UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT SAN ANTONIO
Claude D. Pepper Older Americans Independence Center

Nicolas Musi, M.D.
Principal Investigator
 210 562 6140  Musi@uthscsa.edu
Sara Espinoza, M.D.
Co-PI
  210 617 5197  espinozas2@uthscsa.edu
Randy Strong, Ph.D.
Co-PI
 210 562 6126  strong@uthscsa.edu
Hanyu Maggie Liang
Program Administrator
 210 386 5632  liangh0@uthscsa.edu
     
CENTER DESCRIPTION

A core tenet of the geroscience concept is that multiple human diseases arise from aging itself. Thus, the central theme of the San Antonio (SA) Claude D. Pepper Older Americans Independence Center (OAIC) is translational geroscience – moving research on the basic biology of aging from the laboratory bench to the clinic, with the overarching goal of promoting healthy aging and developing desperately needed treatments, mainly pharmacological, for aging-related diseases. This goal is achieved through the following Aims:

1) Expand the knowledge base in translational geroscience by catalyzing transformative research;

2) Create a cadre of multidisciplinary early-stage investigators with customized expertise in translational geroscience;

3) Serve as a resource and partner to investigators from other OAICs and institutions; and

4) Provide intellectual leadership, disseminate knowledge, and stimulate discussion on translational geroscience-related themes.


CORES
Leadership and Administrative Core (LAC)
Leader 1:    Nicolas Musi, MD   musi@uthscsa.edu
Leader 2:    Sara Espinoza, MD   espinozas2@uthscsa.edu
Leader 3:    Randy Strong, PhD   strong@uthscsa.edu
The Leadership and Administrative Core (LAC) fosters integration of aging-related basic and clinical sciences, catalyzes scientific discoveries, promotes education and mentorship, and partners with other scientists and the community at large to develop novel interventions to improve the health, quality of life, and independence of older Americans. The LAC monitors, stimulates, sustains, evaluates, and reports progress toward our OAIC’s goal through the following Specific Aims:

  1. Provide logistical support and promote operational cohesiveness to the SA OAIC.
  2. Promote research protocol adherence and maintain regulatory compliance with university and governmental policies for the responsible and ethical conduct of OAIC-supported research.
  3. Disseminate the scientific innovation accomplished by OAIC investigators, inside and outside our institution, regarding the latest knowledge on geroscience and promotion of healthy life extension.
  4. Stimulate and facilitate interdisciplinary collaboration among OAIC investigators, cores, committees, and projects, to advance basic science in aging biology from the bench to the clinic.
  5. Select and monitor pilot and exploratory studies and progress of Scholars aligned with the OAIC theme.
  6. Monitor and evaluate OAIC progress, foster institutional collaborations, and leverage resources.
  7. Provide programmatic and scientific guidance to training programs, pilot studies, and resource cores (RCs).
  8. Participate actively in the national OAIC network to help advance its mission of promoting independence in older Americans.


Research Education Component (REC)
Leader 1:    Paula Shireman, MD, MBA   SHIREMAN@UTHSCSA.EDU
Leader 2:    Peter Hornsby, PhD   hornsby@uthscsa.edu
The REC promotes the Aims of the San Antonio Older Americans Independence Center (OAIC) by supporting career development, mentoring, and research training for early-stage investigators to transition to independent research careers. The Aims of our REC are:

Aim1: Oversee the recruitment, selection, monitoring, and evaluation of a highly qualified, dedicated and diverse group of early-career REC Scholars; assisting with their development into clinical and translational scientists in geroscience who can effectively lead and contribute to interdisciplinary research teams.

Aim 2: Provide active multidisciplinary supervising (mentoring) teams that regularly monitor, evaluate, and guide the progress of each REC Scholar through their research and career development programs; Scholars and their mentors will develop individualized structured research education plans with clearly defined responsibilities and milestones based on their investigative needs and focused on cross-training in translational sciences.

Aim 3: Recruit and advance the careers of a diverse cadre of Scholars across multiple dimensions, including women, underrepresented minorities and active-duty military and veterans representative of our patient population to build a geroscience workforce with expertise in medicine, nursing, psychology, pharmacy and other health care disciplines necessary for advancing geriatric care in a team science environment.

Aim 4: Promote cross-fertilization and assure integration of the REC participants' career development and activities with a) all San Antonio OAIC programs and b) the national OAIC network.


Pilot and Exploratory Studies Core (PESC)
Leader 1:    Robert A. Clark, MD   clarkra@uthscsa.edu
Leader 2:    Randy Strong, PhD   strong@uthscsa.edu
The PESC plays a key role in the San Antonio OAIC’s central theme of translational geroscience by supporting projects that move research on the basic biology of aging from the laboratory bench to the bedside, in order to extend healthy life expectancy. The PESC will provide merit-based support for rigorously designed pilot studies that test both the efficacy and side effect profiles of promising pharmacologic, as well as nonpharmacologic cell-based and behavioral interventions, in pre-clinical marmoset models and early human clinical studies. The PESC will strive to achieve its objectives through the following specific aims:

Aim 1: To promote innovative, collaborative, multidisciplinary research to test interventions designed to extend healthy life expectancy, both in early human trials and in non-human primate marmoset models.
Aim 2: To work closely with the Resource Cores and Research Education Component to provide infrastructure, scientific support, and funding for innovative pilot proposals from mentored junior faculty investigators, as well as established researchers.
Aim 3: To encourage pilot studies that will develop and apply novel methods and technologies.
Aim 4: To sustain effective processes to solicit, review, and fund pilot projects, as well as ensure study completion, robust tracking of downstream impact, and optimal dissemination and implementation.


Preclinical Research Core (RC1)
Leader 1:    Adam Salmon, PhD   salmona@uthscsa.edu
Leader 2:    Cory Ross, PhD   cross@txbiomed.org

RC1 plays a central role in the SA OAIC by providing the knowledge, skills, and technical support to assist OAIC investigators in using the common marmoset (Callithrix jacchus) as a pre-clinical model for aging interventions (mainly pharmacological). RC1 achieves its mission through the following Specific Aims:

1) To provide OAIC investigators access to a unique colony of aging marmosets.

2) To provide resources required for studying effects of aging interventions on marmoset healthspan.

3) To provide and maintain a bank of tissues from marmosets across the age range.

4) To provide services to assess analytical pharmacology in marmosets.

5) To support the research training and dissemination missions of the OAIC.




Clinical Research Core (RC2)
Leader 1:    Sara Espinoza, MD, MS   espinozas2@uthscsa.edu
Leader 2:    Nick Musi, MD   musi@uthscsa.edu
The overarching goal of RC2 is to offer comprehensive, centralized, clinical trial support for study design, regulatory compliance, recruitment, retention, assessment, procedures, pharmacology, and data management. RC2 achieves its mission through the following Aims:

1) Provide expertise and advice for investigators to plan and design innovative clinical studies to rigorously
test interventions to improve healthspan;
2) Enhance the SA OAIC support infrastructure to ensure successful subject recruitment and safe and ethical conduct of all OAIC-supported clinical studies;
3) Catalyze translational human studies and trials through provision of comprehensive core services;
4) Provide analytical and clinical pharmacology expertise supporting drug pharmacokinetic, and pharmacodynamic analyses as well as toxicity and safety assessment;
5) Disseminate to the lay public and scientific community the latest research on geroscience-related health promotion and the importance/relevance of translational geroscience research; and
6) Support training in translational geroscience for early-stage faculty and those new to clinical research.




Trial Design and Integrative Informatics Core (RC3)
Leader 1:    Jonathan A. L. Gelfond, MD, PhD   gelfondjal@uthscsa.edu
Leader 2:    Meredith Zozus, PhD   zozus@uthscsa.edu

The goals of RC3 are to provide biostatistical collaboration and expertise, as well as centralized research information services to ensure ready access to superior data quality for SA OAIC members. The Core will greatly facilitate data sharing and integrated analyses within the OAIC. Importantly, RC3 develops and implements unique services within UTHSCSA, capitalizing on its members’ biostatistical and informatics expertise in aging-related research. RC3 brings these substantial resources to support the SA OAIC through these Specific Aims:

Aim 1: Trial design: Provide biostatistics and informatics support and expertise for the OAIC, including: study design, power analysis, and planning; protocol development; and EHR-based feasibility analysis.

Aim 2: Trial conduct, reporting, and integrated analysis: Provide OAIC clinical trials with advanced research informatics tools to support the conduct, analysis, and reporting of clinical studies.

Aim 3: Training and education: Provide expertise, education and hands-on training in the collection, management, and analysis of data in translational geroscience, and analytics mentoring for OAIC trainees.

Aim 4: Developmental projects (DPs) and novel informatics methodology: 4A. Create a database of geroscience-focused clinical trials to identify promising therapeutics and sensitive/specific aging-related biomarkers (DP4). 4B. Develop and validate predictive algorithms to identify cohorts within large databases that both meet trial criteria and are likely to enroll efficiently (DP5).



