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

George A. Kuchel, Ph.D.
Principal Investigator
  860-679-6796   kuchel@uchc.edu
Richard H. Fortinsky, Ph.D.
Co-Principal Investigator
    fortinsky@uchc.edu
Anthony Barresi & Christine Zonghetti
Center Administrator
  860-679-3959 860-679-4596   barresi@uchc.edu
     
CENTER DESCRIPTION

The mission of the UConn Pepper Center is to establish a thriving interdisciplinary research program to promote health, function and independence in old age.  The UConn Pepper Center provides numerous resources to catalyze the growth of multidisciplinary, collaborative aging-related research ranging from basic and preclinical to clinical and community-based to population based research in a sustained fashion.  Our theme of Precision Gerontology seeks to leverage an understanding of the growing heterogeneity of aging into interventions rendered more effective by being better targeted.

The aims of the UConn Pepper Center are:

  • To develop a strong understanding of the multiple facets of heterogeneity aging.  With an extensive understanding, we'll be able to develop targeted, precise and effective interventions to improve care provided to aging adults.
  • To develop and collaborate with researchers from multidisciplinary teams in order to address questions or problems related to aging from the levels of bench to the bedside and institution to out in a community.  
  • To foster career development opportunities in an effort to train and collaborate with the next generation of leading geriatric researchers. 

CORES
Leadership & Administrative Core (LAC)
Leader 1:    George Kuchel, MD   kuchel@uchc.edu
Leader 2:    Richard H. Fortinsky, PhD   fortinsky@uchc.edu
Leader 3:    Julie Robison, PhD   jrobison@uchc.edu
The Leadership and Administrative Core (LAC) provides the administrative infrastructure and scientific leadership necessary to achieve the overall aims of the UConn Pepper Center. The long-range goal of the LAC is to lead the way in establishing a highly productive research and education program in aging and geriatrics at the University of Connecticut, spanning laboratory, clinical and community, and population-based science collectively guided by the theme of Precision Gerontology.

Research and Education Core (REC)
Leader 1:    David Steffens, MD   steffens@uchc.edu
Leader 2:    George Kuchel, MD   kuchel@uchc.edu
The overarching goal of the Research Education Component (REC) of the UConn Older Americans Independence Center is to cultivate the next generation of investigators and clinician-scientists to become leaders in their career focused on aging with exposure to multidisciplinary translational science, mentorship and expertise in Precision Gerontology. A key component of the Research Education Component (REC) is the Pepper Scholar Program. This program provides financial support, education and training to Pepper Scholars to advance their research careers. Pepper Scholars apply and are chosen as showing particular promise as independent investigators in the field of geriatrics and gerontology. The REC, led by Dr. David Steffens, includes several senior research leaders at UConn who serve as mentors to the Pepper Scholars. The mentors provide each of the scholars with personalized educational opportunities, career development and different networking opportunities in order to facilitate their research interests.

Pilot & Exploratory Studies Core (PESC)
Leader 1:    Lisa Barry, PhD   libarry@uchc.edu
Leader 2:    Rogina Blanka, PhD   rogina@uchc.edu
The UConn Pepper Center Pilot and Exploratory Studies Core (PESC) works to develop and support innovative pilot and exploratory studies that will enhance function and independence in older adults while also advancing knowledge in the field of Precision Gerontology. The PESC provides funding and access to resources offered by each of the UConn Pepper Center research cores, including guidance in research subject recruitment, regulatory and compliance issues, research plan implementation, biostatical considerations, and biomarker analysis. In addition, the PESC provides mentorship and oversight to pilot study investigators to ensure each project is developed and carried out in a timely fashion, and that results are disseminated to optimize scientific impact to the world of aging research.

Biomarkers and Preclinical Research Core (Resource Core 3)
Leader 1:    Laura Haynes, PhD   lhaynes@uchc.edu
Leader 2:    Duygu Ucar, PhD   duygu.ucar@jax.org
The UConn Pepper Biomarkers and Preclinical Research Core assists investigators with the expertise and various tools needed to integrate biomarkers, drivers of aging and underlying mechanisms of chronic diseases in humans and animal models in order to promote function and independence in the late stages of life. Resource Core 3 is managed by Sandra Jastrzebski (jastrzebski@uchc.edu).

