Claude D. Pepper Older Americans Independence Center

Nicolas Musi, M.D.
Principal Investigator
  210 562 6140
Sara Espinoza, M.D.
  210 617 5197
Randy Strong, Ph.D.
  210 562 6126
Marisa Lopez-Cruzan
Program Administrator
  210 363 3066

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;

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

Leadership and Administrative Core (LAC)
Leader 1:    Nicolas Musi, MD
Leader 2:    Sara Espinoza, MD
Leader 3:    Randy Strong, PhD
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:    Robert Clark
Leader 2:    Peter Hornsby, PhD
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
Leader 2:    Randy Strong, PhD
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
Leader 2:    Cory Ross, PhD

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
Leader 2:    Nick Musi, MD
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
Leader 2:    Meredith Zozus, PhD

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).

REC Scholar, Research & Grants Funded During Pepper Supported Time Years /
Jamie Walker, MD
Assistant Professor of Pathology / UTHSCSA
Establishing a San Antonio Longevity and Successful Aging Cohort
The goal is to establish a successful aging cohort where we will recruit these resistant and resilient individuals and learn their secrets of healthy aging. We will be studying both the physical and cognitive aspects of aging and how these interact.
2021-2023 /
34 (total)
12 (1st/Sr)
Juan Pablo Palavicini, PhD
Assistant Professor of Medicine, Diabetes Division / UTHSCSA
Effects of mTOR inhibition on central and peripheral ceramide metabolism in old marmosets and cognitively impaired human subjects
2021-2023 /
32 (total)
10 (1st/Sr)
Tiffany Cortes, MD
Assistant Professor of Medicine, Division of Endocrinology / UTHSCSA
The Effect of GLP1 Receptor Agonists on Physical Function, Body Composition, and Biomarkers of Aging in Older Overweight/Obese Adults with Insulin Resistance
2021-2023 /
11 (total)
2 (1st/Sr)

Past Scholars
Mitzi Gonzales, Biggs Institute, UT Health Science Center San Antonio (2019-2021)
Jia Nie, Barshop Institute, UT Health Science Center San Antonio (2019-2021)
Rozmin Jiwani, School of Nursing, UT Health Science Center San Antonio (2019-2021)
Gustavo Almeida, UT Health San Antonio (2020-2022)
Christopher Shannon, Department of Medicine, UT Health San Antonio (2020-2022)

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: 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.

