2024-25 Pilot Grand Awards

Sungjin Park, PhD
Dept of Neurobiology 

Revealing the structural dynamics of the extracellular matrix in the aged brain 

Abstract

Age-related cognitive decline impacts the quality of life of nearly every individual [1]. In an ever-aged society, it causes a growing burden to individuals, families, and society as a whole. Aging causes structural and functional alterations of the brain cells and their niche, but understanding the underlying mechanism remains limited [2]. Noting that the brain’s extracellular matrix (ECM) critically regulates neuronal plasticity and is implicated in age-related cognitive decline [3], we aim to uncover the structural dynamics of the ECM in the aged brain and its reversibility.

ECM and neuronal plasticity: Learning and memory are often conflated, yet the paradoxical tasks demand a delicate balance between the flexible adaption to new information and the stabilization of existing and consolidated memories. The equilibrium between synaptic flexibility and stability is tightly controlled during development. In early critical periods, the brain is highly plastic, and consolidated memories are vulnerable to erasure. As the transition from juvenile to adult occurs, the balance shifts to stabilize the neuronal wiring while maintaining a low tone of experience-dependent neuronal plasticity. Recent studies show that the increase in the aggregation of the brain’s ECM during the juvenile-adult transition is correlated with the close of critical periods [4]. Enzymatic digestion of the clustered ECM with chondroitinase ABC (ChABC, a bacterial enzyme that digests chondroitin sulfate of the ECM) after the close of a critical period reinstates juvenile levels of neuronal plasticity [5]. It also reduces the stability of a consolidated memory [6]. These findings show that ECM clustering regulates the balance between flexibility and stability of neuronal plasticity. Structural alterations in the aged brain: Aging particularly impacts cognitive flexibility and working memory, whereas procedural and historical memory remains relatively intact, indicating reduced flexibility of neuronal wiring in the aged brain [1]. Neuronal loss is not the main cause of cognitive decline during normative aging. Instead, a loss of synapses accompanies the cognitive decline [2]. Notably, in aged animals, enzymatic and genetic manipulations that loosen the brain’s ECM improve cognitive performance to young adult levels, revealing the critical role of the ECM in age-related cognitive decline [3]. While these findings imply that ECM homeostasis is dysregulated with aging, how aging impacts the brain’s ECM is poorly understood. We hypothesize that excessive ECM stiffening on dendrites may prevent spine dynamics, leading to cognitive decline in aged animals (Fig. 1). Using novel genetic tools revealing ECM dynamics, we will investigate whether aging reduces neuronal ECM turnover, leading to excessive ECM accumulation (Aim 1 and Aim 2). Physical exercise and reversibility of age-related cognitive decline: Physical exercise (PE) ameliorates a variety of age-related dysfunctions including cognitive decline. Voluntary wheel running in rodents enhances spine density in the entorhinal cortex and hippocampus and prevents age-related spine loss [7, 8]. While PE induces various processes, including hippocampal neurogenesis, myelination, angiogenesis, and the release of neurotrophic factors (e.g., BDNF and IGF-1) [9], how PE facilitates neuronal plasticity is not fully understood. Notably, PE regulates the expression of ECM components and their regulatory enzymes [10, 11]. For example, PE increases the circulating level of MMP-9, a major ECM remodeling enzyme, and MMP-9 activity in the hippocampus [12, 13]. Both PE and ECM loosening induce the recovery from amblyopia (imbalance of two eyes) and enhance neuronal plasticity in the primary visual cortex [5, 14, 15]. These findings imply that PE may regulate ECM homeostasis to increase neuronal plasticity. We aim to investigate this possibility in the future direction of Aim 3.

Limitations of current ECM assays and development of a novel approach: Current studies on the brain’s ECM rely on the immunohistochemistry of ECM components and lectin staining (e.g. Fig. 1C, WFA staining). However, these end-point assays cannot reveal the dynamic remodeling process of the ECM architecture. Noting that link proteins are universally required to assemble hyaluronan-based brain ECM, we generated a genetic tool to label neuronal ECM architecture. The fusion of HaloTag to a link protein (named H-Link) revealed detailed structural features of the neuronal ECM clusters (Fig 1A-B). Expression of H-Link in vivo shows not only conventional ECM clusters on parvalbumin (PV) inhibitory neurons (called perineuronal net: PNN) but also novel clusters on excitatory neurons (we named it perineuronal coat: PNC) (Fig. 1C). Importantly, ECM clusters on excitatory neurons extend to distal dendrites during the juvenile-adult transition (Fig. 1D). Furthermore, the versatility of HaloTag enables dual-color ECM birthdating, distinguishing preassembled vs newly-organized architecture within the same neuron.

 

Anna Parks, MD
Division of Hematology & Hematologic Malignancies

Co-Is: Drs. Robby Campbell, Xiangyang Ye, Nicholas Frost, Mark Supiano, Matt Rondina 

Anti-amyloid monoclonal antibodies for dementia & intracranial hemorrhage: elucidating underlying mechanisms

Abstract

Alzheimer’s disease and related dementias (ADRD) affect an estimated 55 million people worldwide, spurring development of effective therapies to slow the course of disease.1 Lecanemab, a third-generation anti-amyloid antibody, recently received accelerated US Food and Drug Administration approval for the treatment of mild ADRD or mild cognitive impairment (MCI) based on a phase 3 randomized controlled trial showing modest reductions in cognitive decline.2 Enthusiasm for lecanemab is tempered by the finding that lecanemab leads to intracranial bleeding called amyloid-related imaging abnormalities with hemosiderin deposits (ARIA-H) in nearly 1 out of 5 patients.3 Although most participants with ARIA-H had asymptomatic imaging changes, 0.7% presented with symptomatic intracranial hemorrhage. Critically, we remain unable to predict or prevent ARIA-H because the mechanism remains unknown.

Platelets and the coagulation system play a major role in the pathogenesis of both ADRD and intracranial bleeding and could be used to predict ARIA-H.4,5 Platelets contain amyloid precursor protein, are activated in ADRD, and are essential for vessel integrity. ADRD and intracranial hemorrhage are both associated with coagulation dysregulation. Functional assays of platelets and the coagulation system are therefore appealing candidate ARIA-H biomarkers. The goal of this proposal is to fill gaps in understanding of the mechanism of ARIA-H by examining its association with platelet and coagulation function, with the long-term goal of predicting and preventing ARIA-H. Our Specific Aims are:

Aim 1: Determine the relationship between coagulation system function and the development of ARIA-H on lecanemab therapy. Working Hypothesis: Abnormal baseline or abnormal change in coagulation functional parameters over time is associated with development of ARIA-H. Approach: We will obtain blood samples from 20 patients with mild ADRD or MCI eligible for lecanemab treatment at two timepoints, 1) at baseline before initiation of lecanemab, and 2) after 4 doses (8-10 weeks) of lecanemab. We will measure standard laboratory coagulation tests and research tests of coagulation function. Using a control group for comparison, we will examine if coagulation testing at both time points predicts ARIA-H. Aim 2: Determine the relationship between platelet function and the development of ARIA-H on lecanemab therapy. Working Hypothesis: Abnormal baseline or change in in platelet function over time is associated with development of ARIA-H. Approach: Using the same cohort and blood samples (baseline and 8-10 weeks), we will measure standard laboratory platelet tests and research tests of platelet function. We will examine if coagulation testing at both time points predicts ARIA-H controlling for confounders. Our project focuses on the timely and large-scale public health problem of the need for predictive biomarkers for complications from anti-amyloid therapies. This could help identify individuals who are at risk for ARIA-H, informing patient selection and monitoring. Our group of investigators has multifaceted experience in clinical hematology and outcomes research in older adults (Parks),6–9 platelet and coagulation biology in aging and inflammation (Campbell).10–14, biostatistics (Ye),15–17, neurodegenerative cognitive disorders (Frost),18,19 and geriatrics and vascular aging (Supiano)20,21 that we will apply toward successful completion of our aims. Our results will form the basis of a developmental R21/R01 to expand our sample to multiple centers to validate our findings. Results of this proposal will jumpstart our collaborative team’s line of inquiry and will naturally lead to multiple larger research endeavors to identify patients at risk of ARIA-H and prevent its occurrence.

Cali Johnson, MD/EdD
Division of Vascular Surgery

Co-Is: Drs. Megan Puckett, Amy Cizik, Sara Knight, Benjamin Brooke

Incorporating Patient Outcomes using the 4M Geriatric Framework for Vascular Surgical Care

Abstract

Atherosclerotic and aneurysmal vascular disease increases with age, impairing health-related quality-of-life and conferring significant mortality risk with advanced disease stages. Treatment varies, including conservative management, endovascular, and open surgical techniques, depending upon patient preferences and disease factors. The 4M Geriatric Framework for an Age-Friendly Health System provides a conceptual model for shared decision-making (SOM) in older populations, addressing 1) what matters, 2) the impact of therapeutic medication, and 3) post-operative complications that may impair mentation or 4) mobility.

Identifying surgery specific 4M measures for SOM will require a thorough understanding of which measures are already captured through routine clinical care and if the measure is unavailable developing a platform for which non-captured 4M metrics can be collected from patients.

This project seeks to address the gap in knowledge to identify measures from a surgical perspective that reflect the 4M principles and how those measures can be collected whether from the medical record or obtaining them directly from the patient. The 4M Geriatric Framework has potential to be a common language across medical providers and with patients and their caregivers. This study is foundational for work engaging patients on data collection, presentation, and acceptability of using 4M principles for SOM in vascular surgery.

Aim 1: Conduct a scoping review of measures associated with each of the 4M Geriatric principles that could be candidate metrics for vascular surgery patients. Published and recommended metrics used in each of the 4M domains will be gathered via a scoping review of peer-reviewed articles, book chapters, and organizational standards, with particular attention given to geriatric surgical patients.

Aim 2: Extract 4M Geriatric metrics from the electronic data warehouse (EDW) or through electronic health record (EHR) review for vascular surgery patients. Metrics identified through Aim 1 will be mapped to data availability in the EOW or EHR and categorized by ease of data abstraction and presentation.

Aim 3: Collect non-EDW/EHR 4M metrics from vascular surgery patients via a digital health platform. Many of the metrics of 4M will need to be directly assessed or patient-reported and not be part of normal clinical practice for patients. Vascular surgery patients will be asked to complete these metrics via a recently piloted mobile application. Participant experiences and successful completion of these non-EOW/EHR metrics will be assessed.

Erika Pliner, PhD
Dept of Mechanical Engineering

Co-Is: Dr. Peter Fino

Electrocortical Activity of Effective Stepping 

Abstract

Falls are a healthcare problem. A third of older adults experience a fall each year with over 38 thousand fall- related deaths recorded in the US in 2021¹. Injuries of fall survivors are commonly severe, leading to urgent care, fear of falling, and disability - reducing the quality of life². Projections for fall accidents are exponential with our aging population³. Falls will overwhelm the healthcare system if fall prevention interventions are not maximized.

Fall risk in older adults can be reduced via interventions that target fall risk factors (e.g. balance, strength, cognition)². To maximize societal impact of fall prevention interventions, these paradigms need to be effective and accessible. Step training is a promising intervention as it has been effective at reducing fall rate in older adults⁴ and can be successfully implemented in the home^s, 6. Step training preserves and strengthens cognitive and motor processes⁴. Specifically, step training has shown benefits to essential components of mobility (i.e. balance and strength) and mentation (i.e. cognitive processing speed). Step training also benefits everyday activities of mobility (i.e. gait speed, time up and go, and sit-to- stand)⁴. Maintaining mobility (e.g. feeling healthy and not physically limited) and mentation (e.g. being able to manage on their own) matter to many older adults⁷, making these aspects critical to individual healthcare needs. Despite prior effectiveness on step training, there is no consensus on the necessary components of step training. The effects of step training on fall rate has shown considerable variability across paradigms and participants⁴ that are likely linked to the paradigm demands (e.g. instruction/cue, target location, feedback) and participant age-related ability. Regardless of paradigm and age, step training requires individuals to execute cognitive (e.g. target detection) and motor (e.g. stepping) processes. Variability in the benefits of step training emphasizes the need for a mechanistic understanding of step training. Such essential knowledge will guide population-specific design criteria of step training interventions that are optimized toward the highest efficacy of fall rate reduction.

Mechanistic understanding of step training can be achieved by quantifying the cognitive-motor processes of effective step training across paradigm demands and age groups. Innovative methods using high-density electroencephalogram (EEG)^8-13 facilitate this quantification with high temporal resolution to phase-lock to stepping cues. This presents a promising method to assess the effects of step training design factors on underlying neural mechanisms of the training.

The goal of this research is to quantify the cognitive-motor processes of effective step training. Specifically, we aim to determine the electrocortical activity of effective stepping across age groups (Aim 1) and paradigm design factors (Aim 2). First, we will quantify stepping performance metrics across age groups (younger and older adults) and design factors (cue, feedback). Second, we will quantify the electrocortical activity by age group and design factors to gain insightful pilot data on cognitive-motor processes of effective step training. H1.1: Younger adults will demonstrate more effective stepping performance metrics than older adults. H1.2: Simple cues and feedback will lead to more effective stepping performance metrics than complex cues and no feedback. For electrocortical data, we expect younger adults and feedback to display greater power fluctuations in electrocortical data than older adults and no feedback. In addition, we expect these power fluctuations to be primarily in the alpha (8-12 Hz) and beta (13-30 Hz) frequency bands in the occipital and sensorimotor cortices. This study will initiate the fundamental knowledge of electrocortical activity of effective stepping. This foundational knowledge is critical in optimizing clinical interventions. Specifically this knowledge will be leveraged to increase the efficacy of clinical interventions and reduce the time and resources on implementing these interventions. In addition, this knowledge can improve healthcare practices of  mentation and mobility through improved diagnoses of central processing motor deficits and cognitive processing issues (e.g. depression, dementia, delirium) that are patient-specific.

2023-24 Pilot Grand Awards

Tanya Halliday, PhD/RD
Division of Health & Kinesiology

Co-Is: Drs. Micah Drummond, Kelly Baron

Impact of AM vs PM Resistance Exercise on Glycemic Control and Sleep Physiology in Older Adults at Risk for Type 2 Diabetes

Abstract

Aging is associated with reduced skeletal muscle mass and increased fat mass, a combination termed "sarcopenic obesity". It is well established that aging and obesity individually increase the risk of type 2 diabetes (T2DM), and recently, sarcopenic obesity has been shown to increase the risk of T2DM by 38%. In addition to sarcopenic obesity, aging is associated with sleep disturbances including short sleep duration, sleep fragmentation, and lower slow wave sleep (SWS). Data from us and others show sleep disturbances can result in adverse cardiometabolic risk including increased fat mass and impaired insulin sensitivity. Thus, sleep disturbances in older adults may contribute to the risk of sarcopenic obesity and T2DM. Given the increased risk of sarcopenic obesity, sleep disturbance, and T2DM in older adults, interventions that simultaneously address these risk factors are urgently needed. We, and others, have shown that resistance exercise is an evidence-based approach to increase skeletal muscle mass and improve glycemic control. Although findings are mixed, some data also show resistance exercise can help improve sleep quality in older adults, potentially by promoting a faster decline in core body temperature at bedtime which improves sleep quality. One potential factor contributing to the mixed findings on the health benefits of resistance exercise is the timing of exercise. Emerging evidence suggests that PM aerobic exercise may be superior for improving cardiometabolic health compared to AM aerobic exercise. Furthermore, preliminary data from us shows PM vs AM resistance training leads to greater improvements in glucose homeostasis in older adults with prediabetes. However, despite the importance of resistance training for reducing sarcopenic obesity and promoting healthy aging, no randomized controlled trials have examined how the timing of resistance training impacts insulin sensitivity and sleep. An improved understanding of how AM vs PM resistance training impacts glycemic control and sleep has the potential to enhance treatment and prevention of age associated disease in older adults, including T2DM. Thus, we propose the following Specific Aims:  Aim 1: Compare insulin sensitivity (Matsuda Index calculated from oral glucose tolerance test) the day after a single bout of AM vs. PM resistance exercise in older adults with overweight and obesity. Hypothesis: Insulin sensitivity will be higher following PM versus AM resistance exercise.  Aim 2: Compare differences in sleep physiology following a single bout of AM vs. PM resistance exercise in older adults with overweight and obesity. Hypothesis: Sleep duration (primary outcome), efficiency, SWS, and sleep satisfaction will be higher following PM versus AM resistance exercise.

Timothy Hanley, MD/PhD
Dept of Pathology

Co-Is: Drs. Adam Spivak, Vincente Planelles

HIV-Induced DNA Damage as a Driver on Inflammaging in People Living with HIV

Abstract

With the advent of antiretroviral therapy (ART), human immunodeficiency virus (HIV) infection has become a chronic manageable disease for those with access to therapy. Despite durable viral suppression by ART, there is no cure and people living with HIV (PLWH) are at increased risk for aging-related morbidities, including cardiovascular, metabolic, and neurologic disease. As the population of PLWH in the United States continues to age, defining the mechanisms leading to senescence in ART-treated HIV infection is of vital importance.  A hallmark of aging-related disease is the accumulation of senescent cells within tissues. Cellular senescence is characterized by the expression of genes promoting cell-cycle arrest and resistance to apoptosis, as well as a senescence-associated secretory phenotype (SASP) marked by the production and release of proinflammatory and profibrotic mediators. Many ART-treated PLWH develop a well-described immunosenescent phenotype that contributes to age-associated end-organ disease. Senescence is caused by a variety of cellular stressors, including DNA damage, that are sensed by innate immune receptors. Chronic stimulation of the innate immune system leads to an age-related increase in proinflammatory mediators in blood or tissues, a process termed "inflammaging",  that contributes to increased morbidity and mortality. Prior studies have demonstrated that HIV infection induces DNA damage; however, the mechanism(s) of virus-induced DNA damage and resulting inflammation have not been fully elucidated. The overarching goal of our research is to define the mechanisms by which myeloid cells contribute to "inflammaging" in PLWH with an eye toward developing therapeutic strategies to prevent or reverse immunosenescence. Our preliminary studies suggest that DNA damage induced by HIV in chronically infected myeloid cells contributes to senescence. We hypothesize that HIV-induced DNA damage in macrophages and microglial cells is a driver of "inflammaging" in PLWH and contributes to HIV-associated morbidities, including neurocognitive disorders. We will test this hypothesis through the following specific aims:    Aim 1. Determine the mechanism of HIV-induced DNA damage and its contribution to senescence in myeloid cells. We have identified cGAS/STING signaling as a driver of inflammation and suggest that this pathway serves as a target to prevent or reverse HIV-induced cellular senescence. We will define the role of cGAS/STING signaling in sensing DNA damage products using CRISPR technology. We will then determine whether pharmacologic inhibitors of this pathway prevent or reverse senescence. Aim 2. Evaluate the efficacy of the senolytic drugs dasatinib and quercetin on reversing senescence. A number of compounds, termed senolytics, have been identified that target anti-apoptotic pathways and result in the death of senescent cells. These include the tyrosine kinase inhibitor dasatinib and the flavonoid quercetin. We will determine whether dasatinib and quercetin, alone or in combination, can reverse the senescent phenotype that HIV-infected macrophages and microglial cells develop in vitro and induce their cell death. These preclinical translational studies will allow us to evaluate the role of HIV-induced DNA damage in the development of senescence and to identify potential targets for the prevention or reversal of age-related diseases in PLWH. Our findings will have therapeutic implications for other diseases associated with immunologic aging.