CAREER DEVELOPMENT
REC Scholar, Research & Grants Funded During Pepper Supported Time Years /
Publications
 
Christopher Shannon
Assistant Professor / Department of Medicine, UT Health San Antonio
Effects of SGLT2 Inhibition on Liver Fat and Plasma Lipidome in Older Adults
Dr. Shannon will study hepatic metabolism in older adults with insulin resistance. Pilot trials at the San Antonio Pepper Center are currently exploring whether the pleiotropic effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors, a glucose-lowering class of drugs for the treatment of type 2 diabetes, can be repurposed to improve biomarkers of aging in humans. As part of these efforts, Dr. Shannon’s project will evaluate the impact of SGLT2 inhibition on hepatic and plasma lipids in an aging population at high risk of developing metabolic liver disease.
2021-2023 /
17 (total)
5 (1st/Sr)
 
Gustavo Almeida
Assistant Professor / UT Health San Antonio
Effect of prehabilitation blood-flow restriction training on muscle function in older adults with knee osteoarthritis awaiting total knee replacement: A Pilot Randomized Controlled Trial
The proposed project aims to evaluate the effect of a prehabilitation program (before surgery) using blood-flow restriction training (BFRT) on quadriceps muscle function in older adults (60+) with knee osteoarthritis (KOA) awaiting total knee replacement (TKR). Results from this study will elucidate how tolerable and efficacious prehabilitation BFRT is and early on after TKR as well. We predict that BFRT will be highly acceptable and feasible before and after TKR. BFRT will produce significant positive changes in muscle function, joint inflammation, physical function and physical activity. This pilot study will allow better understanding of this novel intervention in older adults with KOA awaiting TKR and will provide pivotal preliminary support for a large-scale randomized trial.
  • School of Health Professions Pilot Seed Grant Program – UT Health San Antonio, Role: PI
  • Foundation for Physical Therapy's Center of Excellence in Health Services Research, Role: Co-Investigator

2020-2022 /
32 (total)
8 (1st/Sr)
 
Mitzi Gonzales
Assistant Professor / Biggs Institute, UT Health Science Center San Antonio
Pilot investigation of the role of cellular senescence on gait dysfunction in Alzheimer’s disease
Dr. Gonzales’ RL5 project evaluates senolytic treatment as a novel intervention for reducing gait dysfunction in Alzheimer’s disease. Pre-clinical studies have demonstrated the combination of dasatinib and quercetin cleared senescent cells and decreased tau accumulation, diminished white matter hyperintensities, and rescued aberrant cerebral blood flow. As inflammation, tau accumulation, and altered cerebral blood flow have been linked to gait abnormalities, senolytic treatment may have efficacy for restoring gait dysfunction and improving functional status in Alzheimer’s disease.
  • Institute for Integration of Medicine & Science/Clinical and Translational Science Award (IIMS/CTSA); Title: Pilot Study of Efficacy and Safety of Rapamycin in Early Alzheimer's Disease; Role: PI.

2019-2021 /
34 (total)
10 (1st/Sr)
 
Jia Nie
Postdoctoral Fellow / Barshop Institute, UT Health Science Center San Antonio
Effect of Aging and mTOR Inhibition on Islet Cell Molecular Profiling in Marmosets
In this RL5 project, Dr. Nie will use the common marmoset (Callithrix jacchus) to determine changes in islets molecular profiles during aging, evaluate the contribution of these molecular changes to metabolic disease, and test the effects of lifespan-extending interventions on pancreatic islets. This RL5 opportunity will allow her to develop a unique niche, which can directly translate findings from basic studies to primates, with hope to improve the prevention and treatment of metabolic disease in older adults.
  • The Irene Diamond Fund/AFAR Postdoctoral Transition Awards in Aging; Title: The Irene Diamond Fund/AFAR Postdoctoral Transition Awards in Aging; Role; PI

2019-2021 /
19 (total)
6 (1st/Sr)
 
Rozmin Jiwani
Assistant Professor / School of Nursing, UT Health Science Center San Antonio
Effect of Behavioral Intervention on Frailty in Older Adults with Type 2 Diabetes
This RL5 project aims to determine the feasibility of a behavioral lifestyle intervention using smartphones for the self-monitoring of diet and physical activity for the improvement of frailty measurements (primary outcome) and on weight management and glycemic control (secondary outcomes) in the overweight/obese community-dwelling older adults with T2D.
2019-2021 /
7 (total)
4 (1st/Sr)
 

Past Scholars

PILOT/EXPLORATORY PROJECTS (5 Pilot Projects Listed)
1. Project Title: Effect of aging on hepatic steatosis in marmosets: A model of non-alcoholic fatty liver disease (NAFLD)
  Leader: Amrita Kamat, PhD
 

The objective of the proposed study is to investigate for the first time whether there are age-related changes in hepatic fat accumulation, a hallmark of NAFLD, in marmosets. We hypothesize an age-associated increase in hepatic steatosis and alterations in serum lipid profile in the marmoset model. To test our hypothesis, we propose the following Aims.

Aim 1) To investigate whether hepatic fat accumulation increases with age in marmosets. In this aim, we will measure liver and abdominal fat in young and old male and female marmosets using magnetic resonance imaging (MRI) and spectroscopy (MRS). We will also utilize diffusion-weighted imaging (DWI) which is an emerging tool to evaluate liver fibrosis. 

Aim 2) To elucidate whether there are changes in serum lipid profile with age in marmosets. A serum lipidomic profile will be determined and evaluated to look for significant changes in the lipids with aging. To investigate associations between hepatic fat accumulation and cardiovascular health, blood pressure measurements will also be conducted. 

 
2. Project Title: Tuberculosis reactivation in BCG-vaccinated marmosets treated with an IL-17 antagonist
  Leader: Deepak Kaushal, PhD
 

The Th17 response mediated by interleukin-17A (IL-17) offers protective immunity against primary Mycobacterium tuberculosis (Mtb) infection. IL-17 induces a pro-inflammatory response by facilitating neutrophil recruitment, cytokine secretion and early granuloma formation. Interestingly, IL-17 has been implicated in the pathogenesis of chronic inflammatory arthritis. In the U.S., chronic autoimmune conditions like psoriatic arthritis and ankylosing spondylitis, affect approximately 4 to 5 million people in their forties and fifties. Various drug therapies used in the management of these conditions, such as Secukinumab (Cosentyx®), have improved the quality of life by reducing pain and inflammation. Secukinumab, an antagonist of cytokine IL-17, has recently been approved by the WHO to treat chronic psoriasis, psoriatic arthritis and ankylosing spondylitis and shows promises as a therapeutic for an evolving list of conditions. It is projected that 2 to 3 million individuals greater than forty years old will be prescribed this drug over the next decade.

We propose a study to investigate the risk of TB reactivation in BCG vaccinated marmosets that are treated with Secukinumab. Analysis from five human clinical trials, indicate that latent TB infected individuals treated with this drug show no increase in TB reactivation, however there is no data to support this claim. Additionally, no animal studies have been conducted to examine the risk of reactivation of latent TB reactivation. Marmosets are an ideal candidate for this study because these monkeys are the only non-human primates that give birth to twins. This offers us a unique opportunity to study immune responses to vaccination and drug treatment by reducing host variability in the model. Additionally, marmosets have a very high susceptibility to aerosol Mtb infection and a heterogeneous host response that is dose and strain dependent.

 
3. Project Title: Transposable element activation in brain and cerebrospinal fluid from patients with Alzheimer’s disease (AD)
  Leader: Susan Bess Frost, PhD
 

Transposable elements, known colloquially as “jumping genes,” constitute approximately 45% of the human genome. We and others have reported an increase in transposable element mobilization over the course of physiological aging in the brain and other tissues in invertebrate models. We have recently identified transposable element activation as a key mediator of neuronal death in tauopathies, a group of age-related neurodegenerative disorders including Alzheimer’s disease that are pathologically defined by deposits of tau protein in the brain. Cellular defenses that limit transposable element mobilization include 1) formation of silencing heterochromatin and 2) generation of small RNAs (piwi-interacting RNAs/piRNAs) that facilitate clearance of transposable element transcripts. Using genetic approaches in Drosophila melanogaster models of tauopathy, we found evidence for a causal relationship between pathogenic tau-induced heterochromatin decondensation and piwi/piRNA depletion, active transposable element mobilization, and neurodegeneration. We reported a significant increase in transcripts of the human endogenous retrovirus class of transposable elements, among others, in postmortem brain tissue from human Alzheimer’s disease and progressive supranuclear palsy, a “primary” tauopathy. Endogenous retroviruses are retrotransposons derived from ancient retroviruses that inserted into the human genome. Like retroviruses, retrotransposons encode machinery, including a reverse transcriptase, polymerase, capsid protein, and integrase needed to reverse transcribe their RNA copy into DNA and insert the new DNA copy into the genome. We found that (?)-L-2?,3?-dideoxy-3?-thiacytidine (3TC/Lamivudine), a water soluble, FDA-approved nucleoside analog inhibitor of reverse transcriptase, suppresses retrotransposon mobilization and neurotoxicity in tau transgenic Drosophila. Taken together, our studies identified heterochromatin decondensation, piwi/piRNA depletion and consequent transposable element activation as a novel, conserved, pharmacologically targetable, mechanistic driver of neurodegeneration in tauopathy.

