventing mobility loss and improving quality of life in the large and growing number of people with PAD.

28.	Project Title:	MECHANISMS OF OXYTOCINS ANALGESIA IN OLDER ADULTS
	Leader(s):	CRUZ-ALMEIDA, YENISEL ; EBNER, NATALIE C ;
		UNIVERSITY OF FLORIDA
		NIH R01AG059809 / (2018-2023)
	ABSTRACTOsteoarthritis (OA) represents a significant cause of disability worldwide in individuals aged 65 and older, arapidly growing segment of our population. The knee is the most commonly affected joint with pain being theprimary symptom, negatively impacting physical, cognitive, and emotional functioning. Symptomatic knee OAhas been traditionally attributed to peripheral mechanisms, but measures of joint damage only modestly accountfor the presence or severity of OA-related pain. The neuropeptide oxytocin (OT) has been recognized as amediator of endogenous analgesia in animal and human studies. However, little is known about theneurobiological mechanisms underlying OT's pain-relieving properties. This proposal is based on a mechanisticmodel of OT's analgesic effects leveraging pilot data supporting efficacy and safety of self-administeredintranasal OT over 4-weeks in older individuals. Relative to placebo (P), daily administration of intranasal OTdiminished self-reported pain intensity, reduced experimental pain sensitivity, and increased self-reportedphysical and emotional functioning. Further, participants treated with OT, compared to P, showed decreases inbrain metabolite concentrations associated with inflammation. Thus, our overarching goal is to evaluate theeffects of intranasal OT on pain and function in aging and to determine the extent to which central and peripheralinflammatory mechanisms contribute to these analgesic responses. We aim to 1) determine the effect ofintranasal OT administration on clinical and experimental pain sensitivity in older adults with symptomatic kneeOA and 2) characterize inflammatory mechanisms contributing to the inter-individual variability in analgesicresponses to OT. Older adults with symptomatic knee OA will self-administer intranasal OT or P over 4 weeksusing a double-blinded, parallel study design. With strong support from the University of Florida and the McKnightBrain Institute, our interdisciplinary project, using a comprehensive multi-methods approach, will be the first todetermine the potential benefit of OT as a novel analgesic therapy for knee OA pain in aging. OT is currentlyused in obstetrics and may be an inexpensive, effective method for pain management in older adults with littlepotential for addiction. Embedded in a biopsychosocial framework, our proposal will help pave the way for futureinvestigations using a mechanism-based treatment optimization strategy for individuals suffering from chronicpain.

29.	Project Title:	GENOMIC ANALYSIS OF THE CALERIE TRIAL TO GENERATE NEW KNOWLEDGE FOR GEROSCIENCE
	Leader(s):	BELSKY, DANIEL WALKER
		COLUMBIA UNIVERSITY HEALTH SCIENCES
		NIH R01AG061378 / (2019-2024)
	SUMMARYThe graying global population makes interventions to extend healthy lifespan (healthspan) a public heathpriority. Therapies targeting basic biological processes of aging show proof-of-concept in animals: early-to-midlife intervention can delay disease onset and prolong healthspan. But translating these geroprotectivetherapies to humans faces the barrier that human clinical trials of midlife geroprotective therapy wouldrequire decades of follow-up to measure healthspan extension. An alternative is a short-term acceleratedgeroprotector trial that tests if geroprotective intervention can slow the rate of biological aging. Biologicalaging is the gradual and progressive decline in system integrity that occurs with advancing chronologicalage. This process is thought to be the root cause of increases in morbidity and disability in later life. Newresearch shows that biological aging can be measured in humans and that measures of biological agingpredict human healthspan. Geroprotective therapies that target basic biological processes of aging arehypothesized to slow the rate of biological aging. But this has not been tested. Our study will test if the best-established geroprotective intervention in animals, long-term caloric restriction, slows the rate of biologicalaging in midlife humans, who are still young enough for age-related disease to be delayed or prevented.We will conduct new assays of stored biospecimens from the National Institute on Aging's recently-completed CALERIE Trial, which randomized 220 non-obese adults to 25% caloric restriction (CR, N=145)or ad libitum normal diet (AL, N=75) for a period of 2 years. We have already shown that CR slows aging-related deterioration in organ-system integrity. Now, we propose to extend this test to genomic measures ofbiological aging. We will assay whole-genome DNA methylation (using Illumina chips) and gene expression(using RNA sequencing) from blood samples collected at CALERIE baseline, and at 12-, and 24-monthfollow-ups. We will use this 3-time-point repeated-measures multi-omics dataset to test (i) Does CR slowsthe rate of biological aging as measured from DNA methylation? (ii) Does CR cause changes to geneexpression in the pathways known to mediate healthspan-extending effects of CR in animals, e.g. themTOR pathway? (iii) Do changes to DNA methylation and gene expression mediate effects of CR on organsystem functioning? We will share the multi-omics data we generate with the CALERIE Biorepository,making the resource freely available to all interested researchers. The proposed project will generate newknowledge about effects of caloric restriction on biological aging in humans and test proof of concept for anaccelerated geroprotector trial design that can speed translation of new age-delaying therapies fromanimals to humans. Open data sharing through the CALERIE Biorepository will enable research beyond thescope of this project to improve understanding of caloric restriction and advance the field of geroscience.

30.	Project Title:	FUNCTIONAL LIMITATIONS AND DISABILITY AMONG MIDDLE-AGED ADULTS
	Leader(s):	BOWLING, CHRISTOPHER BARRETT
		DUKE UNIVERSITY
		NIH R01AG062502 / (2020-2023)
	Project summary/Abstract The burden of functional limitations (restrictions in basic physical actions) and disability (problems with daily activities and life participation) may be more common in middle-aged US adults than previously recognized. However, studies of middle-age populations have not typically included functional assessments. The Coronary Artery Risk Development in Young Adults (CARDIA) study provides a unique opportunity to study functional status in a diverse, aging cohort. The Year 35 in-person exam is scheduled for 2020 and 2021, at which time, participants will be 53 to 65 years old. We propose a CARDIA ancillary study to obtain measures of function by self-report and physical performance to be paired with the existing data collected from early adulthood through middle age to address the following aims: 1. To quantify the burden of functional limitations and disability in middle age and assess the degree to which this can be attributed to the accumulation of chronic conditions, 2. To assess domains of functional limitations and disability captured by physical performance versus self-report, 3. To identify health-related risk factors in early adulthood for functional limitations and disability in middle-age, 4. To identify health-related, socioeconomic, and psychosocial factors that contribute to between- and within- race differences in functional limitations and disability among middle-aged adults. We will add measures of physical performance (fast and usual gait speed, single leg balance, timed chair stands, 6-minute walk test, and grip strength) to the CARDIA Year 35 exam (projected N=3,270; 1,563 black, 1,707 white). Also, self- reported functional limitations (Patient-Reported Outcomes Measurement Information System [PROMIS] Physical Function Short Form 20a) and disability measures (basic and instrumental activities of daily living) will be added to the Year 35 exam and annual telephone calls (1 call prior to and 2 after the Year 35 exam). As studies of younger populations have not often included functional assessments, the conceptualization, measurement approaches, risk factors, and implications of functional limitations and disability are poorly understood. Filling this knowledge gap by adding appropriate functional measures to an ongoing population based cohort, that represents the next wave of aging black and white adults will lead to new approaches to prevent functional decline and improve population health.

31.	Project Title:	ACTIVE ROLES OF GLIAL CELLS IN OLFACTION AND AGE-RELATED OLFACTORY DECLINE
	Leader(s):	XIAO, RUI
		UNIVERSITY OF FLORIDA
		NIH R01AG063766 / (2019-2024)
	Project SummaryAge-dependent olfactory decline (presbyosmia) is widely present in many species, including humans. At leastfifteen million Americans over 55 years old suffer from presbyosmia. By affecting the well-being, quality of life,and overall health, presbyosmia presents a significant challenge to public health. Patients with presbyosmiaoften show a decreased interest in food, can withdraw socially, and exhibit higher rates of depression.Furthermore, many age-related neurological diseases, including Parkinson's disease and Alzheimer's disease,are commonly associated with olfactory dysfunction. In fact, olfactory loss often precedes various motoricsymptoms in these deadly neurological diseases. Despite the importance of olfaction to human physiology andhealth, the cellular and molecular mechanisms underlying presbyosmia are poorly understood (knowledgegap).As a major cell type in the nervous system, glial cells are typically considered as passive modulators duringneural development and synaptic transmission. Whether glial cells play active roles in sensory transductionand brain aging is not well understood. C. elegans is a well-established model organism for neuroscience andaging research due to its simple nervous system, short lifespan, and powerful genetic tools. Very importantly,genetic studies from multiple model organisms have shown that the evolutionarily conserved genetic programsand signaling pathways play pivotal roles in regulating sensory transduction and aging process across species.This proposal will bring together in vivo calcium imaging, optogenetics, molecular genetics, and behavioralanalysis to investigate and discover the molecular mechanisms through which the olfactory glial cells playactive roles in odorant detection and age-dependent olfactory decline. Since both olfaction and aging areregulated by the evolutionarily conserved genes and signaling pathways, our innovative studies on C. elegansglial cells in olfaction and age-associated olfactory decline will provide mechanistic insights into similarprocesses in other species.

32.	Project Title:	BIOBEHAVIORAL BASIS OF KNEE OSTEOARTHRITIS PAIN
	Leader(s):	CRUZ-ALMEIDA, YENISEL
		UNIVERSITY OF FLORIDA
		NIH R01AG067757 / (2020-2025)
	Discovery and validation of strong candidate biomarkers and clinical endpoints for pain is urgently needed that can be used to facilitate the development of non-opioid pain therapeutics from discovery through Phase II clinical trials. Emerging research using a combination of biomarkers deliver individualized predictions about future brain and body health. Our own findings suggest that behavioral chronic pain characteristics are associated with multiple biological biomarkers where a greater pain burden is associated with accelerated detrimental biological processes. However, prospective research is urgently needed to determine pain?s impact on the heterogeneity of these biological processes within an individual to elucidate the underlying patterns of biological changes using a biobehavioral perspective which is needed for predicting future health and to be able to use as clinical endpoints for interventions. The proposed study will prospectively address biobehavioral factors (i.e., cognitive, psychological, social and cultural) affecting the experience and interpretation of knee pain and physical function across racial/ethnic groups over time. We will prospectively assess pain along with multiple biomarkers as predictors of cognitive, psychological and physical functional progression among middle-aged and older non- Hispanic Blacks and non-Hispanic Whites with knee pain and controls over a four-year study period. With strong support from the University of Florida, our interdisciplinary project, using a comprehensive biobehavioral multi- methods approach, we will be the first to prospectively determine the trajectory and interactions among pain, biological biomarkers and multiple domains of function within race/ethnic groups in OA pain. Findings will contribute towards increased understanding of pain and its biobehavioral basis, with the potential to reduce race/ethnic group disparities and improve pain-related health and functional outcomes.

33.	Project Title:	QUALIFICATION OF PROGNOSTIC AND DIAGNOSTIC BIOMARKERS OF KNEE OSTEOARTHRITIS
	Leader(s):	KRAUS, VIRGINIA
		DUKE UNIVERSITY
		NIH R01AR071450 / (2017-2020)
	AbstractA cure for osteoarthritis (OA) remains elusive. This is due in large part to two major obstacles, inability todetect OA sufficiently early before the onset of irreversible signs and recalcitrant symptoms, and inability toidentify individuals at high risk of progression based on traditionally used metrics (age, sex, body mass index,knee pain and joint space width). The latter challenge is responsible for low powering of clinical trials andnumerous drug trial failures. Using a systematic, unbiased and iterative approach, we have created a multiplereaction monitoring (MRM) proteomic panel for serum-based prediction of knee OA structural progression anddiagnosis of knee OA. The selection of proteins was based on results of extensive discovery proteomic studiesin synovial fluid, urine, and serum from knee OA radiographic progressors and non-progressors (with 3-4 yearfollow-up) and controls. The ultimate goals of this work are to qualify these new biomarker candidates in thecontexts of knee OA progression and OA diagnosis in larger well-phenotyped cohorts from the OsteoarthritisInitiative, the Johnston County Osteoarthritis Project and the Chingford cohorts. With this further qualification,these new biomarker tools will be very significant for their potential utility for clinical trial and clinical use toinform strategies for phenotyping and earlier identification and treatment of OA patients. We also intend topursue formal Food and Drug Administration (FDA) qualification of the optimal marker set yielded by thisproposal to facilitate their use as drug development tools.

34.	Project Title:	THE EFFECT OF INTERMITTENT HEMIDIAPHRAGM STIMULATION DURING SURGERY ON MITOCHONDRIAL FUNCTION, SINGLE FIBER CONTRACTILE FORCE AND CATABOLIC PATHWAYS IN HUMANS
	Leader(s):	SMITH, BARBARA K ; BEAVER, THOMAS M ;
		UNIVERSITY OF FLORIDA
		NIH R01AR072328 / (2017-2021)
	Although mechanical ventilation (MV) is life-sustaining in patients with respiratory failure, it comes with a cost.MV dramatically reduces diaphragm contractility, induces ventilator-induced diaphragm dysfunction (VIDD) andsometimes leads to weaning failure. VIDD includes reduced mitochondrial respiration and increased oxidativestress, muscle fiber damage and decreased diaphragm force production. In animal models, intermittentdiaphragm contraction during MV support attenuates VIDD. However, there are only limited data addressingthis problem in humans. Here, we propose to directly test the hypothesis that intermittent electrical stimulation(ES) of the human hemidiaphragm during prolonged cardiac surgeries with MV support prevents/attenuatesVIDD in the active hemidiaphragm.Mitochondrial function is central to energy metabolism and skeletal muscle function in a chronically activemuscle, such as the diaphragm. Although abnormal mitochondrial function is thought to precipitate VIDD inanimal models, limited data are available concerning mitochondrial contributions to VIDD in humans. Of evengreater importance, there are no interventions available to attenuate these defects in humans. Here, we willtest the impact of an innovative experimental treatment, intermittent electrical stimulation (ES) of thehemidiaphragm during prolonged surgeries with MV, on mitochondrial function, single fiber contractileproperties and catabolic muscle pathways in human diaphragm. Using a within-subjects experimental design,muscle samples from a stimulated hemidiaphragms will be compared with samples from the unstimulatedhemidiaphragm. We will investigate mitochondrial dysfunction and oxidative stress during prolonged CTS/MV,and the potential of ES to attenuate or prevent VIDD (Aim 1). Next, we will investigate the effects of ES onsingle fiber contractile properties and Titin integrity (Aim 2). Finally, we will study the effect of ES on proteolyticpathways (caspase, calpain and ubiquitin-proteasome) and ribosomal RNA markers of decreased proteinsynthesis implicated in VIDD (Aim 3).This research will provide evidence concerning the ability to improve mitochondrial function in the stimulatedhemidiaphragm, and identify mechanisms contributing to human VIDD. Our long-term goal is to test variousintermittent hemidiaphragm ES protocols on a larger population to determine its ability to prevent or attenuateVIDD. Data from this R01 application will advance our understanding of mechanisms giving rise to humanVIDD, and may inspire new therapeutic strategies to maintain human diaphragm function during MV support.