Bradley King, PhD
Division of Health & Kinesiology

Co-Is: Drs. Genevieve Albout, Adriana Coletta, Vincent Koppelmans, John Allan Maschek, Yin Li

Exercise and inhibition in the aging brain

Abstract

As the worlds' population becomes increasingly older, there is a critical need to develop and implement interventions capable of enhancing cognitive resilience and minimizing the negative consequences of aging on cognitive functioning. Importantly, the success of these interventions depends, in part, on a comprehensive understanding of the associated neural underpinnings. This information is vital for such interventions to be optimized and result in the greatest cognitive improvements. One potential intervention that holds tremendous promise is physical exercise. There is evidence that links exercise to increases in the volume as well as alterations in the microstructural properties of the aging hippocampus, a brain region critical for learning and memory processes. And paralleling research in young adults, there is data from non-invasive brain stimulation protocols indicating that exercise leads to decreased inhibition in the older adult cortex, and these modulations in inhibition are linked to greater learning. However, whether exercise specifically modulates inhibition in the deeper brain regions vital for learning and memory functioning (e.g., the hippocampus) is an open question of the utmost importance. The current proof-of-concept study will employ beyond state-of-the-art magnetic resonance spectroscopy (MRS) to reveal the impact of acute exercise on in-vivo levels of the brain's principal inhibitory neurotransmitter (gamma aminobutyric acid - GABA) in the older adult hippocampus. This neuroimaging approach affords the assessment of inhibitory processes in deeper brain regions that are not accessible by other methodologies that probe neural inhibition (e.g., non-invasive brain stimulation). MRS of GABA will be complemented with measures of peripheral blood biomarkers of brain plasticity (i.e., brain-derived neurotrophic factor (BDNF) and anandamide (AEA)) that play a key role in the regulation of GABAergic synaptic transmission.      This project will thus achieve the following specific aims:   Aim 1: To reveal the effect of exercise on hippocampal GABA levels in healthy older adults.   Aim 2: To reveal whether the effect of exercise on GABA levels in older adults is linked to the modulation of neural plasticity-related blood biomarkers involved in the regulation of GABA (i.e., BDNF and AEA).     It is hypothesized that acute aerobic exercise, as compared to a control intervention, will result in a decrease in hippocampal GABA; and this effect will be related to an exercise-induced modulation in the concentration of blood biomarkers of GABA-related neuroplasticity.     Results from this pilot study will provide critical insights into the effects of aging on hippocampal function and the potential of exercise to modulate hippocampal inhibition - and ultimately cognitive functioning - in older adults. Importantly, and consistent with the strategic directions outlined by the National Institute of Aging (NIA), this proof-of-concept research will provide the foundation for a future NIA proposal that will: a) test whether exercise-induced changes in hippocampal inhibition is a viable option to minimize learning and memory-related deficits that are frequently observed in older adults; and, b) optimize exercise prescription in order to maximize the modulation of hippocampal inhibition and ultimately cognitive functioning in older individuals.

Kouskik Roy, PhD
Dept of Pathology

Co-I: Dr.Thomas Zangle

Role of the transcription factor, NFkB, in generating humoral immunity at younger and older ages

Abstract

Humoral immunity following vaccination at older age is typically poor. Antibodies are produced in two-phase, with the first phase producing short-lived plasma cells for an immediate response and the second phase producing long-lived plasma cells with a delay of more than a week. Upon antigen encounter, antigen-activated B-cells grow in size (mass) following proliferation and differentiate into short- and long-lived plasma cells. The cell signaling and transcriptional networks of B-cell response at younger and older ages are unknown. Here, our objective is to define the cell signaling and transcriptional networks that regulate B cell growth, proliferation, and the generation of short- and long-lived plasma cells in a mouse model at younger and older ages. It is well established that transcription factors NFkB cRel and RelA are critical for physiological B cell responses and that their misregulation leads to B cell lymphoma and B cell-mediated autoimmunity in older age. cRel is required for B cell growth and proliferation. RelA is essential for generating plasma cells. Our preliminary data suggest that cRel knock-out B cells enhance generation of plasma cells at older age whereas in younger age plasma cell proportion remain similar. The activation of cRel and RelA depends on the degradation of NFkB inhibitors, IkBs. IkBa and IkBe have different binding preferences to cRel and RelA. The network of IkBa, IkBe, cRel, and RelA is defined here as the NFkB signaling network. The role of the NFkB signaling network in generating B cell growth, proliferation and short-lived and long-lived plasma cells at younger and older ages is unknown. Our hypothesis is that poor B cell response in older age is due to misregulation of cRel expression at older age. In this project, we will define the role of the NFkB signaling network in regulating B cell growth, proliferation and short-lived and long-lived plasma cells at younger and older ages. The objective of Aim 1 is to define the molecular mechanism of how NFkB signaling network regulates B cell growth and proliferation at younger and older age using quantitative phase imaging and flow cytometry (Zangle and Roy labs). The objective of Aim 2 is to define the role of NFkB signaling network to the generation of short-lived and long-lived plasma cells in-vivo mouse model at younger and older ages (Roy lab). These aims are based on interdisciplinary collaboration between Koushik Roy (PI, a new investigator, and also new to the aging research) and Thomas Zangle (quantitative phase imaging). The proposed research is innovative because it connects B cells' cell signaling and transcriptional network to the B cell growth, proliferation, and generation of short- and long-lived plasma cells. We will use in-vivo mouse model of newly generated cRel fluorescence reporter and B cell-specific IkBe, IkBa, cRel and RelA knock-out. We will utilize combination of single-cell/bulk RNA-Sequecing, flowcytometry, and quantitative phase imaging to directly measure cell mass. The proposed research is expected to define the mechanism that allows the NFkB signaling network to regulate B cell response following vaccination at younger and older ages. 

Chun Yuan, PhD
Dept of Radiology

Co-Is: Drs. Karen Schliep, Xiaodong Ma, Scott McNally

Neurovascular Imaging Core for Aging Studies: Promoting Technical Development, Training, and Collaboration

Abstract

The University of Utah currently has many faculty and ongoing projects studying aging in different capacities, including vascular compliance, hemodynamical conditions of blood vessels, neuroscience, multi-organ disease evaluation, and cardiovascular disease and stroke diagnosis, treatment, and prevention.  These projects will benefit from imaging to measure the effects of aging and disease-related changes in the properties of neuro-vasculatures, blood flow, and brain metabolic function. However, these faculty and projects often operate independently from each other, as they are located in different departments and funded by different institutions. In this proposal, we aim to create a central Neurovascular Imaging Core that will facilitate collaboration inside and outside the University, and build a pipeline to provide imaging and image analysis tools that can be used for multiple aging-related studies.  Our goal is to enhance collaboration, initiate new projects and ideas, and provide streamlined tools for current and future aging-related research.   To further collaboration, we plan to organize a symposium about state-of-the-art neurovascular imaging on aging. We will invite faculty interested in potential collaborations to attend and speak. We will also initiate or assist imaging experiments on a small number of populations, which can be used for preliminary data for future extramural funding submission. These collaborations will not be limited to within Utah, but also leverage connections with other Universities who are actively engaged in aging-related research, such as the University of Washington. These collaborations will result in new, large-scale aging studies, such as NIH R21 and R01 grants that are planned to be submitted by the end of the pilot funding period.   We have developed a novel 3D MRI technique called "neurovascular blood flow, vessel wall compliance and lesion characterization [VESSEL-tracker]" that is able to acquire high-quality images to measure intra- and extra-cranial vessel wall and blood flow conditions. Our software tools and pipeline plan to take several existing pieces of image analysis software, developed both at Utah and other institutions, and combine them into an easy-to-use software that will provide both existing and new measurements of aging-related disease in blood vessels in the brain. An example of this is ICafe, which leverages artificial intelligence to analyze intracranial vessels in the brain from magnetic resonance images.  We will also incorporate tools to measure vessel compliance, cerebral blood flow, and metabolic measurements.  Specific aims:  Aim 1. Enhance internal and external collaborations among faculties related to neurovascular imaging for aging research.  Aim 2. Integrate our developed neurovascular imaging and image analysis tools to support aging-related studies.  This project will be headed by Dr. Chun Yuan, PhD, Vice-Chair of Research at the University of Utah, with a long history of expertise in developing vessel wall imaging techniques and analysis tools, and Dr. Xiaoding Ma, PhD, who has expertise in the development of MRI acquisition and reconstruction techniques. In addition, Dr. Yuan remains Professor Emeritus at the University of Washington to facilitate collaboration. We believe this proposal can have an outsized impact on aging-related research by expanding existing resources and building new collaborations.

Makota Kondo, PhD
College of Pharmacy

Co-Is: Drs. David Grainger, Jeffrey Weiss, Travis Maak

In vivo therapeutic effect and mechanisms of human juvenile cell sheets for elderly cartilage regeneration

Abstract

Cartilage defects rarely heal, leading to joint osteoarthritis (OA), impacting 70 million patients globally. Some 42.6% of US adults over 65 report OA disease, affecting frailty and activities of daily living. Conventional drugs mitigate pain but cannot reverse OA progression. Currently, all cell-based cartilage treatments use patientderived, autologous cell sources and are only recommended for ages under 65 based on historical failures, due to elderly patients' 1) poor donor cell quality and 2) possible inferior response of articular tissues. Therefore,
reliable regenerative cartilage therapy for all ages, and especially the significant elderly fraction with OA, remains unrealized. Our long-term goal is to develop an efficacious allogeneic living cartilage regenerative therapy for all OA patients. Cell proliferation and chondrogenic capacity both decline with donor age, impacting geriatric autologous treatment. To address this, we have successfully isolated human juvenile cartilage-derived chondroprogenitors (JCC) from polydactyly surgical discards, establishing a unique JCC bank with UU Orthopaedics and Intermountain Primary Children's Hospital partners. This cell bank is leveraged to fabricate scaffold-free, JCC-based cartilage "sheet" transplants using our intact cell recovery system. JCC sheet production is scalable, preserving intercellular interactions and adhesive extracellular matrix that facilitate sheet integration with target tissue sites, overcoming clinical issues reported in current cartilage tissue- and cell-based treatments. Significantly, JCCs proliferate exuberantly, yielding sheets that regenerate type 2 collagen-positive, type 1 collagen-negative native-like hyaline cartilage within 4 weeks in our young rodent cartilage defect model developed together with Orthopaedics faculty, T. Maak. However, regenerative and molecular responses of elderly recipients remain untested. The specific project objective is to address challenges for standard cartilage defect treatments currently limited to younger patients by determining: 1) efficacy of JCC sheets in elderly recipients in our established animal models, and 2) differential molecular responses to JCC sheets between young and aged cartilage-injured recipient animals. These Aims will be pursued: Aim 1. Compare JCC sheet cartilage regenerative capacity in young adult and elderly rat cartilage defect models. Working hypothesis: Given highly potent juvenile donor cell quality, JCC sheets exert in vivo cartilage regenerative capacity in elderly recipients. Equivalent quantitative scores for young and elderly recipients after JCC sheet implantation are expected in 3 benchmarks: histological scores, functional weight-bearing and neocartilage mechanics measured together with Biomedical Engineering faculty Grainger and Weiss. Aim 2. Distinguish host tissue responses between young adult versus elderly rats. Understanding different host tissue responses to JCC sheets between young adult versus elderly cohorts at molecular levels is essential. To address this, we employ spatial transcriptomics analyses on JCC-regenerated tissues from young and aged rats, leveraging pre-established species-specific cell labeling. We expect to identify key signaling molecules differentially expressed in each host tissues with spatial information that addresses age-dependent healing mechanisms in cell-based therapies. Impact statement: This proposal specifically addresses the CoA P30 submission aims by assessing resilience of elderly cohorts' healing responses to potent unique JCC sheet implants to overcome unmet clinical needs in treating OA in the elderly. 

Marta McCrum, MD
Dept of Surgery

Co-Is: Drs. Megan Puckett, Alyssa Nelson

A Collaborative Care Approach to Improving Outcomes for Older Adults after Emergency Laparotomy

Abstract

Emergency General Surgery (EGS) diseases constitute a significant public health burden in the United States, with over 3 million admissions and 500,000 operations annually. Of this population, nearly half are older (≥65 years of age) and frail adults who experience an increased risk of morbidity and mortality that extends past acute hospitalization and influences long-term recovery. Recent interventions for older adults undergoing surgery have focused on patient optimization in the elective setting; however, patients presenting with emergent conditions
are not able to benefit from such programs prior to surgery. There is therefore a critical need for care models that address the unique needs of geriatric patients undergoing emergency laparotomy that extends through the inpatient stay and into post-discharge recovery. Emergency laparotomy is one of the most common and highestrisk EGS procedures, with an estimated mortality rate of 10-18%, making it an ideal target for intervention in this population. The objective of this proposal is to develop and implement an Older Adult Emergency Laparotomy
Collaborative Care Program (ELCP). Our central hypothesis is that developing a standardized, interdisciplinary approach to care of older adults undergoing emergency laparotomy will be feasible in a tertiary hospital setting and will improve both short- and long-term patient outcomes. The development of the ELCP will integrate the acute surgical care of this high-risk population with ongoing ambulatory geriatric care to improve long-term recovery after emergency surgery. To accomplish these goals, we have established an interdisciplinary team with
expertise in emergency surgery, geriatric medicine, critical care, physical therapy, nursing, palliative care, case management, nutrition, implementation science, mixed-methods research, and biostatistics. Aim 1: Develop an interdisciplinary Older Adult Emergency Laparotomy Collaborative Care Program Approach: Using the Institute for Healthcare Improvement's Breakthrough Series Collaborative Model, we will convene an interdisciplinary team of experts from all aspects of perioperative and ambulatory care for EGS patients.3 Over 9 months, we will
develop a Collaborative Care program that integrates high-quality inpatient surgical care with ongoing geriatricspecific ambulatory care post-discharge. Aim 2: Determine the feasibility, acceptability, and preliminary efficacy of the ELCP Approach: We will then conduct a hybrid type 1 implementation-effectiveness pilot study of the ELCP. We will include all patients ≥65 years with a Clinical Frailty Score ≥ 4, and all adults ≥80 years undergoing emergency laparotomy at the University of Utah. Through multistakeholder qualitative analysis, we will establish facilitators and barriers to ELCP implementation. After implementation, we will evaluate the program's effect on inpatient mortality, complications, length of stay, and functional recovery. The proposed research is innovative because it represents a new and substantive departure from the status quo of surgical care for older adults. Current models for acute care surgery lack specific acknowledgment of the needs of older adults and fail to collaborate with primary care longitudinally through the patients' post-discharge care. This study will have a substantial impact for care of older adults undergoing high-risk emergency surgery and will lay the foundation for development of a scalable intervention and a larger, multi-institutional trial. 

Innovations

Healthy Aging and Resilient Places (HARP) Lab: Promoting Health and Resilience in Aging through Interdisciplinary Collaboration

Andy Hong, PhD, MUP, MPA
Department of City & Metropolitan Planning

Sarah Canham, PhD, FGSA
Sollege of Social Work

Michelle Sorweid, DO, MPH
Division of Geriatrics

2021-22 Pilot Grant Awards

Claire Acevedo, PhD
Dept of Mechanical Engineering

Co-Is  Owen Kingstedt, PhD & Vishnu Sunderesh, MD

Contribution of Collagen Cross-Linking to Skeletal Fragility in Aging Bone

Abstract

The main clinical predictor of fracture risk in the elderly is low bone mass, but this does explain less than half of fractures in people over 55 years of age. Age is also known to affect bone quality, namely bone geometry and material properties. Our previous studies have shown that age is affecting bone quality, and more specifically tissue plasticity and toughness conferred by the collagen phase via an accumulation of non-enzymatic collagen cross-linking with age. Emerging research pointing that falls in the elderly might be the consequence of fracture rather than its cause has raised fundamental questions about the origin of fragility fractures. This indicates that we do not know yet whether change in bone quality and properties makes aged bones more prone to break under a dynamic event, such as a fall, or under a daily static loading event. The proposed collaborative research approach leverages experts in tissue biomechanics, high-strain-rate fracture mechanics and bone metabolism to investigate the role of bone quality and collagen cross-linking on the mechanisms governing fracture under static and fall conditions. Collagen cross-linking in human bones of different ages will be measured with fluorimetric microplate assays. Mechanical testing will measure the resistance to bone fracture (i.e., fracture toughness) in three age groups (young 20-30 y.o., postmenopausal 50-60 y.o. and senile osteoporosis age over 70 y.o.) at low-strain-rates, and critical stress intensity factors at high-strain-rates as a function of collagen cross-linking. Changes observed in fracture toughness and critical stress intensity factor will provide evidence of the role of collagen cross-linking on the fracture behavior of bone and will lead to the identification of most prevalent mechanisms of fracture in aged population (e.g., static versus dynamic loading). These combined experimental approaches will provide new insights in the origin of fragility fractures in the elderly, ultimately identifying a novel pathway to prevent and treat fracture targeting collagen quality and cross-linking on top of bone mass.