We are now working to further translate our studies to human tauopathy in order to test the potential utility of nucleoside analog reverse transcriptase inhibitors as tauopathy therapeutics. In our first Aim, we will determine if transposable elements actively mobilize in human Alzheimer’s disease. Experiments in this Aim will involve single nucleus DNA sequencing from neuronal nuclei isolated from control and human Alzheimer’s disease brain tissue. In our second Aim, we will determine if brain tissue and cerebral spinal fluid from patients with Alzheimer’s disease have elevated levels of reverse transcriptase activity compared to controls. If successful, our studies will provide a) Additional evidence that transposable elements are activated in human tauopathy, and b) An assay for target engagement for future clinical trials in which patients are administered reverse transcriptase inhibitors as a tauopathy therapeutic.

 
4. Project Title: Integrating social determinants of health and frailty in predictive modeling for a Medicare population
  Leader: Bradley Brimhall, MD; Liem Du, MD.
 

Approximately 315,000 seniors > 65 yo reside in Bexar County and the surrounding areas; our senior population is rapidly growing with estimates of almost doubling in size by 2050. With the aging of the US population, identifying risk factors and improving outcomes are imperative for delivering patient-centered, cost-effective care. Predicting outcomes in geriatric patients usually focuses on medical comorbidities. Growing data demonstrate that frailty and low socioeconomic status (SES) are powerful predictors of outcomes; these variables represent an opportunity to improve outcome prediction and design pathways to improve outcomes. Unfortunately, these variables are not routinely measured or incorporated into care plans. Our long-term goal is to combine easy to use frailty measures and social risk factors in a parsimonious model to identify at-risk geriatric patients to drive the design of more effective clinical care pathways.

WellMed specializes in managed care for Medicare and certain Medicare Advantage health plans and contracts with University Health System (UHS) for ~3,000 patients assigned to University Medical Associates, the clinician group for UHS. UHS ancillary support teams will routinely contact patients for care navigation and also will gather data on the social determinants of health and frailty. In addition, the American Community Survey1 contains SES data at the block group level used to estimate individual level SES, assisting in identifying patients with social risk factors. A major issue in modeling outcomes is underestimating hospitalizations and emergency department (ED) visits due to patients being seen in outside facilities; this limitation can be overcome by health claims data from WellMed. We will use WellMed administrative data, combined with more granular data from UHS and UT Health to determine outcomes and develop predictive models that go beyond medical comorbidities using SES and frailty data from the ancillary support teams that are not normally collected by medical personnel.

Aim 1: Improve high-risk patient identification & risk adjustment by assessing the contributions of ethnicity, SES & frailty to hospitalizations, ED visits and mortality in a geriatric population
Hypothesis: Frailty and SES will predict a significant portion of the risk for hospitalizations, ED visits and mortality and identify factors that can be used in care pathway design.


Approach: We will combine data from the Clinical Informatics Research Division data warehouse containing UHS and UT Health electronic health records with proxy SES data from the American Community Survey at the block group level1 and WellMed administrative data. We will supplement this data with structured notes for routine telephone calls by the ancillary support teams for frailty, SES and social support to determine factors that contribute to outcomes.

 
5. Project Title: Effect of SGLT2 inhibition on aging-related biomarkers in older obese adults with pre-diabetes
  Leader: Carolina Solis-Herrera, MD; Curtis Triplitt, PharmD.
 

Inhibitors of the sodium-glucose co-transporter (SGLT2) are FDA-approved for the treatment of type 2 diabetes (T2DM). Their mechanism of action involves lowering of blood glucose concentration secondary to increased glucose excretion of glucose by the kidney. These drugs also cause significant improvements in body weight, blood pressure and cardiac function. Based on these pleiotropic effects, including its calorie restriction-mimetic properties, we hypothesize that SGLT2 drugs will impact several markers related to aging, including reductions in oxidative damage to DNA and proteins, DNA methylation, advanced glycation end products-receptor for AGE (AGE-RAGE), cellular senescence, and improvements in mitochondrial function.

Aim 1: To determine whether SGLT2 inhibitors improve biomarkers of aging in older obese adults with pre-diabetes
Aim 2: To determine whether changes in aging-related biomarkers are linked to changes in glucose metabolism and healthspan.

 
DEVELOPMENT PROJECTS (5 Development Projects Listed)
1. Project Title: Comparative assessment of the role of mTOR in cardiac aging
  Leader: Marc Feldman, MD and Yuji Ikeno, MD, PhD
  Core(s): Preclinical Research Core (RC1)
Clinical Research Core (RC2)
Trial Design and Integrative Informatics Core (RC3)
 

Study Question: Does rapamycin improve age-related changes in cardiac compliance and reduce fibrosis/collagen?

Preliminary RC2-supported studies using cardiovascular magnetic resonance imaging (CMR) suggest that rapamycin treatment improves diastolic function in healthy older adults (see RC2). Now,  this DP will use CMR with late gadolinium enhancement (LGE) to evaluate the effects of 2 months of rapamycin (vs. placebo) on parameters related to cardiovascular aging in 20 healthy adults over 70 years old. CMR data will include measurements of global and regional ventricular systolic and diastolic function, and LGE measurements of myocardial extracellular volume to assess fibrosis. RC1 will conduct parallel studies in marmosets; from an ongoing study, Dr. Ikeno will quantify collagen and elastin in banked aorta and heart samples from young (<5 yrs.) and older (5-15 yrs.) marmosets previously treated with rapamycin (or placebo) for up to 3.5 years. RC3 will carry out the required statistical analyses. If positive, findings from this study will lay the foundation for a clinical trial in older adults with heart failure with preserved ejection fraction, a growing population with few treatment options.

 
2. Project Title: Comparative lipidomics of aging
  Leader: Xianlin Han, PhD,
  Core(s): Preclinical Research Core (RC1)
Clinical Research Core (RC2)
Trial Design and Integrative Informatics Core (RC3)
 

Study Question: Can changes in the circulating lipidome be developed as a cross-species biomarker of aging, age-related disease, and functional decline?

Diverse lipid signaling pathways can modulate the aging process and systematic analyses of the total lipid structure – the lipidome – in clinically relevant samples can reveal novel mechanisms in aging biology, biomarkers for diagnosis, and targets for therapeutics. As an initial step, using samples provided from generally healthy marmosets (RC1) and humans (RC2) across the normal age range for both species, this DP will assess the effects of age on the plasma lipidome. RC1 will provide plasma from ~20 each young (2-5 yrs.), middle-aged (6-9 yrs.) and old (10+ yrs.) naturally aging marmosets. All animals will be phenotyped by our common battery and resilience assessment. RC3 will assist with statistical comparisons of effects of age on changes and test the extent to which the lipidome reflects health and functional status. Identification of similarities in the aging lipidome across species may elucidate important biomarker targets for geroscience. Reflecting the growing interest in this topic, NIA recently released RFA-AG-20-039, “Lipid Signaling in Healthspan and Longevity Regulation”.

 
3. Project Title: Development of senescence biomarkers for clinical trials
  Leader: Paul Hasty, PhD
  Core(s): Clinical Research Core (RC2)
Trial Design and Integrative Informatics Core (RC3)
 

Senolytic/senomorphic drugs hold promise for aging and aging-related diseases. However, clinical trials to evaluate these drugs will require sensitive and specific senescence biomarkers. The goal of this project is to lay the foundation for the development and evaluation of non-invasive measures of cellular senescence. The ongoing repository (STARR) will be leveraged to (i) link known markers of senescence [p16 in CD3+ cells, senescence associated secretory phenotype (SASP) gene expression, and b-gal staining] obtained from tissues (blood, skin, fat) with healthspan outcomes; and to (ii) identify novel senescence biomarkers. This DP will also leverage ongoing and future trials on drugs/interventions with senolytic/senomorphic activity (e.g. dasatinib, polyphenols, metformin, mTOR inhibitors, exercise, weight loss) to determine which biomarkers change with the intervention and can predict functional outcome measures. In the future, this DP will conduct earlyphase precision medicine research on senolytics. For example, it will evaluate whether transcriptomic profiling (by RC3) of adipose tissue obtained in vivo can be used to determine which senolytics are most effective in clearing senescent cells and reducing SASP using in vitro cell functional assays. We could then test if molecular profiling predicts in vitro and in vivo clearance of senescent cells and whether their clearance is linked with changes in putative peripheral (non-invasive) senescence biomarkers and healthspan-related outcomes.

 
4. Project Title: Aging trial meta-analytic database (ATMDb)
  Leader: Joel Michalek, PhD
  Core(s): Clinical Research Core (RC2)
Trial Design and Integrative Informatics Core (RC3)
 

RC3 is focused on designing aging-related trials that are rigorous, efficient, feasible, and based on solid preliminary data. This can be challenging because 1) trials with multimorbidity endpoints are novel; 2) biomarkers related to these endpoints are in development; and 3) treatment effect sizes are unknown.

Goal: Through this DP, we will create a database of aging-related clinical trials involving drug classes related to aging, multimorbidity endpoints, and aging-specific biomarkers. The database and research publication will include trials’ primary clinical endpoints, anticipated/realized effect sizes, sample sizes, inclusion/exclusion criteria, durations of treatments, classes of compounds, secondary endpoints and related effect sizes. 