35.	Project Title:	MECHANOTRANSDUCTION IN MENISCUS HEALTH AND REPAIR
	Leader(s):	MCNULTY, AMY L
		DUKE UNIVERSITY
		NIH R01AR073221 / (2019-2023)
	ABSTRACT.Meniscal injuries are a significant clinical problem as each year 850,000 meniscal surgeries are performed in theUnited States and nearly twice as many worldwide. Meniscal tears in the avascular inner zone of the tissue donot heal well with suturing or conservative treatments and can ultimately lead to the development of osteoarthritis(OA). Therefore, new strategies are needed to enhance endogenous meniscus repair and tissue regeneration.The menisci play a critical biomechanical role in the knee, providing load support, joint stability, and congruity.Meniscus tissue is maintained through a balance of anabolic and catabolic activities of meniscus cells. Thesecellular activities are controlled not only by biochemical factors in the joint but also by physical factors associatedwith joint loading. Mechanobiology, which is the influence of mechanical factors on the biologic response of cells,is important in converting physical signals into metabolic and inflammatory responses in meniscus. However,the mechanisms by which mechanical signals are transduced in meniscus cells have yet to be identified. Ouroverall goal is to identify critical meniscus mechanotransduction pathways and modulate thesepathways to promote meniscus repair and prevent OA development.Our work has shown that transient receptor potential vanilloid 4 (TRPV4) is a critical component in cartilagemechanotransduction and metabolism. The activation of TRPV4 can block IL-1 induced catabolic responses andalso increases cell migration and proliferation, which are important processes to enhance tissue repair. Whilewe have found that TRPV4 is expressed in the meniscus, the function of this mediator in meniscus health anddisease is currently unknown. In this proposal, we will determine how mechanotransduction occurs throughTRPV4 in meniscus and identify modulators of this pathway that will be used to enhance tissue repair and preventOA development. We hypothesize that mechanotransduction by TRPV4 plays a key role in meniscus metabolismand can be modulated to enhance meniscus repair and prevent the development of OA. In this proposal, we willdetermine the effects of mechanical stimulation on TRPV4-mediated metabolism in healthy meniscus cells.Next, we will elucidate alterations in TRPV4-mediated mechanotransduction pathways in meniscus pathology.Finally, we will enhance integrative meniscus repair and prevent the development of OA by modulation ofmechanotransduction pathways. In this proposal, we will identify the key signaling pathways downstream ofTRPV4 that may function as novel drug targets to 1) treat patients with immobilized joints to simulate exerciseand maintain joint health; 2) enhance meniscus tissue regeneration using tissue engineering strategies; and 3)enhance meniscus repair and prevent the development of OA. Novel therapeutic targets identified in thisproposal can subsequently be developed into drugs to enhance meniscus repair and prevent the developmentof OA.

36.	Project Title:	REVIVE - RESVERATROL TO ENHANCE VITALITY AND VIGOR IN ELDERS
	Leader(s):	ANTON, STEPHEN D
		UNIVERSITY OF FLORIDA
		NIH R01AT007564 / (2013-2019)
	A large and growing number of older adults experience progressive declines in physical function, culminating in age-related physical disability with no clear connection to a single disease. Although the etiology of age-related physical disability is complex and multi-factorial, emerging evidence implicates the mitochondria as playing a key role in the initial onset and progression of functional decline in many older adults. Additionally, our pilot data strongly suggest functional declines are associated with reductions in mitochondrial respiration, as well as decreases in oxidative mitochondrial enzyme activities and enzyme content. These changes were linked to a large decline in peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1a) and specific Sirtuins (i.e., SIRT3) in skeletal muscle, both of which are regulators of mitochondria biogenesis. The natural compound resveratrol appears to oppose the reductions in mitochondrial function associated with aging by affecting the expression of key genes, such as PGC-1a;, which support oxidative phosphorylation and mitochondrial biogenesis. In another recently completed pilot study, we found resveratrol, at a dose of 1000 mg/day, significantly enhanced resting muscle oxidative metabolism (measured using near infrared spectroscopy), as well as cognitive and physical function, in older adults (age > 65 years). Despite promising findings from one recent clinical trial involving obese, middle-age men, no study to date has examined the effects of resveratrol supplementation on mitochondrial function in older adults, or whether the hypothesized changes in mitochondrial function translate to improvements in physical functioning. Thus, the proposed randomized, parallel study will determine, in older men and women (> 70 years), whether 90 days of resveratrol supplementation is associated with (i) increases in muscle mitochondrial function (State 3 & 4 respiration), (ii) increases in levels of PGC-1a, AMP-activated protein kinase (AMPK), and Sirtuins (i.e. SIRT1 and SIRT3), and (iii) improvements in functional performance, as well as metabolic risk factors. To achieve these aims, 60 moderate to low functioning participants will be randomized to receive a placebo (n=20), 1000 mg/day of resveratrol (n=20), or 1500 mg/day of resveratrol (n=20) for a 90-day period. We will collect muscle specimens from the vastus lateralis and blood at baseline and 90 days for biochemical analyses, as well as monitor blood chemistries and adverse events at monthly clinic visits. If our hypotheses are supported, this study will be the first to show that resveratrol improves mitochondrial function in muscle, and that these changes are associated with increased levels of physical function in moderate to low functioning older adults - the population who is at greatest risk of functional decline and physical disability.

37.	Project Title:	THE BENEFITS AND HARMS OF LUNG CANCER SCREENING IN FLORIDA
	Leader(s):	BIAN, JIANG ; GUO, YI ;
		UNIVERSITY OF FLORIDA
		NIH R01CA246418 / (2020-2023)
	Lung cancer is the leading cause of cancer related death in both men and women in the United States. Currently, approximately 70% of lung cancer patients are diagnosed at advanced stages, and the 5-year survival rate of advanced stage lung cancer is very low, at only 16%. Investigators have been searching for effective screening modalities for the early detection of lung cancer so that patients can receive curative treatments at an early stage. When the National Lung Screening Trial (NLST) demonstrated the effectiveness of using low-dose computed tomography (LDCT) scan for lung cancer screening (LCS), researchers and physicians hope to save lives from lung cancer by screening high-risk population who aged 55 to 77 years and have a 30 pack years making history or former smokes who have quitted within the past 15 years. Since the release of the landmark NLST results, many medical associations published guidelines to recommend LDCT-based screening for individuals at high risk for lung cancer and the Centers for Medicare and Medicaid Services (CMS) also decided to cover the LCS for Medicare beneficiaries who are at high risk for lung cancer. While many efforts have been made to accelerate the dissemination the beneficial LCS, the concerns over the high false positive rates (96.4% of the positive results), invasive diagnostic procedures, postprocedural complications and health care costs may hinder the utilization of lung cancer screening. This concern was magnified as researchers and policy makers started questioning whether the complication rate and false positives in real-world settings would be even higher than the rates reported in the NLST, which was conducted in a setting with well-established facilities and proficiency in cancer care. Therefore, we propose to understand the contemporary use of lung cancer screening and associated health care outcomes and costs using data from a real-world setting. Our study has three goals: 1) to develop an innovative computable phenotype algorithm to identify high-risk and low-risk individuals for LCS from both structured and unstructured (i.e., clinical notes) electronic health record (EHR) data and to develop advanced natural language processing (NLP) methods to extract LCS related clinical information from clinical notes such as radiology reports; 2) to determine the appropriate and inappropriate use of LDCT among high-risk and low-risk individuals in Florida and to examine the test results of LDCT, the rates of invasive diagnostic procedures, postprocedural complications, and incidental findings in real-world settings; and 3) to develop and validate a microsimulation model of the clinical courses of LCS incorporating the real-world data in LCS to estimate the long-term benefits and the cost-effectiveness of LCS. Our proposed study has the potential to reduce lung cancer incidence and mortality by informing policymakers and practitioners on the appropriateness of contemporary use of LCS. This knowledge will help both patients and physicians better understand the harm- benefit tradeoff of lung cancer screening and transform such knowledge into practice to prevent avoidable postprocedural complications.

38.	Project Title:	COCHLEAR DETOXIFICATION SYSTEM
	Leader(s):	SOMEYA, SHINICHI
		UNIVERSITY OF FLORIDA
		NIH R01DC014437 / (2015-2020)
	DESCRIPTION (provided by applicant): Living organisms are continuously exposed to and must defend against naturally occurring toxins and non- nutrient foreign chemicals (1-3). Cells possess a wide range of detoxification enzymes capable of removing thousands of toxic and foreign compounds. The glutathione transferase (GST) detoxification system converts a non-polar toxic compound into a more water-soluble and less toxic form by conjugating the toxic compound to reduced glutathione by a variety of GST enzymes. GSTs are a superfamily of enzymes that are divided into several classes on the basis of their primary structure (1-3). Because of their cytoprotective role and involvement in the development of resistance to anti-cancer agents, GSTs have become attractive drug targets. Epidemiological studies found a significant association between age-related hearing loss and GSTT1 and GSTM1 null polymorphisms was found in a Finnish population (5) and a Hispanic population (6). McElwee et al (7) conducted a cross-species comparative analysis to compare gene expression changes in long-lived worms, flies, and mice, and found that GST and other cellular detoxification gene categories were significantly up- regulated in long-lived members of the three species, suggesting the GST detoxification system plays a major role in longevity or protection against aging in multiple species. Consistent with these reports, our preliminary studies found that long-living calorie-restricted C57BL/6 mice display increased expression of Gsta4, Gstm1, Gstm5, and Gstt1 genes in the cochlea. Collectively, these results suggest that GST detoxification enzymes may play an important role in ototoxicity. Cisplatin, a platinum-containing compound, is one of the most widely used chemotherapeutic agents (8-10). Evidence indicates that one-third of all cisplatin-treated patients develop hearing loss. Such hearing impairment is dose-dependent, irreversible, and associated with loss of hair cells. Wheeler et al (11) performed meta-analyses of over 3 million single-nucleotide polymorphisms (SNPs) for cisplatin-induced cytotoxicity in 608 lymphoblastoid cell lines from seven HapMap panels. The study found that increased GSTM1 and GSTT1 expression was associated with increased cisplatin resistance. Our preliminary study also found that cisplatin treatment up-regulates GSTA and GSTM genes in mouse cochlear organotypic cultures. Yet, how the cochlear detoxification system fights such ototoxic drugs at the molecular level remain poorly understood. The overall goal of our research proposal is to provide new basic knowledge of the molecular basis for the cochlear detoxification system and its role in the elimination of foreign chemicals throughout the lifespan.

39.	Project Title:	AUTOPHAGY IN LIVER INJURY
	Leader(s):	KIM, JAE-SUNG
		WASHINGTON UNIVERSITY
		NIH R01DK079879 / (2007-2020)
	DESCRIPTION (provided by applicant): Mitochondrial dysfunction is the major mechanism precipitating I/R injury which commonly occurs during liver surgery, trauma, hemorrhagic shock and liver transplantation. Sirtuin 1 (SIRT1) is an NAD+-dependent deacetylase that induces longevity, stress resistance and tumor suppression. The role of SIRT1 in ischemia/reperfusion-mediated liver injury is unknown. The goal of this study is to investigate the role of SIRT1 in I/Rinjury to liver and to develop therapeutic strategies to improve liver function after I/R. Our principal hypothesis is that calpain-dependent SIRT1 loss causes a sequential chain of defective mitophagy, mitochondrial permeability transition (MPT) onset and hepatocyte death after I/R. Accordingly, we propose that restoration or enhancement of hepatic SIRT1 will promote mitophagy and consequently ameliorate mitochondrial failure and liver dysfunction after reperfusion. To test our hypothesis, we will use hepatocytes isolated from SIRT1 wild type (WT) and knockout (KO) mice for characterization of cellular mechanisms causing SIRT1 depletion, defective mitophagy, and onset of the MPT and cell death after I/R. In addition, we will use anesthetized WT and KO SIRT1 mice to confirm and extend our in vitro findings to an in vivo model of hepatic I/R. Finally, we will extend and translate our findings from mice into human liver biopsies. These studies provide critical mechanistic insights into lethal I/R injury to the lver, and will establish novel therapeutic approaches for improving I/R-mediated liver failure.

40.	Project Title:	Evaluation of an Adaptive Intervention for Weight Loss Maintenance
	Leader(s):	ROSS, KATHRYN MARIE
		UNIVERSITY OF FLORIDA
		NIH R01DK119244 / (2019-2024)
	Obesity remains a substantial public health challenge in the United States. Behavioral weight management programs have demonstrated effectiveness for weight loss, but long-term maintenance of these weight losses after the end of treatment tends to be poor. Evidence has demonstrated that individuals who can maintain their changes in eating and activity can successfully maintain their weight loss; thus, attempts to improve weight loss maintenance have often involved provision of continued support through monthly ?extended-care? intervention sessions. While these interventions have demonstrated significant improvements in weight loss maintenance, effects have been modest. A key challenge is continued participant engagement (often assessed as attendance at intervention sessions). Attendance has been closely tied to weight outcomes, but rates tend to be poor and decline over time. The once-per-month, static treatment schedules of existing programs may contribute to these suboptimal outcomes; a participant experiencing a small lapse in weight-related behaviors may not receive support for several weeks, by which point they may be experiencing a larger lapse or weight regain. This can lead to feelings of frustration, shame, or embarrassment and disengagement from intervention. In contrast, tailoring intervention delivery such that sessions are provided when individuals are at ?high risk? for weight regain offers potential to disrupt this cycle and significantly improve program engagement, adherence to program goals, and long-term weight maintenance outcomes. We propose to evaluate an innovative method of providing phone-based extended-care adaptive to participant needs. We have built a smartphone application that can be used by participants to track weight, dietary intake, and physical activity (key self-monitoring behaviors in traditional behavioral weight management programs) and can further query participants throughout the week regarding self-report factors (e.g., ratings of hunger and the importance of staying on track with weight management goals) that indicate high risk for weight regain. We have also developed a predictive algorithm that uses this data to identify when individuals are at ?high risk? of weight regain. We propose to conduct a randomized controlled trial evaluating the impact of ADAPTIVE (delivered only when indicated by our algorithm or when initiated by participants via an in-app support request) versus STATIC (the monthly, pre-scheduled format used in existing extended-care programs) treatment provision on weight regain at 24 Months in 258 adults who successfully lose = 5% of initial weight during a gold-standard 16-week behavioral weight management program. Results of this study have clear treatment implications for the timing/frequency of sessions within extended-care weight maintenance programs, and this study will result in an innovative, low-cost, and easily scalable intervention for weight loss maintenance. Further, the proposed research will fill a critical gap in the weight management literature by building a foundational evidence base of proximal predictors of weight-related behaviors for future adaptive intervention development.

