UCLA Older Americans Independence Center
Career Development Awards (Year 16: 2006-2007)
Tara L. Gruenewald, PhD, MPH – firstname.lastname@example.org
Assistant Professor of Medicine/ Geriatrics, David Geffen School of Medicine at UCLA
Title of Research: Social Environment Effects on Functional Ability and Health Status in Older Adults
The quantity and quality of individuals’ social relationships have been shown to be important predictors of morbidity and mortality in a number of epidemiological and health investigations. However, interventions to enhance levels of social integration have thus far yielded disappointing results, suggesting that we have yet to identify critical elements of the social environment that affect health and functioning.
This research project is designed to investigate one hypothesized feature of the social environment that has not been a focus of much research attention to date – namely, the degree to which one’s social relationships generate feelings of being needed, valued, and useful to others and the relation of these feelings to health and well-being. Such feelings are thought to be a benefit of social relationships and an important human need, but these feelings have not been a primary focus of research on social relationships and health. The primary objective of this research is to examine the relationship between feeling useful/valued and trajectories of positive functioning and health status, measured as cognitive and physical functioning, disease morbidity, and mortality, in two large cohorts of middle-aged and older adults. A secondary objective is to identify the psychosocial, behavioral, and physiological pathways that may underlie relationships between feeling useful/valued and cognitive and physical functioning and health status. A third objective is to identify aspects of social environment, as well as behavioral, health status, and demographic predictors of feeling useful and valued. The ultimate objective of this research is to identify factors that promote feelings of usefulness and value within individuals’ social networks and to better understand the pathways through which these feelings promote positive functioning and better health outcomes with the goal of informing interventions to improve the lives of older adults.
Kathrin Maedler, PhD - email@example.com
Title of Research: Effect of aging on β-cell apoptosis: importance in the progression of diabetes
Type 2 diabetes is a heterogeneous disease, caused primarily by metabolic and genetic factors, in which the pancreatic β-cell can no longer adapt to the higher insulin demand to maintain normoglycemia in the face of insulin resistance. The disease is characterized by an impaired β-cell function as well as a decrease in β-cell mass, and occurs especially in older persons with a hereditary predisposition. Our preliminary data suggest that with increasing age, β-cells become more sensitive to the deleterious effects of environmental factors. The mechanisms of this effect are unknown and will be investigated in the current proposal.
The underlying mechanism of the decreased β-cell mass in type 2 diabetes is not well understood. However, β-cell apoptosis, which is a hallmark of the β-cell destruction that occurs in type 1 diabetes, has recently also been observed in type 2 diabetes. Chronically elevated glucose levels impair β-cell function and survival in human islets in vitro. For example, we have observed a dose dependent decrease in proliferation and an increase in apoptosis under these conditions. The underlying mechanism appears to be an activation of the apoptotic machinery induced by glucose via the Fas receptor pathway. Fas is up-regulated by glucose in the human β-cell, and its binding to the Fas ligand (FasL), which is constitutively expressed by human islets, leads to downstream cleavage of capsases. Furthermore, IL-1β, a pro-inflammatory cytokine, is produced and secreted by the β-cell itself after long term exposure to glucose, initiating a self destruction cycle.
To date, we have studied human islets from a large number of organ donors in vitro and have observed an increased sensitivity to glucose induced apoptosis with increasing donor age. The goal of the proposed studies will be to further investigate the basis of age related differences in the sensitivity of human β-cells to apoptotic stimuli induced by a diabetic milieu in vitro. We will first analyze changes in β-cell apoptosis, function and proliferation in vitro in isolated islets maintained at elevated glucose concentrations (5.5-33.3 mM) and free fatty acid concentrations (0.1-0.5 mM palmitate, oleate and a 2:1 mixture of both) with increasing age (17-80 years) of the pancreas donor. We will compare the results from these in vitro studies in isolated pancreatic islets (β-cell proliferation and apoptosis) with immunohistochemical and biochemical observations in islets in pancreatic sections obtained at autopsy from non-diabetic individuals of different ages (17 to 80 years).