Methods: RC3 will formally examine translational geroscience-focused trials (completed and in-progress) through a systematic review of the literature and clinicaltrials.gov. This online database of multimorbidity and disease-agnostic healthspan-extending trials will be freely available to all OAICs. The initial trial searches will focus on SA OAIC priority agents such as rapamycin, metformin, senolytics, and other compounds under study by OAIC investigators. This database will also include a meta-analytic perspective on the sensitivity to intervention of the assessed aging biomarkers so that investigators will be informed by empirical evidence in selecting cost-effective assays to measure treatment effects. Initial biomarker searches will focus on SA OAIC priority outcomes, namely frailty, epigenomic aging assays, and senescence markers. Article search criteria will be aided by a research librarian (funded by RC3). Abstraction will be done by Dr. Michalek (Project Lead) and Dr. Gelfond, with quality control and abstraction done in coordination with RC2 lead Dr. Espinoza. RC3 will record trial design consultations and note those consultations that use the meta-analytic database. The web-accessible database will allow for crowdsourcing feedback to evaluate accuracy and adapt search criteria. Reporting will comply with Preferred Reporting Items for Systemic Reviews and Meta-Analyses guidelines. This systematic review and meta-analysis will inform power calculations and primary/secondary outcome selection in future studies supported by RC3 of the SA OAIC as well as other scientists in the field.

 
5. Project Title: Adaptive cohort identification (ACI)
  Leader: Meredith Zozus, PhD
  Core(s): Trial Design and Integrative Informatics Core (RC3)
 

Rationale: To help with recruitment of OAIC studies during the current grant cycle, RC3 investigator Dr. Alex Bokov used the i2b2 application and data warehouse containing de-identified electronic medical record (EMR) data for 1.7 million patients to pull data from diverse sources (Epic Clarity, Sunrise, IDX, etc.), seeking potential participants who meet trial inclusion/exclusion criteria. While this uncovered participants who met highly specific criteria, subjects were not always efficiently enrolled. Goal: This DP will use machine-learning methods to leverage information within the EMR and clinical trial operational databases to more efficiently identify eligible participants who are more likely to enroll in the trial. Methods: Dr. Zozus (Project Lead) and Dr. Gelfond will use machine learning to adaptively model the full i2b2 patient profiles to match participant characteristics with those associated with successful trial enrollment. Using machine-learning tools (KNN, SVM, LASSO, etc.), subjects more similar to enrolled participants will be prioritized for screening. The effectiveness of this algorithm will be measured by a changepoint analysis that compares the enrollment rate (proportion who successfully enroll) before and after project implementation and examines the accrual rates in specific randomization strata to minimize sampling bias. Efficiency will also be measured by in-person screenings per enrolled subjects. We hypothesize that adaptive cohort identification will enhance accrual rates. If our hypothesis is supported, this algorithm will be made available to other scientists in the OAIC network and broad scientific community.

 
RESEARCH (9 Projects Listed)
1. Project Title: ALZHEIMER?S DISEASE-ASSOCIATED TAU TOXICITY INDUCES CELLULAR SENESCENCE IN THE BRAIN.
  Leader(s): ORR, MIRANDA ETHEL
    SOUTH TEXAS VETERANS HEALTH CARE SYSTEM
    VA IK2BX003804 / ( 2017 - 2022 )
  Core(s):
  Tau protein aggregation is the most common pathology among neurodegenerative diseases, whichcollectively are termed tauopathies. These diseases encompass over 15 distinct disorders that greatly affectVeterans, including Alzheimer's disease (AD) and traumatic brain injury. As the most common cause ofdementia in the United States, AD affects more than 5 million Americans, including 600,000 military personneland costs $200 billion per year. Effective treatment strategies remain elusive. We are applying freshperspectives from different disciplines and are investigating cellular senescence as a novel cell stressresponse involved in tau-associated neurodegeneration. Large insoluble tau-containing aggregates, neurofibrillary tangles (NFTs), are the closest histopathologicalcorrelate with neuron loss and cognitive decline in AD. However, because NFT-containing neurons do not die,their role in neurodegeneration remains unclear. We suggest that NFTs may evoke toxicity through secondary,non-cell autonomous mechanisms. Specifically, we propose that NFT-containing cells may contribute to tissuedestruction by secreting toxic soluble factors in a mechanism similar to cellular senescence. Cellular senescence is generally characterized by a permanent cell cycle arrest and alterations in geneexpression, metabolic state, morphology, and cytokine secretion. In neurons, senescence has been used todescribe age-associated changes that include swelling of the soma, loss of dendritic spines, and progressive choking of cytoplasmic space with abnormal material; phenotypes in good agreement with NFT-containingneurons. While there is no single unifying marker that defines the complex senescence stress response, robustphenotypes include elevated gene expression of tumor suppressor p16INK4a (p16) and inflammatory cytokines.Studies have illustrated that senescent cells contribute to tissue damage and functional decline with age.Recently, we found that transgenic mice with NFTs have a significant elevation in senescence markers in thebrain, including p16. The increase in p16 was associated with an elevation in brain cytokines, Tnfa and Il1 .Only mice with NFTs, but not age-matched controls with high levels of soluble tau, expressed senescence-associated factors. Collectively, these data suggest that pathogenic tau and cellular senescence areinterconnected. The research goal is to elucidate whether tau-associated pathogenesis induces a senescence-like phenotype that reciprocally contributes to brain pathology and behavioral deficits in tau-associatedneurodegenerative diseases. Ongoing studies with transgenic mice will focus on molecular mediators ofcellular senescence in the brain, specific cell types involved and the mechanistic interplay among cellularsenescence, tau pathology, neurodegeneration and cognitive decline. Through the activities proposed in this CDA-2, I will achieve my ultimate career goal: to become anindependent investigator dedicated to the pursuit of understanding AD while improving the health andwellbeing of Veterans and their families. I have developed a comprehensive program, guided by anoutstanding mentoring team. They represent leaders within the VA and in the research of AD, senescence andinflammation. Through the planned activities, I will acquire new technical skills to achieve my research goalsand lay the foundation for my independent career. My mentoring team will advocate for my career developmentwithin the VA, including providing me opportunities for leadership and supporting my greater communityoutreach activities. The exceptional training opportunities at the South Texas Veterans Health Care System inSan Antonio, and community involvement in Military City, USA , provide an ideal environment for myambitions as a well-rounded scientist. By the completion of the CDA-2 I expect to be fully prepared to (1) leadan independent research program focused on AD; (2) have generated sufficient data to compete for MeritReview Award funding; (3) and joined the VA scientific workforce.
 
2. Project Title: BINGE EATING SPECTRUM TREATMENT IN OLDER WOMEN (BESTOW): AN INVESTIGATION AND INTERVENTION-TAILORING PROJECT
  Leader(s): KILPELA, LISA
    UNIVERSITY OF TEXAS HLTH SCI CTR SAN ANT
    NIH K76AG060003 / ( 2019 - 2023 )
  Core(s):
  PROJECT ABSTRACTThis Beeson Emerging Leaders in Aging Career Development Award (K76) seeks to equip Dr. Lisa Kilpela withthe expertise and professional skill set needed to become a leading gerontological expert in disordered eatingand nutrition pathology, and to advance this emerging and important field. As women age, biological,psychological, and lifestyle changes can contribute to nutritional disorders and associated health problems.Among older women, an increasingly recognized factor that can exacerbate these concerns is eating disorderpathology, which constitutes a group of complex psychiatric disorders characterized by dysregulated andabnormal eating behaviors. When left untreated, eating disorders can cause significant morbidity and mortality.Historically conceptualized as disorders of youth, a rapidly evolving body of research suggests that eatingdisorder symptoms are surprisingly prevalent in older women. Dr. Kilpela s preliminary research as a PepperCenter RL5 Scholar found that the most common form of disordered eating in older women is binge eating(BE; defined as eating an unusually large amount of food while feeling a loss of control), with 26.5% of womenaged 60+ reporting at least weekly BE episodes. BE is closely linked to obesity and depression and, evenindependent of these comorbidities, is associated with metabolic dysfunction, sleep problems, disability, andpoorer quality of life. Therefore, BE appears to represent a significant health problem for older women withgreater prevalence than once thought. Although evidence-based treatments for BE exist for younger women,these treatments need to be tailored for older women in order to address aging-related factors not present inyounger women that have implications for treatment (e.g., cognitive decline, menopausal symptoms). As such,the proposed research aims to: (1) identify factors that uniquely impact older women in relation to BE, (2)utilize information gathered in Aim 1 to guide development of a theory-driven, behavioral intervention tailoredfor older women with BE and pilot implementation to determine its feasibility, and (3) integrate work completedin Aims 1 and 2 within a career development program to advance the Dr. Kilpela s knowledge and expertise in(a) clinical gerontology, (b) women s health in aging, and (c) their integration in the context of BE, to support anR01 application for a full-scale trial. Complementary to the proposed research, Dr. Kilpela will complete aprogram of career development to gain the scientific and professional development skills to transition to anindependent investigator. This proposal is supported by a mentorship team of renowned scientists in agingresearch (Drs. Musi and Espinoza), women s health (Dr. LaCroix), and eating disorders (Dr. Keel), andadvisors in geriatric medicine education (Dr. Sanchez-Reilly) and biostatistics (Dr. Gelfond). This team, alongwith resources available through the San Antonio Pepper Center and Barshop Institute for Longevity and AgingStudies, comprise an ideal environment for Dr. Kilpela to successfully reach her goal to promote healthy agingin older women by addressing disordered eating and nutrition pathology.
 