3. Project Title: Differential effect of glucose regulating drugs on the onset and progression of frailty: healthcare analytics meets aging research
  Leader: Tiffany Cortes, MD; Alex Bokov, PhD
  The purpose of this proposal for the 2021 San Antonio Calude D. Pepper Older American Independence Center Pilot and Exploratory Studies Core Pilot application is to understand the factors that lead and the effect of anti-hyperglycemics on frailty progression and incidence in older adults with diabetes. Briefly, our specific aims are: (1) Examine predictors of frailty progression in older adults with Type 2 diabetes from our UT Health San Antonio/University Hospital patient population. (2) Determine the effect of timing of metformin initiation and different classes of diabetes medication on frailty in older adults with Type 2 diabetes. Analyses will be conducted in older adults with well controlled diabetes who are either prescribed metformin alone or no drug treatment (Aim 2a) and in patients who have been prescribed at least one additional antihyperglycemic agent to manage their diabetes (Aim 2b). a. Compare the trajectories of frailty in older adults with well-controlled type 2 diabetes (HbA1c ?7.5%) on metformin monotherapy versus no anti-hyperglycemic agents in the UT Health San Antonio/University Hospital population over four years. b. Compare the trajectories of frailty among older adults with type 2 diabetes who are prescribed metformin monotherapy compared to those prescribed metformin plus a second line antihyperglycemic agent. We hypothesize that hyperglycemia, adiposity and increased inflammation will accelerate frailty progression in older adults with diabetes (Aim 1).
4. Project Title: Development of marmoset age-dependent iPSC line resources to determine single cell transcriptome and regulome atlas
  Leader: Marcel Daadi, PhD
  With a significant gap between preclinical success and clinical failure and the stagnant development of effective treatments for age-associated diseases, it is essential to develop relevant and reliable biological materials with information resources to guide the development of novel groundbreaking therapies. We propose to generate high quality validated induced pluripotent stem cell (iPSC) from marmosets at two ages, young adult and aged, to be used to conduct comprehensive characterization of the effect of donor age on these cells, at the single cell level. We will generate a single-cell transcriptome and regulome atlas of gene regulatory networks in marmosets that’s age-specific. These studies will determine for the first time whether age of donor significantly affects outcomes, which will be invaluable for developing models of age-associated biological variations towards understanding age-associated disease pathogenesis and development of novel interventions. IPSCs offer powerful model systems, including standardized organ and cell-specific assays to understand organ-specific responses to aging and for screening drugs or vaccines. Looking forward, iPSCs have the potential to be powerful translational interventions to improve or reverse numerous age-related pathologies and diseases. This proposal will be the initial step in understanding what role age may play in development of potential iPSC-derived treatment options. In Aim 1 we will generate, in vitro characterize and authenticate iPSC lines from young adult marmosets 4-6 year old (3 males, 3 females) versus aged marmosets >10 year old (3 males, 3 females). We will compare age-related changes in the mitochondrial functions and cellular resilience in a fluorescent-based high throughput-screening assay. The iPSC lines will be generated from skin biopsies or blood from live animals and thus will require no animal euthanasia. In Aim 2 we will use high-resolution single-cell RNA sequencing and single-cell ATAC sequencing on the iPSC lines and iPSC-derived brain organoids to generate a single-cell transcriptome and regulome atlas of age-associated gene regulatory networks that will serve as a blueprint for novel discoveries and interventions relevant to human aging. When complete, these resources will for the first time uncover whether age of donor significantly alters iPSC in marmosets. As potential project extensions, these data will be used, in collaboration between Daadi’s and Salmon’s lab in high throughput screening assays for anti-aging small molecules. The proposed project will develop into broadly applicable and invaluable resources stimulating new collaborations to expedite translational research and discoveries of novel insights into the human aging, health and diseases.
5. Project Title: Direct measurement of high?energy phosphate compounds in breast cancer survivors in response to exercise ± creatine supplementation
  Leader: Darpan Patel, PhD; Geoffrey Clarke, PhD