Data Resource Core (Resource Core 2)
Leader 1:    Richard H. Fortinsky, PhD   fortinsky@uchc.edu
The UConn Pepper Center Data Resource Core (RC2) provides help in the selection and interpretation of geriatric health-related outcome measures; database design; and data collection, management and analysis. Content expertise is available to aid in the selection and interpretation of measures evaluating gait, mobility, affect, cognition, behavior, voiding symptoms, incontinence, body composition, bone density, caregiving, and self-reported quality of life. RC2 team members offer advice and guidance in biostatistics, genetic epidemiology, spatial analysis, computational genomics, and microbiome analysis techniques. Resource Core 2 is managed by Nicole Diggens (diggens@uchc.edu).

Recruitment and Community Engagement Core (Resource Core 1)
Leader 1:    Julie Robison, PhD   jrobison@uchc.edu
Leader 2:    Wizdom Powell   wpowell@uchc.edu
The UConn Pepper Center Recruitment and Community Engagement Core (RC1) provides expertise in the design and development of recruitment plans and implementation of multidisciplinary complex research projects involving older adults. These efforts address recruitment needs for clinical trials, community-based research and studies with a translational clinical to community and health policy emphasis. The Core also partners with the UConn Health Disparities Institute to ensure research includes and asks questions relevant to communities of color and/or communities most vulnerable to adverse health effects, and to strengthen culturally sensitive approaches in all phases. In addition to these recruitment and community outreach efforts, RC1 also provides regulatory services (e.g., IRB application support) and helps investigators with Human Subjects and Clinical Trials Information grant sections and IRB protocol development. RC1 is managed by Lisa Kenyon-Pesce, MPH (Kenyon-pesce@uchc.edu).

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

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

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

2022-2024 /
2 (total)
0 (1st/Sr)
 

Past Scholars

PILOT/EXPLORATORY PROJECTS (3 Pilot Projects Listed)
1. Project Title: Re-Engaging Black/African American Older Adults During the COVID-19 era: Developing A Community-Based Intervention
  Leader: Rupal Parekh, PhD (PL) Christine Tocchi, PhD (co-PL)
  The sudden closure of churches and senior centers caused by the the COVID-19 pandemic has disproportionately impacted the health and well-being of communities of color, particularly Black/African American older adults. Prior to the pandemic these community centers provide social engagement by providing spiritual healing, health-related education, social interaction and activities and political activism. With the closure of these resources, African American older adults involuntary disengaged their involvement. Previous research shows such disengagement is associated with a decrease in quality of life and negative mental and health outcomes. As churches and senior centers have reopened and resumed their services, African American older adults have either completely become disengaged or utilize the senior centers/churches less frequently than they did prior to the pandemic. This study will develop a psychoeducational intervention to address the needs and concerns of African American older adults as a means of preventing or reducing depressive symptoms of disability.
 
2. Project Title: The Heterogeneity of Vulnerabilities in Aging Cohort (HVAC): A new resource for early biomarker discovery and validation
  Leader: Laura Haynes, PhD (PL) George Kuchel, MD (co-PL) Co-Investigators: Jake Earp, PhD Oh Sung Kwon, PhD Jenna Bartley, PhD Zhichao Fan, PhD Ming Xu, PhD D. Nehar-Belaid, PhD
  In years 1-2, Drs. Earp and Kwon will recruit a sex balanced cohort of 20 healthy young, 20 healthy old, 20 frail, and 20 frail and obese older adults. In years 2-3, fresh and frozen blood samples will permit Drs. Bartley, Kwon, Xu, and Nehar-Belaid to study immunometabolism, autophagy and mitophagy, p21 senescence markers and single cell genomics, respectively. This will offer opportunities for pilot studies to begin validating novel biomarkers helpful in the design and implementation of future geroscience-guided therapies.
 
3. Project Title: Apathy: An Early Manifestation of Frailty and Disability in Older Adults with Depression?
  Leader: Kevin Manning, PhD (PI)
  This project will study whether apathy is an early manifestation of frailty and disability involving both behavioral and physical measures in older adults with depression. This approach may allow for earlier detection of risk factors for disability, with opportunities for some initial insights into role of inflammation, as well as opportunities for improved targeting of higher risk population subsets.
 