3. Project Title: NOVEL APPROACHES TO IDENTIFYING AND ENGAGING DISADVANTAGED PATIENTS WITH ALZHEIMER?S DISEASE (AD) IN CLINICAL RESEARCH
  Leader(s): GILMORE-BYKOVSKYI, ANDREA L
    UNIVERSITY OF WISCONSIN MADISON
    NIH K76AG060005 / ( 2018 - 2023 )
  Core(s):
  Despite well-documented disparities in Alzheimer s disease (AD) prevalence, incidence, diagnosis, treatment, and mortality, individuals from disadvantaged backgrounds (e.g. racial/ethnic minorities) are disproportionately under-represented in clinical AD research. Current recruitment methods for AD research predominantly identify patients from outpatient clinics and community settings, or with pre-existing diagnoses. Reliance on these recruitment approaches may create barriers to participation for disadvantaged individuals as they are more likely to lack information about AD services, be undiagnosed and have limited access to outpatient care. Yet, greater enrollment of disadvantaged individuals into AD studies is critically needed to achieve national goals for AD research. Targeted AD screening and tailored recruitment within acute care settings has strong potential to address these gaps, as disadvantaged individuals often rely on these settings to meet their health needs. This K76 proposal is designed to provide Dr. Gilmore-Bykovskyi, PhD, a geriatric trained nurse and expert in AD symptom management with the training required for success as an independent clinician-scientist focused on improving AD identification to promote greater participation in research and access to effective care and therapies, specifically targeting high-risk disadvantaged populations. The overarching objective of the proposed research is to design screening and recruitment approaches for identifying and engaging disadvantaged AD patients/caregivers and their biological children in research from acute care settings. The proposal consists of validation of an electronic health record (EHR) Phenotype Model for AD using EHR clinical data identified in preliminary studies (Aim 1), and specification of this Model for performance among disadvantaged individuals (Aim 1a). To address recruitment from acute care environments, mixed methods strategies will inform the design of tailored recruitment approaches appropriate to acute care (Aim 2) which will be piloted with 30 AD patients/caregivers to determine their feasibility, acceptability and preliminary impact on willingness to enroll in a Trial Registry (Aim 2a). As a junior faculty member at an institution with extensive support for early stage investigators and significant infrastructure in AD disparities and EHR Phenotyping, Dr. Gilmore-Bykovskyi is in an ideal environment to complete the proposed research and pursue advanced training relevant to her career goals. Dr. Gilmore-Bykovskyi s career development plan integrates didactic and practical training, individual mentoring and mentored research activities in the areas of 1) clinical trial design, 2) advanced statistical and machine learning techniques, 3) acute care research, 4) AD health disparities, 5) recruitment and retention of vulnerable populations and 6) leadership. This proposed award addresses fundamental gaps and barriers to improve inclusion of disadvantaged individuals in AD research while affording training and mentored research critical for Dr. Gilmore-Bykovskyi to lead an independent research program in clinical AD research.
 
4. Project Title: METFORMIN FOR PREVENTING FRAILTY IN HIGH RISK OLDER ADULTS
  Leader(s): ESPINOZA, SARA ELYSE
    UNIVERSITY OF TEXAS HLTH SCI CTR SAN ANT
    NIH R01AG052697 / ( 2017 - 2022 )
  Core(s):
  ABSTRACT Frailty is a geriatric syndrome which leads to poor health outcomes in older adults, such as falls, disability,hospitalization, institutionalization, and death. Due to the dramatic growth in the U.S. aging population and thehealth care costs associated with frailty (estimated at more than $18 billion per year), frailty is a major healthcare problem. There has been little research into potential pharmacologic interventions that would delay orreduce the incidence of frailty. Thus, the major goal of this study is to test metformin as a novel intervention forthe prevention of frailty. We propose that diabetes/insulin resistance and inflammation are major contributors tofrailty, and that the use of metformin to modulate diabetes/insulin resistance and inflammation will preventand/or ameliorate the progression of frailty.The rationale for testing metformin for frailty prevention is based on the following: 1) Insulin resistance has been linked to the pathogenesis of frailty and our own research shows that diabetes is a significant predictor of frailty onset or worsening in community-dwelling older adults; 2) Several studies have shown that frail older subjects (compared with non-frail) are under a state of chronic low grade sterile inflammation, as evidenced by increase plasma concentration of inflammatorymarkers; 3) In addition to frailty, inflammation also plays a key role in the pathogenesis of insulin resistance; 4) Metformin has both insulin sensitizing and anti-inflammatory properties, and; 5) Our analyzed clinical administrative data from 2,415 adult veterans with diabetes shows that those who were taking metformin as monotherapy were at 34% reduced risk of becoming frail compared to patients taking sulfonylureas.We hypothesize that metformin will lead to reduced inflammation and insulin resistance present inolder glucose-intolerant subjects and that these changes will consequently prevent the onset and/orprogression of frailty in this sub-population of older adults.We propose to study glucose intolerant subjects, a population which encompasses approximately one-third ofolder adults, and is most likely to benefit from metformin. To our knowledge, this research will be the first tostudy a potential intervention targeted toward a central mechanism involved in the etiology of frailty. We willalso assess potential molecular mechanisms (insulin signaling, AMPK signaling, etc.) as potential cellulardefects in frailty that are alleviated by metformin. Because of the enormous costs associated with frailty (bothpersonal and economic), a treatment that prevents or delays frailty, even in a sub-population of older adults,would have a major positive impact in our society.
 
5. Project Title: PRIMARY FIBROBLAST RESILIENCY AS A PREDICTOR OF HEALTH AND LIFESPAN IN MICE
  Leader(s): SALMON, ADAM
    UNIVERSITY OF TEXAS HLTH SCI CTR SAN ANT
    NIH R01AG057431 / ( 2017 - 2022 )
  Core(s):
  In response to RFA-AG-17-040, Short-term Measurements of Physical Resilience as aPredictor of Healthspan in Mice , we propose testing primary fibroblast resilience with a panel ofdifferent cellular insults as a means to predict individual mouse longevity and healthspan. As outlinedby the funding announcement for this RFA, there is a need to develop these standardized tests foruse among the aging community to accelerate research towards revealing mechanisms that underlythe physiological decline of aging. We previously have shown that primary fibroblasts isolated fromthe tail skin of mice likely retain characteristics of the in vivo environment of the mouse (or otherspecies) from which they were established. For example, we showed in a series of studies that skin-derived primary fibroblasts isolated from long-lived mice with deficiencies in growth hormone/insulin-like growth factor 1 levels are resilient to multiple cytotoxic and metabolic insults. These differencespersist even after numerous population doublings in culture using identical conditions as fibroblastlines from control mice. In addition, we have shown in this fibroblast model that resiliency to one formof insult predicts resiliency to multiple other forms of insult in an individual cell line. Our overallhypothesis is that cellular resiliency of skin-derived primary fibroblasts represents the vitality of anindividual in vivo and predicts both healthspan and longevity of individual mice. We have designedthis study to test this hypothesis and meet the goals outlined by this RFA. In our first aim, we testwhether fibroblast resiliency is predictive of individual longevity and healthspan in a normally aginggroup of genetically heterogeneous mice. Because of the unique fibroblast resiliency panel of testswe have outlined, we can test physical resiliency of mice with little to no effect on the overall healthand longevity of the animals. That is, in an individual mouse we will measure fibroblast resilience(including repeated assessments throughout middle age) and longevity and use these data todevelop a predictive model. In our second aim, we test the effect on fibroblast resiliency ofinterventions in mice known to alter longevity and/or healthspan. This will test whether this model canpredict novel interventions that may alter these parameters within a population. Because we currentlylack standardized research tools to probe resiliencies at the cellular level, this marker of resiliencehas the potential to be a highly important marker of healthspan and longevity in mouse studies.
 