41.	Project Title:	HEMATOPOIETIC STEM CELL DYSFUNCTION IN THE ELDERLY AFTER SEVERE INJURY
	Leader(s):	EFRON, PHILIP A
		UNIVERSITY OF FLORIDA
		NIH R01GM113945 / (2015-2020)
	DESCRIPTION (provided by applicant): People of advanced age (greater than 55 years old) have significantly increased morbidity and mortality after trauma. Since the elderly population is expanding, research into this disease process is increasingly relevant, especially with the escalating economic and health care burdens on our society. Despite decades of promising preclinical and clinical investigations in trauma, our understanding of this entity and why its effects are exacerbated in the elderly remains incomplete, with few therapies demonstrating success in any patient population. Recently, several aspects of innate immunity have been determined to be of vital importance to the young adult immune response, and this response is suboptimal in the aged after severe injury and subsequent infections. Specifically, neutrophils are replaced after inflammation through a process known as 'emergency myelopoiesis.' This occurs after severe injury when bone marrow granulocyte stores are rapidly released, and increased stem cell proliferation and differentiation along myeloid pathways results. Proper differentiation of myeloid cells from stem cells is dependent on activation of nuclear factor kappaB (NFB), a protein complex that partially controls DNA transcription after stressful stimuli. Anappropriate emergency myelopoietic response to inflammation is essential to host survival but appears to be inadequate in the elderly as compared to younger patients. Specifically, we hypothesize that the myelodysplasia associated with aging modifies the emergency myelopoietic response to traumatic injury, resulting in inappropriate differentiation and maturation of myeloid cells, leaving the host susceptible to subsequent infection. We further propose that this failure of emergency myelopoiesis is due to age-associated, chronic activation of NFB-dependent inflammatory pathways, and a failure of hematopoietic stems cells (LSK populations) after trauma to create functional myeloid populations in a NFB-dependent manner. Using a novel murine polytrauma (PT) model of murine hemorrhagic shock and injury that better recapitulates the human condition, we will: (1) determine if certain hematopoietic stem cells (HSCs), specifically short term-HSCs (ST-HSCs), fail to properly expand and differentiate along myeloid pathways in the elderly response to trauma, and, if the resultant dysfunctional neutrophil population seen in the elderly after trauma results from these suboptimal ST-HSCs; (2) determine if the defects in aged ST-HSC function after severe injury, as compared to their juvenile counterparts, are caused by a chronic low-grade NFB-dependent inflammatory state and a subsequent failure to appropriately activate NFB-dependent pathways after trauma; and, (3) determine if the HSC senescence associated with elderly humans after severe trauma is also due to a failure to appropriately activate NFB-dependent pathways in bone marrow HSCs. This work proposes that increased susceptibility to infection after trauma in aging is due, at least in part, to defects in myelopoiesis that lead to genotypically, phenotypically and functionally deranged PMNs that fail to control infection. The third specific aim will translate our 'bench side' animal work to humans and this innovative approach could identify areas for intervention in cell types that are still exhibit plasticity.

42.	Project Title:	THE ROLE AND MECHANISMS OF LIPID AND LIPOPROTEIN DYSREGULATION IN SEPSIS
	Leader(s):	GUIRGIS, FAHEEM W
		UNIVERSITY OF FLORIDA
		NIH R01GM133815 / (2020-2025)
	Sepsis is a dysregulated response to infection that has both fatal and non-fatal morbid consequences. Unfortunately, initial survival does not provide relief from morbidity for most sepsis survivors. Initial clinical trajectories include rapid recovery, early in-hospital death, and progression to chronic critical illness (ICU stay = 14 days with organ dysfunction). Late complications include sepsis readmission and late death, both of which have rates of approximately 40% at 90 days and 6 months, respectively. Circulating lipids play an important role in sepsis and cholesterol levels of both high density lipoproteins (HDL-C) and low density lipoproteins (LDL-C) are dynamically regulated in sepsis. HDL and LDL are both thought to play protective roles in sepsis via several mechanisms (antioxidant/anti-inflammatory function, bacterial toxin clearance, steroid synthesis), but the exact mechanisms by which HDL and LDL protects against sepsis are not known. Lipid and lipoprotein dysregulation occurs in early sepsis, leading to failure to protect against sepsis. We have shown that: 1) HDL becomes dysfunctional (pro-oxidant and pro-inflammatory) in early sepsis (Dys-HDL); 2) elevated Dys-HDL levels positively correlate with and predict organ failure severity and are associated with poor outcomes including 28-day mortality; 3) HDL from older septic patients exhibits impaired cholesterol efflux capacity (required for toxin clearance and steroidogenesis); 4) HDL and LDL levels drop precipitously during sepsis, and the severity of the drop is predictive of death; and 5) low baseline LDL levels are associated with increased long-term community-acquired sepsis risk. Highly biologically active lipid metabolites are also present in the circulation during sepsis that may propagate and promote inflammation resolution and contribute to cholesterol dysfunction. Our data strongly suggest that lipid and lipoprotein dysregulation occurs in sepsis and leads to altered function, oxidation, and reduced levels that may influence clinical outcomes. We hypothesize that specific functional, lipidomic, and genomic changes in lipid and lipoprotein metabolism occur in early sepsis and relate to relevant clinical trajectories (rapid recovery, early death, and chronic critical illness and sepsis recidivism). To test our hypothesis, we will capitalize on an established and experienced sepsis research team and the opportunity provided by an existing bank of samples from a diverse cohort of 80 community-acquired (CA) and 85 hospital-acquired (HA) sepsis patients from two-centers. This approach has several advantages: 1) cost-savings from use of existing samples with isolated mRNA, 2) a recent cohort of sepsis patients (2016-2018) consistently treated with institutional evidence-based management bundles, 3) availability of serial samples over time (enrollment, 48h, 28d, and 90d), sepsis readmission samples, and mRNA for the CA cohort, 4) age/gender matched control samples, 5) available clinical and outcomes data. We also propose two-site prospective enrollment of a small cohort of sepsis readmission patients to study this novel and important outcome. This project satisfies the NIGMS mission of researching biological mechanisms that underlay the foundation for advances in treatment of diseases such as sepsis.

43.	Project Title:	IMPROVE PAD PERFORMANCE WITH METFORMIN. THE PERMET TRIAL
	Leader(s):	MCDERMOTT, MARY MCGRAE
		NORTHWESTERN UNIVERSITY AT CHICAGO
		NIH R01HL131771 / (2016-2021)
	PROJECT SUMMARY Improve PAD PERformance with METformin: The PERMET Trial. Our work and that of others has established that people with lower extremity peripheral artery disease(PAD) have greater functional impairment, faster functional decline, and increased rates of mobility losscompared to people without PAD. However, few therapies are available that improve functioning or preventfunctional decline in people with PAD. Metformin is an inexpensive, widely available, well tolerated biguanide medication and the mostcommonly prescribed drug for Type 2 diabetes mellitus worldwide. Recent pre-clinical and preliminary humanevidence suggest that metformin has previously unrecognized therapeutic properties. Therapeutic propertiesof metformin in pre-clinical models that may benefit people with PAD include: calf skeletal muscle increases inperoxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1a) (a major regulator ofmitochondrial biogenesis), calf skeletal muscle increases in mitochondrial protein expression and activity,increases in capillary density in ischemic tissue, reductions in oxidative stress, increased autophagy (repair ofcellular damage), and improved endothelial function. These therapeutic properties target pathophysiologicconditions present in PAD. Therefore, we hypothesize that metformin will improve lower extremity functioningin people with PAD, by facilitating favorable changes in calf skeletal muscle and by increasing calf skeletalmuscle perfusion. No randomized clinical trials have studied whether metformin improves lowerextremity functioning in PAD. A definitive trial is needed. We propose a placebo controlled double-blind randomized clinical trial to establish whether metformin(2,000 mgs daily) improves and/or prevents decline in walking performance in people with PAD. Participantswill be 212 people with PAD who do not have diabetes mellitus, since metformin is a first-line therapy for Type2 diabetes. Our primary outcome is change in six-minute walk at 6-month follow-up. Secondary outcomes are6-month changes in treadmill walking performance, brachial artery flow-mediated dilation, calf skeletal musclebiopsy measures, patient-reported walking performance, and quality of life. Calf muscle outcomes consist ofchanges in PGC-1a abundance, mitochondrial quantity, mitochondrial enzyme activity, capillary density,reactive oxygen species (ROS)-induced tissue damage, and autophagy. If metformin improves functional performance and prevents functional decline in PAD, this widelyavailable, inexpensive, and well tolerated medication will have a major impact on preventing mobility loss andimproving quality of life in the large and growing number of people with PAD.

44.	Project Title:	TRANSCRIPTIONAL REGULATION OF KCNH2
	Leader(s):	DELISLE, BRIAN P
		UNIVERSITY OF KENTUCKY
		NIH R01HL141343 / (2019-2023)
	SummaryCircadian rhythms help to match the optimal function of the cardiovascular system to the daily changes in theenvironment. Normal cardiovascular rhythms provide a physiological advantage to people. Unfortunately,normal circadian signaling can also unmask a time-of-day pattern in adverse events like heart attack, stroke,and sudden death in patients with underlying cardiovascular disease.Emerging data now show that abnormal or unhealthy daily rhythms can create a negative impact on normalhealth too. For example shiftwork, which repeatedly causes shifts in endogenous circadian rhythms, is anindependent risk factor for cardiovascular disease.In mammals the suprachiasmatic nucleus (SCN) in the brain is the primary circadian pacemaker that helps toentrain endogenous rhythms to the environment. SCN rhythms are synchronized to the environment via light,and its signaling helps to coordinate the molecular rhythms in cells throughout the body. What is new aboutthis application is we determine how repeated changes in light cycle will impact molecular circadian signaling inthe heart.Most cells have a molecular clock signaling mechanism that cycles with a periodicity of ~24 hours. We foundgenetic disruptions in the molecular clock mechanism of heart cells (cardiomyocytes) primarily causesabnormal changes in cardiac electrophysiology by disrupting the regulation of ion channel function.The goal of this application is to determine how repeated shifts in the light cycle impact molecular clocksignaling in the mouse heart and its regulation on ion channel function.Aim 1. To identify new mechanisms with which the cardiac molecular clock regulates different ion channels.Aim 2. To determine how repeated changes in light impact molecular clock signaling in the heart and ionchannel regulation.This project creates new knowledge at the interface between chronobiology and cardiac electrophysiology.

45.	Project Title:	IMPAIRED MITOCHONDRIAL ENERGETICS IS A DRIVER OF HEMODIALYSIS ACCESS RELATED HAND DYSFUNCTION
	Leader(s):	SCALI, SALVATORE T.
		UNIVERSITY OF FLORIDA
		NIH R01HL148597 / (2019-2024)
	PROJECT SUMMARYCurrently, in the United States, there are ~425,000 patients receiving hemodialysis (HD) and it is estimated that30-60% of this population have some element of hand dysfunction after hemoaccess surgery. The underlyingpathophysiologic mechanisms responsible for this devastating problem are poorly understood. The renaldysfunction (RD) milieu causes a variety of physiologic derangements in HD patients including increasedoxidative stress (OS) and chronic inflammation that have been implicated as major contributors to acceleratedatherosclerosis and elevated mortality. Profound changes in OS contribute to skeletal muscle and neuromuscularjunction dysfunction associated with muscle atrophy and frailty in this population. AVF surgery causes significanthemodynamic changes in the extremity which presents an adaptive challenge to the skeletal muscle andneuromotor end-plate. Supported by our previous work, as well as preliminary data on RD associated skeletalmuscle mitochondrial phenotypic changes, we propose that RD driven mitochondrial dysfunction alters skeletalmuscle and neuromuscular junction responses to AVF induced ischemia leading to clinically apparent handdysfunction. Further, these pathways can be modified either prior to AVF creation or at first evidence of handdysfunction to reverse/prevent the functional impairment. Our hypothesis is that the RD milieu disruptsmitochondrial and cellular energetics resulting in elevated OS predisposing patients undergoing AVF surgery todeveloping skeletal muscle and neuromuscular junction perturbations causing clinically significant handdysfunction. RD mediated mitochondrial impairments are further exacerbated by local hemodynamic changesfollowing AVF creation through maladaptive OS metabolic responses that drives the diversity of clinicallyapparent hand dysfunction. Aim 1 will establish how RD impacts mitochondrial and cellular energetics that areexacerbated by AVF-induced limb ischemia. Using a series of in vitro experiments, we will uncover thebiochemical mechanisms by which RD impacts mitochondrial energetics leading to impaired oxidativephosphorylation and increased OS. Aim 2 will determine the efficacy of global or mitochondrial-targetedantioxidant therapies delivered prior to- and following AVF surgery in mice. Using a novel RD murine AVF model,we will determine whether global (N-acetylcysteine) or mitochondrial-targeted (AAV delivery of mitochondrialtargeted catalase) antioxidant therapy have therapeutic potential for AVF-induced muscle dysfunction. Aim 3will evaluate the association between mitochondrial health and AVF-induced hand dysfunction in humanpatients. Mitochondrial health will be examined in-situ using permeabilized myofibers prepared from RD patientsbefore and after AVF surgery: mitochondrial phenotypic changes will be evaluated and their association withchanges in serial hemodynamic, neurophysiological and biomechanical outcomes modulating the spectrum ofhand function will be determined.