DEVELOPMENT PROJECTS (3 Development Projects Listed)
1. Project Title: Gait Velocity Detection Device for Targeted Recruitment in Geriatric Clinic
  Leader: Lisa Barry, PhD (PL) Song Han, PhD (Co-I) Jatupol Kositsawat, MD (Co-I)
  Core(s): Recruitment and Community Engagement Core (Resource Core 1)
  Gait speed is often used as an eligibility criterion for and/or a means of stratifying research study participants. The Center on Aging at UConn Health has developed a Radio Frequency Identification (RFID)-based system that offers a feasible and valid means of assessing gait speed in the clinic setting. In addition to being simple, practical, and unobtrusive, this system holds promise as a research recruitment strategy. The objective of this Developmental Project is to use this RFID-based system in the UConn Health geriatrics clinic to expand RC1 recruitment strategies in a novel way. The project will aim to implement a Best Practice Advisory (BPA) in the UConn Health EMR system that indicates if a patient is willing to have contact information added to the Research Volunteer Registry (RVR) so that they may be notified about studies for which they may be eligible. Consequently, following IRB protocol regarding extraction and storage of medical record-extracted data, the medical records of patients who checked “Yes” can be searched to identify individuals who may qualify for a study based on their gait speed. Following implementation of the BPA, the project will evaluate the utility of the RFID-based system as a means of expanding the RVR. We will track the number of patients asked about RVR inclusion and determine the proportion of who opts in/out of joining the RVR through the BPA and determine the proportions of who opts in/out of joining through the BPA. This Developmental Project is expected to substantially increase the pool of older individuals who may be willing to participate in research studies.
 
2. Project Title: Analysis of scRNAseq data from metformin flu vaccine study
  Leader: Duygu Ucar PhD (co-PL), Jenna Bartley (co-PL)
  Core(s): Data Resource Core (Resource Core 2)
  This particular project is a collaboration between the UConn OAIC and The Jackson Laboratory for Genomic Medicine (JAX) in Farmington, CT. Human peripheral blood mononuclear cells (PBMCs) are routinely obtained and cryopreserved for future use in many different studies at UConn COA. The single cell approach is essential given the remarkable heterogeneity of human blood which increases with aging and, we also believe, with frailty. In our aging and flu vaccination studies we have observed major robust changes involving only rare PBMC subpopulations. Such information could help lead to discoveries of risk factors, mechanisms and treatment effects involving metformin and/or flu vaccine. It could also help guide development of interventions targeting shared risk factors, shared mechanisms, or be used in targeting population subsets. The project will explore the role of specific biological hallmarks of aging associated with frailty, obesity and late life vulnerability. Sample data will be analyzed from samples generated in the OAIC Developmental Project 3 (DP3) project. PBMC samples will include existing samples from the Vaccination Efficacy with Metformin in Older Adults: A Pilot Study (VEME) (conducted by Jenna Bartley, PhD) as well as in future years prospective samples that will be obtained as part of the Pilot and Exploratory Project entitled "The Heterogeneity of Vulnerabilities in Aging (HVAC) Cohort: A new resource for early biomarker discovery and validation” (PES3).
 
3. Project Title: Generation of scRNAseq data using samples from metformin flu vaccine study & HVAC pilot cohort
  Leader: Laura Haynes, PhD (PL), Duygu Ucar, PhD (Jax GM; co-PI)
  Core(s): Biomarkers and Preclinical Research Core (Resource Core 3)
  This particular project is a collaboration between the UConn OAIC and The Jackson Laboratory for Genomic Medicine (JAX) in Farmington, CT. Human peripheral blood mononuclear cells (PBMCs) are routinely obtained and cryopreserved for future use in many different studies at UConn COA. The single cell approach is essential given the remarkable heterogeneity of human blood which increases with aging and we also believe with frailty. In our aging and flu vaccination studies we have observed major robust changes involving only rare PBMC populations. Such information could help lead to discoveries of risk factors, mechanisms and treatment effects involving metformin and/or flu vaccine. It could also help guide development of interventions targeting shared risk factors, shared mechanisms or be used in targeting population subsets. The study will generate data using CITE-Seq and single cell ATAC-Seq to interrogate PBMCs using study samples generated by PESC3, The Heterogeneity of Vulnerabilities in Aging (HVAC) Cohort: A new resource for early biomarker discovery and validation Project Leaders: Laura Haynes and George Kuchel) in future years. In year 1, samples already generated collected in the Vaccination Efficacy with Metformin in Older Adults study (VEME, PI: Bartley, IND#18974, NCT#03996538, IRB#19-205-2) will be processed for CITE-Seq and single cell ATAC-Seq.
 