6. Project Title: MEMBRANE LIPID PEROXIDATION IN PATHOGENESIS OF ALZHEIMER?S DISEASE
  Leader(s): RAN, QITAO
    UNIVERSITY OF TEXAS HLTH SCI CTR SAN ANT
    NIH R01AG064078 / ( 2019 - 2024 )
  Core(s):
  ABSTRACT Alzheimer's disease (AD) is the most common neurodegenerative disease affecting millions of Americans.Neurons have a large amount of polyunsaturated fatty acids in membrane phospholipids that are vulnerable toattack by reactive oxygen species to result in lipid peroxidation. Lipid peroxidation is increased in AD brains andis believed to play a key role in driving neurodegeneration of AD. However, supplementation of lipid solubleantioxidants yields only mixed results in clinical trials. So the importance of lipid peroxidation in AD remainsunproven. Glutathione peroxidase 4 (Gpx4) is a glutathione peroxidase that can suppress lipid peroxidation bydirectly reducing phospholipid hydroperoxides in membranes. Therefore, Gpx4 suppresses lipid peroxidationthrough a mechanism distinct from that of lipid antioxidants. Gpx4's role in reducing phospholipid hydroperoxidesin cells such as neurons is critical and indispensable. Gpx4 also serves as the master regulator of ferroptosis.We have demonstrated that Gpx4 plays a critical role in ensuring heath and survival of neurons in adult animals,such as forebrain neurons that are severely afflicted in AD. In preliminary studies, we obtained data indicatingthat there is a Gpx4 dysfunction in AD brains that could lead to exacerbated pathogenesis and that enhancedGpx4 function retards cognitive impairment of AD mouse models. In this project, we will determine whetherincreased membrane lipid peroxidation induced by Gpx4 deficiency aggravates disease pathogenesis such asneurodegeneration, and determine the efficacy of Gpx4 overexpression in retarding cognitive impairment andneurodegeneration in AD mice. The overall hypothesis tested in this project is: Membrane lipid peroxidationaggravates A neurotoxicity in vivo, and augmentation of Gpx4 function to suppress membrane lipid peroxidationwill retard AD pathogenesis. The hypothesis will be tested by three specific aims. Aim 1 is to determine the effectof membrane lipid peroxidation induced by Gpx4 deficiency on AD pathogenesis. Aim 2 is to determine whetheroverexpression of Gpx4 can suppress neurodegeneration and improve cognition in AD mice. Aim 3 is todetermine whether Gpx4 overexpression via transduction with viral vector can retard progression of disease inAD mice at different disease stages. Our study will establish the importance of membrane lipid peroxidation inneurodegeneration of AD and provide proof-of-concept evidence for the efficacy of Gpx4 as a target ofintervention to retard progression of AD.
 
7. Project Title: MARMOSETS AS A MODEL FOR UNDERSTANDING SOCIAL, NEUROENDOCRINE, AND VASCULAR CONTRIBUTIONS TO COGNITIVE AGING
  Leader(s): PHILLIPS, KIMBERLEY ANN
    TRINITY UNIVERSITY
    NIH R01AG064091 / ( 2019 - 2024 )
  Core(s):
  Project SummaryThe number of U.S. residents over age 65 is projected to be 98.2 million by 2060, comprisingapproximately 1 in 4 U.S. residents. According to the Pew Research Center, approximately 26%of older adults live alone. While loneliness does not necessarily correlate with living alone, morethan 40% of seniors regularly experience loneliness. Loneliness is thought to acceleratecognitive decline in older adults, possibly mediated through rising glucocorticoid levels andincreasing inflammation. There is a great unmet therapeutic need for the development ofcognitive therapeutics for the treatment of neurocognitive disorders associated with agingincluding dementias and Alzheimer s disease. Identifying characteristics of animal models thatmay contribute to the development of such a cognitive therapeutic would have significantimpact. Common marmosets are poised to become an important nonhuman primate model inthe study of age-related disease. The focus of this research is healthy brain aging, and thesocial, neuroendocrine, and vascular contributions associated with normal aging rather thandisease states. The population will be characterized using standardized cognitive assessmentsto define those that have good vs poor cognitive aging. The likelihood of the following variablesas determinants of cognitive aging outcomes will be modeled: sex, social history, currenthousing condition, cerebral blood flow (imaging assessments), and myelination. Aim 1 will focuson assessing whether social support buffers the effects of stress on cognitive andneuroendocrine function during aging. An experimental manipulation of a period of separation ofa long-term pair, then reunion, will allow us to investigate the role of social buffering on cognitionand examine how quality of the social support affects cognition and regulation of the HPA axis.Aim 2 will focus on identifying vascular contributions to aging. We will assess cognitiveperformance and cerebral blood flow (CBF) by arterial spin labeling in aged and geriatricmarmosets. We expect cognitive outcomes will be positively correlated with CBF and brainvascular density. Aim 3 will determine whether changes in white matter integrity are associatedwith cognitive dysfunction. The results of this study will contribute novel insights and deeperunderstanding of the role of social stress and neuroendocrine disruption in age-associatedcognitive dysfunction. We anticipate that identifying these links will fundamentally advanceresearch in the study of aging, and may advance the establishment of the marmoset as a highlytranslational model of these conditions.
 
8. Project Title: UNIVERSITY OF TEXAS ADULT CLINICAL CENTER
  Leader(s): RASMUSSEN, BLAKE B; MUSI, NICOLAS ;
    UNIVERSITY OF TEXAS MEDICAL BR GALVESTON
    NIH U01AR071150 / ( 2016 - 2022 )
  Core(s):
  PROJECT SUMMARYThe University of Texas Medical Branch at Galveston (UTMB) and the University of Texas Health ScienceCenter at San Antonio (UTHSCSA) jointly propose the creation of a University of Texas Adult ClinicalCenter (UTACC) for the Molecular Transducers of Physical Activity Consortium (MoTrPAC).We will integrate resources and combine our expertise to provide a state-of-the-art center forcomprehensive studies on physical activity in adults. The Specific Aims of the UTACC are: 1) Toparticipate in the planning of the multi-center trial; 2) To enroll 450 participants in the acute and chronicexercise training studies, conduct physiological assessments, and collect biospecimens (muscle, adipose,and blood); and 3) To analyze and interpret outcome data and disseminate findings to the scientificcommunity. We will use innovative tools to maximize participant retention and enhance fidelity andadherence to the exercise training protocols.The UTACC will have a significant impact on the MoTrPAC and advance the field of exercise science based on our strengths, feasibility of the proposed study, and expected outcomes:The strengths of the UTACC include our long-track record of performing human studies on moleculartransducers of exercise; shared resources and years of networking through the Claude D. Pepper OlderAmericans Independence Center network and the Texas Regional CTSA Consortium; and our successwith enrolling understudied populations such as older individuals and Hispanics-Latinos.The feasibility for the UTACC is high due to our experience with clinical trials on physical activity; oursubstantial expertise in collecting muscle and adipose biopsies in humans undergoing exercise studies;and our access to outstanding clinical research facilities in which to conduct human research in a safeenvironment.Expected outcomes of this program include the determination of baseline molecular signatures associatedwith metabolic health and physical performance; the integration of multi-omic data for the elucidation ofmolecular networks that control metabolic responses to exercise and how they influence physicalperformance; and discovery of novel mediators (proteins, metabolites, miRNAs) of the beneficial effects ofexercise.
 
9. Project Title: HARNESSING THE POWER OF CTSA-CDRN DATA NETWORKS: USING SOCIAL DETERMINANTS OF HEALTH, FRAILTY AND FUNCTIONAL STATUS TO IDENTIFY AT-RISK PATIENTS AND IMPROVE RISK ADJUSTMENT
  Leader(s): SHIREMAN, PAULA K
    UNIVERSITY OF TEXAS HLTH SCI CTR SAN ANT
    NIH U01TR002393 / ( 2018 - 2022 )
  Core(s):
  Postoperative complications and readmissions rates are higher in minority and low socioeconomic status (SES)patients. Low SES is associated with frailty, one of the best predictors of 30-day postoperative complicationsand early hospital readmission. Despite their influence on health outcomes, frailty and social risk factors are notconsidered in risk adjustment for reimbursement and quality measures. CMS developed financial incentive-based programs to improve quality of care. Yet this strategy disproportionately penalizes minority-serving, majorteaching and safety net hospitals (SNH), further constraining resources for the care of vulnerable populations.Our long-term goal is to use frailty and social risk factors to identify at-risk patients to design moreeffective clinical care pathways. Frailty can be derived retrospectively using the American College of SurgeonsNational Surgical Quality Improvement Program (ACS NSQIP) dataset.Data networks are powerful research tools that can be used to answer important questions. However, extractingdata from EHR is challenging. The Patient-Centered Outcomes Research Institute (PCORI) developed 13Clinical Data Research Networks (CDRN) that have considerable overlapping membership with ClinicalTranslational Science Award (CTSA) institutions. While steady progress has been made, multiple barriers existto efficiently access and use data. We will engage 3 CTSA hubs, each members of a different CDRN, to locallymerge identified datasets developing data accessing and linking strategies at diverse institutions fordissemination across sites within CDRNs and to ultimately perform similar studies across CDRNs. We will usethe SMART IRB reliance platform to harmonize the regulatory approval process as much as possible for eachstep of this project to identify barriers to use in data networks. We propose the following Aims:1) Determine the predictive power of ethnicity, race, SES, and frailty for postoperative complications, mortality and readmissions to improve risk adjustment at 3 CTSA/CDRNs2) Estimate postoperative functional status using natural language processing (NLP) and machine learning algorithms on inpatient physical therapy (PT), occupational therapy (OT) and nursing notes for ACS NSQIP patients to predict long-term functional status3) Develop methods to predict long-term loss of independence after major surgery4) Determine hospital resource utilization stratified by SES, frailty and minority statusThe significance of our study is the incorporation of social risk factors, frailty and functional status in riskadjustment forming the basis for future interventions by targeting patients at the highest risk for postoperativecomplications and reducing health care disparities. Our innovative approach harnesses data sources at diverseinstitutions with the goal of disseminating these methods across 3 CDRNs and the CTSA network.
 