  Individuals with breast cancer are at high risk for skeletal muscle wasting that may be exacerbated by chemotherapy or tumor-related factors. Given the implications of treatment toxicities in relation to muscle mass, identifying strategies to enhance muscle post treatment are required. Exercise after treatment has been found to be beneficial in rehabilitating breast cancer survivors post chemotherapy, helping improve muscle strength, physical function and quality of life. However, fatigue can impair adaptations to exercise. Fatigue in breast cancer survivors is hypothesized to be associated with reductions high energy phosphates leading to reduced intramuscular adenosine triphosphate. Creatine is one of the most widely studied supplements with research demonstrating its efficacy in augmenting training adaptations such as improved strength and physical function in a variety of healthy populations. In cancer-related physical impairments, supplementing creatine phosphate may promote muscle hypertrophy, strength and endurance; reversing the deleterious effects of chemotherapy observed in this population. No studies to date have been conducted in breast cancer patients. The primary objective of this proposal is to is to test the hypothesis that creatine phosphate supplementation will increase high energy phosphates in vivo and accelerate adaptations associated with exercise in breast cancer survivors that have recently completed chemotherapy. The secondary objectives are to (1) compare in vivo high energy phosphate concentrations in breast cancer survivors compared to age-matched controls; (2) determine if high energy phosphate concentrations are associated with muscle cross-sectional area, body composition or physical function; and (3) determine the effects of creatine phosphate supplements in modulating strength and physical function in cancer survivors. To test the primary objective’s hypothesis, we will conduct an open-label, randomized controlled trial of exercise ± creatine phosphate supplementation, enrolling 15 breast cancer survivors into each arm of the study (30 breast cancer survivors in all). All participants will complete 12 weeks of exercise, 3 times per week, administered virtually via Zoom. Creatine phosphate supplementation will be administered at 20 grams per day for 7 days (loading phase), later reduced to 5 grams per day for the subsequent 11 weeks (maintenance phase). To complete the secondary objectives of this study, we will conduct a cross-sectional study comparing in vivo high energy phosphate concentrations, body composition and physical function in the 30 breast cancer survivors recruited for the clinical trial to 30 age-matched controls.
6. Project Title: Mechanisms to Reduce Mental and Physical Fatigue Following Diet and Exercise Training in Older Adults
  Leader: Monica Serra, PhD; Jason O'Connor, PhD
  Fatigue is a strong predictor of negative health outcomes in older adults. Tryptophan, an essential amino acid, may play an integral role in fatigue progression. The accumulation of oxidative metabolites of tryptophan metabolism (i.e., kynurenines) is strongly associated with fatigue. Reductions in fatigue observed with exercise training appear to be mediated by skeletal muscle peroxisome proliferator-activated receptor-? co-activator-1? (PGC-1?), inducing a shift of kynurenine to kynurenic acid. This is catalyzed by kynurenine aminotransferase (KAT) enzymes, which precludes oxidative kynurenine metabolism and its. However, we find that subjects participating in exercise training often continue to report fatigue after the intervention, suggesting a need to identify additional methods to maximize the fatigue response to exercise. In the past two decades, numerous studies have shown the advantageous effects of branched-chain amino acids (BCAAs) on exercise performance. Further, studies in animal models suggest that BCAAs decrease the transport of tryptophan and its metabolites into the CNS because BCAAs and tryptophan compete for the same carrier system. Thus, combining BCAA with exercise may synergize to divert metabolism away from formation of neurotoxic tryptophan metabolites with known deleterious effects on mental and physical fatigue. This randomized pilot examines the influence of systemic and skeletal muscle tryptophan metabolism on mental and physical fatigue following exercise training with and without BCAA supplementation in fatigued older adults. Our central hypothesis is that eight weeks of BCAA added to exercise will increase expression of KATs shifting kynurenine metabolism towards enhanced synthesis of kynurenic acid, thereby reducing fatigue. Aim 1) Evaluate the impact of EX+PLA vs. EX+BCAA on changes in mental fatigue, in association with changes in systemic and skeletal muscle tryptophan metabolism. We hypothesize that EX+BCAA will result in greater increases in PGC-1?, KATs, and kynurenic acid and decreases in kynurenine in plasma and skeletal muscle, leading to declines in mental fatigue measured by Brief Fatigue Inventory. Aim 2) Determine the effects of EX+PLA vs. EX+BCAA on changes in physical fatigue, in association with changes in systemic and skeletal muscle tryptophan metabolism. We hypothesize that EX+BCAA will result in greater changes in tryptophan metabolism (as outlined in Aim 1), leading to improvements in physical fatigue measured by aerobic capacity and strength. The discovery that kynurenine concentrations are associated with fatigue and are responsive to BCAA supplementation during exercise training could have important implications for the development of future interventions, both lifestyle and pharmacologic, to treat fatigue in older adults.