46.	Project Title:	MOLECULAR MECHANISMS REGULATING PERIPHERAL ARTERIAL DISEASE PATHOBIOLOGY IN CHRONIC KIDNEY DISEASE
	Leader(s):	RYAN, TERENCE E
		UNIVERSITY OF FLORIDA
		NIH R01HL149704 / (2019-2024)
	Peripheral artery disease (PAD) is caused by atherosclerosis in the lower extremities which leads to a spectrum of life-altering symptomatology, including claudication, ischemic rest pain, and gangrene requiring limb amputation. Complicating the etiology of PAD, patients typically present with comorbid conditions or risk factors that accelerate disease evolution and substantially worsen pathology contributing to increased mortality risk. Among these, chronic kidney disease (CKD) accelerates the development of atherosclerosis, decreases functional capacity, and increases risk of amputation or death, however the underlying biologic mechanism(s) are poorly understood and vastly understudied compared with other comorbidities (i.e. smoking and diabetes). We have uncovered a novel molecular pathway that may link CKD and PAD pathobiology. We find that many uremic metabolites, which accumulate in CKD, cause chronic activation of the aryl hydrocarbon receptor (AHR) which leads to disruption of the mitochondrial electron transport system that exacerbates ischemic muscle injury and impairs angiogenesis. Preliminary experiments demonstrate that genetic knockdown of the AHR is protective against uremic toxicity, whereas expression of a constitutively active AHR causes mitochondrial dysfunction. Thus, we propose to test the novel hypothesis that the chronic activation of the AHR pathway results in ischemic muscle injury and impaired angiogenesis, thereby linking CKD and PAD pathobiology. This hypothesis will be tested using muscle- and vascular-specific inducible knockout of the AHR as well as adeno- associated virus-mediated expression of the a constitutively active AHR in pre-clinical models of CKD/PAD. Finally, our recent human data indicate elevated AHR signaling in PAD patients with CKD. We propose to extend these findings to establish a clinical link between muscle health/function, mitochondrial energetics, and AHR signaling in human PAD patients. Success in these studies will provide mechanistic insight into the impact of CKD on PAD pathobiology, and would provide a novel target for therapeutic development aimed to treat a patient population that currently has few available options.

47.	Project Title:	CIRCADIAN CLOCK REGULATION OF MYOCARDIAL ION CHANNEL EXPRESSION AND FUNCTION
	Leader(s):	ESSER, KARYN A ; DELISLE, BRIAN P ;
		UNIVERSITY OF FLORIDA
		NIH R01HL153042 / (2020-2024)
	The overall objectives of this proposal are to 1) define the genomic and transcriptomic mechanisms by which the cardiomyocyte clock regulates ion channels that contribute to cardiac excitability; and 2) disrupt the cardiomyocyte clock to link changes in circadian-ordered gene expression with electrophysiological properties of atrial and ventricular cardiomyocytes. The outcomes will address significant gaps in our understanding for how the myocardial circadian clock regulates the expression of key cardiac ion channels and how abnormal cardiac clock function contributes to arrhythmia vulnerability. The mechanism regulating circadian timing, the molecular clock, exists in virtually all cell types in the body. A critical function of the molecular clock is to link time of day with a large-scale transcriptional program to support cellular homeostasis To date, our labs have used an inducible cardiomyocyte specific mouse model to knock out the core clock gene, Bmal1 (iCSBmal1). These studies showed that disruption of the myocardial clock is sufficient to decrease ventricular K+ and Na+ channel gene expression, disrupt current levels, disrupt cardiac excitability, and increase arrhythmia susceptibility. These studies establish a critical role for the cardiomyocyte clock, independent of the central clock, in regulating the expression of different families of ion channel genes that impact the ionic balance needed for normal excitability. One goal of this project is to utilize large scale genomic and transcriptomic approaches with our mouse model system to define the circadian clock dependent control of temporal gene expression in both atrial and ventricular tissues. To address abnormal circadian clock function, our lab has used different models of circadian disruption, such as chronic phase advance or time restricted feeding to test links between circadian disruption and arrhythmia vulnerability in mouse models. We have found that disrupting either light or feeding time cues is sufficient to induce pathological changes in cardiac rhythms in normal mice and to accelerate sudden cardiac death in a genetic mouse model of arrhythmia susceptibility. These studies support our premise that disruption of day- night rhythms through environmental factors leads to altered myocardial clock function with outcomes that include modified ion channel expression, cardiac excitability and arrhythmia vulnerability. The aims of this proposal are designed to test the following hypotheses: 1) The molecular clocks in both atrial and ventricular cardiomyocytes are necessary to direct daily chromatin accessibility and transcriptional output including expression of key ion channel and ion channel regulatory genes. 2) Chronic disruption of the cardiomyocyte clock using altered time of feeding is sufficient to cause dysregulation of the cardiac clock resulting in an imbalance in cardiac ion channel expression and currents leading to altered excitability and increased arrhythmia vulnerability.

48.	Project Title:	EMOTIONAL ENGAGEMENT DRIVEN BY COMPLEX VISUAL STIMULI: NEURAL DYNAMICS REVEALED BY MULTIMODAL IMAGING
	Leader(s):	DING, MINGZHOU ; KEIL, ANDREAS ;
		UNIVERSITY OF FLORIDA
		NIH R01MH112558 / (2017-2022)
	Project?Summary??Emotional?dysfunction?is?at?the?core?of?many?psychiatric?disorders,?in?particular?fear,?anxiety,?post-?traumatic,?and?mood?disorders.?Describing?the?neural?mechanisms?associated?with?emotional?processing?is?therefore?a?critical?issue?in?mental?health?care.?Previous?attempts?to?define?the?neurophysiology?of?human?emotions?in?the?cognitive? neuroscience? laboratory? have? been? hampered? by? the? unavailability? of? conceptual? and?methodological? frameworks? for? studying? complex? emotional? responses? in? context? and? with? conflicting?information?present.?The?proposed?research?establishes?a?novel?technique?for?combining?electrophysiological?recordings,? high? in? temporal? precision,? with? functional? brain? imaging,? which? is? high? in? spatial? precision.? This?approach,?called?steady-?state?potential?frequency-?tagging,?achieves?stimulus?specificity,?temporal,?and?spatial?resolution?across?the?whole?brain.?It?is?unique?in?that?it?allows?researchers?to?identify?distinct?brain?networks?selectively?activated?by?different?elements?of?a?complex?visual?scene?even?when?the?elements?are?spatially?overlapping? and? accompanied? by? stimulation? in? other? sensory? modalities.? We? combine? this? innovative?approach?with?a?novel?conceptual?framework?that?considers?changes?in?visual?perception?an?active?part?of?an?observer?s? emotional? response,? to? address? the? following? Aims:? (1)? We? characterize? the? large-?scale? brain?dynamics? mediating? the? emotional? response? to? an? element? that? is? embedded? in? a? complex? visual? array.? (2)?We? determine? how? conflicting? appetitive? and? aversive? information,? visual? and? auditory,? affects? these? brain?dynamics.? (3)? Finally,? we? translate? this? novel? method? to? socially? anxious? observers,? testing? mechanistic?hypotheses? regarding? the? interactive? effects? of? trait? anxiety? and? chronic? stress? on? short-?term? reactivity? to?emotional? challenge.? The? long-?term? clinical? implications? of? the? proposed? research? are? manifold:? For?diagnostic?assessment?and?for?monitoring?treatment?efficacy,?a?quantitative?brain-?based?marker?of?emotional?engagement? opens? avenues? for? objectively? evaluating? pre-?? to? post-?treatment? changes? in? appetitive/aversive?neural? reactivity.? It? also? enables? measuring? neural? circuit? function? to? enable? quantitative? measurements? of?specific?psychopathology?and?for?identifying?treatment?targets?in?a?personalized?medicine?framework.?

49.	Project Title:	BIOBEHAVIORAL MECHANISMS UNDERLYING SYMPTOMS AND HEALING OUTCOMES IN OLDER INDIVIDUALS WITH CVLU
	Leader(s):	STECHMILLER, JOYCE K. ; LYON, DEBRA E ;
		UNIVERSITY OF FLORIDA
		NIH R01NR016986 / (2018-2023)
	ABSTRACT Our long-term goal is to elucidate the complex biobehavioral mechanisms responsible for symptoms andhealing outcomes for older adults? with venous leg ulcers (VLUs) for the development of targeted therapies thataddress both the patient-oriented outcomes and healing outcomes in this growing group of affected individuals.VLUs, which account for 70?90% of ulcers found in the lower leg, affect 2 million persons annually, includingnearly 4% of people over age 65 years. To date, the basic biology underlying the development and persistenceof VLUs and the influence of aging and multiple disease conditions on wound healing are generally not wellunderstood. Individuals living with chronic VLU (CVLU) have a high symptom burden of both wound-relatedsymptoms and symptoms of pain, depression, anxiety, fatigue and cognitive dysfunction, collectively labeled as?psychoneurologic symptoms (PNS).? Guided by the National Institutes of Health Symptom Science Model(NIH-SSM) framework, the central hypothesis of this application is that there are interrelated molecularmechanisms by which the immune activation that contributes to the development and persistence of CVLUalso leads to the development, persistence and severity of PNS. The specific aims of the proposed study areto: (1) Characterize the strength of the associations at baseline among patient-host factors, systemicinflammation, and wound microenvironment with wound area and symptoms (PNS and wound-related); and,(2) Test associations and models over time for: (a) Patient-host factors and systemic inflammation with woundmicroenvironment; (b) Patient-host factors and wound microenvironment with systemic inflammation; (c)Patient-host factors, systemic inflammation, and wound microenvironment with wound healing; (d) Patient-hostfactors, systemic inflammation, and wound microenvironment with symptoms (PNS and wound-related) and (e)Patient-host factors, systemic inflammation, wound microenvironment and wound healing with symptoms (PNSand wound-related). To achieve the specific aims, we will longitudinally examine 200 older adults (age >60)who are receiving state of the art, standardized wound treatment biweekly across eight weeks time. We willfully characterize patient-host characteristics (age, comorbidities, sex, race/ethnicity, BMI, nutritional status,lifestyle habits, and wound treatment [pressure therapy, debridement, antibiotics]); systemic inflammatoryactivation (C-reactive protein and cytokines); wound microenvironment factors (local inflammation [Matrixmetalloproteinase (MMP) enzymes C-reactive protein, cytokines], biofilm, and micro RNAs); symptoms (PNS[cognitive dysfunction, pain, fatigue, and depressive/anxiety symptoms] and wound-related); and woundcharacteristics and healing trajectory at the five timepoints. This knowledge is critical to provide a foundationfor developing targeted interventions to address this critical health problem from a holistic perspective and toprovide a basis for preventing or reversing the adverse health outcomes of CVLUs, a condition thatdifferentially affects older and minority individuals.

50.	Project Title:	OPTIMIZING AAV VECTORS FOR CENTRAL NERVOUS SYSTEM TRANSDUCTION
	Leader(s):	HELDERMON, COY D
		UNIVERSITY OF FLORIDA
		NIH R01NS102624 / (2017-2022)
	Project SummaryMucopolysaccharidosis (MPS) IIIB is a neurodegenerative lysosomal storage disease (LSD) caused by deficientdegradation of heparan sulfate. Clinically this manifests as cognitive decline, developmental regression, impairedmobility and ultimately premature death. There are currently no effective therapies. Due to the neurodegenerativenature of this disease, optimal CNS transduction is necessary for human trials. Several groups havedemonstrated improvement of the mouse model using different adeno-associated viral (AAV) vectors. We haverecently demonstrated that AAV8 has better brain gene delivery in MPS IIIB than wild type mice. A similar findingof altered brain delivery in Sly Syndrome compared to wild type mice has been published for AAV9. However,for translation to human trials, it is essential to identify a highly effective AAV capsid serotype which will deliverto cells in the requisite brain regions. More generally, for any treatment of human neurologic disease in whichthe central nervous system (CNS) is of substantially larger volume and is phylogenetically distant compared toour current mouse models, we will need to identify an optimal vector and delivery method for CNS approaches.To this end, we have developed a novel two-step bar code AAV vector system that allows assessment of multipleAAV vector serotypes within the same animal, greatly reducing the number of animals needed for statisticalcomparisons of brain delivery. This system has a genetic bar code that identifies each vector and a second barcode that is incorporated during PCR amplification of each brain region isolated. The bar code system allowsdetermination of distribution and the expression levels of each serotype in anatomical areas of interest. We willuse this novel two-step barcoded AAV vector system to simultaneously identify brain delivery of 40 AAVserotypes and capsid variants in wild type and MPS IIIB mice as well as in non-human primates - the closest tohuman model available to us. We will identify whether injections into the body of the brain or the less invasiveinjection into the fluid around the brain method provides a better vector distribution. We will identify which wild-type AAV serotypes or capsid mutants provide the best delivery by region, are altered by presence of the disease,and are similar between primate and mouse models. The results will inform clinical trial vector selection acrossthe spectrum of central neurologic disorders, including MPS III. Subsequently, our MPS IIIB gene construct willbe packaged into the optimal vector to assess treatment effect in MPS IIIB mice. We hypothesize that CNStransduction and distribution will differ by serotype and species and that some serotypes will transduce differentlybetween wild type and Sanfilippo Syndrome mice. Our specific aims are therefore:1. We will determine the brain delivery of AAV serotypes in non-human primates (NHP) and in wild type and MPS IIIB affected mice. We will use a novel two-step bar-coded AAV vector system to allow simultaneous delivery and assessment of 40 serotypes with capsid variants in each animal via injections into the brain or surrounding fluid. Brain distribution for each serotype will be assessed by quantitative next generation RNA sequencing of the various brain regions. The top three vectors for brain delivery by this method will be used individually to identify the cell types treated and pattern of gene expression in mice and NHP.2. Assess the effect of the AAV serotype with the best distribution in the thought processing and motor coordination regions of the brain carrying the MPS IIIB gene to treat the MPS IIIB mouse. We will use day/night activity, hearing, coordination, lifespan, lysosomal storage and enzyme assays to determine preclinical benefit in the mouse model.Overall, these studies will determine the effects of species, delivery site and disease state on brain delivery froma multitude of AAV serotypes. Through this study, we will identify the most promising vector(s) for clinical trialdevelopment in MPS IIIB and other neurodegenerative disorders. If this project is successful, we will be in aposition to quickly move towards such clinical trials.