Sarah Creem-Regehr, PhD
Dept of Psychology

Co-Is Peter Fino, PhD & Jeanine Stefanucci, PhD

Effects of Older Age on Sensory Integration in Navigation

Abstract

The ability to navigate through both familiar and new environments is critical for independent, safe living, yet such navigation becomes increasingly difficult as one ages. People who experience pathological aging—such as those with Alzheimer’s disease—experience failures in navigation due to disorientation at an even greater rate. Further, deficits in navigation ability are often cited as early markers of pathology. Current models of navigation include mechanisms that rely on visual and self-motion cues to support spatial orientation and wayfinding. However, these models do not consider that changes in balance with aging may also play a role in successful navigation and mobility more broadly. To better understand the role that each of these factors may play in successful navigation across the lifespan, we will determine the relative contributions of visual environmental cues, self-motion cues, and balance control in older adults as compared to younger adults. The goal of the proposed project is to develop and test the feasibility of a virtual reality (VR) paradigm that varies cues for navigation and allows for assessment of performance in both young and older adults. The paradigm will measure spatial orientation—the ability to keep track of self position and heading while moving through an environment—which is a common problem with navigators of an older age and an early marker of pathological aging. Our first aim is to compare age-related differences in the use of visual and self-motion cues in a spatial orientation “homing” task (navigating along a path and returning to home) across virtual reality and the real world to establish the utility of the virtual reality paradigm. We predict that older adults will show relatively worse performance in both environments and (given prior work conducted in the real world) that older adults may weight visual and self-motion cues for navigation differently than younger adults. Our second aim will further assess individual differences in balance (as assessed before and during the navigation task) in order to understand whether postural control also contributes to spatial orientation in older and younger adults. We believe that decreases in balance abilities will relate to increased errors in spatial orientation, but this relationship has not been tested before in either age group. Together, this work will provide a necessary validation of the VR spatial orientation task paradigm for use across the lifespan and address a critical gap in understanding how balance control relates to spatial cue combination in navigation.

2020-21 Pilot Grant Awards

Peter Fino, PhD
Dept of Health, Kinesiology & Recreation

Co-Is: Drs. Leland Dibble, Melissa Cortez, Elisabeth Wilde, Colby Hansen, Ramesh Grandhi 

Falls and mTBI in Older Adults

Abstract

Fall-related traumatic brain injuries (TBIs) in adults 65 years and older result in an estimated 498,000 emergency (ED) visits, hospitalizations, and deaths in the US each year. The majority of these older adults (OA) are discharged from the ED, but they experience an 11-fold increase in future fall-related mortality after their TBI. Evan OAs with mild TBI (mTBI), the least severe and most common form of TBI, experience a 12% mortality rate after their mTBI. Yet, the clinical implications of sequelae of mTBI in OAs remain relatively unknown because OAs are commonly excluded from mTBI research. Evidence from young adults suggests mTBI may substantially increase the risk of future falls; established risk factors for mTBI in young adults. However, the relationship between fall-risk and mTBI in OAs remains unclear. Consewuently, OAs rarely recieve outpatient rehabilitation, and when they do, it does not focus on fall prevention. Our long-term goal is to reduce fall-related mortality in OAs by developing guidelines for precise, targeted rehabilitation after mTBI in OAs. The short-term goal of this pilot project is to determine the association between mTBI-related dysfunction and fall-risk. Using clinical indicators of fall risk and by tracking falls for six months after injury, we will establish preliminary estimated of fall-risk in OA witha  fall-related mTBI comparted to OAs with a fall-related injury but without mTBI and to healthy, age-matched OA control subjects. To further characterize the presentation of mTBI in OAs, detailed quantative assessments of balance, cognitation, mood, and autonomic function will be obtained ipon discharge to home. Combining these detailed, quantitative, and objective assessments with fall data will identify potential mechanisms the underlie fall-risk to serve as future targets for rehabilitation for OAs with mTBI. The current pilot proposal facilitates the crucial first step to demonstrate feasibility andto collect effect size to guide a long-term, federally-funded research program.

Richard Gurgel, MD
Dept of Surgery

Co-Is: Drs. Angela Presson, Ken Smith, Carol Sweeney 

Do Cohlear Implants Mitigate the Risk of Alzheimer's in Older Adults?  

Abstract

Age-related hearing loss and Alzheimer's disease dementia (Alzheimer's) are distinct neurologic conditions that affect millions of older adults worldwide. Age-related hearing loss is the third most common, chronic condition and the most common sensory deficit among older adults. From prior work, we have identified hearing loss as a risk factor for dementia through epidemiologic studies. The mechanisms of how age-related hearing loss cause Alzheimer's or whether treating hearing loss decreases the risk for Alzheimer's, however, are unknown. For patients on the extreme end of the hearing loss spectrum with severe-profound hearing loss, the most effective form of hearing restoration is with a cochlear implant (CI). It is unknown how an intervention to restore hearing via cochlear implantation will have any cognitive benefit or will decrease the risk of developing Alzheimer's. We hypothesize that restoring hearing via cochlear implantation in older adults with severe-to-profound sensorineural hearing loss will mitigate the risk of AD. We also hypothesize CI will improve neuropsychological well-being, as determined by clinical and social metrics, in older adults with hearing loss, thus reducing risk for Alzheimer's. To evaluate whether CI can mitigate the risk and decrease the incidence of AD, we propose using the Utah Population Database (UPDB) to answer this important question. The Utah Population Database (UPDB) is a unique database that contains records of over 11 million individuals linked with health histories, and genealogies, spanning from the 1800's to current day. It serves as a powerful epidemiologic tool that can be used to look at trends of incidence and prevalence of disease over time. The UPDB has not yet been utilized to evaluate cochlear implant outcomes in older adults. Using the UPDB is an innovative and novel way to evaluate the impact of hearing loss on cognition and Alzheimer's. This project will evaluate the largest cohort of older Cl recipients to be studied to answer important questions
relating to aging research. Utilizing this database could provide new insights into the pathology and management of how treating hearing loss may prevent dementia.

Brennan Payne, PhD
Dept of Psychology

Co-IP: Dr. Sarah Ferguson  

Neurocognitive Effects of Listening Effort in Age-Related Sensorineural Hearing Loss

Maintaining effective language understanding is crucial to continued social and community engagement, health management, and learning new information through adulthood. However, age-related changes in sensory functioning can have a profoundly negative effect on language, limiting communicative competence and quality of life. One of the most striking examples of this is in the effects of sensorineural
hearing loss (SNHL) (Wingfield et al., 2015). Everyday conversations include environmental challenges to speech perception arising from background noise or unclear speech that adults with SNHL report as effortful and frustrating (Stephens et al., 2010). Even when adults with SNHL can successfully perceive speech, the additional effort required to decode the degraded sensory input draws away from shared cognitive resources for higher-level language processes, leading to a negative impact on comprehension and memory, even for intelligible speech. This increased listening effort is an oft-cited "hidden effect" of hearing loss and is crucially important in understanding the challenges listeners face in daily life (Pichora-Fuller et al., 2016). At the same time, we do not currently understand how SNHL and LE impacts real-time language processes in the aging brain. As a result, there is an urgent need to understand the cognitive mechanisms of LE in order to develop sound assessments and evidence-based interventions to improve comprehension and memory in SNHL. To address this need, we propose drawing on the field of cognitive neuroscience, which has developed methods to measure real-time language processes via ERPS (Payne et al., 2020). The research team will leverage their expertise in audiology and speech perception (Dr. Ferguson) and cognitive neuroscience and aging (Dr. Payne) to examine how noise-induced listening effort impacts electrophysiological and behavioral indices of language and memory functioning. The proposed experiments will provide critical foundational knowledge about the cognitive and neural mechanisms relating hearing loss, effort allocation, language processing, and memory in the aging brain. Such information will place clinicians in a much stronger position to design and evaluate evidence-based interventions to promote language and memory functioning across the adult lifespan.

Frank Sachse, PhD
Cardiovascular Research and Training Insititute

Co-I: Dr. Stavros Drakos

Aging of Excitation-Contraction Coupling in the Human Heart

Abstract

Our long-term aims are to improve understanding of functional decline of the aging human heart and to identify therapies that counter this decline. Currently, progress in this field is hindered by limited translatability of findings from animal models of aging and the scarce availability of healthy aged human hearts for research. This scarcity explains the lack of knowledge on effects of aging on human
cardiovascular tissues and cells. The proposed project aims at establishing a research setting that resolves this issue and supports investigations on various aspects of aging. In Specific Aim 1, we will establish a framework for research on cells and tissues from the aged human heart. We will implement a pipeline to procure hearts from organ donors that, while providing others organs for transplantation, are commonly not considered for heart donation because their age is above 55 years. We will evaluate the framework by determining the monthly availability of hearts. We will also assess tissue quality. Specific Aim 2 is motivated by prior work of us and others on functional decline in heart failure caused by remodeling of subcellular architecture. In myocytes from healthy human hearts, we found progressive reduction of the density of the transverse tubular system (t-system) and increased distance to associated ryanodine receptor clusters with age. Here, we will complement these studies with an investigation of age-associated deficiencies of excitation-contraction (EC) coupling. We will test the hypothesis that Ca transients are increasingly disorganized with aging using spinning disk confocal microscopy. We will calculate the gain of EC coupling. We expect that age-associated remodeling of t-system and associated proteins leads to decreased gain. Also, we will measure Ca extrusion from the cell and Ca uptake into the sarcoplasmic reticulum, and relate those to age-associated structural remodeling. Together, the proposed studies constitute a significant step towards establishing a setting for research on cardiovascular aging. Our studies will improve understanding of functional decline in the aging healthy human heart. Our studies will set the stage for basic science investigations to identify therapies to counter functional decline of the aging heart and, furthermore, reduce its vulnerability to cardiovascular disease.

Alessandro Venosa, PharmD, PhD
Dept of Pharmacology and Toxicology

Acute Inflammatory Exacerbations of Pulmonary Fibrosis in the Aging Lung

Abstract

Understanding morbidity and mortality in the elderly is a major public health concern and an important issue for governmental and health care agencies. Pulmonary fibrosis (PF) is a debilitating chronic disease with higher incidence in the elderly population (mean diagnosed age of 66 years). Progression of PF in humans is often punctuated by inflammatory bursts, clinically termed "acute exacerbations", that drastically accelerate the disease and reduce life expectancy. Clinical evidence show that mutations in the epithelial cell-specific gene encoding surfactant protein-C (SP-C) are linked to PF, and that repeated episodes of acute exacerbations are central in fibrogenesis. Although it is understood that aging and genetic mutations predispose to PF, the exact mechanisms by which their combination affect disease are not fully understood. One of the major clinical roadblocks in studying PF is represented by our limited ability to temporally model cellular and molecular events underlying disease progression in a spatially restricted, end-stage fibrotic lung. We therefore developed a novel mouse model that develops spontaneous lesions over time, as a result of inducible expression of the most common PF-linked SP-C mutation (SP-C173T). This preclinical model provides a platform to investigate the critical cell-cell interactions that occur in the homeostatic and fibrosing aging lung. Our proposal, entitled "Acute Inflammatory Exacerbations of Pulmonary Fibrosis in the Aging Lung" will identify age-dependent pathways elicited during acute exacerbations of PF. Our published work exhaustively examined epithelial and inflammatory cell dynamics during pulmonary fibrosis elicited by induction of mutant SP-C in the young lung (12 week old). Furthermore, recent preliminary results show that middle-age (52 week) SP-C mutant cohorts exhibit progressive structural damage and heightened sensitivity
to low-dose challenge (ozone), compared to aged-matched SP-C wild type and young SP-C mutant mice. Our experimental plan will build on this evidence and examine age-dependent responses in a genetically susceptible lung during homeostasis and upon acute fibrosing challenge. Our hypothesis is that SP-C17³ mutation accelerates age-dependent lung senescence during homeostasis (hypomorphic mutants) and upon acute fibrotic challenge (mutant induction). Our Specific Aims are to: 1) investigate parenchymal alterations in the aging hypomorphic SP-C¹7³ lung; and 2) define inflammation and fibrosis in the aging induced SP-C¹7³T lung. Together, this work will elucidate
epithelial and inflammatory cell responses in the aging fibrotic lung.

Innovations

One U for Caregiving Science: Strengthening Partnerships and Leveraging Existing Expertise for Excellence 

Lee Ellington, PhD
College of Nursing

Debra Scammon, PhD
The David Eccles School of Business

Rebecca Utz, PhD
Department of Sociology

2019-20 Pilot Grant Awards

Jessica Cohan, MD, MAS
Dept of Surgery

Co-I  Benjamin Brooke, MD
Dept of Surgery

Disease and Treatment Patterns in Older Adults with Diverticulitis

Abstract

Diverticulitis is a common inflammatory disease of the colon accounting for over 260,000 emergency room visits and 2.2 million outpatient visits per year in the US. Given its prevalence, diverticulitis one of the most common reasons for colectomy. Older adults (65 years and older) are disproportionately affected by diverticulitis and develop more severe disease than their younger counterparts, resulting in significant morbidity and mortality. This study uses a comprehensive population-based resource, the Utah Population Database (UPDB), to study disease and treatment patterns for diverticulitis in older adults. First, we will examine the use of emergency surgery and disease recurrence in older and younger adults with diverticulitis. Second, we will compare healthcare utilization in older and younger adults undergoing elective surgery for diverticulitis. This study will significantly improve our understanding of the natural history and treatment patterns for diverticulitis in older adults. The results will facilitate the identification of optimal age-appropriate treatment strategies and will therefore be critical in reducing diverticulitis-related morbidity and mortality.

Katsu Funai, PhD
Dept of Physical Therapy & Athletic Training

Co-I Micah Drummond, PhD
Dept of Physical Therapy & Athletic Training

Ferroptosis and Disuse-Induced Muscle Atrophy

Maintenance of skeletal muscle is essential for healthy aging and plays a significant role in quality of life. Age-induced skeletal muscle atrophy (sarcopenia) not only reduces mobility but also increases the propensity to develop metabolic and cardiovascular diseases. Although skeletal muscle atrophy has broad clinical impact in the increasingly sedentary and aging population, a pharmacologic therapy for muscle mass loss does not exist. Reactive oxygen species (ROS) induces likely muscle atrophy by accelerating proteolysis and depressing protein synthesis. However, ROS refers to a collection of radical molecules whose cellular signals are vast, and it is unclear which ROS molecules are responsible for the loss of muscle mass and function that occurs with age or disuse. In this application, we will test our hypothesis that lipid ROS (LOOH) promotes muscle atrophy through ferroptosis, a novel cell death mechanism only recently described. Ferroptosis is regulated by phospholipid hydroperoxidase (GPx4) that neutralizes LOOH that are produced as a result of oxidative damage. Our preliminary data show that disuse and aging both reduces skeletal muscle GPx4 in humans. In cell culture and in genetically-modified mice, lack of GPx4 promotes reduction of muscle size. In this proposal, we will test our hypothesis that neutralization of LOOH by GPx4 overexpression will suppress disuse-induced atrophy in mouse skeletal muscle. We will also examine the possibility that accumulation of LOOH promotes atrophy by accelerating autophagy.

Robert Campbell, PhD

Assistant Professor; Department of Internal Medicine

Co-I Matthew Rondina, MD, MS

Associate Professor; Department of Internal Medicine

Co-I Anthony Donato, PhD, MS

Associate Professor; Department of Internal Medicine

Inflammation in Aging Increases Platelet Hyperactivity and Thrombosis

Abstract

Aging is accompanied by a decreased tolerance to physiological stress, which promotes increased susceptibility to inflammatory illnesses. Critical illnesses such as sepsis, disportionately effect people over the age of 65, leading to increased morbidity and mortality in older adults. Thrombosis is a common complication from sepsis, contributing to organ failure and death. Emerging evidence supports the concept that dysregulated platelet functions mediate the injurious host response during inflammation. Nevertheless, the molecular mechanisms and functional consequences of dysregulated platelet functions during aging and inflammation remain incompletely understood. Our proposal, entitled "Inflammation in
Aging Increases Platelet Hyperactivity and Thrombosis" will identify new pathways by which inflammatory agonists, including, interferons (IFNs) regulate gene expression in platelets and their parent cell, the megakaryocyte (MK) in aging. Our preliminary studies have identified that the expression of IFITM3 is robustly induced in human platelets during sepsis. Interestingly, MKs and platelets from aged human and mice express more IFITM3 after IFN stimulation compared to younger controls. Our data suggest that IFITM3 promotes fibrinogen endocytosis in MKs and platelets, leading to platelet hyperreactivity and thrombosis. Our findings also suggest in aging and during inflammatory stress, the mammalian target of rapamycin (mTOR) pathway is activated, triggering IFITM3 synthesis and thrombosis. The expression and function of IFITM3 in MKs and platelets and its regulation by mTOR is a pathway not previously examined. In this proposal, we will couple studies in older and younger septic patients with in vitro and in vivo murine models using aged mice. These complementary human and murine studies will allow us to establish clinical relevance, while also dissecting the mechanisms by which IFITM3 governs MK and platelet function during inflammation. These studies are translational and innovative as IFITM3 regulation of endocytosis, a process critical for cellular function has not previously been studied in MKs, platelets, or - for that matter - any primary human cells. They will also determine for the first time whether if aging alters the effect of inflammatory agonists on transcriptional and translational events in MKs and platelets. This work will test an important functional hypothesis and clarify pathophysiologic mechanisms of thrombosis aging during inflammation.

Vincent Koppelmans, PhD

Assistant Professor; Department of Psychology 

Co-I Kevin Duff, PhD

Associate Professor; Department of Psychology

Co-I Sara Weisenbach, PhD

Assistant Professor; Department of Psychology 

Co-I Robert Welsh, PhD

Associate Professor; Department of Psychiatry                 

Ecological Assessment of Emotion Regulation in Amnestic Mild Cognitive Impairment

Abstract

Emotion regulation (ER) is important for emotional well-being and partly relies on intact neurocognitive functions. Not much is known about ER in older adults with or without amnesitc Mild Cognitive Impairment (aMCI). Cognitive problems in aMCI may further hamper ER in these subjects and thus reduce emotional well-being. This study will assess differences in emotion regulation ER strategies and mood fluctuation between healthy older adults, and a group of demographically-matched subjects with aMCI. Because most ER measures have not been validated in older adults with or without aMCI, we will use ecological momentary assessment (EMA) to measure ER in everyday life and relate that to identical and similar
measures collected in a lab environment. With the EMA we will measure mood and ER at on multiple days at several time points. We will use this data to assess the ecological validity of the conventional ER measures using the EMA ER data. In a next step we will relate the conventional and EMA ER data to measures of cognitive functioning to test if executive functioning and ER are differentially related in healthy older individuals and individuals with aMCI. Within subjects with aMCI we will look if the extent of executive dysfunction relates to type and extent of use of ER strategies. Finally, we will use the EMA data to calculate an index of mood fluctuation. Mood fluctuation cannot be derived from conventional emotion self reports, but could provide new information on the differences in emotional well-being and ER between healthy older adults and individuals with aMCI.