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 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 (4 Projects Listed)
  Leader(s): KILPELA, LISA
    NIH K76AG060003 / ( 2019 - 2023 )
  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.
    NIH K76AG060005 / ( 2018 - 2023 )
  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.
  Leader(s): RAN, QITAO
    NIH R01AG064078 / ( 2019 - 2024 )
  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.
    NIH R01AG064091 / ( 2019 - 2024 )
  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.
  1. Stress-Busting Program for Family Caregivers: Validation of the Spanish version using biomarkers and quality-of-life?measures.
    Ar?valo-Flechas LC, Flores BP, Wang H, Liang H, Li Y, Gelfond J, Espinoza S, Lewis SL, Musi N, Yeh CK
    Res Nurs Health, 2022 Apr, 45(2): 205-217 | PMID: 35174517
    Citations: | AltScore: 7.25
  2. Genetic and pharmacologic proteasome augmentation ameliorates Alzheimer's-like pathology in mouse and fly APP overexpression models.
    Chocron ES, Munk?csy E, Kim HS, Karpowicz P, Jiang N, Van Skike CE, DeRosa N, Banh AQ, Palavicini JP, Wityk P, Kalinowski L, Galvan V, Osmulski PA, Jankowska E, Gaczynska M, Pickering AM
    Sci Adv, 2022 Jun 10, 8(23): eabk2252 | PMID: 35675410 | PMCID: PMC9177073
    Citations: | AltScore: 18.2
  3. Senolytic Therapy to Modulate the Progression of Alzheimer's Disease (SToMP-AD): A Pilot Clinical Trial.
    Gonzales MM, Garbarino VR, Marques Zilli E, Petersen RC, Kirkland JL, Tchkonia T, Musi N, Seshadri S, Craft S, Orr ME
    J Prev Alzheimers Dis, 2022, 9(1): 22-29 | PMID: 35098970 | PMCID: PMC8612719
    Citations: 7 | AltScore: 32.058
  4. The emerging role of lipidomics in prediction of diseases.
    Han X
    Nat Rev Endocrinol, 2022 Jun, 18(6): 335-336 | PMID: 35393579
    Citations: | AltScore: 21.65
  5. Deadenylase-dependent mRNA decay of GDF15 and FGF21 orchestrates food intake and energy expenditure.
    Katsumura S, Siddiqui N, Goldsmith MR, Cheah JH, Fujikawa T, Minegishi G, Yamagata A, Yabuki Y, Kobayashi K, Shirouzu M, Inagaki T, Huang TH, Musi N, Topisirovic I, Larsson O, Morita M
    Cell Metab, 2022 Apr 5, 34(4): 564-580.e8 | PMID: 35385705
    Citations: 1 | AltScore: 112.95
  6. Exercise and Creatine Supplementation to Augment the Adaptation of Exercise Training Among Breast Cancer Survivors Completing Chemotherapy: Protocol for an Open-label Randomized Controlled Trial (the THRIVE Study).
    Patel DI, Gonzalez A, Moon C, Serra M, Bridges PB, Hughes D, Clarke G, Kilpela L, Jiwani R, Musi N
    JMIR Res Protoc, 2022 Apr 1, 11(4): e26827 | PMID: 35363152 | PMCID: PMC9015753
    Citations: | AltScore: 2.5
  7. Differential protein expression in the hippocampi of resilient individuals identified by digital spatial profiling.
    Walker JM, Kazempour Dehkordi S, Fracassi A, Vanschoiack A, Pavenko A, Taglialatela G, Woltjer R, Richardson TE, Zare H, Orr ME
    Acta Neuropathol Commun, 2022 Feb 14, 10(1): 23 | PMID: 35164877 | PMCID: PMC8842950
    Citations: | AltScore: 14.9
  8. Arachidonic Acid Cascade and Eicosanoid Production Are Elevated While LTC4 Synthase Modulates the Lipidomics Profile in the Brain of the HIVgp120-Transgenic Mouse Model of NeuroHIV.
    Yuan NY, Maung R, Xu Z, Han X, Kaul M
    Cells, 2022 Jul 5, 11(13):
    pii: 2123. | PMID: 35805207 | PMCID: PMC9265961
    Citations: | AltScore: NA
  9. Orally-active, clinically-translatable senolytics restore a-Klotho in mice and humans.
    Zhu Y, Prata LGPL, Gerdes EOW, Netto JME, Pirtskhalava T, Giorgadze N, Tripathi U, Inman CL, Johnson KO, Xue A, Palmer AK, Chen T, Schaefer K, Justice JN, Nambiar AM, Musi N, Kritchevsky SB, Chen J, Khosla S, Jurk D, Schafer MJ, Tchkonia T, Kirkland JL
    EBioMedicine, 2022 Mar, 77: 103912 | PMID: 35292270 | PMCID: PMC9034457
    Citations: | AltScore: 167.198


Douglas Seals
University of Colorado Boulder
Serving since 2015 (8 years)

James Kirkland
Mayo Clinic
Serving since 2015 (8 years)

Stephanie Studenski
University of Pittsburgh
Serving since 2015 (8 years)

Stephen Kritchevsky
Wake Forest University
Serving since 2015 (8 years)


Recognition and Awards not specified.


General Brief Description of Minority Activities:
Not defined.

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

Minority Grant(s):