51.	Project Title:	ADHERENCE TO VENOUS THROMBOEMBOLISM PROPHYLAXIS GUIDELINES IN HOSPITALIZED ELDERS
	Leader(s):	PAVON, JULIESSA M
		DUKE UNIVERSITY
		NIH R03AG048007 / (2014-2016)
	DESCRIPTION (provided by applicant): There are important public health concerns related to inappropriate use of venous thromboembolism (VTE) prophylaxis among medically ill hospitalized elderly patients with low risk of VTE occurrence. Specifically, use of anticoagulants (heparin products) for VTE prophylaxis when not medically indicated may be harmful, and is a major patient safety issue that also has a significant cost effect on health systems. To this end, the American College of Chest Physician (ACCP) 9th Edition guidelines explicitly recommend a risk-stratification approach, rather than universal use of anticoagulants for VTE prophylaxis. Even though many medical inpatients are at high risk for VTE, there are others whom do not have sufficient risk to warrant prophylaxis, and use in this population is inappropriate. The firstaim of this application proposes to determine the magnitude and scope of inappropriate use of anticoagulant VTE prophylaxis in low risk older adults. This aim will be achieved by using data abstraction from the Duke University Health System electronic records to determine (1) the prevalence of low risk elders using criteria proposed by ACCP guidelines, and (2) anticoagulant VTE prophylaxis use in this group. Guideline directed use of pharmacologic VTE prophylaxis also emphasizes mobility evaluation. Mobility is a key component of risk stratification. Poor mobility evaluation by providers may be a significant barrier to appropriate use of VTE prophylaxis. Our second aim proposes to determine whether level of mobility during hospitalization is being used to influence use and duration of VTE prophylaxis among medically ill hospitalized elders. To achieve this aim, we will collect prospective observational data to objectively measure inpatient mobility using patient mounted accelerometers during patient hospital stays. Our goal is to improve the appropriateness of use of VTE prophylaxis among those in which the risks of harm may outweigh the benefit. Results from our study will provide important insights about use of risk assessment, and the relationship between patient mobility and VTE prophylaxis. These results are critical to understanding how to take the next steps toward improving the appropriate use and safety of anticoagulants in hospitalized older adults. Information from this study could be used in future proposals to study interventions to ultimately improve hospital practice in the care of older adults. Our investigative team at Duke is unique since we have expertise in all key fields of study: geriatrics, hospital medicine, hematology, and physical activity, that also have a longstanding history of working well with each other. As such, this collaborative team and research plan is designed to provide the principal investigator with a foundation from which to pursue an independent career in geriatric and hospital medicine research.

52.	Project Title:	METABOLOMICS OF LOW-TRAUMA FRACTURE AMONG OLDER WOMEN WITH DIABETES
	Leader(s):	LEE, RICHARD H.
		DUKE UNIVERSITY
		NIH R03AG048119 / (2014-2017)
	DESCRIPTION (provided by applicant): Among its associated medical complications, diabetes is associated with low-trauma bone fracture: Compared to older women without diabetes, older women with diabetes have 2-times the fracture risk. Paradoxically, this increased risk occurs despite diabetic women having a higher average bone mineral density. The long-term goal is to understand how diabetes among older adults contributes to osteoporosis and low-trauma bone fractures. The objective of this application is to identify, among older, diabetic women, candidate fracture-related metabolic profiles. The central hypothesis is that compared to older, diabetic women without a fracture history, the metabolic profiles of those women with a low-trauma fracture will be significantly different. As prior studie have shown, there are significant differences in metabolic profiles, related to fatty acid and amino acid metabolism, associated with diabetes. Additionally, in an animal-based model of osteoporosis, significant differences were observed in the levels of fatty acids and branched chain amino acids, using targeted metabolomics. The rationale for the proposed study is that the contribution to incident fracture risk among older women with diabetes can be determined in prospective studies, once candidate metabolic profiles are known in this population. In this proposed, cross-sectional study of diabetic women, age 65 years, recruited from general endocrine and primary care clinics, the following aims will be addressed: 1) Assess the levels of amino acids, organic acids, and acylcarnitines in older women with diabetes, both with and without a history of low-trauma fracture; 2) Compare the metabolic profiles of older, diabetic women without a history of low-trauma fracture to those with a history of fracture. Under the firstaim, after controlling for both measures of bone metabolism and functional status, the association between a history of low-trauma fracture and the levels of branched-chain amino acids and acylcarnitines, will be measured using targeted metabolomics. Under the second aim, the association between a history of low-trauma fracture and other metabolite classes will be measured using non-targeted metabolomics. The approach is innovative in identifying candidate, fracture-associated metabolic profiles, by utilizing metabolomics. Given the increasing prevalence of diabetes and substantial fracture-related morbidity among older adults, the proposal is significant because it is critically important to understand the key factors in thi population that contribute to low-trauma fractures. The results from the proposed study will inform the design of future studies to develop clinically applicable prospective screening tools toidentify at-risk individuals.

53.	Project Title:	EFFECTS OF AGING AND THE URINARY MICROBIOME ON RECURRENT URINARY TRACT INFECTIONS
	Leader(s):	SIDDIQUI, NAZEMA Y
		DUKE UNIVERSITY
		NIH R03AG060082 / (2018-2020)
	PROJECT SUMMARY/ABSTRACT Urinary tract infections (UTIs) are one of the most commonly diagnosed infections in olderadults. UTIs cost $1.6 billion annually, impair health-related quality of life, and can have serioussequellae such as hospitalization, sepsis, or death. At all ages, UTIs are more prevalent inwomen than men, with up to 50% of all women experiencing a UTI during their lifetime. Theincidence of UTI rises in older women with over 10% of women older than 65 and almost 30% ofwomen older than 85 reporting a UTI within the prior 12 months. Among women with UTIs, there exists a subgroup with recurrent UTIs, defined as 3 or moreculture proven infections within 12 months, or >2 culture proven infections in a 6 month period.Recurrent UTI is not only more common in women, but especially more common in the post-menopausal life stage. In some women with recurrent UTIs, genetic factors facilitate bacterialadherence and repeated infection. However, recurrent UTI prevalence rises significantly in post-menopausal women, suggesting additional non-genetic mechanisms associated with aging. The urinary microbiome is one potential non-genetic factor that could influence recurrentUTIs with aging. We now have significant evidence that a urinary microbiome exists, and thatdysbiosis may be associated with health versus disease. Our long-term goal is to improve ourunderstanding of the microbes that occupy the urinary niche, how these microbes change withaging, and to determine whether particular microbial community types are associated withrecurrent UTI. We aim to compare urinary lactobacilli in populations of women without recurrentUTIs to assess how lactobacilli change with aging and with the presence of vaginal estrogentherapy. Next, we aim to assess whether urinary lactobacilli or other microbes are associatedwith recurrent UTI in postmenopausal women who are using vaginal estrogen. Finally, we aim todetermine whether there are distinct microbial community types that are associated withrecurrent UTI in older women.

54.	Project Title:	HEAT SHOCK PROTEINS AND DISUSE MUSCLE ATROPHY
	Leader(s):	JUDGE, ANDREW ROBERT
		UNIVERSITY OF FLORIDA
		NIH R03AR056418 / (2009-2013)
	DESCRIPTION (provided by applicant): Project summary/Abstract Skeletal muscle disuse atrophy is a widespread physiological phenomenon associated with immobilization, bed rest, denervation, and space flight, or any general reduction in weight bearing activity. However, our understanding of the signaling molecules that regulate muscle mass during disuse are ill defined. Therefore the long-range goal of our research program is to understand the regulation of signaling pathways that cause muscle atrophy during disuse. Eventually improved understanding will lead to the identification of targets for specific interventions. Heat shock proteins (Hsps) are a family of proteins that are constitutively expressed in cells, but whose expression is further, and rapidly, induced by a variety of cellular stresses. This induction has been shown to provide a variety of cytoprotective functions. During muscle disuse a member of the heat shock family, Hsp70, is consistently down-regulated and overexpression of Hsp70 during disuse abolishes the increase in NF-:B and Foxo3a transactivation, and completely prevents skeletal muscle atrophy. This is important since NF-:B and Foxo3a are required for disuse muscle atrophy. However, it is currently unknown whether Hsp70 overexpression is sufficient to specifically inhibit NF-:B-induced or Foxo3a-induced muscle atrophy. It is also unknown whether knock down of Hsp70 is sufficient to cause skeletal muscle atrophy. The objective of the current proposal is to determine in Aims 1 and 2 if an increase in Hsp70 expression is sufficient to inhibit NF-:B-induced or Foxo3a-induced muscle fiber atrophy, and in Aim 3 if knock down of Hsp70 is sufficient to cause muscle fiber atrophy. To address these specific aims we will inject WT IKK2 plus Hsp70 expression plasmids (Aim 1), WT Foxo3a plus Hsp70 expression plasmids (Aim 2), or a plasmid producing shRNAs specific for Hsp70 (Aim 3) into the skeletal muscle of rats and measure NF-:B or Foxo3a activity, the mRNA expression of specific atrophy genes and muscle fiber cross sectional area. If an increase in Hsp70 expression inhibits NF-:B activity and/or Foxo3a activity we will determine the mechanisms of this by determining the proteins in each pathway that Hsp70 binds. The findings from these experiments will lead to a greater understanding of Hsp70 in the regulation of NF-:B and Foxo3a signaling during skeletal muscle atrophy. PUBLIC HEALTH RELEVANCE: Project Narrative Skeletal muscle wasting due to disuse is associated with immobilization, bed rest, denervation, and space flight, or any general reduction in weight bearing activity. In the proposed work we will genetically overexpress or knock down a protein that is believed to regulate muscle size and is known to be down-regulated during muscle wasting caused by disuse. This will allow us to directly determine the involvement of this protein in the regulation of skeletal muscle mass, and could identify the protein as a novel therapeutic target for muscle wasting.

55.	Project Title:	PROSOCIAL BEHAVIOR AND EXERCISE AMONG OLDER ADULTS
	Leader(s):	FOY, CAPRI G
		WAKE FOREST UNIVERSITY HEALTH SCIENCES
		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.

56.	Project Title:	A PILOT STUDY TO ADVANCE TRANSLATION OF MOLECULAR SIGNATURES OF BIOLOGICAL AGING
	Leader(s):	BELSKY, DANIEL WALKER
		COLUMBIA UNIVERSITY HEALTH SCIENCES
		NIH R21AG054846 / (2017-2020)
	PROJECT SUMMARYThe broad aim of this proposal is to determine if any of several proposed methods to quantify biological agingin humans are promising for use in trials of interventions to increase healthy lifespan. The biological processof aging is thought to drive risk for many disabling health conditions and mortality. There is evidence thattrajectories of aging begin to diverge as early in life as young adulthood. If this process can be measured, itwill speed development of interventions to prevent disease and disability and prolong healthy life. Onemeasurement approach is to calculate a ?biological age.? In contrast to a person's chronological age, whichcounts time since birth, a person's biological age reflects the condition of their body and mind relative to theirpeers. For example a 30-year-old person with the body and mind of an average 50-year-old would have abiological age of 50. Interventions shown to reduce biological age or slow its increase would thus be strongcandidates for increasing healthy lifespan. But in order to identify such interventions, measures of biologicalage are needed. Several algorithms have been proposed to calculate a person's biological age from panelsof clinical biomarkers and whole-genome data on blood DNA methylation and RNA expression. Thesealgorithms represent highly-scaleable methods ideal for implementation in intervention trials. But a criticalknowledge gap is whether the algorithms actually measure the process of biological aging that, if modified,would extend healthy lifespan. The research proposed in this application aims to fill that knowledge gap byimplementing and testing five of the most promising algorithms in an already-created database, the DunedinStudy. The Dunedin Study follows a population-representative birth cohort now in it's fifth decade of life. Thedatabase includes genome-wide DNA-methylation, RNA-expression, SNP, and clinical biomarker data on 954individuals along with extensive physical and cognitive function testing. Research aims will test if the differentalgorithms measure a common process of biological aging that drives disease and disability. Studying all ofthe algorithms together in a young, still-healthy cohort followed over time will answer three questions: 1) Arethe different algorithms related to one another, i.e. do they measure the same thing? 2) Can they measurechanges occurring in young adults as their trajectories of aging begin to diverge ? the time interventionswould likely have their greatest benefit? and 3) Do they measure real-life experiences of health decline inaging ? deficits in physical and cognitive functions and subjective perceptions of aging? Results will informwhich, if any, of the proposed biological aging algorithms show promise for implementation in interventiontrials. This could lead immediately to their implementation in archived biospecimens from completed trials.Results will also inform future approaches to developing measures of biological aging by identifying whatworks and what doesn't.

57.	Project Title:	MOBILE INTERVENTION TO REDUCE PAIN AND IMPROVE HEALTH (MORPH) IN OBESE OLDER ADULTS
	Leader(s):	BROOKS, AMBER K ; FANNING, JASON ;
		WAKE FOREST UNIVERSITY HEALTH SCIENCES
		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.

58.	Project Title:	WEARABLE TECHNOLOGY INFRASTRUCTURE TO ENHANCE CAPACITY FOR REAL-TIME, ONLINE ASSESSMENT AND MOBILITY (ROAMM) OF INTERVENING HEALTH EVENTS IN OLDER ADULTS
	Leader(s):	MANINI, TODD ; RANKA, SANJAY ;
		UNIVERSITY OF FLORIDA
		NIH R21AG059207 / (2019-2021)
	ABSTRACTOlder Americans experience approximately 29 million falls and 13 million hospitalizations per year. Theseintervening health events (IHE - episodic falls, injuries, illnesses, and hospitalizations) are strong precipitants ofdisability in older adults. Because of their episodic nature, IHEs are extremely difficult to study. Continuous,long-term monitoring with remote capabilities using wearable technology is an ideal solution for capturinginformation surrounding an IHE and in particular, preceding it. This R21/R33 project aims to develop asustainable research infrastructure built on the foundation of a smart watch application and server calledROAMM (Real-time Online Assessment and Mobility Monitor). It will offer long-term and continuousconnectivity, bidirectional interactivity and remote programming. ROAMM will create a detailed narrative aboutmobility (activity patterns, walking speed, life space), patient reported outcomes/symptoms (pain, poor mood,fatigue, disability), cognition (working memory, processing speed, and executive functioning) and reports ofhealth events (falls and hospitalizations). The infrastructure is composed of a diverse group of investigatorswith expertise in mobile technology/data science and applied/medical sciences who will serve in the followingcores: Wearable Technology, Phenotyping, Clinical Outcomes, Data Science Management & Quality, andRecruitment, Retention & Compliance. In the R21 phase, we will create the ROAMM framework consisting ofthe watch application and accompanying server. We will also assess test-retest reliability, convergent validityand participant usability/acceptability. Each year, an Independent Advisory Panel and External AdvisoryCommittee will evaluate milestone-driving activities and our Go/No-Go checkpoints for transitioning to the R33phase. Work proposed in the R33 phase will showcase the ROAMM infrastructure by conducting aprospective, longitudinal study (range 1.25-2.5 yrs) in 200 community-dwelling persons aged 70+ yrs. Thisphase will test a field deployable version of ROAMM in real world settings to address the following hypotheses:1) Pre-event patterns of low mobility, disability, fatigue, pain and depressive mood collected by ROAMM areindependent predictors of incident IHE's; 2) IHE's will negatively impact the course of ROAMM measures; and3) Additional value will be gained for explaining the change variability and recovery trajectories. An exploratoryaim will evaluate safety while using ROAMM features and identify predictors of ROAMM adherence using bothkey-informant interviews and examine demographic and health histories to create boundaries for usingROAMM and other systems like it for long-term, continuous monitoring in research and practice. We willsustain ROAMM by targeting grant opportunities for the wearable technology surge for remote patientinteraction, adopting licensing fees, and aligning our services with larger entities to become the go-to place forremote data capture. These activities will create a sustainable infrastructure to ensure research on older adultsis keeping pace with the state-of-the-art ?smart and connected? health with wearable technology.