RESEARCH (5 Projects Listed)
1. Project Title: Resilience and brain health of older adults during the COVID-19 pandemic
  Leader(s): LENZE, ERIC J; DINIZ, BRENO SATLER; WETHERELL, JULIE L;
    WASHINGTON UNIVERSITY
    NIH R01AG072694 / ( 2021 - 2026 )
  Core(s):
  Abstract: Exercise and mindfulness are believed to be effective stress reduction interventions, but research to date has not been able to assess their benefits while individuals are coping with a major stressor in real time. The COVID-19 pandemic is an unwanted natural experiment in the deleterious effects of stress especially social isolation (social disconnectedness and loneliness), a stressor particularly strongly associated with the pandemic - on older Americans cognitive and emotional health and risk for Alzheimer s Disease (AD). This project will elucidate whether exercise and mindfulness can mitigate the effects of pandemic stress on cognitive function and emotional health in later life, including neurobiological measures of risk for AD. We will leverage a unique resource: the NIH-funded trial, Mindfulness-Based Stress Reduction and Exercise for Age-Related Cognitive Decline (MEDEX). By leveraging MEDEX and following these participants, who continue to attend monthly booster sessions of their randomized condition remotely during the pandemic, we will have repeated sets of clinical, cognitive, molecular, and neuroimaging measures covering 7.5 years during the pre-, during-, and post-pandemic period. We can examine intervention effects, as well as individual factors such as resilience, on long-term outcomes. Among other innovative aspects of the project, we will analyze effects on two novel peripheral biomarkers: Senescence-Associated Secretory Phenotype (SASP), which measures mechanisms of biological aging, and plasma amyloid A 42 and A 40, which measure AD risk. In the proposed project, (1) during the pandemic, we will use novel methods such as Ecological Momentary Assessment (EMA) to characterize social isolation both objectively (e.g., number of social contacts) and subjectively (e.g., loneliness), and its biological mechanisms on aging (such as elevations in SASP and plasma amyloid); (2) post-pandemic, we will assess downstream effects on cognitive function, emotional well-being, and brain health, including AD risk, using neuropsychological assessments, EMA, and neuroimaging. Outcomes include (Aim 1) changes in cognitive performance and emotional well-being, and decline in emotional well-being measured by positive and negative affect and sleep quality; increases in biological aging and decreasing A42/40 ratio in the post-pandemic phase, indicating higher risk of AD; atrophy in hippocampal and prefrontal volume (structural MRI) and reduced global functional connectivity (resting-state fMRI). Modifiers of these effects (Aim 2) include exercise and mindfulness; psychological resilience; COVID-19 exposure; medical morbidities; and APOE genotype. Mechanisms of cognitive, emotional, and brain health changes (Aim 3) include amyloid (A 40 and A 42), SASP, DNA methylation, and cortisol during the pandemic. This project will advance our knowledge of the impact of social isolation and other stressors on older adults, including mechanisms by which these stressors produce deleterious cognitive, emotional, and brain health changes over time, and whether exercise and mindfulness have durable protective effects.
 