Michelle Litchman, PhD, FNP-BC, FAANP 

Assistant Professor; College of Nursing   

Co-I Nancy Allen, PhD, ANP-BC

Assistant Professor; College of Nursing

A Feasibility Study of Older Adults and their Care partners using RT-CGM Share

Abstract

This Center on Aging Pilot Grant will examine the use of 1) real-time continuous glucose monitoring (RTCGM) in older adults with and without cognitive decline and comorbid type 1 diabetes and 2) RT-CGM data sharing with care partners via mobile app. Adults with type 1 diabetes are living longer. Age related changes, coupled with diabetes-related complications, such as hypoglycemia and cognitive decline, places older adults at risk for cardiac events, loss of consciousness, falls, seizures, and hospitalizations. There is little information about older adults with cognitive decline who use RT-CGM or older adults who share RTCGM data with care partners. The objective of this research is to determine if older adults with and without cognitive decline can effectively share RT-CGM information with care partners to improve hypoglycemia and glycemic variability. Our three aims are: 1) adapt a RT-CGM data sharing training manual for older patients and care partners that includes the technical and behavioral components of this technology, 2) evaluate the feasibility, acceptability, adherence and clinical outcomes of RT-CGM with data sharing and 3)
evaluate hypoglycemia confidence, quality of life and RT-CGM data sharing experience. This study is a critical first step in determining how older adults and care partners can use RT-CGM with data sharing to improve hypoglycemia and glucose variability. Findings from this study will be used as preliminary data to develop a fully powered randomized control trial.

Marc Porter, PhD

USTAR Professor; Nano Institute of Utah    

Co-I Phillip Kithas, MD, PhD

Associate Professor; Division of Geriatrics

Sensitive Detection of Age-Related Biomarkers Using Surface-Enhanced Raman Scattering

Abstract

Preventative or curable age-related diseases such as heart disease and diabetes can be successfully treated if detected early in their development via routine physician visits and preventative screening. An emerging area in geriatric medicine centers on the detection of advanced glycation end-products (AGEs), which are proteins or lipids that become glycated as a result of exposure to sugars. AGEs have been linked to the development or worsening of conditions such as diabetes, Alzheimer’s and heart disease. Currently, there is no “gold standard” method to screen for AGEs. We propose the development of a multiplexed immunosorbent assay for three abundant blood-borne AGEs – carboxymethyllysine (CML), methylglyoxal 5-hydro-5-methylimidazolone (MG-H1), and glycated hemoglobin (Hb1Ac). This platform, which is based on an extensive body of work at the University of Utah, provides a snapshot of serum AGE levels and can be used for screening or monitoring of therapeutic interventions.

Karen Schliep, PhD, MSPH 

Assistant Professor; Department of Family & Preventive Medicine/Public Health   

Association Between Women's Reproductive Health and Later Dementia   

Abstract

Hypertensive disorders of pregnancy (HDP), including preeclampsia, is the leading cause of fetal and maternal morbidity and mortality, complicating 3–10% of all pregnancies. Little is known regarding the association between HDP and long-term adverse maternal neurological outcomes with similar inflammatory vascular etiologies, including the two most common forms of dementia—Alzheimer’s disease (AD) and
vascular dementia (VaD). However, emerging experimental models demonstrating distinct etiologies between HDP and AD as well as HDP and VaD make a strong biological case for such an association. An estimated 5.4 million Americans currently suffer from dementia, two-thirds of whom are women. As the US aging population increases, prevalence of dementia is expected to approach 16.0 million cases by 2050. Why AD and VaD disproportionately affect women is not known. This project sets out to test our central hypothesis that women with versus without HDP will have increased risk for dementia, with four specific aims: 1) increase diagnostic accuracy of AD, VaD, and other dementias within a large population database containing routinely collected health information; 2) investigate the association, and dose-response, between HDP and AD and/or VaD; and 3) evaluate the mediating effects of depression on HDP–AD and/or VaD risk. Our study proposes to use four complementary, unique, and rich data resources. Three have notably low measurement error in regards to definitive dementia diagnoses. The fourth has low sampling error: a statewide database of over 11 million individuals with linked family history, sociodemographic, and medical/vital records. In Aim 1, we use a machine learning approach to develop AD and VaD classification models to analyze longitudinal, individual-level routinely collected health information data to maximize both the sensitivity and specificity of identifying the gold standard AD and/or VaD cases. In Aim 2 and 3, after
optimally classifying and linking AD/VaD diagnoses within UPDB, women with HDP will be identified (n ~ 65,000) and then tested for risk for AD and/or VaD, taking into account important confounding factors and mediating effects of depression. The results of the aims will inform a life-course approach to women’s health research, with a goal of contributing to our understanding of gender disparities in dementia risk. This
research will prepare the research team to design and implement a novel R01 application to explicate the mechanistic relationship between women’s reproductive health and subsequent dementia risk leading to timely interventions targeting those with a high-risk maternal health history.

Lauren Theilen, MD

Assistant Professor; Department of Obstetrics and Gynecology

Co-I Russ Richardson, PhD

Professor; Division of Geriatrics

Co-I Michael Varner, MD

Professor; Department of Obstetrics and Gynecology

Vascular Aging in Women with a History of Recurrent Hypertensive Disease of Pregnancy

Abstract

Women with a history of hypertensive disease of pregnancy (HDP) have increased risks for chronic diseases later in life. Cardiovascular disease is the leading cause of death among women in the United States, and HDP is now recognized as an important risk factor for the later development of cardiovascular disease. Our data have shown that women who have had HDP in more than one pregnancy (recurrent HDP) have significantly increased risks for death from heart disease and stroke before the age of 50; however, an important knowledge gap remains regarding the timeline and pathophysiology of cardiovascular risk following HDP. We hypothesize that women with recurrent HDP will have an accelerated vascular aging phenotype that may be identified before the onset of clinical cardiovascular disease via noninvasive studies of vascular function. To test this hypothesis, we propose to identify a cohort of women with a history of recurrent HDP who delivered their first affected pregnancy 10-15 years ago (exposed women). We will match them to women who have also had more than one pregnancy, but who have no history of HDP (unexposed women). We will test both groups of women in order to determine if exposed women, compared to unexposed women, 1) exhibit
increased arterial stiffness, as measured by pulse wave velocity, and 2) exhibit impaired endothelial function, as measured by the hyperemic response to passive leg movement. Our pilot study will provide preliminary data to guide subsequent investigation regarding the underlying pathophysiology and prevention of cardiovascular disease among women with a history of HDP. 

Micah Drummond, PhD 

Assistant Professor; Physical Therapy & Athletic Training; College of Health

Co-I Matthew Rondina, MD, MS 

Associate Professor; Division of Internal Medicine

Role of Metformin on Muscle and Metabolic Function in Older Adults After Bed Rest

Abstract

Hospitalizations for disease, injury, and/or surgery in older adults are likely to impair physical mobility and, therefore, the older adults capacity to be physically active both during hospitalization and beyond. The resulting sedentary lifestyle is likely to be accepted as the “new normal”, ultimately increasing the risk of skeletal muscle and metabolic dysfunction (e.g. insulin resistance and sarcopenia). These devastating outcomes are neither inevitable nor necessary if prevented with an appropriate mechanism-based intervention.
Muscle atrophy and insulin resistance are common after bed rest in healthy older adults. We have observed with our bed rest studies in older adults that in addition to muscle and metabolic changes, we also notice increased skeletal muscle inflammation, impaired glucose uptake signaling and an upregulation of enzymes related to de novo ceramide biosynthesis. The accumulation of ceramide, a toxic lipid intermediate, can disrupt glucose homeostasis and impair muscle growth. Metformin treatment has been shown to improve insulin sensitivity and attenuate muscle loss in insulin resistance adults through a mechanism that may involved ceramide synthesis. Metformin used as a preventive strategy to maintain muscle and metabolic health in bed ridden older adults has not been investigated.
Therefore, Drs. Drummond and Rondina have proposed to conduct a clinical study in older adults to test whether metformin treatment during bed rest will attenuate insulin resistance, muscle loss and accumulation of ceramides. These preliminary findings generated from this pilot grant will be foundational for assembling a competitive R01 grant application and future development of treatments to prevent insulin resistance and muscle atrophy in inactive older adults.

Raphael Franzini, MSc, PhD 

Assistant Professor; College of Pharmacy

Development of Function-Discriminatory SIRT6 Activity Modulators

Abstract

SIRT6 plays important roles in longevity and healthspan. Aberrant SIRT6 function accelerates aging and causes premature progeria phenotypes, whereas overexpression of SIRT6 protects model animals from aging effects and can increase lifespan. Despite the great prospect of targeting SIRT6 for delaying and reversing aging-associated diseases, potent SIRT6 activity modulators are unavailable. We here propose to
develop SIRT6 activity modulators as tools compounds for biological studies and as structural leads for the future development of SIRT6-targeting anti-aging drugs. One developed molecule will individually inhibit the de-fatty-acylase activity of SIRT6 without interfering with its deacetylase function. The biological role of the de-fatty-acylase activity remains little explored even though it is the dominant SIRT6 activity in enzyme
assays. Activity-discriminatory SIRT6 inhibitors could be used in the future to decipher the roles of the individual functions in cell-based assays or animal models of aging and related diseases. A second molecule that we aim to develop will activate the deacetylase activity of SIRT6. Several studies indicated that it is the deacetylase activity of SIRT6 that is predominantly responsible for the aging-protective roles of SIRT6, and
SIRT6 activators have been proposed as pharmaceuticals to delay or reverse aging phenotypes. We will pursue a novel screening approach to identify function-discriminatory SIRT6 modulators. We will screen DNA-encoded chemical libraries against defined SIRT6-substrate complexes and compare affinity-selection fingerprints to identify molecules that are good candidates for interfering with one but not the other SIRT6
activities. Candidate molecules will be synthesized, structurally optimized, and evaluated in enzyme assays. The effect of SIRT6 activity modulators will be validated in cultured cells. This pilot project will lay the foundation for a state-of-the art pharmaceutical aging research program.

Jon Rainier, MD, PhD 

Professor; College of Science/Chemistry 

Co-I Paul Bernstein, MD, PhD 

Professor; Department of Ophthalmology

The Synthesis and Study of VLC-PUFAs in Age-Related Macular Degeneration

Abstract

Age-related macular degeneration (AMD) is a multifactorial disease that is the leading cause of blindness amongst the elderly worldwide. Among other etiology, a deficit of very long chain polyunsaturated fatty acids (VLC-PUFAs) have been proposed to play a significant role in the retinal atrophy, neovascularization, and scarring that is associated with AMD. In spite of this, there are no reports of the use of VLC-PUFAs as
supplements to combat this disease nor have any synthetic approaches to the VLC-PUFAs been reported. When one considers the role that these fatty acids have been shown to play in retinal health, this is surprising. This proposal aims to address the accessibility of VLC-PUFAs and their use as supplements through a new interdisciplinary collaboration that builds on the strengths of both research groups. Over the course of these
preliminary studies we will develop and optimize a new modular approach to VLC-PUFAs that will ultimately allow us to (a) carry out the synthesis of all 21 VLC-PUFA substrates that are known to exist in human retinal tissue; (b) carry out the synthesis of one of the VLC-PUFA on multi-gram scale; (c) carry out the synthesis of deuterated VLC-PUFAs and; (d) track the ability of VLC-PUFAs to reach the retina.

 

Adam Spivak, MD 

Assistant Professor; Division of Infectious Diseases; School of Medicine  

Modulating Immune Function in Chronic HIV Infection via MTOR Inhibition in Peripheral Blood Effector Lymphocytees

Abstract

Combination antiretroviral therapy (ART) has transformed HIV-1 infection from an untreatable, lethal condition into a manageable medical problem for the majority of patients with access to therapy. Despite the restoration of the CD4+ T cell compartment and durable suppression of viremia by ART, these drugs are not curative. HIV persists in resting memory CD4+ T cells, and will reemerge if ART is stopped. Furthermore, the immune system does not return to a state of full fitness despite the success of ART. The mammalian target of rapamycin (mTOR) is a kinase active in innate and adaptive immune cells that governs cellular metabolism, growth and survival. While the mTOR inhibitor rapamycin is FDA-approved and widely used for chronic immune suppression in organ transplant recipients, this drug has also been shown to be immune-stimulatory, boosting both anti-pathogen and anti-tumor responses. HIV-1-positive kidney transplant recipients treated with rapamycin were found to have smaller HIV-1 reservoirs than those taking other immunomodulatory agents, suggesting a possible role of mTOR signaling in regulating viral persistence. These lines of evidence identify mTOR signaling as a high yield target to ameliorate the immunologic dysfunction of chronic, treated HIV-1 infection. The importance of understanding the mechanisms leading to immunosenescence in treated HIV-1 infection is underscored by the chronologic aging of the HIV-1 infected population in the United States, with over half of individuals living with HIV-1 infection over
age 50. We propose hypothesis-driven experiments in order to evaluate the role of mTOR inhibition on the immunophenotype and function of circulating CD8+ T cells and NK cell subsets in the peripheral blood of treated HIV-1 infected individuals. Exploring the drivers of immunosenescence in treated HIV-1 infection will have therapeutic implications for HIV-1 infection and a multitude of disease states associated with immunologic aging.

Corrine Welt, MD 

Professor; Division of Endocrinology and Metabolism; School of Medicine  

Primary Ovarian Insufficiency Genetics as a Marker of Early Aging 

Abstract

Primary ovarian insufficiency (POI) is part of the continuum of ovarian dysfunction ranging from infertility with a high FSH level to early menopause before age 45 years, and affects 5-10% of women. Using next generation sequencing in women with familial POI, we recently identified a novel, heterozygous, stop gained mutations in an affected family. The mutation was found in POLR2C, the third largest subunit of RNA polymerase II, which appears to cause earlier menopause in each generation. We will now apply unique DNA sequence analysis software developed at the University of Utah to discover novel gene mutations in additional familial POI cases. In addition, we will examine the familial segregation of POI and comorbid disease and age at death. Specific Aim 1 will identify familial cases of POI in the Utah Population Database, the most extensive genealogical database in the U.S. The inheritance pattern, associated phenotypes and comorbid diseases and age at death will be analyzed in familial POI to determine its effect on overall health and to determine families at risk for POI. Specific Aim 2 will determine the breadth of genetic mutations in women with familial POI that have undergone whole genome sequencing. We will use novel software (VAAST, pVAAST and Phevor) developed at the University of Utah and controls recruited for health in old age to prioritize variants and will replicate the data in sporadic cases of POI (n~300). The software identifies rare, damaging variants in genes that have a strong relationship to the POI phenotype. The work will illuminate our understanding of the genetics of the reproductive aging transition. It will also address fertility as a marker of overall health by documenting longevity and identifying diseases associated with decreased ovarian reserve and POI. We will then be able to use family history and associated disorders to identify women at risk for POI. New gene mutations and pathways will inform software algorithms such as Phevor, which will use the new information to prioritize variants discovered in next generation sequencing to determine the genetic cause of POI in additional women. Early identification will bring the potential to preserve fertility and create targeted treatment options for these women.

Heather Hayes, DPT, PhD

Assistant Clinical Professor

Department of Physical Therapy  

Psychological, physical, and social influences on elder caregivers of stroke

Abstract

The purpose of this project is two-fold, 1) Determine the change in self-reported outcomes in psychological, physical, and social factors and physical activity (steps/day) in elder caregivers of persons with stroke over a 3-month time period; and 2) Determine the relationship between the self-reported outcomes (psychological, physical, and social factors) and physical activity level in elder caregivers of a person with stroke. We will enroll 100 aging caregivers (55 years and older) who are taking on a new role of caring for a person with stroke in the home setting. The results of this study will allow us to measure changes in caregiver emotional health across time, specifically after they have completed formal rehabilitation and are in their home setting without the additional resources available. Furthermore, we will gain an understanding of the relationship of physical activity and emotional health of elder caregivers of stroke survivors. The innovation in this study stems from the utilization of quick quantitative standardized assessment tools, such as the Patient Reported Outcome Measurement Information Systems (PROMIS®). We will use the PROMIS® measures to assess subjective psychosocial and physical components of elder caregivers. This combined information of subjective psychosocial and physical experiences as well as physical activity levels will allow us to identify the stressors the caregiver is experiencing and to determine whether physical activity influences effects of these stressors negatively or positively. This information will enable us in the future to assess the influence of interventions aimed at improving psychological, physical, social factors, and physical activity levels of caregivers, thereby improving quality of life and health of both the caregiver and the patient.

Kalani Raphael, MD, MS 

Associate Professor

Department of Internal Medicine

Sodium bicarbonate, a potential therapy to prevent chronic kidney disease

Abstract

Bicarbonate levels in the blood are commonly measured in clinical practice and partly assess the acid state of a person. In generally healthy older individuals, low bicarbonate levels point to a higher risk of developing kidney disease and death. The purpose of this study is to determine if bicarbonate levels can be raised with sodium bicarbonate (baking soda) in older individuals without kidney disease. If so, then it would support studying long-term health effects of sodium bicarbonate in older individuals.

Joel Trinity, PhD 

Assistant Professor

Department of Internal Medicine 

Orthosatic Hypotension and Fraility in Geriatric Hypertension

Abstract

Geriatric hypertension impacts nearly 70% of adults over the age of 65. Despite this high prevalence, controversy exists regarding the most appropriate course of medical treatment in this population. Antihypertensive drug therapy reduces cardiovascular risk; however, the concurrent impact of drug therapy on the risk of falls and serious injury resulting from orthostatic hypotension and syncope in geriatric hypertensive patients is equivocal. These conflicting results may be linked to the impact of these drugs on cerebral perfusion or underlying frailty that is common in the elderly. Importantly, serious injuries associated with falls including hip fracture and traumatic brain injury have a similar impact on physical function and mortality as cardiovascular events (myocardial infarction and stroke) associated with hypertension. Specific Aim #1 will determine how antihypertensive drug therapy impacts cerebral perfusion and the regulation of blood pressure during an orthostatic challenge in geriatric hypertension. It is hypothesized that antihypertensive medications will evoke greater orthostatic hypotension and reductions in cerebral perfusion during a head-up tilt test compared to when these drugs are withheld. Specific Aim #2 will determine if the detrimental impact of antihypertensive drug therapy is increased in frail geriatric hypertensive individuals. It is hypothesized that frail geriatric patients will be negatively and severely impacted by antihypertensive medications and their susceptibility to orthostatic hypotension and falls will be augmented. A comprehensive battery of tests to determine frailty will be implemented and associations between frailty, orthostatic tolerance, and cerebral perfusion will be assessed. The overall goal of the proposed pilot research is to identify the impact of antihypertensive drug therapy on physiological and functional parameters directly associated with the increased propensity of falls in the geriatric hypertensive population. This information will serve as a foundation for clinicians to identify the most appropriate course of antihypertensive treatment without compromising functional mobility.