59.	Project Title:	SYSTEMATIC ANALYSIS OF CLINICAL STUDY GENERALIZABILITY ASSESSMENT METHODS WITH INFORMATICS
	Leader(s):	HE, ZHE ; BIAN, JIANG ;
		FLORIDA STATE UNIVERSITY
		NIH R21AG061431 / (2019-2021)
	Clinical studies are often conducted under idealized and rigorously controlled conditions to improve their internal validity and success rates, but compromise their external validity (i.e., generalizability to the target populations). These idealized conditions are sometimes exaggerated and reflected as overly restrictive eligibility criteria. Certain population subgroups are often excluded with unjustified criteria and are subsequently underrepresented. Older adults have been especially underrepresented in cancer studies. The underrepresentation of these population subgroups reduces the treatment effects and increases the likelihood of adverse outcomes in diverse populations when the interventions were moved into clinical practice. It is imperative to rigorously assess the generalizability of a clinical study, so that stakeholders including pharmaceutical companies, policymakers, providers, and patients would be able to understand and anticipate the possible effects of the interventions in the real world. In the past two decades, a large number of studies have assessed generalizability, but mostly were after the fact, ad hoc, not systematic, and focused on specific diseases and sets of trials without a formalized approach. So far, there is a significant knowledge gap between the available methods for generalizability assessment and their adoption in research practice. Most generalizability assessments have been conducted as an ad hoc auditing effort by a third party after the fact. We believe the key barriers are two-fold: (1) the lack of evidence to demonstrate their validity, which also leads to the lack of consensus on the best practice for generalizability assessments; and (2) the lack of readily available, well-vetted statistical and informatics tools. Motivated to fill this gap, we propose to first systematically review the extant methods for generalizability assessments, and then use a data-driven strategy to reproduce, evaluate, and compare these methods with our unique data resource, the OneFlorida Data, one of the 13 PCORI-funded Clinical Data Research Networks that contains linked EHRs, claims, and cancer registry data for ~15 million Floridians. We will develop an open-source generalizability assessment software toolbox and its accompanying documentations and tutorials. The success of this R21 project will (1) fill a knowledge gap on the validity and utility of the different generalizability assessment methods; (2) provide an easy-to-use toolbox ctGATE for assessing study generalizability much-needed by the clinical research community; (3) help the clinical researchers choose the most appropriate generalizability assessment methods with readily available implementations; and (4) build a body of evidence to support the development of an eligibility criteria design tool for optimizing study generalizability at the study design phase.

60.	Project Title:	ADVANCING INTERDISCIPLINARY SCIENCE OF AGING THROUGH IDENTIFICATION OF IATROGENIC COMPLICATIONS: THE UF EHR CLINICAL DATA INFRASTRUCTURE FOR ENHANCED PATIENT SAFETY AMONG THE ELDERLY (UF-ECLIPSE)
	Leader(s):	INGIBJARGARDOTTIR BJARNADOTTIR, RAGNHILDUR ; LUCERO, ROBERT J ;
		UNIVERSITY OF FLORIDA
		NIH R21AG062884 / (2019-2021)
	Iatrogenic conditions are a continuing public health concern, causing death among an estimated two hundred and fifty thousand older adults annually in United States (US) hospitals. Hospital-acquired falls and hospital- induced delirium are among the most common and costly iatrogenic conditions, and their occurrences are linked to each other. Advances in computing technology and availability of electronic data presents opportunities to more accurately identify identifying patients at risk of suffering a hospital-acquired fall or hospital-induced delirium. Clinical data is now being captured electronically for about 80% of the US population. Approximately 75-80% of clinical data is text data which cannot be analyzed using traditional statistical methods. The development of a research data infrastructure that supports the use of text and structured data is critical for a learning health system aimed at improving care and patient outcomes. In this project, we propose to expand the research infrastructure for electronic data-driven knowledge generation through the development of the University of Florida (UF) EHR Data Infrastructure for Patient Safety among the Elderly (UF-ECLIPSE). The long-term goal of our research program is to enhance the safety of hospitalized older adults by reducing iatrogenic conditions through an effective learning health system. We plan to carry out the following aims: Specific Aim 1 (R21 Phase): Identify and test the feasibility of text-mining pipelines to process registered nurses' (RNs) progress notes for prediction of hospital-acquired falls. We will employ a combination of supervised and unsupervised text-mining methods to identify text attributes associated with patient falls. We will then leverage a predictive model of patient fall risk factors developed in previous work to generate a composite model of text and structured data to predict the odds of a patient falling. Specific Aim 2 (R33 Phase): Determine and evaluate the structural and human resources of an expanded research-data infrastructure to support sustained interdisciplinary aging studies. We will develop and pilot test text-mining pipelines to generate a prediction model of hospital-induced delirium. We will then integrate the developed pipelines into the existing UF Health Clinical Data Warehouse (CDW) infrastructure and test to assess functionality, durability and scalability. In addition, we propose to develop the human resource infrastructure to support data-driven interdisciplinary aging research. This will be achieved by training graduate students in interdisciplinary data science for aging research. The UF-ECLIPSE research team will be among the first to implement and test an integrated data repository that utilizes nurse-generated structured and text data to support a learning health system. This study will create important new research data infrastructure, and will be a model for health care organizations to increase safe effective care for the millions of older adult Americans hospitalized every day.

61.	Project Title:	NICOTINAMIDE RIBOSIDE AS AN ENHANCER OF EXERCISE THERAPY IN HYPERTENSIVE OLDER ADULTS: THE NEET TRIAL
	Leader(s):	MANKOWSKI, ROBERT
		UNIVERSITY OF FLORIDA
		NIH R21AG064282 / (2019-2021)
	ABSTRACTMore than 80% of older adults have hypertension, with higher prevalence of high systolic blood pressure (SBP)putting them at high risk for cardiovascular (CV) disease and death. Because drug therapy that lowers SBP isassociated with side effects such as hypotension, syncope, and kidney dysfunction, there is a great need foreffective lifestyle SBP-lowering interventions for the older population that can replace drug therapy. Whileaerobic exercise is a recommended lifestyle intervention for controlling SBP and preventing CV diseasenaturally, in older adults it has been shown to be less effective in vascular-tissue remodeling because ofarterial stiffness, resulting in less efficient SBP control. Reduced bioavailability of nicotinamide adeninedinucleotide (NAD+), a cofactor for the deacetylase sirtuin1 (SIRT1), may contribute to age-related vasculardysfunction via oxidative stress and reduced nitric oxide (NO). Exercise-induced overexpression of NAD+-dependent SIRT1 improves the bioavailability of NO. Preclinical evidence suggests that poor vascular-functionimprovement in response to exercise in older mice is caused by insufficient NAD+ levels to stimulate SIRT1activity. Importantly, replenishment of NAD+ levels induced vascular remodeling, improved vascularfunction, and reduced SBP in mice. An objective of this study, therefore, is to test a combination of aerobicexercise and nicotinamide riboside, a compound that replenishes NAD+ levels, to optimize exercise's SBP-lowering effect in hypertensive older adults. Initial human clinical trials demonstrated that nicotinamide ribosidesupplementation (1,000 mg/day) was safe and showed a higher potential to reduce SBP and arterial stiffnessin participants with elevated SBP. As we have preclinical evidence that combining NAD+ replenishment withexercise is an ideal strategy for improving vascular function, our central hypothesis is that the intervention ofaerobic-exercise training combined with nicotinamide riboside supplementation will reduce SBP inhypertensive older adults more effectively than will exercise alone. We will enroll 45 participants 65 years andolder into either: (1) 1,000 mg/day of nicotinamide riboside plus 3 days/week of supervised, center-basedwalking exercise, or (2) the same exercise program combined with placebo, or (3) 1,000 mg/day ofnicotinamide riboside alone. All participants will undergo daytime continuous SBP and arterial-stiffnessmeasurements by pulse-wave velocity at baseline and at 6 weeks. Elevated SBP will then be determined asdaytime average above 130 mmHg, measured by the 24-hour blood-pressure device. To our knowledge, thisstudy will be the first attempt to enhance exercise therapy with nicotinamide riboside in hypertensive olderadults. We believe that nicotinamide riboside is ?the missing piece of the puzzle? in improving vascularremodeling and SBP management in older adults. Preliminary evidence from this pilot study may support a full-scale Phase III clinical trial in hypertensive older adults. The ultimate goal of this line of research is to findadjuvant strategies to improve the exercise's SBP-lowering effects in older adults.

62.	Project Title:	EVALUATING EFFECTS OF AGE-RELATED MICROBIOTA MODULATIONS IN HEMATOPOIETIC STEM CELL TRANSPLANT PATIENTS
	Leader(s):	SUNG, ANTHONY ; CHAO, NELSON J. ;
		DUKE UNIVERSITY
		NIH R21AG066388 / (2019-2021)
	Allogeneic hematopoietic stem cell transplant (HCT) has the potential to cure patients with hematologicmalignancies. However, HCT is associated with significant treatment related mortality (TRM) ranging from 20-30%. (1). TRM is particularly high in patients with advanced age (hazard ratio 1.84, age >60 years vs. <20) anddecreased physical function (hazard ratio 2.94, bottom quartile vs. top quartile). A major cause of TRM is graft-versus-host disease (GVHD), which affects 40-60% of patients. We hypothesis that age related microbiomechanges will affect the HCT clinical outcomes, and in addition to age other factors such as diet, physical activityand the care environment can influence the microbiome profiles as well. Correlations between GVHD and disruptions in the gut microbiota have been reported in several studies,though it remains unclear how the microbiota causes or prevents GVHD. While lengthy hospitalizations arestandard for HCT patients, caring for patients in a more normal care environment may preserve the naturalmicrobiota. We hypothesized that shifting the care environment from the hospital to a more normal environmentlike the home can preserve the gut microbiota, thereby decreasing intestinal inflammation and GVHD. We havesuccessfully piloted home HCT in a phase 1 trial (co-PIs Chao, Sung, clinicaltrials.gov NCT01725022) and haveexpanded our pilot into a randomized phase 2 study of home vs. standard care (clinicaltrials.gov NCT02218151,co-PIs Chao, Sung) funded by NCI 1R01CA203950 (PI Chao, co-I Sung). While age cannot be changed, other strategies to overcome the negative effects of aging-relatedmicrobiome changes can be the use of dietary and physical activity interventions. We have started a Phase I/II,pre- and peri-HCT optimization program (PPOP). PPOP has two pieces: a clinical component (C-PPOP), whichestablishes a new standard of care for the pre-HCT evaluation of all Duke HCT patients, and a researchcomponent (R-PPOP), which includes additional assessments and interventions to optimize health and functionincluding diet and physical activity. In this proposed project we aim to: 1) evaluate the age related microbiomechanges and their implications on HCT outcomes including TRM (primary endpoint), infections, GVHD, andimmune function; 2) evaluate the effects of a dietary and physical activity intervention on the aged microbiomeand implications on HCT outcomes. For this study will be able to utilize existing samples from the Duke Hematologic MalignanciesBiorepository. This study can provide new insights into the underlying mechanisms of GVHD in Leukemia andother malignant diseases. If successful, this study will identify the impact of age related microbiome changes onHCT outcomes and the immune system, as well as strategies to target the aged microbiome to promote betteroutcomes for HCT patients.

63.	Project Title:	DYSREGULATION OF SARCOMERE STABILIZING PROTEINS CAUSE MUSCLE ATROPHY AND WEAKNESS DURING CANCER CACHEXIA
	Leader(s):	JUDGE, ANDREW ROBERT
		UNIVERSITY OF FLORIDA
		NIH R21CA194118 / (2015-2018)
	DESCRIPTION (provided by applicant): Cachexia is characterized by progressive skeletal muscle and body weight loss and affects up to 80% of cancer patients. This loss of muscle mass contributes to significant muscle weakness and diminished physical function and is associated with reduced tolerance to chemotherapy and increased complications from surgical/radiotherapeutic treatments. Consequently, cachexia decreases both quality of life and survival time in cancer patients and cachexia itself is responsible for up to 30% of all cancer-related deaths. Interestingly muscles from preclinical models of cancer cachexia as well as cachectic human cancer patients show disruptions in sarcomere and myofiber membrane integrity despite the lack of an injury stimulus, and there is speculation that these disruptions may initiate catabolic processes which lead to the muscle atrophy and weakness. Unpublished and preliminary data from our lab has identified that Kyphoscoliosis peptidase (Ky), which is essential to the structural integrity of the sarcomeric Z-disk, and Myocilin (Myoc), which is important to the sarcolemmal dystrophin associated protein complex (DAPC), are highly downregulated at the mRNA and protein level at time points which precede and parallel muscle atrophy and weakness during tumor progression. Moreover, preliminary data show that overexpression of Ky in the muscles of tumor bearing mice inhibits muscle fiber atrophy. These observations support our first hypothesis that the downregulation of Ky and Myoc are causative to the loss of muscle structure leading to muscle wasting and weakness during the progression of cancer cachexia. Unpublished bioinformatics analyses of the -1kb to +1kb proximal promoters of genes significantly downregulated in skeletal muscle of C26 tumor-bearing mice revealed a conserved consensus binding motif for myocyte enhancing factor-2 (MEF2) among the top most commonly shared motifs. Moreover, both the Ky and Myoc gene promoters contain conserved MEF2 binding motifs. This observation, coupled with the findings that MEF2 protein c (MEF2c) is decreased at the mRNA and protein level in tumor bearing mice, supports our second hypothesis that loss of MEF2c transcriptional activity in skeletal muscle of tumor-bearing hosts is causative in the downregulation of Ky and Myoc, and initiates disruptions in muscle fiber integrity and muscle wasting. Thus, our two specific aims are: Specific Aim 1: To test the hypothesis that the downregulation of Kyphoscoliosis peptidase (Ky) and Myocilin (Myoc) play causative roles in the cancer-induced loss of muscle fiber integrity and the initiation of muscle wasting. Specific Aim 2: To test the hypothesis that loss of MEF2c transcriptional activity is causative in the cancer- induced downregulation of Ky and Myoc and initiates muscle wasting. The results of these studies will provide new insight into transcriptional mechanisms involving protein downregulation which initiate cancer-induced muscle wasting and weakness, opening up new avenues for therapeutic interventions.