2. Project Title: Can Senolytics Improve the Aged Response to Viral Infection
  Leader(s): HAYNES, LAURA ; XU, MING ;
    UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
    NIH R21AG071292 / ( 2021 - 2023 )
  Core(s):
  PROJECT SUMMARY Influenza (flu) is foremost among all infectious diseases causing death and disability in older adults, despite widespread vaccination programs. Age-related changes in the immune system contribute to declines in the ability to mount a highly protective immune response following flu infection in both humans and mouse models. With advancing age, we observe slower viral clearance and lingering lung inflammation, which could set the stage for secondary bacterial infection. Importantly, aging impacts almost every aspect of the adaptive immune response including generation of virus-specific CD4 and CD8 T cell effectors and high affinity antibody production. While flu infection is entirely localized to the lungs, functional decrements in skeletal muscle are also observed with upregulation of inflammatory and atrophy genes and downregulation of positive muscle regulators, ultimately resulting in loss of physical function. Importantly, the impact of flu infection on these molecular changes and overall functional declines is more pronounced and prolonged with aging, suggesting decreased physiologic resilience. Even though much research has been done, the ultimate cause of these age-related decrements has not been elucidated. One of the most prominent features of aging is the accumulation of senescent cells and in this project we will explore their role in the age-related changes in response to flu infection. Cellular senescence is characterized by irreversible growth arrest that occurs when cells experience a range of stresses. The number of senescent cells increases with chronological aging, resulting in many age-related pathologies and disease. Factors secreted by senescent cells can also have a direct impact on surrounding cells driving dysfunction and influencing cell subset differentiation. Interestingly, many of these factors are cytokines that are of vital importance for an effective anti-viral immune response. Senescent cells play a causal role in the progression of many age-related disorders, indicating that clearance of senescent cells might slow down the entire aging process. Importantly, we and others have started to develop drugs, which can specifically kill senescent cells (termed senolytics). Intermittent administration of senolytics can alleviate a range of age-related diseases. However, the impact of senolytics on immune system function in aged population has not yet been examined. The overall hypothesis that we will be addressing in this proposal is that senescent cells play a causal role in the age-related impaired response to flu infection. We will test this hypothesis by eliminating senescent cells in aged mice using senolytic drugs. This approach will allow us to simultaneously examine the role of cellular senescence in the compromised immune response and the associated changes in skeletal muscle and declines in physical function during flu infection in an aged mouse model.
 
3. Project Title: Geroscience Education and Training (GET) Network
  Leader(s): KUCHEL, GEORGE A; ESPINOZA, SARA ELYSE; JUSTICE, JAMIE NICOLE; NEWMAN, JOHN C; PIGNOLO, ROBERT JOHN;
    UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
    NIH R25AG073119 / ( 2021 - 2024 )
  Core(s):
  PROJECT ABSTRACT/SUMMARY Aging is by far the main risk factor for chronic conditions that jointly account for most morbidity, mortality, and health care costs. Geroscience-guided therapies seeking to alleviate such disorders as a group by targeting basic aging processes are now entering early stage clinical trials. The discovery, validation, and implementation into routine clinical care of such transformational therapies will require the creation of a robust and diverse geroscience workforce and training pipeline. The focus of this application is to address manpower, training, and educational gaps that were identified at a 2017 conference on this topic funded by an earlier Geroscience Network R24 grant (AG044396) with findings published in JAGS (Newman et al., 2019). We are now proposing to create the NIA Geroscience Education and Training (GET) Network through the R25 funding mechanism (PAR-20-095) as a complementary sister network to the Translational Geroscience Network (TGN; R33 AG061456), since educational, curricular, and training goals outlined in this proposal were not suitable for inclusion in a R33 grant. More specifically, we are proposing the creation of a network model designed to leverage and integrate relevant expertise, knowledge, and resources across multiple institutions and organizations to address the following Specific Aims: Aim 1: Develop shared geroscience curricula and educational materials initially targeting: 1A. Medical and 1B. PhD students needing foundational geroscience knowledge irrespective of career plans 1C. Geriatric Medicine Fellows who require a deeper level of geroscience knowledge Aim 2: Develop a Certificate in Geroscience Research Program to train the next generation of geroscience researchers by offering multidisciplinary training in geroscience. Track 1 will address the specific training needs of basic scientists Track 2 will focus on clinicians and others conducting human subject research. This cross-institutional program would be accessible to all eligible trainees wishing to pursue a career in geroscience. Aim 3: Ensure optimal dissemination of the educational materials developed through this award. 3A. Videotaped lectures and other educational materials will be posted on POGOe with feedback surveys 3B. Our longer-range goal is to create a Geroscience Section in UpToDate an evidence-based, continually updated resource to ensure sustainability beyond the life of this NIA award
 
