2014-15 Pilot Grant Recipients
Kara B. Dassel, PhD
Director, Gerontology Interdisciplinary Program
College of Nursing
The Influence of Disease Type on End-of-Life Care Preferences
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
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
Exercise and Sport Sciences
Links among autophagy, mitophagy, and nitric oxide bioavailability in aging
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
Sequencing analysis of high risk pedigrees to identify bone density predisposition
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
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
Informative linkage analysis of extended longevity pedigrees in Utah
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
Ophthalmology and Visual Sciences
Elucidating functional mechanisms in the normal aging retina and AMD
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
College of Nursing
Utilizing space-time paths to study triage patterns of older adult trauma care
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
Division of General Medicine
Department of Internal Medicine
Platelets: Unexamined Contributors to Immunosenescence
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
College of Social and Behavioral Science
Filial Piety and Health of Older Adults in China: A Mixed-Method Study
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
Respiratory muscle work and oxidative stress in the elderly: impact on blood flow and fatigue.
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
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.
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)
Phenotype of ischemic stroke and stroke outcomes in high risk pedigrees
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
Department of Surgery
Microarray analysis of age related changes in sperm DNA methylation.
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
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
Designing effective digital technology to improve seniors' cognitive functioning.
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
College of Nursing
Aging and Dying in Prison: Toward an Effective and Sustainable Model of Prison Hospice
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
Providers' Information Needs in the Care of Older Adults
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
Sensory Integration and Motor Planning Exercise in Parkinson Disease
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
Department of Internal Medicine, Division of Geriatrics
Aging and Telomere Structure and Function in the Human Vasculature
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
Cognitive Training in Impaired Samples
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
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
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
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
Development and Enhancement of a Medical Home Model for Low-Income Older Adults
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
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
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
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
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
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,
Role of Sirtuins in the Aging Gut
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
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
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
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
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
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
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
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
We previously hypothesized that a common polymorphism (A16V) in MnSOD - shown to impair mitochondrial import  - 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
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
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
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
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
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 . MnSOD (-/-) mice however die within 8 days of birth with dilated cardiomyopathy due to increased superoxide damage to mitochondrial DNA (mtDNA) and enzymes . 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 . 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
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.