64.	Project Title:	DEVELOPING RESEARCH AT THE INTERFACE OF HIV AND AGING
	Leader(s):	HIGH, KEVIN P.
		WAKE FOREST UNIVERSITY HEALTH SCIENCES
		NIH R24AG044325 / (2013-2019)
	DESCRIPTION (provided by applicant): Effective antiretroviral therapy (ART) has resulted in many people with chronic HIV surviving into middle and old age. However, even those with controlled HIV viral replication, are more likely than uninfected subjects to experience premature chronic illness, multi-morbidity and functional decline. For example, 58% of HIV- infected subjects age >= 50 years have one or more of the following: renal failure, diabetes mellitus, bone fracture, hypertension or overt cardiovascular disease vs. only 35% of HIV-uninfected controls. Further, geriatric syndromes such as frailty and falls are becoming more prevalent in HIV-infected adults. While the need for research in HIV and aging is widely recognized, challenges in methodology, data acquisition and sharing, and research workforce education/training have hampered this goal. Multi-morbidity, functional decline and disability are typically research domains of geriatrics and gerontology. The Claude D. Pepper Older Americans Independence Centers (OAlCs; aka 'Pepper Centers') were established to advance research into the causes, mechanisms, prevention and treatment of functional decline with age, but lack expertise in HIV. In contrast, the Centers for AIDS Research (CFARs) have unparalleled expertise in HIV- related basic, clinical and social/behavioral research, but lack resources or expertise in aging biology, clinical phenotypes, or functional measures. This proposal leverages CFAR/OAIC expertise to create a shared research platform, enhancing and accelerating investigation at the interface of HIV and aging by: 1) Harmonizing processes for data collection across OAlCs and CFARs and providing a coordinated platform for data collection; 2) Validating key instruments/measures of function and geriatric phenotypes in HIV- infected subjects age > 50 years; 3) Supporting pilot projects at the interface of HIV and aging; 4) Identifying and mentoring junior faculty with a research focus in HIV and aging; and 5) Disseminating information and data sharing opportunities to the larger scientific community. Accomplishing these aims will efficiently amplify NIAID investment in the CFARs, NIA investment in the OAlCs, and, more importantly, address critical healthcare needs in a rapidly growing population aging with HIV.

65.	Project Title:	EPIGENETIC MECHANISMS PROMOTING LONGEVITY
	Leader(s):	KRAUS, VIRGINIA
		DUKE UNIVERSITY
		NIH R56AG054840 / (2017-2018)
	AbstractCirculating sRNAs are short non-coding RNAs (typically ~19-25nt in size). They mediate a broad spectrum ofbiological processes through regulation of gene expression. Experimental evidence indicates that the serumlevels of sRNAs change considerably--the vast majority increasing?with age. The ability of circulating miRNAsto travel among tissues enables them to transmit signals and regulate a broad spectrum of biological functions.sRNAs exist in a variety of RNase-insensitive ribonucleoprotein or lipid complexes, or are encapsulated insidedifferent types of extracellular vesicles. Consequently, in contrast to messenger RNA, sRNAs are protectedfrom extracellular RNases and are measurable and stable in samples stored for decades. Despite numerousrecent developments, we are far from understanding the role of sRNAs in aging. An understanding of their rolein aging mammals, and humans in particular, is still very limited due to the increased complexity and longerlife-spans of mammals compared with invertebrates. This project leverages existing human sample resourcesfrom three completed NIH-funded studies (EPESE, STRRIDE and CALERIE) to discover and validatelongevity-associated sRNAs in humans. Our preliminary analysis of 175 circulating microRNA--in the NIA-funded Duke Established Populations for Epidemiologic Studies of the Elderly (Duke EPESE) community-based cohort of elders--identified 32 differentially expressed circulating miRNAs (p<0.05) associated withlongevity; in all cases, their concentrations at baseline were higher in long-term survivors (10+ years)compared with age, sex and race matched but short-term survivors (<2 years); a subset of these miRNAspredicted longevity independent of age, gender, race and functional status. The Duke EPESE cohort was aged71 and older at the time of blood sampling and now has nearly 25 years of longitudinal life-span data withwhich to address key questions about sRNA and longevity in humans. sRNA discoveries in Duke EPESE willbe validated in samples from completed human clinical trials of relevance to longevity that investigated thehealth promoting effects of exercise (STRRIDE cohort) and caloric restriction (CALERIE cohort). A humanthree-dimensional muscle tissue organ system will be used to understand their mechanisms of action (with andwithout simulated exercise and calorie restriction) by testing sRNA mimics and inhibitors. Together these aimswill determine if sRNAs associated with longevity are favorably modulated in humans by exercise and/orcaloric restriction; and if they appear to mediate any of the observed health benefits of these interventions.The totality of the data (in vivo and in vitro generated), will be systematically examined to identify pathways ofsRNA action in humans and profiles of sRNA and other factors that could serve as biomarkers to predictlongevity status.

66.	Project Title:	EXTRACELLULAR VESICLES AND THEIR ROLE IN HALLMARKS OF AGING
	Leader(s):	KRAUS, VIRGINIA
		DUKE UNIVERSITY
		NIH R56AG060895 / (2018-2019)
	AbstractExtracellular vesicles (EVs) are membranous particles released from nearly all cell types into all bodily fluidsevaluated to date ? including serum and plasma. Depending on tissue of origin, health state and organismage, they carry a variety of complex cargo consisting of nucleic acids (5,000 microRNA documented to date),proteins (93,000 documented to date including cytokines) and metabolites. Due to their coordinate regulationof tissue homeostasis and biological processes through intercellular trafficking of microRNA and protein cargo,EVs are particularly attractive for this project because they can potentially serve as DIRECT biomarkers ofaging, namely indicators AND mediators of the aging process. The goal of this project is to establish EVswith their microRNA and protein constituents as biomarkers of healthspan and lifespan and to informbiological mechanisms promoting healthspan and lifespan. We focus particularly on three of the hallmarksof aging, epigenetic alterations, cellular senescence and altered inter-cellular communication. Increasingevidence suggests that EVs secreted from senescent cells have unique characteristics and contribute tomodulating the phenotype of recipient cells; thus, they have been newly deemed novel senescence associatedmolecular pattern (SASPs). We hypothesize expression of different amounts and different compositions of EVsare associated with different lifespan and healthspan of humans, and with different senescence states inmurine models. In collaboration with Meso Scale Diagnostics, LLC (MSD), a premier developer of highlyreliable and highly sensitive biomarker assays, we will develop new biomarkers of EVs informing agingmechanisms and test their function in vitro. These biomarkers will be qualified in the context of aging in ourexisting extensive human sample sets: individuals (n=3056) from multiple longitudinal cohort studies (EPESEaged >71 years; PALS aged 20-100 years) and NIH-funded controlled trials of geroprotective interventions(STRRIDE exercise aged 18-70 years; and CALERIE caloric restriction aged 22-45 years). Complementingthis new biomarker development work, we will validate and qualify: the new S-PLEX high sensitivity (femtomolelevel detection) assays by MSD for soluble cytokines and circulating microRNAs we have identified asassociated with healthspan and lifespan in elders. Taken together, we believe our broad expertise inbiomarkers and aging, our interdisciplinary team and our partnership with a company with the capability tocommercialize assays provide a unique project responsive to RFA-AG-18-018 for ?Development of validreliable markers of aging-related biologic mechanisms for human studies?.

67.	Project Title:	MOLECULAR BIOLOGY IN BURNS AND TRAUMA
	Leader(s):	MOLDAWER, LYLE L
		UNIVERSITY OF FLORIDA
		NIH T32GM008721 / (1999-2024)
	This Ruth Kirschstein NRSA training Program proposes to take primarily surgeons and other critical caremedicine physicians during the second or third year of their general residency programs, and expose them totwo, three and even four years of mentored research in inflammation biology with highly productive basic sciencementors focused on inflammation-related topics. Four training positions are requested. The overall researchprogram will focus on mastery of molecular biology, functional genomics and gene regulation, as it appliesbroadly to inflammation research. Although the bulk of the training program will be in the laboratory of anexperienced research mentor, trainees will be expected to participate in didactic experiences that complementtheir research experience. Select trainees will have the opportunity to complete a Ph.D. program in the GraduateSchool in three to four years. Other trainees can participate in graduate certificate programs which are formalcollections of courses that together form a coherent program of study offered through an academic unit. Thistraining program takes advantage of the unique strengths of the College of Medicine in the expanding field offunctional genomics and molecular biology, as well as the existing collaborations between basic scientists andclinicians committed to the training of future clinical academicians. The interface between molecular biology andinflammation research will be targeted to trauma, sepsis syndromes, ischemia/reperfusion injury, vascular injury,delayed wound healing and the burn wound. The faculty will be drawn from funded basic and clinical scientistsin the Surgery, Medicine, Pathology, Aging and Geriatric Research and Molecular Genetics and MicrobiologyDepartments, who will serve as research mentors to the trainees. Clinical mentors from the Surgery, Medicineand Pathology Departments will interact with the trainees and the research faculty to assure that the traineesare being exposed to clinically-important issues in inflammation research. Overall direction of the program willrest with the Program Director and an Executive Committee. Candidates for the fellowship are recruitednationally and from the University of Florida College of Medicine (Gainesville, Jacksonville). Successfulapplicants with the Executive Committee will identify a research and clinical mentor who will help formulate aformal training program and periodic review of the trainee?s progress. Furthermore, trainees are expected toparticipate in basic science seminars in the Institute on Aging, Emerging Pathogens Institute and GeneticsInstitute, and in their own basic science departments, as well as laboratory research meetings. They will also beexpected to attend clinical seminars, including Surgery and Critical Care Medicine Grand Rounds and theDepartment of Surgery Academic Research Conference. Based on our past experiences, it is anticipated thatsuccessful graduates of this training program will possess sufficient research skills to successfully compete fortransitional funding in inflammation research and become leaders in academic surgery.

68.	Project Title:	THE ENRGISE STUDY
	Leader(s):	PAHOR, MARCO ; AMBROSIUS, WALTER T ;
		UNIVERSITY OF FLORIDA
		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.

69.	Project Title:	THE ENRGISE STUDY
	Leader(s):	PAHOR, MARCO ; AMBROSIUS, WALTER T ;
		UNIVERSITY OF FLORIDA
		NIH U01AG050499 / (2015-2019)
	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 Interleuk

70.	Project Title:	THE ENRGISE STUDY
	Leader(s):	PAHOR, MARCO ; AMBROSIUS, WALTER T ;
		UNIVERSITY OF FLORIDA
		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.

71.	Project Title:	UF PASS: REGULATION OF EXERCISE TRANSDUCERS
	Leader(s):	ESSER, KARYN A
		UNIVERSITY OF FLORIDA
		NIH U01AG055137 / (2016-2022)
	Abstract Exercise is a powerful and pleiotropic physiological stimulus that helps prevent many chronicdiseases and is used as a therapeutic for disease. While the beneficial effects of exercise are extensivelyacknowledged there is still very little understood about the molecular transducers of the systems-wide effects.The goal of this University of Florida Molecular Transducers of Physical Activity Preclinical Animal StudySites application (UF PASS) is to conduct experiments in animals that will provide tissues/blood (i.e.biospecimens) to the Chemical Analysis Sites for identification of molecular transducers induced by definedmodels of physical activity from tissues that cannot be obtained from humans as well as to conductmechanistic studies that can support screening of novel transducers to quickly move the field forward.In Phase 1, UF PASS proposes to collect biospecimens for the Chemical Analysis sites following endurance(run-training) or resistance exercise protocols on male and female Fischer 344xBrown Norway rats (F344-BN)at three different ages. To better capture the dynamics of the exercise/adaptation responses we propose to:1) Collect biospecimens at 5 selected timepoints following an acute bout of exercise on na?ve and trained rats;2) Collect biospecimens following short duration training (after 5 bouts) and 3) Collect biospecimens followinglong-term (8 weeks) training.For Phase 2, our hypothesis is that factors released from muscle (i.e. myokines) are the molecular transducersthat function throughout the system to improve the well-established stress tolerance. The goal of these studieswill be to employ high throughput screening technologies to test up to 1500 myokines. We will then usesecondary screening techniques to test 100 candidates from which we will select up to 3 candidates for in vivotesting. The results of the experiments in Aim 3 will provide molecular evidence identifying a set of transducers,released from muscle, that are necessary for exercise induced systemic health. The goals of the UF PASS willbe pursued by the following Specific Aims:Specific Aim 1: Center Coordination Phase.Specific Aim 2: Phase 1 Studies. To perform endurance and resistance exercise using male and femaleF344BN rats at 3-4, 16-18, and 27-29 mo.Specific Aim 3: Phase 2 Studies. The goal in Aim 3 is to test myokines as the exercise transducers forimproved stress tolerance.