PUBLICATIONS
2021
  1. Predominance of Non-carbapenemase Producing Carbapenem-Resistant Enterobacterales in South Texas.
    Black CA, So W, Dallas SS, Gawrys G, Benavides R, Aguilar S, Chen CJ, Shurko JF, Lee GC
    Front Microbiol, 2020, 11: 623574
    https://doi.org/10.3389/fmicb.2020.623574 | PMID: 33643226 | PMCID: PMC7902696
    Citations: | AltScore: NA
  2. Increasing skeletal muscle carnitine content in older individuals increases whole-body fat oxidation during moderate-intensity exercise.
    Chee C, Shannon CE, Burns A, Selby AL, Wilkinson D, Smith K, Greenhaff PL, Stephens FB
    Aging Cell, 2021 Feb, 20(2): e13303
    https://doi.org/10.1111/acel.13303 | PMID: 33464721 | PMCID: PMC7884033
    Citations: | AltScore: 18
  3. Rapamycin enhances BCG-specific d T cells during intravesical BCG therapy for non-muscle invasive bladder cancer: a randomized, double-blind study.
    Ji N, Mukherjee N, Reyes RM, Gelfond J, Javors M, Meeks JJ, McConkey DJ, Shu ZJ, Ramamurthy C, Dennett R, Curiel TJ, Svatek RS
    J Immunother Cancer, 2021 Mar, 9(3):
    pii: e001941. https://doi.org/10.1136/jitc-2020-001941 | PMID: 33653802 | PMCID: PMC7929866
    Citations: 1 | AltScore: 0.5
  4. Methodology for task-shifting evidence-based psychological treatments to non-licenced/lay health workers: protocol for a systematic review.
    Kanzler KE, Kilpela LS, Pugh J, Garcini LM, Gaspard CS, Aikens J, Reynero E, Tsevat J, Lopez ES, Johnson-Esparza Y, Ramirez AG, Finley EP
    BMJ Open, 2021 Feb 1, 11(2): e044012
    https://doi.org/10.1136/bmjopen-2020-044012 | PMID: 33526503 | PMCID: PMC7852942
    Citations: | AltScore: 6.85
  5. Chloride channel accessory 1 integrates chloride channel activity and mTORC1 in aging-related kidney injury.
    Lee HJ, Donati A, Feliers D, Sun Y, Ding Y, Madesh M, Salmon AB, Ikeno Y, Ross C, O'Connor CL, Ju W, Bitzer M, Chen Y, Choudhury GG, Singh BB, Sharma K, Kasinath BS
    Aging Cell, 2021 Jun 12 e13407
    https://doi.org/10.1111/acel.13407 | PMID: 34118180
    Citations: | AltScore: 1
  6. Insulin resistance is mechanistically linked to hepatic mitochondrial remodeling in non-alcoholic fatty liver disease.
    Shannon CE, Ragavan M, Palavicini JP, Fourcaudot M, Bakewell TM, Valdez IA, Ayala I, Jin ES, Madesh M, Han X, Merritt ME, Norton L
    Mol Metab, 2021 Mar, 45: 101154
    https://doi.org/10.1016/j.molmet.2020.101154 | PMID: 33359401 | PMCID: PMC7811046
    Citations: 3 | AltScore: NA
  7. Comparison of rectal swab, glove tip, and participant-collected stool techniques for gut microbiome sampling.
    Short MI, Hudson R, Besasie BD, Reveles KR, Shah DP, Nicholson S, Johnson-Pais TL, Weldon K, Lai Z, Leach RJ, Fongang B, Liss MA
    BMC Microbiol, 2021 Jan 14, 21(1): 26
    https://doi.org/10.1186/s12866-020-02080-3 | PMID: 33446094 | PMCID: PMC7809826
    Citations: | AltScore: 0.75
  8. Responses to acute infection with SARS-CoV-2 in the lungs of rhesus macaques, baboons and marmosets.
    Singh DK, Singh B, Ganatra SR, Gazi M, Cole J, Thippeshappa R, Alfson KJ, Clemmons E, Gonzalez O, Escobedo R, Lee TH, Chatterjee A, Goez-Gazi Y, Sharan R, Gough M, Alvarez C, Blakley A, Ferdin J, Bartley C, Staples H, Parodi L, Callery J, Mannino A, Klaffke B, Escareno P, Platt RN 2nd, Hodara V, Scordo J, Gautam S, Vilanova AG, Olmo-Fontanez A, Schami A, Oyejide A, Ajithdoss DK, Copin R, Baum A, Kyratsous C, Alvarez X, Ahmed M, Rosa B, Goodroe A, Dutton J, Hall-Ursone S, Frost PA, Voges AK, Ross CN, Sayers K, Chen C, Hallam C, Khader SA, Mitreva M, Anderson TJC, Martinez-Sobrido L, Patterson JL, Turner J, Torrelles JB, Dick EJ Jr, Brasky K, Schlesinger LS, Giavedoni LD, Carrion R Jr, Kaushal D
    Nat Microbiol, 2021 Jan, 6(1): 73-86
    https://doi.org/10.1038/s41564-020-00841-4 | PMID: 33340034 | PMCID: PMC7890948
    Citations: 6 | AltScore: 205.83
  9. The treatment of neurogenic lower urinary tract dysfunction in persons with spinal cord injury: An open label, pilot study of anticholinergic agent vs. mirabegron to evaluate cognitive impact and efficacy.
    Trbovich M, Romo T, Polk M, Koek W, Kelly C, Stowe S, Kraus S, Kellogg D
    Spinal Cord Ser Cases, 2021 Jun 10, 7(1): 50
    https://doi.org/10.1038/s41394-021-00413-6 | PMID: 34112758
    Citations: | AltScore: NA
 