4. Project Title: A deep longitudinal analysis of next generation influenza vaccines in older adults
  Leader(s): UCAR, DUYGU ; GARCIA-SASTRE, ADOLFO ; KUCHEL, GEORGE A;
    JACKSON LABORATORY
    NIH U01AI165452 / ( 2022 - 2026 )
  Core(s):
  PROJECT SUMMARY The WHO estimates that annual epidemics of influenza result in 3-5 million cases of severe illness and 300,000- 500,000 deaths. 90% of influenza-related deaths occur in older adults despite widespread vaccination programs with vaccines tailored for this high-risk group. The estimated effectiveness of the influenza vaccine in the U.S. for the 2018-2019 influenza season overall was 47%, but only 12-13% in older adults. There is therefore an urgent need to understand the mechanisms that are turned on/off in older adults that result in their limited response rate to the most commonly used influenza vaccine, Fluzone High-Dose. There is also a need to understand whether and why next-generation influenza vaccines might be more efficacious. Immunosenescence is known to be associated with declines in optimal B cell and T cell adaptive immunity, however, our overall understanding of the mechanisms of immunosenescence is incomplete. The central goal of this proposal is to understand the mechanisms that lead to a loss of response to influenza vaccine in older adults through establishment of the 3FluAging cohort of healthy older adults who will be vaccinated with three different influenza vaccines three years in a row. We hypothesize that aging impacts specific regulatory mechanisms of humoral immunity to reduce vaccine effectiveness. In Aim 1, we will establish a cohort of 60 healthy older adults (=65yrs) who will sequentially receive three different annual influenza vaccines, with serial blood and microbiome sample collection during three years of follow-up. Participants will undergo regular clinical assessments. In Aim 2, we will decipher the magnitude and immunodominance pattern of the humoral response to influenza virus in healthy older individuals upon vaccination. For each vaccine, we will characterize antibody titer and quality and will define responders and non-responders. In Aim 3, we will characterize the epigenome, transcriptome, cytokine production, and cell proportions of blood leukocytes in vaccinated healthy older participants. We will identify specific (epi)genomic and functional signatures, and their longevity, associated with vaccine response. We will also sequence all participants to uncover the role of genetic variation on influenza vaccine responses. In Aim 4, we will assess the function of T helper cells and antigen presenting cells, specifically dendritic cells, in influenza vaccine responders and non-responders. By identifying responders and non-responders for each vaccine and integrating these data with baseline immune status multi-omic signatures, we will determine which immune features can predict vaccine responsiveness. We expect to identify humoral immunity pathways that are altered in aging that can be used as the basis for designing novel approaches to boost efficacy of the most commonly used, as well as emerging, influenza vaccines.
 
5. Project Title: Bio-Analysis Core
  Leader(s): KUCHEL, GEORGE A
    UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
    NIH U54AG075941 / ( 2021 - 2026 )
  Core(s):
  The KAPP-Sen Tissue Mapping Center (TMC) Biological Analysis Core will be responsible for generating high- resolution and high-content datasets to define senescent cells and their microenvironment in aged non-diseased human tissues, and measure how such cells compare across a range of ages. We will utilize state-of-the-art single cell technologies on dissociated tissues and on intact tissue sections to study this biology. We will coordinate with our KAPP-Sen Biospecimen Core to obtain high-quality human normal kidney, pancreas, placenta, and adipose tissue. By employing unbiased, sequencing-based, single-cell resolution methods, we will generate high-content spatially resolved data to enable the identification of senescent cells. We will work with our KAPP-Sen Data Analysis Core to discover comprehensive mRNA biomarkers for human senescent cells. A selection of target epitopes derived from these biomarkers will be detected within tissue sections at high resolution (1 m) utilizing a highly multiplex antibody imaging approach. Additional tangential experiments in human tissues and ex vivo and induced pluripotent stem cell (iPSC) models will further inform and validate senescence signatures, and identify associated epigenomic features, within intact human tissues. The Biological Analysis Core will achieve its objectives through the following Aims: Aim 1. To establish optimal tissue dissociation and preparation techniques to implement both dissociative and spatially-resolved single-cell transcriptome methods for the identification of senescent cells in human tissues. Aim 2. To scale and standardize the pipeline to generate high-quality, high-resolution, and high-throughput datasets and construct maps of cellular senescence in the four target tissues. Aim 3. To identify mRNA biomarkers of human senescent cells and construct and apply a multiplex antibody panel derived from these. Aim 4. Leverage ex vivo human models to further characterize the functional features of senescent cells. Together, this analytic approach will define the comprehensive tissue signature of senescence at 1 m resolution and begin to uncover the molecular foundations of the senescent cell and its response to therapy. In addition, the data set generated will provide insight into senescence-associated secreted proteins that may inform the design of blood biomarker of senescence. Altogether, our approach and its associated tools will be applicable across a wide array of human tissues types.
 