72.	Project Title:	MULTIMODAL IMAGING OF BRAIN ACTIVITY TO INVESTIGATE WALKING AND MOBILITY DECLINE IN OLDER ADULTS
	Leader(s):	MANINI, TODD ; CLARK, DAVID J. ; SEIDLER, RACHAEL D ;
		UNIVERSITY OF FLORIDA
		NIH U01AG061389 / (2018-2023)
	Project Description: Mobility impairments in older adults decrease quality of life and are associated with highsocietal and economic burden. NIH RFA-AG-18-019 solicits applications ??to investigate the central neuralcontrol of mobility in older adults?using innovative and cutting-edge methods.? Current approaches to studythe neural control of walking are limited by either the inability to measure people during walking (functionalmagnetic resonance imaging, fMRI) or the inability to measure activity below the cortex (functional near-infrared spectroscopy, fNIRS). We assert that a full and accurate understanding of the neural control of walkingin older adults requires real time measurement of active regions throughout the brain during actual walking. Wewill achieve this by using innovative mobile brain imaging with high-density electroencephalography (EEG).This approach relies upon innovative hardware and software to deliver three-dimensional localization of activecortical and subcortical brain regions with high spatial and temporal resolution during walking. The result isunprecedented insight into the neural control of walking. Here, our overarching objective is to determine thecentral neural control of mobility in older adults by collecting EEG during walking and correlating these findingswith a comprehensive set of diverse mobility outcomes (clinic-based walking, complex walking and communitymobility measures). Our first aim is to evaluate the extent to which brain activity during actual walking explainsmobility decline. In both cross sectional and longitudinal designs, we will determine whether poorer walkingperformance and steeper trajectories of decline are associated with the Compensation Related Utilization ofNeural Circuits Hypothesis (CRUNCH). CRUNCH is a well-supported model of brain activity patterns that areseen when older individuals perform tasks of increasing complexity. CRUNCH describes the over-recruitmentof frontoparietal brain networks that older adults exhibit in comparison to young adults, even at low levels oftask complexity. CRUNCH also describes the limited reserve resources available in the older brain. Thesefactors cause older adults to quickly reach a ceiling in brain resources when performing tasks of increasingcomplexity. When the ceiling is reached, performance suffers. The RFA also calls for proposals to?Operationalize and harmonize imaging protocols and techniques for quantifying dynamic gait and motorfunctions?. In accordance with this call, our second aim is to characterize and harmonize high-density EEGduring walking with fNIRS (during actual and imaged walking) and fMRI (during imagined walking). This willallow us to identify the most robust CRUNCH-related hallmarks of brain activity across neuroimagingmodalities, which will strengthen our conclusions and allow for widespread application of our findings. Ourthird aim is to study the mechanisms related to CRUNCH during walking. Thus, our project will address amajority of the objectives in NIH RFA-AG-18-019 and will identify the neural correlates of walking in olderadults, leading to unprecedented insight into mobility declines and dysfunction.

73.	Project Title:	MOLECULAR TRANSDUCERS OF PHYSICAL ACTIVITY AND HEALTH: NC CONSORTIUM CLINICAL SITE
	Leader(s):	KRAUS, WILLIAM E ; HOUMARD, JOSEPH A ; NICKLAS, BARBARA J ;
		DUKE UNIVERSITY
		NIH U01AR071128 / (2016-2022)
	ABSTRACT Exercise is a powerful physiological stimulus contributing to disease prevention and intervention. Theprotective and preventive effects of exercise are well-documented for metabolic, neurodegenerative, andcardiovascular diseases, and certain cancers. While scientists acknowledge the extensive benefits ofexercise, there is still insufficient understanding about the underlying mechanisms by which exercise preventsdisease and improves health across diverse organ systems. The NIH Common Fund has developed aforward-looking funding mechanism ? six tethered RFA's tied to creating a research consortium, the MolecularTransducers of Physical Activity Consortium (MoTrPAC) ? to create resources and critical information forexercise and health investigators well into the future. Two products of the MoTrPAC collective efforts will be apublically available data resource that will enhance and accelerate subsequent mechanistic research ondiseases and conditions affected by physical activity; and a biorepository of clinical and animal model samplesto be used in studying exercise biology. Based on prior collaborative efforts, our group believes that we areideally positioned to propose a protocol that will respond directly to the RFA, while at the same time executethe large volume of tests to complete the ~450 people required at each site within the MoTrPAC consortium.To accomplish all of our Clinical Center goals, we have developed a consortium ? the North Carolina ClinicalSite Consortium (NCCSC). The NCCSC consists of the experienced research teams Duke University Schoolof Medicine; East Carolina University (ECU); and Wake Forest School of Medicine (WFSM). As described inthe study plan, the NCCSC weighed a number of alternatives for training regimens, timing, and type of tissuesampling, sample sizes for the four obligated study groups, and other factors, while staying within budgetconstraints. The following Aims will maximize the value of the data and sample repositories; this will beaccomplished with the enrollment of 540 individuals and finishing 450. ? Aim 1: To determine the response of molecular transducers to a single acute bout of either aerobic or resistance training. ? Aim 2: To determine the responses of molecular transducers to a chronic exercise training program of either aerobic or resistance training. ? Aim 3: To determine the responses of molecular transducers to a detraining period following either aerobic or resistance training.

74.	Project Title:	MOTRPAC CONSORTIUM COORDINATING CENTER
	Leader(s):	PAHOR, MARCO ; MILLER, MICHAEL E. ; REJESKI, WALTER JOHN ; TRACY, RUSSELL P ;
		UNIVERSITY OF FLORIDA
		NIH U24AR071113 / (2016-2022)
	SummaryPhysical 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 molecularmechanisms are poorly known. The coordinated effort of clinical and animal studies supported bybioinformatics 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 ConsortiumCoordinating 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 playa pivotal role in ensuring the cohesion of the MoTrPAC by enhancing communication and integration across allstudy 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 strategicplanning processes by integrating activities of the MoTrPAC investigators with the input provided by the DataSafety Monitoring Board, the External Scientific Advisors, outside experts, and the NIH. The CCC will facilitateinteractions and communications with junior and senior investigators outside the consortium to maximize theuse of the MoTrPAC resources toward achieving the overall research goals. To accomplish these goals andmaximize 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 theprinciples of the dynamic theory of strategy will be fostered to evaluate alternative approaches, maintain thecutting-edge scientific focus, leverage state-of-the-art coordination technologies, anticipate challenges, andmaximize future opportunities to ensure the success of the consortium. The CCC will comprise four integratedcomponents led by four highly qualified PIs who have a long-lasting track record of successfully working insynergy. The four CCC components comprise the Administrative Coordinating Center (PI Dr. Pahor), the DataManagement, 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 toolsand web-based tracking of exercise adherence and diet, and will capitalize on the outstanding track record andexpertise of its investigators in: (a) working together; (b) successfully coordinating, managing, and leadinglarge long-term multicenter clinical trials involving PA and other interventions; (c) implementing rigor andtransparency in research, (d) acquiring, managing, storing and analyzing biological samples; (e) conductinganimal 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 themolecular changes that occur in response to PA, and relating these changes to the health benefits of PA.

75.	Project Title:	1/2 + PROMOTE WEIGHT LOSS IN OBESE PAD PATIENTS TO PREVENT MOBILITY LOSS: THE PROVE TRIAL
	Leader(s):	MCDERMOTT, MARY MCGRAE
		NORTHWESTERN UNIVERSITY AT CHICAGO
		NIH UG3HL141729 / (2019-2020)
	PROJECT SUMMARY for the PROVE Trial More than 65% of people with lower extremity peripheral artery disease (PAD) are overweight or obese.People with PAD who are overweight or obese have greater functional impairment and faster functional declinethan normal weight people with PAD. Walking exercise is first line therapy to improve functional performancein PAD. However, our observational longitudinal data show that overweight and obese PAD participants whocombined weight loss with walking exercise had less functional decline than those who walked for exercise butdid not lose weight. Therefore, we hypothesize that among people with PAD who are overweight or obese, aweight loss intervention combined with exercise (WL+EX) will improve walking ability more than EX alone. However, effects of intentional weight loss in overweight/obese people with PAD are unknown and maynot be beneficial if weight loss exacerbates PAD-related sarcopenia. Behavior change that achieves sustainedWL is challenging in older obese people with chronic disease. Therefore, among people with PAD and BMI>28kg/m2, we will test the hypothesis that WL+EX achieves greater improvement in functional performance thanEX alone. Our innovative weight loss intervention uses a group mediated cognitive behavioral framework,connective mobile technology, remote monitoring by a coach, and a calorie restricted DASH-derivedOMNIHeart diet. In a seven week pilot study, our intervention achieved mean weight loss of 5.6 pounds andimproved the 6-minute walk by 64.1 meters in eight PAD participants with BMI> 28 kg/m2. Preclinical evidence shows that obesity is associated with impaired limb perfusion. Human evidenceshows that obesity is associated with reduced skeletal muscle mitochondrial biogenesis and activity. Theseobesity related changes exacerbate the pathophysiology of PAD. Therefore, we hypothesize that weight losswill improve walking ability in part by improving calf perfusion, and increasing calf mitochondrial activity. We will randomize 212 participants with PAD and BMI > 28 kg/m2 to one of two groups for 12 months:WL+ EX vs. EX alone. Participants will be randomized from Northwestern University, Tulane University, andthe U. of Minnesota. Our primary outcome is change in six-minute walk distance at 12-month follow-up.Secondary outcomes are change in 6-minute walk distance at 6-month follow-up and change in exerciseadherence, physical activity, patient-reported walking ability (measured by the Walking ImpairmentQuestionnaire), and quality of life (measured by the SF12 Physical Component Score) at 12-month follow-up.Tertiary outcomes include MRI measured calf perfusion, MRI-measured calf muscle quantity and fatabundance, and diet quality. We will perform calf muscle biopsies in 50 participants to measure mitochondrialbiogenesis and activity, capillary density, inflammation, and senescent cell abundance. If our hypotheses arecorrect, the PROVE Trial will have a major public health impact by preventing functional decline and mobilityloss in the large and growing number of people with PAD who are overweight or obese.

76.	Project Title:	PHYSICAL RESILIENCIES: INDICATORS AND MECHANISMS IN THE ELDERLY COLLABORATIVE
	Leader(s):	COLON-EMERIC, CATHLEEN S ; WHITSON, HEATHER E. ;
		DUKE UNIVERSITY
		NIH UH2AG056925 / (2017-2019)
	ABSTRACTThe overarching objectives of the PRIME Collaborative (Physical Resilience: Indicators and Mechanisms inthe Elderly) are to characterize specific resilience phenotypes, elucidate biological mechanisms, and validateclinically valuable predictive tools and measures of physical resilience. The application focuses on resilience inthree systems that are central to older adults' overall health: musculoskeletal, cognitive, and immune. Thecentral hypothesis of this application is that resilience to physical stressors is influenced by biologicalmechanisms at the molecular level. We will examine whether mechanisms associated with one or more of theseven ?Pillars of Aging,? which have been described by the trans-NIH Geroscience Interest Group, underlie amore generalized capacity for recovery that applies across multiple stressor/response scenarios. An inter-professional team of aging researchers from has been assembled to accomplish these objectives; the teamrepresents expertise from six NIA-funded Older American Independence Centers (OAICs) and leverages otherexisting resources. The PRIME Collaborative team will use a two-phased approach. In Phase 1, workgroupswill define specific resilience phenotypes in existing datasets using latent class trajectory analysis of sequentialoutcome measures following a stressor. The three resilience phenotypes, selected for their over-archingrelevance to late life health as well as our team's expertise, are: musculoskeletal recovery after orthopedicsurgery, immune recovery after infection, and cognitive recovery after surgery/anesthesia. We will conduct pilotstudies to identify novel clinical tests and biomarkers associated with each of these resiliencies. Feasibility andresponse data from pilot studies will inform the design of a larger cohort study in Phase 2. In the final 6months of Phase 1, the most promising predictive tests and markers will be selected and will inform twoparallel activities in Phase 2. First, a longitudinal cohort study of older patients undergoing elective surgery willbe conducted to validate predictors in a more diverse population. The Phase 2 cohort study will also allow us toassess synergy and interactions between different types of predictors (provocative tests, physiologic outputmeasures, biomarkers) and different types of resilience (musculoskeletal, cognitive, immune). Second,biological mechanisms underpinning resilience will be identified using newly developed mouse resiliencemodels, and in vitro human and mouse myotubule systems. These model systems are suitable for interventionstudies. The Phase 2 biological studies will be designed to identify pathways related to one or more Pillars ofAging so that they are likely to underpin multiple types of resilience, and suggest therapeutic targets and novel,resilience-bolstering interventions.

77.	Project Title:	PHYSICAL RESILIENCIES: INDICATORS AND MECHANISMS IN THE ELDERLY COLLABORATIVE
	Leader(s):	COLON-EMERIC, CATHLEEN S
		DUKE UNIVERSITY
		NIH UH3AG056925 / (2017-2022)
	ABSTRACTThe overarching objectives of the PRIME Collaborative (Physical Resilience: Indicators and Mechanisms inthe Elderly) are to characterize specific resilience phenotypes, elucidate biological mechanisms, and validateclinically valuable predictive tools and measures of physical resilience. The application focuses on resilience inthree systems that are central to older adults' overall health: musculoskeletal, cognitive, and immune. Thecentral hypothesis of this application is that resilience to physical stressors is influenced by biologicalmechanisms at the molecular level. We will examine whether mechanisms associated with one or more of theseven ?Pillars of Aging,? which have been described by the trans-NIH Geroscience Interest Group, underlie amore generalized capacity for recovery that applies across multiple stressor/response scenarios. An inter-professional team of aging researchers from has been assembled to accomplish these objectives; the teamrepresents expertise from six NIA-funded Older American Independence Centers (OAICs) and leverages otherexisting resources. The PRIME Collaborative team will use a two-phased approach. In Phase 1, workgroupswill define specific resilience phenotypes in existing datasets using latent class trajectory analysis of sequentialoutcome measures following a stressor. The three resilience phenotypes, selected for their over-archingrelevance to late life health as well as our team's expertise, are: musculoskeletal recovery after orthopedicsurgery, immune recovery after infection, and cognitive recovery after surgery/anesthesia. We will conduct pilotstudies to identify novel clinical tests and biomarkers associated with each of these resiliencies. Feasibility andresponse data from pilot studies will inform the design of a larger cohort study in Phase 2. In the final 6months of Phase 1, the most promising predictive tests and markers will be selected and will inform twoparallel activities in Phase 2. First, a longitudinal cohort study of older patients undergoing elective surgery willbe conducted to validate predictors in a more diverse population. The Phase 2 cohort study will also allow us toassess synergy and interactions between different types of predictors (provocative tests, physiologic outputmeasures, biomarkers) and different types of resilience (musculoskeletal, cognitive, immune). Second,biological mechanisms underpinning resilience will be identified using newly developed mouse resiliencemodels, and in vitro human and mouse myotubule systems. These model systems are suitable for interventionstudies. The Phase 2 biological studies will be designed to identify pathways related to one or more Pillars ofAging so that they are likely to underpin multiple types of resilience, and suggest therapeutic targets and novel,resilience-bolstering interventions.

UNIVERSITY OF CONNECTICUT HEALTH CENTER Claude D. Pepper Older Americans Independence Center

UNIVERSITY OF CONNECTICUT HEALTH CENTER
Claude D. Pepper Older Americans Independence Center