2020
  1. Effect of prehabilitation in older adults undergoing total joint replacement: An Overview of Systematic Reviews.
    Almeida GJ, Khoja SS, Zelle BA
    Curr Geriatr Rep, 2020 Dec, 9(4): 280-287
    https://doi.org/10.1007/s13670-020-00342-6 | PMID: 33344110 | PMCID: PMC7745772
    Citations: | AltScore: 12.5
  2. Aster-B coordinates with Arf1 to regulate mitochondrial cholesterol transport.
    Andersen JP, Zhang J, Sun H, Liu X, Liu J, Nie J, Shi Y
    Mol Metab, 2020 Dec, 42: 101055
    https://doi.org/10.1016/j.molmet.2020.101055 | PMID: 32738348 | PMCID: PMC7476871
    Citations: | AltScore: 6.7
  3. Mitochondrial-targeted methionine sulfoxide reductase overexpression increases the production of oxidative stress in mitochondria from skeletal muscle.
    Bhattacharya A, Pulliam D, Liu Y, Salmon AB
    Aging Pathobiol Ther, 2020, 2(1): 45-51
    https://doi.org/10.31491/apt.2020.03.012 | PMID: 33829213 | PMCID: PMC8023689
    Citations: | AltScore: NA
  4. Eosinopenia and Binary Toxin Increase Mortality in Hospitalized Patients With Clostridioides difficile Infection.
    Carlson TJ, Endres BT, Le Pham J, Gonzales-Luna AJ, Alnezary FS, Nebo K, Miranda J, Lancaster C, Bass?res E, Begum K, Alam MJ, Reveles KR, Garey KW
    Open Forum Infect Dis, 2020 Jan, 7(1): ofz552
    https://doi.org/10.1093/ofid/ofz552 | PMID: 31993458 | PMCID: PMC6979314
    Citations: 4 | AltScore: NA
  5. Acarbose improved survival for Apc<sup>+/Min</sup> mice.
    Dodds SG, Parihar M, Javors M, Nie J, Musi N, Dave Sharp Z, Hasty P
    Aging Cell, 2020 Feb, 19(2): e13088
    https://doi.org/10.1111/acel.13088 | PMID: 31903726 | PMCID: PMC6996958
    Citations: 3 | AltScore: 10.25
  6. Primary neuron and astrocyte cultures from postnatal Callithrix jacchus: a non-human primate in vitro model for research in neuroscience, nervous system aging, and neurological diseases of aging.
    Dorigatti AO, Hussong SA, Hernandez SF, Sills AM, Salmon AB, Galvan V
    Geroscience, 2020 Oct 15, 43(1): 115-124
    https://doi.org/10.1007/s11357-020-00284-z | PMID: 33063253 | PMCID: PMC8050148
    Citations: | AltScore: NA
  7. Technology-Assisted Self-Monitoring of Lifestyle Behaviors and Health Indicators in Diabetes: Qualitative Study.
    Du Y, Dennis B, Rhodes SL, Sia M, Ko J, Jiwani R, Wang J
    JMIR Diabetes, 2020 Aug 28, 5(3): e21183
    https://doi.org/10.2196/21183 | PMID: 32857056 | PMCID: PMC7486673
    Citations: | AltScore: NA
  8. Rationale and Study Design of a Randomized Clinical Trial of Metformin to Prevent Frailty in Older Adults With Prediabetes.
    Espinoza SE, Musi N, Wang CP, Michalek J, Orsak B, Romo T, Powers B, Conde A, Moris M, Bair-Kelps D, Li Y, Ganapathy V, Jergensen TE, Kelly LC, Jiwani R
    J Gerontol A Biol Sci Med Sci, 2020 Jan 1, 75(1): 102-109
    https://doi.org/10.1093/gerona/glz078 | PMID: 30888034 | PMCID: PMC7175970
    Citations: 6 | AltScore: 4.7
  9. Receipt of Substance Use Counseling Among Ambulatory Patients Prescribed Opioids in the United States.
    Evoy KE, Leonard CE, Covvey JR, Ochs L, Peckham AM, Soprano S, Reveles KR
    Subst Abuse, 2020, 14: 1178221819894588
    https://doi.org/10.1177/1178221819894588 | PMID: 32547047 | PMCID: PMC7249603
    Citations: | AltScore: NA
  10. Assessing acceptability and patient experience of a behavioral lifestyle intervention using fitbit technology in older adults to manage type 2 diabetes amid COVID-19 pandemic: A focus group study.
    Jiwani R, Dennis B, Bess C, Monk S, Meyer K, Wang J, Espinoza S
    Geriatr Nurs, 2020 Nov 19, 42(1): 57-64
    https://doi.org/10.1016/j.gerinurse.2020.11.007 | PMID: 33248357 | PMCID: PMC7933081
    Citations: 1 | AltScore: 2.5
  11. A geriatrics walking clinic improves hemoglobin A1c and timed gait in older veterans with type 2 diabetes.
    Jiwani R, Wang CP, Orsak B, MacCarthy D, Kellogg D, Powers B, Wang J, Padala P, Padala K, Espinoza S
    Geriatr Nurs, 2020 Nov 4, 42(2): 566-569
    pii: S0197-4572(20)30301-3. https://doi.org/10.1016/j.gerinurse.2020.10.001 | PMID: 33158625
    Citations: 1 | AltScore: 1
  12. Changes in Patient-Reported Outcome Measures With a Technology-Supported Behavioral Lifestyle Intervention Among Patients With Type 2 Diabetes: Pilot Randomized Controlled Clinical Trial.
    Jiwani R, Wang J, Berndt A, Ramaswamy P, Mathew Joseph N, Du Y, Ko J, Espinoza S
    JMIR Diabetes, 2020 Jul 24, 5(3): e19268
    https://doi.org/10.2196/19268 | PMID: 32706652 | PMCID: PMC7414397
    Citations: 1 | AltScore: 1
  13. GABAergic but not Antidepressant Medications Increase Risk for Clostridioides difficile Infection in a National Cohort of Veterans.
    Lalani F, Young EH, Panchal RM, Reveles KR
    Open Forum Infect Dis, 2020 Sep, 7(9): ofaa353
    https://doi.org/10.1093/ofid/ofaa353 | PMID: 32939356 | PMCID: PMC7486948
    Citations: | AltScore: NA
  14. TORwards a Victory Over Aging.
    Lamming DW, Salmon AB
    J Gerontol A Biol Sci Med Sci, 2020 Jan 1, 75(1): 1-3
    https://doi.org/10.1093/gerona/glz212 | PMID: 31544928 | PMCID: PMC7328347
    Citations: 1 | AltScore: 6.7
  15. Dying in the face of the COVID-19 pandemic: Contextual considerations and clinical recommendations.
    LeRoy AS, Robles B, Kilpela LS, Garcini LM
    Psychol Trauma, 2020 Aug, 12(S1): S98-S99
    https://doi.org/10.1037/tra0000818 | PMID: 32525368 | PMCID: PMC7676813
    Citations: 4 | AltScore: 3.2
  16. Nanopore Sequencing of the Fungal Intergenic Spacer Sequence as a Potential Rapid Diagnostic Assay.
    Morrison GA, Fu J, Lee GC, Wiederhold NP, Ca?ete-Gibas CF, Bunnik EM, Wickes BL
    J Clin Microbiol, 2020 Nov 18, 58(12):
    pii: e01972-20. https://doi.org/10.1128/JCM.01972-20 | PMID: 32967904 | PMCID: PMC7685901
    Citations: | AltScore: 14.75
  17. Maternal weight affects placental DNA methylation of genes involved in metabolic pathways in the common marmoset monkey (Callithrix jacchus).
    Narapareddy L, Wildman DE, Armstrong DL, Weckle A, Bell AF, Patil CL, Tardif SD, Ross CN, Rutherford JN
    Am J Primatol, 2020 Mar, 82(3): e23101
    https://doi.org/10.1002/ajp.23101 | PMID: 32020652 | PMCID: PMC7154656
    Citations: 1 | AltScore: 6.5
  18. Can oral health and oral-derived biospecimens predict progression of dementia?
    Orr ME, Reveles KR, Yeh CK, Young EH, Han X
    Oral Dis, 2020 Mar, 26(2): 249-258
    https://doi.org/10.1111/odi.13201 | PMID: 31541581 | PMCID: PMC7031023
    Citations: 4 | AltScore: 12.25
  19. Capsule Commentary on Novosad et al., Treatment of Clostridioides Difficile Infection and Non-compliance with Treatment Guidelines in Adults, 10 US Geographical Locations, 2013-2015.
    Reveles KR
    J Gen Intern Med, 2020 Feb, 35(2): 618-619
    https://doi.org/10.1007/s11606-019-05494-6 | PMID: 31667739 | PMCID: PMC7018932
    Citations: | AltScore: NA
  20. Feasibility of fecal microbiota transplantation via oral gavage to safely alter gut microbiome composition in marmosets.
    Ross CN, Reveles KR
    Am J Primatol, 2020 Dec, 82(12): e23196
    https://doi.org/10.1002/ajp.23196 | PMID: 32970852 | PMCID: PMC7679041
    Citations: | AltScore: 5.45
  21. Implementation of Universal Tumor Screening of Colorectal Cancer for Detection of Lynch Syndrome at a Hispanic-Rich County Hospital.
    Snedden TW, McCracken A, Vaidyanathan A, Taranova A, Villarreal R, Qamar S, Arora SP
    JCO Oncol Pract, 2020 Sep, 16(9): e948-e957
    https://doi.org/10.1200/JOP.19.00508 | PMID: 32452745 | PMCID: PMC7489486
    Citations: | AltScore: 10.1
  22. Molecular profile of BRCA-mutated biliary tract cancers.
    Spizzo G, Puccini A, Xiu J, Goldberg RM, Grothey A, Shields AF, Arora SP, Khushman M, Salem ME, Battaglin F, Baca Y, El-Deiry WS, Philip PA, Nassem M, Hall M, Marshall JL, Kocher F, Amann A, Wolf D, Korn WM, Lenz HJ, Seeber A
    ESMO Open, 2020 Jun, 5(3): e000682
    https://doi.org/10.1136/esmoopen-2020-000682 | PMID: 32576609 | PMCID: PMC7312328
    Citations: 12 | AltScore: 8.35
  23. Is Rapamycin a Dietary Restriction Mimetic?
    Unnikrishnan A, Kurup K, Salmon AB, Richardson A
    J Gerontol A Biol Sci Med Sci, 2020 Jan 1, 75(1): 4-13
    https://doi.org/10.1093/gerona/glz060 | PMID: 30854544 | PMCID: PMC6909904
    Citations: 6 | AltScore: 18.1
  24. NFB Regulates Muscle Development and Mitochondrial Function.
    Valentine JM, Li ME, Shoelson SE, Zhang N, Reddick RL, Musi N
    J Gerontol A Biol Sci Med Sci, 2020 Mar 9, 75(4): 647-653
    https://doi.org/10.1093/gerona/gly262 | PMID: 30423026 | PMCID: PMC7328192
    Citations: 3 | AltScore: NA
  25. Aster-C coordinates with COP I vesicles to regulate lysosomal trafficking and activation of mTORC1.
    Zhang J, Andersen JP, Sun H, Liu X, Sonenberg N, Nie J, Shi Y
    EMBO Rep, 2020 Sep 3, 21(9): e49898
    https://doi.org/10.15252/embr.201949898 | PMID: 32648345 | PMCID: PMC7507422
    Citations: 3 | AltScore: 3.85


EXTERNAL ADVISORY BOARD MEMBERS

Douglas Seals
University of Colorado Boulder
Serving since 2015 (6 years)

James Kirkland
Mayo Clinic
Serving since 2015 (6 years)

Stephanie Studenski
University of Pittsburgh
Serving since 2015 (6 years)

Stephen Kritchevsky
Wake Forest University
Serving since 2015 (6 years)


RECOGNITION AND AWARDS (2020-2021)
Gustavo Almeida (2020)
  • George Kudolo Award for Excellence in Health Professions Research, UTHSCSA

MINORITY RESEARCH

General Brief Description of Minority Activities:
Not defined.


Minority Trainee(s):
  • Nothing to report, Nothing to report
    Nothing to report

Minority Grant(s):