Ashley Walker, PhD 

Research Assistant Professor

Department of Internal Medicine 

Preventing age-related arterial stiffening to preserve cognitive function

Abstract

Advancing age is associated with declines in cognitive function and increased risk for neurodegenerative diseases such as Alzheimer’s disease. It has recently become appreciated that the cerebral arteries may have an important role in these impairments in the brain with aging. With advancing age there is an impairment of the cerebral artery endothelial cells, characterized by decreased endothelium-dependent dilation, impaired barrier function, and increased arterial inflammation. We recently demonstrated that increased large artery stiffness, a feature of primary arterial aging, leads to impaired cerebral artery endothelial function. We are now interested in examining if preventing age-related increases in large artery stiffness can preserve cerebral artery endothelial function and prevent cognitive declines. To do so, we propose to utilize treatment with pyridoxamine, a form of vitamin B6, as this has been shown to prevent increases in large artery stiffness with advancing age. In Aim 1, we will establish the time-course for pyridoxamine effects on large artery stiffness, starting with treatment in middle-age and continuing for 1 year in mice. In Aim 2, we will determine the effect of pyridoxamine treatment on cerebral vascular permeability, endothelium-dependent dilation and markers of inflammation in old mice. In Aim3, we will determine the effect of pyridoxamine treatment on learning and memory and markers of neuroinflammation and neurodegeneration in old mice. The expected results of these studies will provide novel insights into how primary aging leads to cerebral artery dysfunction and cognitive impairments. Furthermore, these studies will provide the first evidence that pyridoxamine may be an effective therapeutic to prevent age-associated cerebral artery dysfunction and cognitive decline.

Walter Wray, PhD

Associate Professor 

Department of Internal Medicine

Inflammation and Vascular Function in HFpEF

Abstract

Advancing age is associated with declines in cognitive function and increased risk for neurodegenerative diseases such as Alzheimer’s disease. It has recently become appreciated that the cerebral arteries may have an important role in these impairments in the brain with aging. With advancing age there is an impairment of the cerebral artery endothelial cells, characterized by decreased endothelium-dependent dilation, impaired barrier function, and increased arterial inflammation. We recently demonstrated that increased large artery stiffness, a feature of primary arterial aging, leads to impaired cerebral artery endothelial function. We are now interested in examining if preventing age-related increases in large artery stiffness can preserve cerebral artery endothelial function and prevent cognitive declines. To do so, we propose to utilize treatment with pyridoxamine, a form of vitamin B6, as this has been shown to prevent increases in large artery stiffness with advancing age. In Aim 1, we will establish the time-course for pyridoxamine effects on large artery stiffness, starting with treatment in middle-age and continuing for 1 year in mice. In Aim 2, we will determine the effect of pyridoxamine treatment on cerebral vascular permeability, endothelium-dependent dilation and markers of inflammation in old mice. In Aim3, we will determine the effect of pyridoxamine treatment on learning and memory and markers of neuroinflammation and neurodegeneration in old mice. The expected results of these studies will provide novel insights into how primary aging leads to cerebral artery dysfunction and cognitive impairments. Furthermore, these studies will provide the first evidence that pyridoxamine may be an effective therapeutic to prevent age-associated cerebral artery dysfunction and cognitive decline.

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Kara B. Dassel, PhD
Director, Gerontology Interdisciplinary Program
College of Nursing

The Influence of Disease Type on End-of-Life Care Preferences

Abstract

Preparation for end-of-life (EOL) care is a significant area of interest for both clinicians and researchers in light of the growing older adult population. EOL care preferences have been extensively studied in relation to global “terminal illnesses”, typically cancer, but there is very little literature that has explored EOL wishes with terminal neurodegenerative disorders such as Alzheimer’s disease (AD). The influence of psychosocial factors such as death anxiety, religiosity, and demographic variables such as age, gender, and education level have been explored extensively in the EOL and palliative care literature, but there has been very little investigation of the influence that multi-dimensional health variables have on EOL care preferences.

Furthermore, examination of EOL care preferences in relation to different specific disease trajectories has yet to be conducted. Therefore, the purpose of the current study is to explore EOL care preferences in relation to three different hypothetical progressive disease scenarios (i.e., pancreatic cancer, Alzheimer’s disease, and congestive heart failure) and to examine the influence of participant health status in the areas of mood, health-related quality of life, frailty, comorbid chronic disease, and functional status on these care preferences. Participants age 40 and older will be recruited from a large volunteer research participant database and will complete a series of demographic and health questionnaires. In addition, participants will be asked to select their anticipated preferences for EOL care based on three hypothetical disease models. EOL care preferences for each hypothetical disease model and the influence of health and other demographic variables on EOL preferences will be analyzed using linear mixed effects regression models. The primary objective of the current pilot study is to obtain data that will aid in the future development of a disease-specific EOL preference measure for persons with Alzheimer’s disease and to use this tool to study longitudinal change in EOL preferences in caregiving spousal dyads.

Heidi Hanson, PhD
Research Assistant Professor
Family and Preventive Medicine

The Airderly Study: Air Quality, Health and Mortality in the Medicare Population

Abstract

Ambient air pollution is one of the greatest environmental threats to human health, with approximately 3.7 million, or 6%, of deaths globally per year contributed to the noxious problem. A recent statement from the American Heart Association called for a better definition of susceptible individuals or vulnerable populations. This study uses a comprehensive population-based resource, the Utah Population Database (UPDB) linked to Centers for Medicare and Medicaid Services (CMS) records from 1992 - 2009 to study the effects of ambient air pollution on morbidity and mortality in the 65+ population. We examine the relationship between air pollution and cardiovascular and pulmonary morbidity and mortality for socioeconomically disadvantaged individuals, individuals with preexisting conditions, and individuals with chronic comorbid conditions in this population. This study will significantly improve our understanding of the heterogeneous effects of increased levels of ambient air pollution in the population over age 65.

J.David Symons, PhD
Professor
Exercise and Sport Sciences

Links among autophagy, mitophagy, and nitric oxide bioavailability in aging

Abstract

Autophagy or "self-eating" is a cellular quality-control process wherein damaged proteins and organelles are recycled to ultimately provide new nutrients and energy. This process has been examined in numerous tissues (e.g., liver, heart) and, in general, autophagy is supressed in the context of healthy aging. One study exists concerning autophagy in the vasculature, and supports data from other tissues i.e., autophagy is less robust in arteries from old vs. young mice. Mitochondria produce ATP via oxidative phosphorylation and, as such, are crucial to cell viability. Mitochondria also play the role of signaling organelles by producing reactive oxygen species. During the process of aging, "dysfunctional" mitochondria become producers of excessive reactive oxygen species (ROS) which can limit nitric oxide (NO) bioavailability and contribute to arterial dysfunction. The process of mitochondrial autophagy i.e., mitophagy, is a recently discovered cellular defense mechanism designed to recycle / degrade dysfunctional mitochondria. We will test the overall hypothesis that suppressed vascular autophagy during the aging process leads to: (i) reduced endothelial cell (EC) mitophagy; (ii) increased ROS/reactive nitrogen species generation; (iii) reduced eNOS phosphorylation and NO bioavailability; and (iv) endothelial dysfunction. In Aim 1 we will determine the mechanisms by which suppressed autophagy impairs stimulated endothelial cell(EC), nitric oxide bioavailability in vitro. To do so, aortic ECs isolated from old and young mice will be studied under basal (static, no shear stress) and stimulated (20 dyn/cm2 shear stress) conditions. We hypothesize that when vascular autophagy and mitophagy are suppressed, mitochondrial function is impaired, ROS/RN generation exceeds the cellular antioxidant defense mechanisms to an extent that eNOS enzyme function is disrupted. In Aim 2 we will determine the molecular mechanisms whereby suppressed autophagy impairs stimulated vascular NO bioavailability in vivo. Arteries from young and old mice will be studied at rest and 30-min post 60-min of treadmill-running. We expect exercise-induced increases in NO bioavailability are limited in vessels from old vs. young mice, secondary to decreased autophagy/mitophagy and exaggerated ROS/RNS.

Craig Teerlink, PhD
Research Assistant Professor
Genetic Epidemiology

Sequencing analysis of high risk pedigrees to identify bone density predisposition

Abstract

Prior evidence suggests the presence of strong genetic predisposition to osteoporosis, but the genetic basis of the disease is not fully specified. Because osteoporosis is treatable and even preventable, the identification of genetic variants can enhance disease prediction, screening and treatment. The central aim of the proposed research is to identify predisposing genetic factors for osteoporosis using the well-established high risk pedigree design, which is practical, efficient and powerful for investigating rare variation. We previously created a large resource of extended high-risk osteoporosis pedigrees using a genealogy of the state of Utah linked to medical data for the largest Utah health care provider. The pedigree resource contains 276 multi-generational osteoporosis pedigrees with an average of 14 sampled individuals per pedigree. All sampled individuals were tested for bone mineral density (BMD) at the spine and pelvis. The distribution of normalized BMD at both sites was calculated and severe cases were defined as those in the lowest 5% of the distribution of either site. We propose to identify 2 cases from the 6 most informative high-risk osteoporosis pedigrees with 2 or more sampled cases with normalized BMD score < -2.5 who are distantly related to each other (at least first-cousins). This design will provide us with an informative set of osteoporosis cases most likely to be segregating a predisposition variant. The genetic distance between each pair provides evidence of identity by descent genetic sharing, which serves as an efficient filter for deleterious candidate variants. We will perform whole genome sequencing of the 12 most severe distantly related cases. The sampling strategy is designed to identify predisposition variants that occur in both sequenced severe cases in the same pedigree. This project is intended to leverage the cost effective availability of high-throughput genomic sequence data and provides an opportunity to interrogate a high-risk familial set of osteoporosis families. It is expected that the combination of this analysis approach and this particular set of cases will provide an optimal means to identify specific variants that contribute to this disease. A successful outcome will provide opportunities to expand the project with future funding. 

Peter J. West, PhD
Research Associate Professor
Pharmacology & Toxicology

5-HT6 localization and function: a prototype target for cognitive therapies

Abstract

Treatments that attenuate memory deficits will improve quality of life and diminish the heavy financial and emotional burden of neurological disease. New treatments are needed because currently available therapies are few in number, mechanistically homogenous, and only marginally effective. One approach for future therapy discovery is to first obtain a mechanistic understanding of existing treatments, including those in development, in order to “fine-tune” their targeted effects or discover new therapeutic approaches. One such class of promising treatments currently in development are serotonin (5-HT) 5-HT6 receptor antagonists. However, gaps in our knowledge of 5-HT6 receptor localization and function preclude a mechanistic understanding of their antagonists’ therapeutic effects. This proposal will dissect 5-HT6 receptor localization and physiology, as well as the mechanisms of action of their antagonists', with unprecedented precision. This objective will be accomplished by utilizing transgenic mice expressing a 5-HT6 EGFP reporter to test the hypothesis that 5-HT6 receptor antagonists decrease inhibitory synaptic transmission by reducing the excitability of discrete interneuron subtypes in the dentate gyrus (DG). The specific aims of this proposal are as follows: Specific Aim 1: Determine if 5-HT6 receptors are located on discrete inhibitory interneurons in the DG. We will immunostain tissue from transgenic mice that express a 5-HT6 receptor EGFP reporter. Immunostaining with markers for interneuron subtypes will reveal cell-type specific localization of 5-HT6 receptors in the DG with unprecedented precision. Specific Aim 2: Determine if 5-HT6 receptor antagonists decrease interneuron excitability in the DG. We will use whole-cell patch-clamp technique in acute brain slices to record from htr6-EGFP+ inhibitory interneurons and determine how 5-HT6 receptor antagonists affect excitability. Results from these studies will provide a blueprint for the memory enhancing effects of 5-HT6 receptor antagonists and direct the discovery of new therapeutic approaches for memory impairment in aging. Furthermore, these experiments will set the stage for future studies that will examine how 5-HT6 receptor expression is remodeled in disease such as epilepsy, Down syndrome, and Alzheimer’s disease.

Lisa A. Cannon-Albright, PhD
Professor and Division Chief
Genetic Epidemiology

Informative linkage analysis of extended longevity pedigrees in Utah

Abstract

Living a long and healthy life is a dream of every human. An inherited component to long life is recognized, but there is also much evidence for environmental influences. Although pedigrees including many long-living individuals have been identified, they are typically small, and few DNA samples from related elders are available. Only through a long process of prospective sampling would it be possible to build a powerful resource of samples from informative long-living pedigrees. No such resource of multiple informative long-living pedigrees has ever been created.

Genome wide association studies (GWAS) have been performed for longevity. These studies rely on analysis of unrelated healthy elders compared to control individuals. Such studies are expected to find common variants with low penetrance, but cannot identify rare variants. Existence of rare variants may be one explanation for the relatively small amount of heritability identified by current GWAS findings in longevity. A genome-wide linkage scan could identify rare segregating variants. An important aspect of this proposal is that an optimal search for rare segregating variants affecting longevity has never been completed.

Here we propose the innovative use of unique existing resources in Utah to create the first powerful genome-wide linkage resource for longevity. The PI has studied high-risk cancer pedigrees in Utah for over 3 decades and has noted the confounding of longevity and membership in high-risk cancer pedigrees. Analysis of over 34,000 individuals enrolled in past research studies has identified multiple pedigrees of long-lived individuals. Interestingly, these clusters of long-lived individuals do not overlap with specific highrisk cancer pedigrees, but are clusters of individuals from many different pedigrees. For this pilot project, we have identified elders in multiple informative extended long-lived pedigrees for whom we have stored DNA. Funding from this grant would allow us to genotype approximately 1 million SNP markers in up to 30 individuals and perform the first informative linkage scan of extended long-lived pedigrees.

 

Margaret DeAngelis, PhD
Associate Professor
Ophthalmology and Visual Sciences

Elucidating functional mechanisms in the normal aging retina and AMD

Abstract 
Age related macular degeneration (AMD) is a multifactorial, complex disorder that affects the retinal pigment epithelium (RPE) with the accompanying loss of the overlying photoreceptors in the neural retina. Deposition of drusen, hypo- or hyperpigmentary changes of the RPE typically occurs after the age of 43 years and can occur in both the macula and extra macula but generally concentrates in the macula. The reasons for this are not known. As AMD is a progressive degenerative disease, having the intermediate stage puts one at risk for the advanced forms of the disease. Since the macula is primarily affected this results in central vision being lost and one’s everyday life is impaired by losing the ability to read, drive, and recognize faces. It is estimated that nearly two million U.S. citizens have advanced AMD in at least one eye. Most current treatments require invasive delivery methods, are limited in their applicability, and are not capable of preventing or reversing vision loss over the long term. Although major advances have recently been made in the genomics of AMD, there is a gap in our knowledge with respect to the functional significance of these genes in AMD pathophysiology. Thus, the goal of our project is to perform the functional studies that are needed to provide novel druggable targets for prevention and intervention. We propose to accomplish this goal by characterizing the transcriptome using high throughput RNA-Seq using eye tissues and cell lines from patients that have well-characterized pathological phenotypes on the AREDS grading scale (i.e., intermediate AMD, neovascular AMD, or geographic atrophy) and normal age-matched controls. This approach will go beyond traditional gene expression microarray studies by also examining the transcriptional processes that contribute to gene expression variation to elucidate gene function and mechanism in AMD. By combining analyses of gene expression levels, alternative splicing isoforms, alternative transcription start sites and non-coding RNAs, and comparing them across tissue types and phenotypes, we expect to be able to ascribe specific functions to genes that were previously reported to be associated with AMD as well as novel genes and their pathways.

 

Linda K. Edelman, PhD, RN
Assistant Professor
College of Nursing

Utilizing space-time paths to study triage patterns of older adult trauma care

Abstract 
This Center on Aging Pilot Grant will examine the role of geography in how injured older adults are referred to a Level I Lead Trauma Center (LTC) for care. Older adults account for a disproportionate number of traumatic injury patients and this number is predicted to rise further with the aging population. Age related physiologic changes, diseases and decreased compensatory mechanisms complicate traumatic injuries; still, older adults are less likely than younger adults to be referred to LTCs for care. The under-triage of older adult trauma patients and the geographic disparities associated with trauma access are well documented and the CDC National Expert Panel of Field Triage, 2011 has identified these issues as major priorities for future research. The long term objective of this research is to elucidate how spatial (location of injury and distance from LTC) and temporal (time from injury to LTC admission) factors are associated with older adult trauma referrals and mortality in order to include geographical factors in future trauma referral models. Three years of University of Utah Trauma Registry records and medical record data will be used to address 3 aims: 1) Describe how space and time impact older adult trauma referrals using geographic information systems (GIS) and general multilevel modeling. 2) Determine the association of geographical factors with trauma outcomes such as ICU/hospital length of stay and mortality using GIS and regression modeling. 3) Explore the feasibility of constructing three-dimensional space-time paths of trauma referrals in order to understand where time lags occur in the referral process and their impact on trauma outcomes. This study is a critical first step in determining how geographical factors influence the care that older trauma patients receive. Findings will be used in a future study to develop predictive models of trauma mortality using geographic, individual patient and trauma system factors. Such models can be used to guide the development of referral guidelines to be used by trauma and non-trauma providers when deciding if an injured older adult should be referred to a LTC.