PUBLICATIONS
2022
  1. Hereditary hemochromatosis variant associations with incident non-liver malignancies: 11-year follow-up in UK Biobank.
    Atkins JL, Pilling LC, Torti SV, Torti FM, Kuchel GA, Melzer D
    Cancer Epidemiol Biomarkers Prev, 2022 Jun 16
    pii: cebp.0284.2022-3-14 11:22:41.207. https://doi.org/10.1158/1055-9965.EPI-22-0284 | PMID: 35709753
    Citations: | AltScore: 3.75
  2. Cognitive Frailty is Associated With Elevated Proinflammatory Markers and a Higher Risk of Mortality.
    Diniz BS, Lima-Costa MF, Peixoto SV, Firmo JOA, Torres KCL, Martins-Filho OA, Teixeira-Carvalho A, Grady J, Kuchel GA, Castro-Costa E
    Am J Geriatr Psychiatry, 2022 Jul, 30(7): 825-833
    https://doi.org/10.1016/j.jagp.2022.01.012 | PMID: 35227616 | PMCID: PMC9177532
    Citations: 2 | AltScore: 0.25
  3. Prevalence of dementia and mild cognitive impairment before incarceration.
    Kuffel RL, Byers AL, Williams B, Fortinsky R, Li Y, Ruderman MA, Barry LC
    J Am Geriatr Soc, 2022 Feb 25, 70(6): 1792-1799
    https://doi.org/10.1111/jgs.17724 | PMID: 35212389 | PMCID: PMC9177569
    Citations: | AltScore: 6.8
  4. Geroscience-guided repurposing of FDA-approved drugs to target aging: A proposed process and prioritization.
    Kulkarni AS, Aleksic S, Berger DM, Sierra F, Kuchel GA, Barzilai N
    Aging Cell, 2022 Apr, 21(4): e13596
    https://doi.org/10.1111/acel.13596 | PMID: 35343051 | PMCID: PMC9009114
    Citations: 1 | AltScore: 49.858
  5. Senescence-induced changes in CD4 T cell differentiation can be alleviated by treatment with senolytics.
    Lorenzo EC, Torrance BL, Keilich SR, Al-Naggar I, Harrison A, Xu M, Bartley JM, Haynes L
    Aging Cell, 2022 Jan, 21(1): e13525
    https://doi.org/10.1111/acel.13525 | PMID: 34962049 | PMCID: PMC8761018
    Citations: 2 | AltScore: 34.608
  6. Chronic HIV Infection and Aging: Application of a Geroscience-Guided Approach.
    Masters MC, Landay AL, Robbins PD, Tchkonia T, Kirkland JL, Kuchel GA, Niedernhofer LJ, Palella FJ
    J Acquir Immune Defic Syndr, 2022 Feb 1, 89(Suppl 1): S34-S46
    https://doi.org/10.1097/QAI.0000000000002858 | PMID: 35015744 | PMCID: PMC8751288
    Citations: | AltScore: 2.5
  7. Markers of systemic inflammation are positively associated with influenza vaccine antibody responses with a possible role for ILT2(+)CD57(+) NK-cells.
    Picard E, Armstrong S, Andrew MK, Haynes L, Loeb M, Pawelec G, Kuchel GA, McElhaney JE, Verschoor CP
    Immun Ageing, 2022 May 26, 19(1): 26
    https://doi.org/10.1186/s12979-022-00284-x | PMID: 35619117 | PMCID: PMC9134679
    Citations: | AltScore: 3.7
  8. Impact of psychological resilience on walking capacity in older adults following hip fracture.
    Soliman G, Fortinsky RH, Mangione K, Beamer BA, Magder L, Binder EF, Craik R, Gruber-Baldini A, Orwig D, Resnick B, Wakefield DB, Magaziner J
    J Am Geriatr Soc, 2022 Jul 20
    https://doi.org/10.1111/jgs.17930 | PMID: 35856155
    Citations: | AltScore: 243.25
  9. Association of 1-year change in neuroticism and 3-year change in cognitive performance among older depressed adults.
    Steffens DC, Manning KJ, Wu R, Grady JJ
    Int Psychogeriatr, 2022 Jul, 34(7): 645-650
    https://doi.org/10.1017/S1041610222000084 | PMID: 35287768 | PMCID: PMC9308569
    Citations: | AltScore: 2
  10. Targeting p21Cip1 highly expressing cells in adipose tissue alleviates insulin resistance in obesity.
    Wang L, Wang B, Gasek NS, Zhou Y, Cohn RL, Martin DE, Zuo W, Flynn WF, Guo C, Jellison ER, Kim T, Prata LGPL, Palmer AK, Li M, Inman CL, Barber LS, Al-Naggar IMA, Zhou Y, Du W, Kshitiz, Kuchel GA, Meves A, Tchkonia T, Kirkland JL, Robson P, Xu M
    Cell Metab, 2022 Jan 4, 34(1): 75-89.e8
    https://doi.org/10.1016/j.cmet.2021.11.002 | PMID: 34813734 | PMCID: PMC8732323
    Citations: 5 | AltScore: 191.118
 