To examine the underlying mechanisms of observed effects, we will isolate mRNA from human islets and then determine changes in the gene expression profiles in islets cultured at low and high glucose concentrations. In particular, we will examine the gene expression of factors that the islets secrete into the culture medium. We will focus on genes involved in 1) islet cell apoptosis and proliferation (Fas, FLIP, Bax, Bcl-2, Pax-4, c-Myc), 2) islet function and mitochondrial changes (insulin, pdx-1, UCP-2) and 3) proinflammatory cytokines secreted into the culture medium (IL-1β, IL-1Ra, IL-6). Using human pancreatic sections from autopsy, we will perform immunostaining of the described genes to confirm that similar age dependent changes occur in vivo. It is quite likely that both genetic background and age determine the susceptibility to glucose-induced β-cell apoptosis, since type 2 diabetes occurs more often in older persons with an inherited predisposition. An important question in this regard is the mechanism(s) by which increasing age is on the one hand associated with impaired β-cell insulin processing and secretion, and on the other hand is characterized by increased sensitization of β-cells to apoptotic stimuli. These issues will be addressed in the proposed studies.
Jennifer L. Martin, PhD – Jennifer.firstname.lastname@example.org
Title of Research: Changing caregiving practices to improve nursing home resident sleep: intervention development
Sleep disturbance is common in nursing home (NH) residents, results from treatable and modifiable factors, and is associated with cognitive impairment, poor health, reduced quality of life and increased mortality. Pharmacological treatment of sleep disturbance has significant risks in NH residents due to the potential adverse effects of sleep medications. Improving NH residents’ sleep with nonpharmacological strategies has been the focus of considerable research and shows some promise. Prior studies, however, are typically limited in that: 1) interventions target individual residents, ignoring sleep-disruptive environmental factors, and/or 2) environmental interventions are carried out by trained research personnel rather than NH staff thereby limiting generalizability to community NHs.
The goal of this qualitative research and pilot study is to develop interventional strategies that can be translated into routine caregiving practices within community NHs. To inform intervention development, qualitative data from focus groups with certified nurse’s aides (CNAs) and interviews with supervisory staff will be conducted in 4 community NHs to: 1) provide understanding of factors that would motivate nightshift staff to create a sleep-conducive environment, 2) assess the feasibility of changing sleep-disruptive caregiving behaviors and 3) identify barriers to implementing and maintaining such changes.
These qualitative data will be utilized to develop an intervention to improve sleep-related caregiving practices that can be translated into routine care practices. The intervention will be based upon a well-studied psychological model of behavior change, which suggests feedback from individuals targeted for behavior change should inform intervention design and implementation. The intervention will then be pilot tested in a community NH. This proposal will provide needed background information to develop a nursing staff intervention protocol and obtain funding to empirically test the intervention in community NHs.
Veena K. Ranganath, MD – email@example.com
Title of Research: Clinical Characteristics, Outcomes and Predisposing Genetic Factors for Older Onset Rheumatoid Arthritis
Rheumatoid arthritis (RA) is a destructive inflammatory arthritic disease that has an incidence of ~1% in the general population, with approximately one-third of these patients having onset of RA above the age of 65. Much controversy revolves around clearly delineating clinical characteristics and outcome measures in older onset RA patients, due in part to previous studies with small sample sizes and diagnostic uncertainty. It is also recognized that the incidence of RA increases dramatically with age, which is theorized to be due to genetic risk factors, the aging of the thymus leading to dysfunctional T-cells, and/or environmental factors. This study is comprised of two projects; one to evaluate disease characteristics and the other to examine genetic factors in elderly onset RA patients.
These projects should lead to an improved understanding of the older onset RA clinical entity and its predisposing factors. Ultimately this work should provide the basis for disease and outcome predictions and help to direct patient care to better serve our aging population.
Last Updated: November 21, 2006