 

Matthew Rondina, MD
Assistant Professor
Division of General Medicine
Department of Internal Medicine

Platelets: Unexamined Contributors to Immunosenescence

Abstract 
Platelets are emerging as dynamic and versatile immune effector cells that mediate host responses to respiratory viral infections, including influenza. In older adults, influenza infections are common and cause substantial morbidity and mortality. In parallel, the influenza vaccine is markedly less effective in older adults. The current application, entitled “Platelets: Unexamined Contributors to Immunosenescence” will compare the induction of newly discovered platelet immune proteins in older and younger adults following influenza vaccination. One of these proteins, the interferon-induced transmembrane protein (IFITM)-3, prevents influenza viral replication and infectivity. IFITM-3 has not previously been described in human platelets. Our specific aims and hypotheses are based on a rich pool of preliminary data demonstrating that platelets from older adults have diminished expression of IFITM-3 during influenza infection and following influenza vaccination. We also found that the inability to upregulate platelet IFITM-3 protein correlates with an increased risk of influenza-related mortality. In the proposed research, we will determine whether platelet IFITM-3 induction is blunted in older adults following influenza vaccination. Moreover, we will correlate changes in platelet immune proteins with seroconversion (or lack thereof) to influenza virus, thus linking cellular and humoral immune pathways. While we will examine IFITM-3 in detail, we will also use deep RNAsequencing (RNA-seq) to identify other candidate immunomodulatory platelet transcripts that are differentially expression in older and younger adults. Candidates identified by RNA-seq will be examined indepth at the message, protein, and/or activity level. These investigations are the first studies to characterize IFITM-3 in platelets. As our investigations will be accomplished using human subjects, our findings will have clinical relevance. All techniques and tools are established and in place and we have proven track records of paradigm-shifting, bench-to-bedside discovery research. Thus, we are poised to determine how aging alters immune sensing by platelets and define new mechanisms regulating influenza-induced platelet immune responses in the elderly.

 

Ming Wen, PhD, MS, MA
Professor, Sociology
College of Social and Behavioral Science

Filial Piety and Health of Older Adults in China: A Mixed-Method Study

Abstract

Filial piety refers to a virtue of respect for one's parents and ancestors and support for the living elders in the family; it is arguably the most influential value in Chinese culture that has shaped the expectations and behavior of Chinese families and survived through dramatic social and political changes throughout the Chinese history. However, the practices and expectations of filial piety have changed through time and varied regionally across China, especially in contemporary China where dramatic demographic changes, rapid modernization and urbanization, and frequent state regulations continue to occur. The strength of the sense of filial piety may have weakened in younger generations and can also vary according to personal background such as gender and socioeconomic status. Older adults in China are particularly dependent on their families for old-age care and support. As a dominant framework in Chinese culture, filial piety regulates intergenerational relations and interactions, provides guidance for family expectations, and presumably has direct and indirect impacts on health and well-being of older adults in China. Drawing on survey instrument and in-depth interviews, this proposed study seeks to understand the changes and continuities in filial piety across three generations, namely younger, middle-aged, and older generations, and explore the impact of filial piety on the older generations' health. A range of health outcomes will be examined including self-rated health, self-reported chronic conditions, self-reported pain, positive and negative mental outcomes, and functional health in terms of disabilities. Four dimensions of filial piety will be addressed including emotional support (via in-person visits or phone conversations), practical support (via doing household chores), financial support (direct monetary help), and living arrangement (co-residence with an adult child or not). Information on socio-demographic background and psychosocial factors will be collected in addition to health and filial piety variables.

There were two distinct pilot grant funding opportunities this year - one in January to select applications pertaining to a theme of "Vascular Aging and Mobility" that were included in a NIH P30 Older Americans Independence Center (Pepper Center) grant application and the second, standard call for proposals in June.

Three of the ten applications submitted in January which were included in the Pepper Center application received funding. There were: 

Markus Amann, PhD, MS
Assistant Professor
Internal Medicine

Respiratory muscle work and oxidative stress in the elderly: impact on blood flow and fatigue.

Abstract

Compared to young individuals, older subjects are characterized by substantially increased respiratory muscle work (Wr), and elevated oxidative stress - especially during exercise (14, 18, 22). Considering these observations, two specific findings in young healthy humans form the rationale for this proposed project: First, relieving much of Wr during cycling exercise via ventilatory assist increases leg blood flow (Qleg) and O2 delivery (11, 12). Second, end-exercise locomotor muscle fatigue is significantly ameliorated by relieving much of Wr (1, 7) and oxidative stress (16) normally incurred during sustained endurance exercise.

Micah J. Drummond, PhD
Assistant Professor
Physical Therapy

Improving muscle anabolic sensitivity to amino acids with a potent exercise anabolic stimulus in older adults following hip fracture: role of microvascular blood flow and amino acid transporters.

Abstract

This pilot data will aid in determining in Older adults following hip fracture and surgical repair: 1) the feasibility of protein metabolism experiments, 2) a proposed mechanism associated with anabolic impairment (microvascular blood flow and amino acid transport), and 3) the anabolic effectiveness of acute physical activity coupled with EAA ingestion. This pilot data will be translated into a competitive R01 application aimed at using the anabolic combination of physical activity and EAA supplementation to counter nutrient anabolic resistance in Older adults following hip fracture and surgical repair, ultimately improving muscle mass, strength and mobility.

Jennifer Majersik, MD, MS
Assistant Professor (Clinical)
Neurology

Phenotype of ischemic stroke and stroke outcomes in high risk pedigrees

Abstract
Stroke is a high morbidity, high mortality disease, with heterogeneous subtypes and unclear heritability. Since stroke primarily affects the aged and has a high case fatality, family history data are often limited and survivors are few. Molecular genetic studies have typically been limited to a case-control methodology. Association studies, both candidate-gene and genome wide association studies, have looked for specific polymorphisms associated with increased stroke risk or stroke mortality but most have not been replicated.Frequently-cited reasons for the lack of consistency in results includes small sample sizes, phenotyping errors, and poor (or no) differentiation of subtypes.Regarding subtypes, most studies have not differentiated even the most basic stroke subtypes (hemorrhagic stroke vs. ischemic stroke) and even fewer have differentiated ischemic stroke subtypes (cardioembolic stroke, small vessel stroke, atherosclerotic stroke, other known types (e.g. dissection), and cryptogenic), despite these subtypes having clear and separate pathophysiologies. Recently, due to failures of association studies and lack of knowledge of genetic epidemiology, there has been a call for high quality, large, genetic epidemiologic studies of stroke.

In this study, Dr. Cannon-Albright, PhD, Genetic Epidemiology, and I propose to utilize a pedigree methodology to find families at high risk for stroke and stroke mortality and then determine their excess heritable risk, i.e. the risk beyond that expected from traditional vascular risk factors. We will then deeply phenotype the families to determine what stroke subtypes are highly heritable. We will be able to use results from this preliminary study to form the basis for an external grant application aimed at determining the genetic causes of the excess heritable risk. Though we currently plan to perform high density single nucleotide polymorphism (SNP) analysis followed by exome sequencing of highly linked regions,we will take advantage of any advances in genetic analytic technology at the time of analysis.

The CoA Steering Committee selected three of the 13 applications submitted for the standard pilot grant program for funding. These were: 

Kenneth I. Aston, PhD
Assistant Professor
Department of Surgery

Microarray analysis of age related changes in sperm DNA methylation.

Abstract
The project proposed here involves the evaluation of sperm DNA methylation patterns in healthy, fertile men of reproductive age (Aim 1) as well as changes in sperm DNA methylation in healthy, fertile men in response to age (Aim 2). While the potential for paternal transmission of epigenetic information through paternal gametes is increasingly being considered, the "normal" sperm methylome in healthy, fertile men with normal semen parameters has yet to be described. We will establish a reference sperm methylome by performing microarray DNA methylation analysis on sperm DNA from 10 healthy, fertile men using the Illumina HumanMethylation450 BeadChip, a chip that interrogates the methylation status of > 450,000 CpGs. Subsequent to obtaining these reference data, we will evaluate the sperm DNA methylation patterns in pairs of samples from men for whom we have sperm samples collected 12-21 years apart. This will allow us to directly evaluate the changes that occur to sperm DNA methylation as men age. This is critically important in assessing the potential consequences to offspring health that might arise as delayed fatherhood becomes an ever more frequent feature of modern populations.

Akiko Kamimura, PhD, MA, MSW
Adjunct Assistant Professor
Division of Public Health

Institutionalization among the elderly in Japan and China: A comparative study

Abstract
Japan and China are experiencing rapid changes in the care of the aging population in their societies and the challenges of taking care of the elderly. Institutional aging care drew attention as the nuclear family became more common, and increases in the number of aging family members put a burden on society. Previous research has revealed that functional limitations and availability of adult children are the two key elements increasing the possibility of institutionalization among the elderly. The purpose of this study is to examine factors influencing institutionalization among the elderly in Japan and China. This study intends to establish new interdisciplinary collaboration with the University of Tsukuba and Obirin University in Japan. The overall hypothesis of this study is that factors influencing institutionalization among the elderly are similar in Japan and China, but the types and degree of the factors influencing institutionalization vary between the countries. This study will use three existing data sets: 1) Data from the University of Tsukuba in Japan; 2) Data from Obirin University in Japan and China; and 3) The Chinese Longitudinal Health Longevity Survey (CLHLS). The data will be analyzed using statistical software STATA or SPSS. For the analysis of the Tsukuba data and the CLHLS, a multilevel logistic regression model with a random intercept will be used  to examine factors associated with institutionalization. Descriptive statistics will be used to analyze the Obirin data. Then the results will be compared with more recent results by meta-analysis. The following outcomes are expected: 1) Better understanding about how family structure affects institutionalization in Japan and China; 2) More knowledge about the impact of community and economic resources on institutionalization in Japan and China; 3) Additional information about the association between age cohort and institutionalization; 4) Established collaboration with the University of Tsukuba and Obirin University in Japan; and 5) Pilot data for future projects. By the end of this study, we expect to have sufficient pilot results to prepare for the next step, including applying for an external grant.

Robert Zheng, EdD
Associate Professor
Educational Psychology

Designing effective digital technology to improve seniors' cognitive functioning.

Abstract
The goal of this study is to identify optimal web-based design(s) for learning in older adults seeking healthcare information from the internet. Although web-based health information is available and older persons are accessing the web in greater numbers, current digital resources including the most commonly accessed health information websites are not optimally designed for older adults who experience various levels of frustration and confusion when seeking health information from web resources. This is because web developers seldom consider the unique cognitive characteristics of the older people when designing and developing webpage architecture. The proposed interdisciplinary research project aims to pinpoint factors that critically influence older people is information processes in a web environment and how to incorporate those factors in the design of a maximally accessible web search and access structure for older adults seeking healthcare information.

Approximately 60 participants will be recruited from two senior centers in Salt Lake County. The participants will be randomly divided into three groups: control group, experiment 1 and experiment 2 groups. The control group will learn the caregiving tutorial online which does not include the cognitive principles of multimedia learning in its design; the experiment 1 group will learn the caregiving tutorial online which includes the cognitive principles of multimedia learning in its design; and experiment 2 group will learn the caregiving tutorial online which includes cognitive principles of multimedia learning and cognitive support (e.g., general questions) in its design. Several measures will be used: demographic and computer experience survey,
domain knowledge pretest, recall and knowledge transfer tests. One Way ANCOVA and step-wise regression analyses will be conducted to analyse the data. 

Kristin G. Cloyes PhD, MA, RN
Assistant Professor
College of Nursing

Aging and Dying in Prison: Toward an Effective and Sustainable Model of Prison Hospice

Abstract

The aging US prison population poses formidable challenges for correctional and public health. Elderly inmates are now the fastest growing demographic group in the US prison system, and exponential growth is projected to continue well into the foreseeable future-by 2025, up to 30% of the US prison population will be elderly. According to the most recent statistics available, from 2000 to 2005 the number of federal and state prisoners over 55 increased by more than 4 times the growth of the entire prison population, with 16 US states seeing an average increase of 145% from 1997-2007. This trend, largely due to lengthy determinate sentencing practices that began in the 1980s, intersects with other public health crises that have particularly affected prisons including high rates of HIV and hepatitis infection and high prevalence of chronic illness among people of low SES and minority racial status, who are also at greater risk of being incarcerated. Older prisoners are therefore among the most vulnerable for age-related disability, disease burden, psychosocial stressors associated with unhealthy aging and lack of access to effective end-of-life care. Correctional institutions are now called on to provide a variety of health services, including end-of-life care, to an increasingly older population with complex medical and mental health illnesses. Scientific research is critically needed in the field of prison hospice to show how health care systems that are tasked with caring for older patients with complex medical and social needs can do so effectively within the constraints of a total institution.

This study will examine and describe the practices and policies of one the oldest and most established prison hospice program in the US. Dissemination what is essential and successful in this model including measurable outcomes will establish an evidence base to support best practices for prison hospice programs, and will translate into development and implementation of sustainable models for other institutions including prisons, jails, state hospitals and long term care organizations.

Guilherme Del Fiol, MD, PhD
Assistant Professor
Biomedical Informatics

Providers' Information Needs in the Care of Older Adults

Abstract

The proposed research addresses a significant unsolved problem related to the large percentage of information needs that are raised and not met during the course of care, potentially leading to medical errors and compromising the safety and quality of care. More specifically, this project focuses on understanding providers' information needs in the care of older adults, a population in which the nature and frequency of providers' information needs are largely unknown. Based on this understanding, we will design prototypes of patient-specific computerized knowledge summaries to help providers meet their information needs, supporting health care decision making. In future studies, we plan to integrate the proposed knowledge summaries into electronic health record systems using an open and standards-compliant software architecture. Thus, the proposed research will provide a prototype for an approach to integrating knowledge summaries into the patient care workflow that have the potential to be replicated on a national scale and to play a significant role in the overall improvement of health and health care.

Lee Dibble, PT, PhD
Assistant Professor
Physical Therapy

Sensory Integration and Motor Planning Exercise in Parkinson Disease

Abstract

Left untreated, the motor deficits of PD markedly impair the ability to perform basic mobility tasks safely because of the risk of falls and fall related injuries. The standard treatments for PD motor deficits are medication and deep brain stimulation but both treatments are expensive, have serious side effects, have a limited effect on postural instability, and may in fact worsen overall risk of falls. In contrast, exercise targeted at improving stability in PD has symptomatic benefits and suggests that some components of postural instability may be modifiable. Overall, there is a paucity of research in this area despite the magnitude and modifiable nature of the problem. To address this gap in the research, we are proposing an exploratory study of Sensory Intergration and Motor Planning Exercise in PD (SIMPLE PD). Although motor learning rates are slowed in PD, motor skill remains amenable to improvement. For this reason, the feasibility of a motor learning focused exercise regimen such as SIMPLE PD are needed. To explore The DIMPLE PD study will be the first to determine what dosage of SIMPLE PD that leads to the largest change in postural instability and fall risk. Our overall approach will be to utilize a baseline prospective standard of care control period to determine two distinctly larger dosages of SIMPLE PD (10 times [10x] increase over standard care dosages and 2 times [2x] increase over standard care dosages). In our primary and secondary aims we expect that both dosages of SIMPLE PD will be feasible and efficacious and result in improvements in postural instability and reductions in fall risk relative to the standard care control period. In our exploratory aim we will utilize novel and innovative ambulatory fall risk monitors to determine the impact of SIMPLE PD on instability episodes during community mobility tasks.

Anthony Donato, PhD
Assistant Professor
Department of Internal Medicine, Division of Geriatrics

Aging and Telomere Structure and Function in the Human Vasculature

Abstract

Advancing age is a major risk factor for cardiovascular disease and appears to exert its pathological influence primarily via adverse effects on arteries. Human aging is characterized by vascular dysfunction, of which impaired endothelium dependent dilation (EDD) is a central feature. However, the cellular and molecular mechanisms involved are not well understood. Recent evidence suggests that white blood cells (WBCs) telomere length (a marker of tissue biological aging) is reduced with advancing age and this has some modest prognostic value for age-related diseases. One extremely compelling and unexplored hypothesis is that vascular tissue biologic aging characterized by telomere structure instability and telomere dysfunction lead to vascular dysfunction in advanced (chronologic) age. We propose to measure arterial telomere structure and function and determine if this is related to arterial function (EDD) in excised human arteries across aging (18-80 yrs). Secondary outcomes will reveal if arterial telomere structure is associated with arterial inflammation, cellular senescence and apoptosis. Finally we will determine if the easily accessible WBCs can be used as a surrogate to predict arterial telomere characteristics. The expected results will provide novel insight into the cellular and molecular mechanisms by which aging leads to vascular dysfunction.

Kevin Duff, PhD
Associate Professor
Neurology

Cognitive Training in Impaired Samples

Abstract

Cognitive impairments are common in older adults, and multiple cognitive training programs have recently been validated to improve cognitive functioning in seniors. Two weaknesses remain in this literature: 1. the benefits of cognitive training programs have not been established in patients with current cognitive impairments, and 2. there have been few attempts to identify, a priori, individuals who are likely to benefit from these training programs. The current proposal will examine the effectiveness of a computerized cognitive training program in individuals with Mild Cognitive Impairment or early Alzheimer's disease (Specific Aim #1). Additionally, the proposal will examine if practice effects on cognitive tests can predict which individuals will benefit most from the training program (Specific Aim #2). A single site randomized controlled single-blind design will be used, with two treatment groups (experimental and control) to examine these aims. If successful, these results will have a noticeable impact on the field, as it will provide preliminary information about the utility of these training programs in patients with current cognitive impairments, and it will provide guidance as to whether practice effects can be used to identify patients most likely to benefit from these training programs.

Richard D. King, MD, PhD
Director, Alzheimer's Image Analysis Laboratory
Assistant Professor of Neurology

Integrating Imaging Biomarkers of Alzheimer's Disease

Abstract

Neurodegenerative diseases represent an increasing health care problem in the United States. These conditions become increasingly common with age. For example, Alzheimer's disease (AD), which is the most common neurodegenerative disease in individuals over the age of 65, currently affects over 5.3 million people in the US. That number is expected to increase to over 15 million by 2040. As new targeted therapies emerge over the next decade, it will be increasingly important to accurately identify individuals early in the course of the disease process. The most promising imaging biomarkers include quantitative structural metrics from magnetic resonance images (MRI), measures of cerebral metabolism from 18Fluoro-deoxyglucose Positron Emission Tomography (FDG-PET), and measures of cerebral pathology from Amyloid-PET imaging. The primary objective of this pilot grant is to develop a novel index of cerebral cortical function that integrates structural (from MRI), pathologic (Amyloid-PET) and metabolic (FDG-PET) imaging data into a clinically useful metric known as the Cortical Metabolic-Pathological-Structural (CoMPS) Index.