2021
  1. Older incarcerated persons' mental health before and during the COVID-19 pandemic.
    DePalma A, Noujaim D, Coman E, Wakefield D, Barry LC
    Int J Prison Health, 2021 Dec 3, ahead-of-print(ahead-of-print):
    https://doi.org/10.1108/IJPH-08-2021-0077 | PMID: 34854275 | PMCID: PMC9289938
    Citations: | AltScore: 0.25
  2. Strategies for Targeting Senescent Cells in Human Disease.
    Gasek NS, Kuchel GA, Kirkland JL, Xu M
    Nat Aging, 2021 Oct, 1(10): 870-879
    https://doi.org/10.1038/s43587-021-00121-8 | PMID: 34841261 | PMCID: PMC8612694
    Citations: 5 | AltScore: 106.208
  3. The Role of Citrate Transporter INDY in Metabolism and Stem Cell Homeostasis.
    Kannan K, Rogina B
    Metabolites, 2021 Oct 15, 11(10):
    pii: 705. https://doi.org/10.3390/metabo11100705 | PMID: 34677421 | PMCID: PMC8540898
    Citations: 3 | AltScore: 18.358
  4. Accelerated aging in older cancer survivors.
    Sedrak MS, Kirkland JL, Tchkonia T, Kuchel GA
    J Am Geriatr Soc, 2021 Nov, 69(11): 3077-3080
    https://doi.org/10.1111/jgs.17461 | PMID: 34534355 | PMCID: PMC8595814
    Citations: 1 | AltScore: 43.95
  5. Granzyme B: a double-edged sword in the response to influenza infection in vaccinated older adults.
    Verschoor CP, Pawelec G, Haynes L, Loeb M, Andrew MK, Kuchel GA, McElhaney JE
    Front Aging, 2021, 2:
    pii: 753767. https://doi.org/10.3389/fragi.2021.753767 | PMID: 35441156 | PMCID: PMC9015675
    Citations: | AltScore: NA


EXTERNAL ADVISORY BOARD MEMBERS

Barbara Resnick, PhD, RN, CRNP, FAAN, FAANP
University of Maryland, School of Nursing
Serving since 2022 (0 years)

Heather Allore, PhD
Yale University, School of Medicine
Serving since 2022 (0 years)

Jeremy Walston, MD
John Hopkins University, School of Medicine
Serving since 2022 (0 years)

Lona Mody, MD
University of Michigan
Serving since 2022 (0 years)

Roland Thorpe, PhD MS
John Hopkins University, Center on Aging & Health
Serving since 2022 (0 years)


RECOGNITION AND AWARDS (2021-2022)
David Steffens, MD (2022)
  • Distinguished Life Fellow of the American Psychiatric Association
Richard H. Fortinsky, PhD (2021)
  • Steven Wallace Lifetime Achievement Award from the Aging and Public Health Section of the American Public Health Association

MINORITY RESEARCH

General Brief Description of Minority Activities:

General Brief Description of Minority Activities:

Project # 1

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

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

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

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

Project # 2

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

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

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

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




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

Minority Grant(s):