Expected outcomes from this project include the following: 1) the interpretation of cerebral atrophy will become quantitative rather than qualitative, 2) healthy aging can be quickly distinguished from pathologic cognitive changes on an individual basis, and 3) the differential diagnosis of neurodegenerative disease will be augmented.

Anita Kinney, PhD, RN
Jon & Karen Huntsman Presidential Professor in Cancer Research
Professor, Division of Epidemiology Department of Internal Medicine Cancer Institute

Effects of Qigong on Fatigue & Quality of Life in Elderly Prostate Cancer Survivors

Abstract

Our long-term goals are to understand the behavioral and biological (e.g., epigenetic, neuroendocrine and immune function) mechanisms underlying the intervention's effect. In preparation for a larger randomized clinical trial (R01), this pilot study will provide preliminary data of the feasibility of conducting a Qigong randomized trial and the intervention's preliminary efficacy (in order to determine effect size for a larger definitive trial) on treatment-related fatigue and health-related quality of life (QOL) in an underserved population of elderly prostate cancer survivors receiving androgen deprivation therapy (ADT). Prostate cancer is one of the most commonly occurring cancers in men, is more likely to be diagnosed at an older age, and the survival rates are high. As a result, survivors are likely to have poor QOL due to treatment side effects, compounded with age-related declines. One-third of prostate cancer patients receive ADT and although it is associated with survival benefits, the side effects (i.e., severe fatigue, sexual dysfunction, metabolic changes, etc.) are often detrimental to the patient’s QOL. We have chosen to focus on the side effect of fatigue because, although it is one of the most common symptoms in cancer patients, it is also one of the least understood cancer-related symptoms by patients and healthcare providers, and it is associated with impairments in health-related QOL and psychological distress. The study design is a pilot two-armed, parallel group, randomized clinical superiority trial. Elderly prostate cancer survivors (age >60 years, n=54) with localized or metastatic disease, who have been on ADT for >1year, and have clinically significant fatigue levels will be randomized to Qigong classes or non-aerobic stretch control classes. The classes will be held for 60 minutes, 3 times a week, over a 12 week period and led by certified and trained specialists. Additionally, survey measures to assess fatigue, QOL, psychological distress, cancer worry, prostate cancer treatment symptoms (FACIT-F, SF-36 QOL, BSI-18, Cancer Worry, EPIC-short form), and physical assessments (balance, blood pressure, BMI, waist-hip-ratio) will be collected at baseline prior to randomization and at post-intervention.

Thure Cerling, PhD / Ken Smith, PhD / James Ehleringer, PhD
Biology; Geology & Geophysics / Huntsman Cancer Institute / Biology

Using Hair to Monitor Health and Nutrition among the Elderly

Abstract

The most common method used to monitor diet and water intake is administration of questionnaires, a method that is both expensive and frequently unreliable, and for which validation with biomarkers highly sensitive and specific to intake is needed but undeveloped. Stable isotopes are just such a biomarker. It has been shown that major sources of dietary protein (plant, terrestrial animals and marine animals) can be distinguished based on their stable carbon, nitrogen and sulfur isotope ratios. Stable C, N and S isotope ratios of human hair represent a quantitative measurement of protein intake that can be used to provide an independent assessment of the consumption of different protein sources that will greatly complement on dietary questionnaires. Furthermore, work in our lab with animal and mathematical models show that individuals with higher water turnover(e.g., diabetics) can be distinguished from normal subjects on the basis of hydrogen and oxygen isotopic composition of body water. Thus, stable H and O isotope measurements in human hair can be used to provide an independent assessment of body water turnover and drinking water consumption. Accordingly these measures may prove to be extremely useful in assessing aging and health differentials among the elderly. The overall objective of this study is to use stable carbon, nitrogen and sulfur isotope ratios to quantify the intake of different sources of protein, and to use stable hydrogen and oxygen isotope ratios as a measure of body water balance and water intake. We propose to compare these measurements across four different populations of exceptionally old individuals (probands), a set of middle-aged/young old (45-75) individuals who are the offspring of the probands, and two sets of community based controls, one each for the probands and the offspring. Using these samples allows us to compare individuals who are arguably the healthiest in the population with a set of community controls, a strategy that allows us to detect health and nutrition differences should they exist.

Marilyn Luptak, PhD, MSW, BSW / Frances Wilby, PhD, MSW
Social Work

Development and Enhancement of a Medical Home Model for Low-Income Older Adults

Abstract

The pilot project shall consist of the assessment of 484 geriatric Community Health Center (CHC) patients, to identify critical needs of this special group as to Medicare entitlement and to develop protocols/recommendations to substantially improve the enrollment process. The factors associated with non-entitlement among eligible patients will be assessed. Additionally, we will pilot a case management program that seeks to maximize appropriate utilization and health care navigation within the context of an established community clinic medical home.

The study will include two components which will occur concurrently: a) a needs assessment of older adults living in the study site areas to determine availability and utilization of medical homes and b) an intervention study which will occur in two CHCs in Salt Lake City that serve low-income older adults. The non-intervention at Central City CHC will track patients as to their Medicare entitlement and clinic services utilization, without case management. The intervention group at Stephen D Ratcliffe CHC in Rose Park will receive case management for Medicare enrollment and health care navigation within the context of their existing medical home. Graduate students from the University of Utah will serve as case managers who will work with clinic patients to apply for Medicare if eligible, educate patients regarding access to clinic services regardless of insurance status, and assist them to obtain medications through existing clinic services. Utilization and enrollment will be compared between the two sites.

Codrina Rada, PhD / Zachary Zimmer, PhD, M.A.
Economics / Sociology; Institute of Public and International Affairs

The Impact of Migration of Adult Children on Well-being of Older Parents in Romania

Abstract

The project we propose seeks to examine the impact of migration of adult children on older adults left behind in Romania. We intend to conduct a survey of 1,000 older adults living in eight regions in Romania, analyze the data from the survey, write a report and scholarly publication, and use the results as background and preliminary studies for an R21 proposal to NIH.

Our pilot survey will ask questions about the older person's family, children, social network, money received as remittances, support received from family, change in support over time, employment situation, health and psychological status, and other pertinent exploratory issues. Analytical techniques will be geared towards gaining a preliminary understanding of the situation of older family members in a context of increased outmigration and employment opportunities in alternate settings, both within and outside the country, and will provide a framework from which to launch a regional study. Therefore, this exploratory pilot study is the first step in a multi-stage project, with later funding coming from extramural sources. Romania is an ideal starting ground for this topic given that it has among the highest rates of both population aging and outmigration among countries in the former Soviet-bloc. The project brings together a cross-disciplinary team involving a junior principal investigator from Economics and a senior co-investigator from Sociology, both of whom are breaking new ground with the current proposal. In addition, a Romanian based collaborating organization has been identified. The combination of skills and degree of academic background is also seen as being advantageous for future funding efforts.

Douglas E. Rollins, MD, PhD
Pharmacology and Toxicology; Pharmacy

The Role of Aging in the Formation of Acetaminophen Protein Adducts

Abstract

This project will use a unique, sensitive, and specific liquid Chromatography/mass spectrometry (LC/MSMS) method developed in our laboratory for the measurement of a biomarker of acetaminophen (APAP) hepatotoxicity. Specifically, we will use this method to measure a biomarker of APAP protein adduct formation in young versus old mice. Acetaminophen, a commonly used antipyretic and analgesic, is safe in therapeutic doses, but produces liver cell necrosis if taken in overdose. APAP hepatotoxicity is the result of metabolism to a reactive intermediate that binds covalently to proteins resulting in cell necrosis. Our LC/MS-MS method measures a biomarker in serum and liver of APAP covalent binding to proteins. Recent data has shown that APAP at high therapeutic doses of 4 g/day for 14 days in humans results in the formation of protein adducts and the elevation of serum aminotransferases suggesting liver injury.

We propose to study the role of aging in the formation of APAP protein adducts by measuring a biomarker in the serum, liver, and kidneys of young (3 months) and old (30 months) mice over a broad APAP dose range and at various times after each dose. We will compare the protein adduct formation to the development of hepatotoxicity in mice of different ages. We will also measure the other metabolites of APAP including: APAP-glucuronide, APAP-sulfate, APAP-glutathione, and APAP-cysteine to determine changes in compensatory metabolic pathways. The data from this Pilot Grant will become the basis for a grant to be submitted to the NIH National Institute on Aging to study the formation of APAP protein adducts in aged humans as a result of chronic APAP therapy. The results of the proposed human studies will aid in the determination of safe and appropriate doses of acetaminophen in aged patients.

D. Walter Wray, PhD / John McDaniel, PhD
Department of Medicine; Geriatrics / Geriatric Research, Education and Clinical Center

Efficacy of Antioxidants on Muscular and Vascular Function in the Elderly

Abstract

The objectives of this investigation are to determine if acute and chronic antioxidant 1) alters oxidative stress and total antioxidant capacity (including endogenous antioxidants 2) improves skeletal muscle mitochondrial function, and 3) improves muscle and vascular function in healthy elderly people. Thus, this proposal presents a comprehensive translational approach to determining if chronic antioxidant supplementation is advantageous for healthy aging. This research is highly relevant to the aging population and the objectives of the University of Utah's Center on Aging. There is minimal data regarding the efficacy of chronic antioxidant supplementation to improve oxidative stress and restore vascular and muscular dysfunction in elderly people.

This project aims to enroll a total of 15 sedentary people over the age of 65 years to undergo 10 weeks of antioxidant supplementation (Vitamin E, Vitamin C and lipoic acid). Subjects will be required report the laboratory on 3 occasions (repeated measures design: day 0, day 1 and day 70 of the antioxidant supplementation period) in which they will undergo a blood draw, muscle biopsy and perform a series of muscular and vascular function tests. The blood and a portion of the muscle samples will be utilized to measure specific antioxidants (ascorbic acid, alpha-tocopherol, SOD, CAT), antioxidant capacity (GSH, GSSG and total glutathione) and oxidative stress (lipid hydroperoxides). The remaining portion of the muscle fibers will used to quantify mitochondrial respiration in permeabilized fibers. In addition, the series of functional tests will quantify arterial compliance, exercise induced vasodilatation, forearm and quadriceps strength, and quadriceps fatigability. Data from this translational investigation will help determine the influence of acute and chronic antioxidant supplementation on muscle and vascular function in the elderly population.

Sihem Boudina, Ph.D. Assistant Professor,
Assistant Professor, Department of Internal Medicine, SOM

Role of the Insulin Signaling Pathway on Mammalian Cardiac Aging

Abstract

Cardiovascular disease is the leading cause of death in the United States. Cardiac dysfunction develops in several pathologies such as dilated cardiomyopathy, hypertension-induced left ventricular hypertrophy and diabetes-induced cardiomyopathy. However, similar changes in cardiac function can also occur during normal cardiac aging. Mechanisms that are responsible for normal or pathologies-induced cardiac aging are not fully understood. Studies in invertebrates have suggested a role for insulin signaling in the modulation of normal cardiac aging. Indeed, it was shown that absence of insulin signaling slow cardiac aging in flies. The existence of such mechanism in mammals is unknown. Thus, the aim of this project is to investigate if absence of insulin receptors in the heart delays age-related cardiac dysfunction and cellular damage. We will use mice with insulin receptors deletion in the heart (TIRKO) and their age-matched wild-type mice. This study has two specific aims: (1) to examine if absence of insulin receptors in the heart prevents age-related decline in mitochondrial function and cellular damage; (2) to investigate possible mechanisms involved with specific focus on two major pathways known for their implication in aging mainly the FOXO/SIRT pathway and the autophagy pathway.

Paul J. Carlson, MD
Assistant Professor, Department of Psychiatry, SOM

In vivo creatine kinase activity as a potential biomarker in Alzheimer's Disease

Abstract

Multiple studies implicate bioenergetic dysfunction and impaired oxidative phosphorylation in Alzheimer's disease (AD), suggesting a cohesive bioenergetic and neurochemical model whereby individuals with AD suffer from an insufficient supply of adenosine triphosphate (ATP) in the brain, a compound needed for normal cellular function that is supplied by the enzyme creatine kinase (CK). A novel 31P-MRS technique allows us to directly measure CK activity (kfor, the forward rate constant) in vivo in the human brain. This technique has shown impaired CK function in an animal model of AD, but this has not been tested in humans with AD. We hypothesize that this measure of CK activity will be a useful biomarker which will correlate with progression of cognitive impairment in AD and yield insight into the role of bioenergetic compromise in the pathophysiology of AD.

We plan to test this hypothesis in the current pilot study by measuring kfor of CK in 30 subjects, including an AD group (n=10), an amnestic mild cognitive impairment (AMCI) group (n=10), and a healthy control group (n=10). Comparing results between groups, we expect that subjects with AD will have a lower kfor for the creatine kinase reaction than healthy controls, with intermediate values for A-MCI subjects. For within-subject comparisons, we expect that a posterior cingulate/parietal voxel will have a lower kfor for CK than an anterior cingulate/prefrontal cortex voxel in which glucose metabolism should be relatively preserved. Further, we expect that the values for these voxels will correlate with regional cerebral glucose metabolism for these same regions as measured by FDG PET in the same subjects.

Annette Kirchgessner, Ph.D.
Research Assistant Professor, Division of Gastroenterology, Hepatology, and Nutrition, SOM

Role of Sirtuins in the Aging Gut

Abstract

The incidence of gastrointestinal motility disorders increases with age. More than 38% of neurons in the enteric nervous system (ENS), the intrinsic innervation of the bowel, are lost by the age of 60 years. This is a major contributing factor to motility defects in the aging gut. There is evidence that oxidative stress plays a significant role in this process. However, the mechanisms involved are not known. The overall objective of this proposal is to understand the role of sirtuins in the aging bowel. Sirtuins (SIRTs) are deacetylase enzymes which regulate gene expression, control aging and are active during caloric restriction (CR). CR has been shown to attenuate the age-related neurodegeneration in the CNS and ENS (Cowen et al. 2000). We have recently demonstrated for the first time that sirtuins are expressed in the ENS and that acute starvation and inflammation can regulate their expression. The central hypothesis is that CR activates SIRT1-dependent anti-ageing mechanisms in the bowel. In contrast, the loss of SIRT1 regulation increases cell death, resulting in dysmotility in the aging gut. We will determine if CR protects the ENS by increasing SIRT1 and whether resveratrol, an inducer of SIRT1 mimics the CR effect. We will also use a newly developed method of isolating RNA polymerase II (5' capped) RNA transcripts and Illumina RNA sequencing technologies to define the entire Pol II transcriptome in the ENS for the first time. These studies will provide new insight into the mechanisms leading to gut dysfunction in the aging bowel.

Rajasekaran N. Soorappan, Ph.D.
Research Instructor, Division of Cardiology, SOM

Role of Nrf2 on Age Dependent Regulation of Antioxidant Defense Mechanisms in the Mouse Heart

Abstract

Cellular defense mechanisms are crucial for the maintenance of intracellular redox state and free radical accumulation over the course of aging. Recently, we have discovered that the increased intracellular thiols or reducing equivalents (GSH and NADPH) found to accelerate the process of protein aggregation and cardiac hypertrophy / heart failure in the transgenic mouse overexpressed with human mutant B-Crystallin (hR120GCryAB) in heart tissue (Rajasekaran NS et.al, Cell, 2007). Nuclear erythroid 2 related factor-2 (Nrf2) regulates basal and inducible expression of numerous cytoprotective / antioxidant genes including the ones that involve in glutathione metabolism. Nrf2 is normally tethered with Keap1 in the cytosol. Preliminary findings indicate that the induction of reductive stress in the hR120GCryAB-Tg mouse hearts is strongly associated with the Nrf2 activation. Analysis of Nrf2-KO mice provides credible evidence that these mice are susceptible to various stresses including oxidative stress and pathophysiological conditions. Although oxidative stress increases as people age, leading to shorter lifespan, transcriptional mechanisms that regulate the antioxidant defense system are poorly understood. As Nrf2 being a master transcriptional regulator via antioxidant response elements (ARE) for more than 100 antioxidant and cytoprotective genes, is a key target to understand the regulation of cellular defense mechanisms. This study will examine whether the disruption of Nrf2 modulates cardiac antioxidant defense mechanisms associated with aging.

Hypothesis: Disruption of Nrf2 could compromise the transcriptional mechanisms for potential genes that are responsible for antioxidant defense system, which might potentiate the age dependent oxidative stress disorders including myocardial infarction (MI) and protein aggregation cardiomyopathy.

Cathleen D. Zick , Ph.D.
Professor, Department of Family & Consumer Studies

Retirement Planning Responses to Economic Shocks

Abstract

The current financial crisis has raised many questions about the adequacy of retirement savings, particularly among the baby boomers who will be the next cohort to retire. In our proposed pilot study, we will examine whether and how recent economic events have altered baby boomers' search for financial information and the way they save for retirement. We will consider the influence of perceptions (e.g., risk tolerance), knowledge (e.g., understanding the relationship between saving rates and post-retirement standards of living), socio-demographic characteristics (e.g., marital status), and economic characteristics (e.g., net saver vs. net borrower). Multivariate tests of our initial hypotheses will be undertaken using data that we will gather as from a web-based survey conducted with University of Utah employees in the fall of 2009.

We anticipate writing several scholarly papers based on our pilot study. These publications will form the preliminary studies section for an application that will subsequently be submitted to the National Institute on Aging and/or the American Association of Retirement Persons. In the extramural grant application, we will propose to test the particularly salient findings gleaned from the pilot study by undertaking a national survey and analyzing those data.

Michael K. Gardner, Ph.D.
Professor and Associate Chair, Department of Educational Psychology

Motor skills training of PINS in the elderly with and without MCI

Abstract

The proposed project will explore efficacy of a procedurally-based motor skills training program for teaching older individuals 4 four-digit personal identification numbers (PINS). The rationale for this approach is that procedural memory is supported by different neural systems than delarative memory, and that these systems may be less impacted by the negative effects of aging in general, and certain disease states (e.g., mild cognitive impairment [MCI]) in particular (Squire, 1986, 1987).

The performance of three groups of older (60 years of age or older) adults will be compared: (1) 30 normal, healthy individuals using motor-skills training; (2) 30 individuals diagnosed with MCI using motor-skills training; and (3) 30 normal, healthy individuals in a control condition, in which they are not given explicit memory instructions. It is expected this group will rely on declarative memory strategies such as rehearsal.

Our predictions are: (1) normal individuals given motor-skill training will show increased recall compared to normal individuals in the control condition; and (2) MCI individuals given motor-skill training will show increased recall performance compared to normal individuals in the control condition.

We discuss (briefly) how such procedurally-based training programs could be expanded to other daily living tasks (e.g., programming a microwave oven) in effort to improved the quality of life in older persons who are experiencing memory deficits.

Joanne Lafleur, PharmD, MSPH
Research Assistant Professor, Department of Pharmacotherapy

Gathering evidence for clinical decision support in male osteoporosis in veterans

Abstract

While generally associated with women, men are also at risk for developing osteoporosis; one in four men over age 50 will have a fragility fracture in their remaining lifetime. There are numerous clinical risk factors recognized by research clinical communities that are associated with the risk of osteoporosis-related fracture. Many of these risk factors are routinely recorded in the process of patient care. With the increasing use of electronic medical records (EMRs) there exists a potential to automatically calculate fracture risk using data routinely collected in EMRs to alert health care providers when patients are at high risk of fracture. The hypothesis of this pilot study is that data routinely collected in the Veterans Health Administration (VHA) EMR in the local Veteran Integrated Service Network (VISN) can be used as measures of fracture risk and are therefore predictive of osteoporotic fractures in male veterans. Thus, this study will assess whether data corresponding to fracture risk factors is captured adequately by the VISN database and will estimate the risk for fracture in male Veterans associated with these measured clinical risk factors. This pilot research will also inform the design and implementation of a national level project to validate the predictive power of EMR data for detecting fracture risk in men in the overall VHA system. The ultimate aim of this research is to provide the evidence for the development of an electronic osteoporosis fracture risk tool that would facilitate the identification of at-risk patients for fracture prevention interventions.

Raminder Nirula, MD, MPH
Assistant Professor, Department of Surgery

StO2 monitoring of geriatric trauma patients to stratify outcome

Abstract

Morbidity and mortality are greater for elderly trauma victims compared to similarly injured younger patients. Early, aggressive resuscitation of these patients is associated with an improved outcome; however, many of these patients have a blunted sympathetic response to injury and shock. This leads to delayed recognition and resuscitation of the subclinical shock state which is associated with greater morbidity and mortality.

One approach to this problem is to admit all injured elderly patients to the ICU and place invasive hemodynamic monitors to assess their degree of shock and perfusion. This would lead to significant resource utilization and place many patients at unnecessary risk for complications related to invasive monitoring. Ideally, a rapid, noninvasive measurement of tissue perfusion to identify patients in subclinical shock would permit its early recognition and target resuscitative efforts to those most likely to benefit.

Tissue oxygenation measurement using near infrared spectroscopy (StO2) is a technology that has recently been demonstrated to correlate with shock and the need for emergent interventions. A recent study demonstrated its ability to stratify patients with severe shock from mild to moderate shock; however, this study did not specifically address its utility in identifying patients with subclinical shock - specifically, the elderly.

The proposed study will determine if StO2 measurements during the first 24 hours post injury correlate with mortality, complications, hospital length of stay and discharge disposition. In doing so, this study will provide pilot data to support a multicenter clinical trial of StO2 targeted resuscitation in the elderly trauma patient.

Yong Wang, Ph.D.
Assistant Professor, Department of Surgery, Division of Otolaryngology

Synaptic mechanisms of auditory temporal acuity during aging

Abstract

The fundamental function of the central auditory system is to extract the timing information embedded in the acoustic signal for survival. In humans, temporal processing is also the key for speech recognition because speech is comprised of sounds with spectro-temporal varying cues. As we age, not only our ability to detect sound (hearing sensitivity), but also our ability to extract timing from sound (acuity) deteriorates. It has long been assumed that temporal processing is secondary to hearing loss. However, certain lines of evidence have indicated that there may be age-related reduction in temporal processing that is independent of hearing threshold; i.e., one can hear "just fine" but may have difficulty understanding conversation. So a key unanswered question is: "Are there physiological changes in the central auditory neurons during aging that could account for this observed loss of temporal processing acuity?" In order to tease apart the hearing loss-related acuity change from the age-related acuity change, we intend to study cellular mechanisms that may underlie the loss of temporal acuity in older animals without the presence of hearing loss. This way, we can exclude the hearing loss variable and directly study the effect of aging on central auditory neurons. In this proposal, we will use CBA mice to study neurons in the inferior colliculus (IC), an auditory brainstem nucleus that is principally involved in extracting interaural timing difference in mammals. Our central hypothesis is that there are cellular physiological changes in IC neurons in normal hearing, older CBA mice (12-14 months) compared to normal hearing, young mice (1-2 months). The specific hypotheses we will be testing are: 1) the excitatory synaptic input to IC principal neurons is "sluggish" in older animals; i.e., AMPA receptor-mediated synaptic current has long latency and longer decay time constant, and 2) GABAergic inhibitory synaptic input to IC neurons is weakened such that discrete excitatory inputs show temporal summation and become less discrete. This study will complement our knowledge regarding to changes in IC that are associated with hearing impairment, and provide a foundation to better understand age-related hearing loss (presbycusis).

Zachary Zimmer, Ph.D.
Senior Scholar, IPIA Professor, Department of Sociology

Disability trajectories amond older adults in China and Taiwan

Abstract

Past research has suggested there is no one disability pathway experienced by all older adults. Individuals can experience a variety of transitions into and out of states of disability. Thus, various pathways or trajectories are possible. For instance, some may remain fully functional until they die, others may experience several onsets followed by recovery from disability, and still others may deteriorate steadily. Tracking these trajectories is challenging. First, it requires multi-wave panel data. Second, summarizing multi-wave data to identify typical trajectories is methodologically demanding. Previous strategies, based on subjective classification and latent growth curve modeling, are not ideal. This project will adopt an improved and innovative methodological approach that identifies disability patterns based on group-level analysis. Disability will be measured by items that track ADLs and functional limitations. The approach will categorize individuals with similar disability trajectories and then predict membership in these categories based on a set of determinants that fall within five domains: demographic, socioeconomic, network, behavioral and chronic conditions. The analyses will be based on longitudinal surveys conducted in China and Taiwan. These data are among the best available for such work. Moreover, focusing on these settings will allow for policy statements useful for targeting limited resources within societies undergoing rapid population aging. The methodological advances resulting from the project will have broad implications and have the potential to change the way in which disability trajectories are analyzed and conceptualized. A separate aim is to use the results and experience as a springboard for an NIH submission.

Maurine Hobbs, Ph.D.
Assistant Professor, School of Medicine, Department of Internal Medicine, Division of Infectious Diseases

MnSOD genotypes and Aging-related mtDNA mutations

Abstract

We previously hypothesized that a common polymorphism (A16V) in MnSOD - shown to impair mitochondrial import [7] - would lead to the accumulation of ROS and increase mtDNA damage; this would impact longevity in a normal population as well as the phenotypic expression of a mitochondrial disease (Charcot-Marie-Tooth type 2A (CMT2A)). The A16V genotype did seem to correlate with increased severity of disease in CMT2A families, but did not impact MnSOD mRNA levels, mtDNA damage, or longevity in the normal population. However, a 5' UTR MnSOD polymorphism (G/G genotype) correlated with reduced MnSOD mRNA levels and higher average mtDNA damage (A3243G assay). Additionally, the CEPH longitudinal data allowed us to demonstrate for the first time that individuals with the highest levels of A3243G mtDNA damage had significantly reduced survival among normal individuals.

However, several observations in our study need clarification: 1) severity of phenotype in some CMT2A families correlated with both MnSOD genotype and maternal inheritance (suggesting a possible role of mtDNA genotype in these families), and 2) although MnSOD 5'-UTR G/G genotypes correlated with decreased expression and higher A3243G damage, paradoxically, they seem to have a slightly increased survival. Since only 10% of the CEPH grandparents had this genotype, this may be too few to give an accurate assessment of its effects on survival. We hypothesize that 1) mtDNA genotypes modify the effects of MnSOD genotypes; and 2) increased survival of those with lower MnSOD expression may reflect small sample size, or individuals with lower oxidative stress due to mtDNA genotype, lower inflammation, or leaner body mass. The identification of a relationship between MnSOD genotype, mtDNA haplotypes, mtDNA damage, and alterations in longevity or expression of disease has implications both for biologic mechanisms of aging and mitochondrial disease as well as for therapeutics.

Mary T. Lucero, Ph.D.
Professor, School of Medicine, Department of Physiology

Dysregulation of Fluid Balance and Aging-Related Loss of Regenerative Olfactory Function

Abstract

Humans lose their sense of smell as they age. Dehydration of the body occurs with aging, and may contribute to aging-related loss of olfactory sensory neurons (OSNs) and failure in OSN regeneration. Fluid balance in cells occurs through complex systems of ionic pumps, transporters, and channels that maintain osmotic gradients. Water passively follows ionic gradients via transport through water-specific channels (aquaporins) or non-specifically through other open channels. In the CF mouse, knock-out of the Cystic Fibrosis Transmembrane Conductance Regulator channel disrupts fluid balance in the olfactory epithelium (OE) and causes postnatal loss of OSNs. Normally, transmembrane potassium flow through glial cells is tightly coupled to aquaporin function. In the absence of aquaporins, extracellular potassium increases causing edema and excitotoxicity. In addition, the loss of intracellular potassium causes activation of the apoptotic cascade and cell death. The neuropeptide PACAP is neuroprotective in the OE and cultured olfactory neurons. PACAP reduces both potassium efflux and pro-apoptotic caspases in primary olfactory cultures. We propose to examine whether PACAP can suppress the molecular cascade that causes the dysregulation of OE fluid balance which leads to loss of OSNs and aging- associated anosmia. We will test if PACAP knock-outs exhibit premature OE aging by looking for alterations in cell proliferation, cell type profiles and morphology, and aquaporin expression. A model for OE dehydration, the CF mouse will be examined for potential changes in PACAP and aquaporin expression in vivo. In vitro assays will examine whether PACAP is protective to OE explants grown under hypertonic conditions. Collectively, these studies will identify dehydration-induced changes in OE physiology which lead to age-related anosmia.

Robin Marcus, Ph.D.
Assistant Professor, College of Health, Division of Physical Therapy

Mechanisms of Improved Glucose Utilization in Elders With Type 2 Diabetes

Abstract

The incidence of T2DM is growing at an astronomical rate, and especially hard hit are the elderly in whom the combined prevalence of T2DM and impaired glucose tolerance is nearly 45%. The elderly also suffer from age-related loss of skeletal muscle mass, strength and function, collectively termed sarcopenia. Because lean skeletal muscle is quantitatively the most important tissue involved in maintaining glucose homeostasis under insulin-stimulated conditions, and is a major site of insulin resistance, loss of lean tissue is thought to play an important role in the development of T2DM, especially in the elderly. The focus of this project is on changes in lean muscle mass and its impact on glucose utilization in an insulin resistant elderly cohort. While our overall goal is to capitalize on resistance exercise (a type of exercise that is more easily tolerated than aerobic exercise) to improve glucose utilization in elders with T2DM, we hypothesize that the exercise itself, rather than the muscle size improvement is responsible for the increase in glucose utilization. Two specific aims are proposed: 1)To determine whether increased quadriceps muscle mass will improve LMGU as measured with positron emission tomography (PET), and 2) to determine whether changes in insulin signaling occur 24 hours and 1 week following the final resistance exercise bout of a 12-week RENEW protocol. We are proposing a repeated measures design with subjects serving as their own controls to minimize between subjects variability. We will simultaneously measure mass changes, glucose utilization, and insulin signaling in the quadriceps muscles of insulin resistant elders, something not previously done. Three sources [leg muscle glucose utilization by PET, insulin signaling by mRNA from biopsy samples, mass changes from magnetic resonance imaging (MRI)] from the tissue - the quadriceps - specifically targeted in the resistance exercise program are essential to identify the mechanisms of glucose uptake and will be employed. Outcomes will be measured serially at three times to allow us to answer the important question of whether the acute effects of exercise itself, rather than increased muscle mass is the important factor in improving glucose utilization in the elderly. The answer to this question has practical consequences in terms of the type of exercise that is prescribed for the elderly, where both sarcopenia and glucose intolerance are often important health issues.

Monica Vetter, Ph.D.
Professor, School of Medicine, Department of Neurobiology & Anatomy

Role of Microglia in Glaucoma Onset and Progression

Abstract

A significant health problem for our aging population is the prevalence of progressive degenerative diseases of the central nervous system. Glaucoma is a neurodegenerative disease of the retina that is the leading cause of blindness in the US, and is characterized by a progressive loss of vision due to the decline of retinal ganglion cells (RGCs). This is often due to elevated intraocular pressure (IOP), although many cases of normal tension glaucoma exist. The most consistent risk factor for developing glaucoma is aging - the risk of developing glaucoma increases 6-fold for people over 60 years old. Glaucoma shares many hallmark features with other age-related neurodegenerative diseases including progressive loss of neuronal viability, loss of axonal integrity and function, and involvement of non-neuronal populations including microglia. We have investigated retinal changes in a mouse model of glaucoma and have found significant activation of microglia that precedes other detectable changes in retinal glia or neurons. We hypothesize that microglia are directly involved in the recognition and progressive degradation of declining optic axons. We propose to: 1) determine the earliest age at which adult microglial activation, proliferation and phagocytosis start, 2) characterize the topographical distribution of microglia in relation to declining RGCs, 3) determine whether high-dose irradiation can deplete dysregulated, overactivated microglia from the retina and prevent RGC injury. This treatment has previously been shown to abrogate glaucoma-like pathology through unknown mechanisms. Together these experiments may shed light on the mechanisms underlying neurodegenerative diseases associated with aging.

Jason Watson, Ph.D.
Assistant Professor, College of Social and Behavioral Sciences, Department of Psychology

Localizing Impairment In Executive Function In Early Alzheimer's Disease With Neuroimaging

Abstract

Although memory loss is well-established in early Alzheimer's disease (AD), there is increasing evidence that executive function (EF) is also impaired. EF is defined as the ability to stay on task and to avoid distraction. EF is supported by a complex network of interconnected brain regions including a prominent role for prefrontal cortex in goal-directed, controlled cognition. Although change in EF may not be clinically evident, it can be documented with carefully designed and innovative experimental procedures. For example, functional magnetic resonance imaging (fMRI) could be used to localize the neural correlates of EF. However, few fMRI studies have addressed the integrity of the EF network in early AD with most of the research emphasis concentrated on the neuroimaging of memory. Hence, the primary goal of the current study is to use fMRI to determine the neural mechanisms underlying the breakdown in EF in early AD. To achieve this goal, twenty-five healthy older adults and 25 age-matched early AD patients will receive wholebrain fMRI, white matter diffusion tensor imaging (DTI), and neuropsychological testing. Compared to controls, early AD patients will have (1) reduced neural activity in prefrontal cortex as measured by fMRI due to increased presence of frontal plaques, (2) impaired white matter functional connectivity with prefrontal cortex as measured by DTI, and (3) poorer performance on neuropsychological tests of frontal-executive function. To summarize, the current study represents an application of fMRI to the identification and localization of subtle but clinically important deficits in executive function in early AD.

Maurine Hobbs, Ph.D.

Assistant Professor of Internal Medicine; Division of Infectious Diseases

Abstract

Reactive oxygen species (ROS) generated by the mitochondria have been implicated as a common feature linking age-related diseases and the aging of organisms. One of the enzymes involved in the scavenging of damaging ROS is mitochondrial manganese superoxide dismutase (MnSOD). MnSOD converts superoxide (O2.-) to hydrogen peroxide (H2O2), which is then converted to H2O and O2 by catalase. While increased levels of MnSOD have been associated with increased longevity in drosophila [1,2], a 50% reduction in activity in heterozygous MnSOD (+/-) mice produced no detectable reduction in lifespan [3]. MnSOD (-/-) mice however die within 8 days of birth with dilated cardiomyopathy due to increased superoxide damage to mitochondrial DNA (mtDNA) and enzymes [4]. In humans, the A16V common (49%) polymorphism in MnSOD disrupts the mitochondrial targeting signal (MTS). This polymorphism impairs the transport of the protein across the inner mitochondrial membrane, resulting in 80% lower activity in Val-MnSOD cells [5]. We hypothesize that this reduced activity leads not only to the accumulation of damaging ROS, but also impairs mtDNA replication, maintenance and repair, with accumulation of mtDNA deletions. The resulting accumulation of mtDNA deletions may impact longevity as well as the phenotypic expression of mitochondrial disease. We propose therefore to study the incidence of MnSOD polymorphisms in aged individuals from a well-defined healthy population (CEPH families) and from a population with a variably expressive mitochondrial disorder due to defects in a mitochondrial fusion protein. As part of our proposal we will develop assays to quantitatively measure mitochondrial DNA deletion. We will apply these assays to both healthy, aged individuals and to disease individuals that differ in severity, regardless of MnSOD genotype. The identification of a relationship between MnSOD genotype, mtDNA defects, and alterations in expression of longevity or disease has implications both for biologic mechanisms of aging and mitochondrial disease as well as for therapeutics.

Petr Trvdik, Ph.D. and Scott Rogers, Ph.D.

Research Associate; Department of Human Genetics and Professor; Department of Neurobiology and Anatomy

Abstract

Alzheimer's disease (AD) is the most common neurogenerative disease affecting the elderly, often associated with a marked decline in the cholinergic system in various brain regions. We will use the mouse model to investigate the protective role of the cholinergic system during brain aging. Our initial focus will be on the cholinergic nicotinic receptor alpha 7 (Chrna7), the role of which in AD is poorly understood. We will take advantage of two lines of mice, in which we have altered the endogenous Chrna7 gene: The control line, which co-expresses the green fluorescent protein (GFP); and a mutant line, which in addition to GFP also harbors two amino acid changes that genetically mimic the effect of nicotine by desensitization of the alpha7 receptor channel. Both lines will be crossed to the transgenic mouse model of AD and the development of plaques of amyloid-beta protein in disease-relevant regions will be measured. The outcome will elucidate the relevance of Chrna7 in the early onset and progress of the plaque formation. Next, we will generate targeting vectors allowing us to introduce the Cre recombinase in the Chrna7 and Chrna4 loci. This work will provide foundation for future research that will use the Cre/lox technology to identify cell lineages expressing these two receptors, addressing the question as to whether the decline in the cholinergic system is due to a decrease in gene expression or an increase in specific cell death. The proposed project has a high relevance for assessing the role of smoking in Alzheimer's disease.