Aging and Wellness

EXPERIMENTAL MODEL OF DEPRESSION IN AGING: INSOMNIA, INFLAMMATION, AND AFFECT MECHANISMS
PI: Michael R. Irwin, MD
NIA
Depression, one of the most common diseases in older adults, carries significant risk for morbidity and mortality. Because of the burgeoning population of older adults, the enormous burden of late-life depression, and the limited efficacy of current antidepressants in older adults, biologically plausible models that translate into depression prevention efforts are needed. Insomnia predicts depression recurrence, and is a modifiable target for depression prevention. Yet, it is not known how insomnia gets converted into biological- and affective risk for depression, which is critical for identification of molecular targets for pharmacologic interventions, and for refinement of insomnia treatments that target affective responding to improve efficacy. This study will use an inflammatory challenge (i.e., endotoxin) to probe acute inflammatory- and depression responses (primary outcome) in older adults as a function of insomnia. Older adults with insomnia show chronic inflammation; sleep disturbance also activates inflammatory signaling; chronic inflammation primes acute inflammatory responses; chronic inflammation, as well as acute inflammatory reactivity, predict depression over the following year; and finally, endotoxin induces acute inflammation along with depressive symptoms, with preliminary evidence that “two-hits” (i.e., sleep disturbance and inflammatory challenge) are associated with exaggerated increases in depression, especially in women. In this placebo-controlled, randomized, double-blind study of low dose endotoxin in older adults (60-80 y; stratified by sex) with insomnia (n=80) vs. comparisons without insomnia (n=80), we hypothesize that older adults with insomnia will show heightened inflammatory- and affective responding to inflammatory challenge as compared to those without insomnia. We aim to: 1) examine differences in depressive symptoms and measures of negative affect responding as a function of insomnia and inflammatory challenge; 2) examine differences in measures of positive affect responding as a function of insomnia and inflammatory challenge; and 3) examine differences in experimentally-induced inflammation in relation to depressive symptoms and measures of negative- and positive affect responding as a function of insomnia. If the hypotheses are confirmed, older adults with two “hits”, insomnia and inflammation, would represent a high risk group to be prioritized for monitoring and for depression prevention efforts using treatments that target insomnia or inflammation. Moreover, this study will inform the development of mechanism-based treatments that target affect responses in addition to sleep behaviors, and which might also be coupled with efforts to reduce inflammation to optimize efficacy of depression prevention.

AGING: SLEEP AND INFLAMMATORY MECHANISMS IN DEPRESSION PREVENTION
PI: Michael R. Irwin, MD
NIA
Depression in the elderly is a major public health concern. Indeed, as the population ages in high-income countries, depression is projected to increase by 2030 to a position of the greatest contributor to illness burden. Moreover, because elderly persons with depression often do not receive diagnosis and treatment, and only about one-third of depressed older adults achieve remission using current treatment approaches, over two-thirds of the disease burden remains intact leading to staggering costs in the health care sector. The objective of this study is to evaluate the ability of a behavioral intervention, cognitive behavioral therapy for sleep quality (CBT-SQ) to reduce sleep complaints, depression recurrence, and cellular and genomic markers of inflammation in older adults with sleep complaints who have a prior history of depression. We aim to: 1) evaluate the effects of CBT-SQ vs. Sleep Seminar (SS) on objective (actigraphy) and subjective (sleep diary; questionnaire) measures of sleep symptoms over a two-year follow-up; 2) determine the effects of CBT-SQ vs. SS on recurrence of depressive symptoms and depression episode(s) over a two-year follow-up. We will also secondarily examine the effects of CBT-SQ vs. SS on cellular and genomic markers of inflammation over a two-year follow-up, and explore whether markers of inflammation and cytokine genes can explain variability in the risk of depression recurrence in those older adults receiving CBT-SQ vs. SS. The present study is highly significant by being the first study, to our knowledge, to focus on the prevention of depression in community dwelling older adults who have a history of depression, and by targeting sleep disturbance, a modifiable risk factor to prevent depression recurrence.

CHRONIC MODERATE SLEEP RESTRICTION IN OLDER LONG SLEEPERS AND OLDER AVERAGE SLEEPERS 
PI: Youngsteadt, PhD Univ. of South Carolina, Michael R. Irwin, MD UCLA PI
NIH
People who sleep little (less than 7 hours) and people who sleep a lot (8 hours or more) tend to die sooner and have other health problems compared with people who sleep 7-8 hours. There are many studies that show that experimental sleep deprivation has a lot of negative effects. However, these studies have mostly been short (5 days or less) and have involved extreme levels of sleep deprivation. There is little information about what happens following more prolonged (weeks) and modest reduction in sleep (1 hour), which is much more common. Long sleepers could even benefit from modest restriction of sleep. It is especially important to examine whether long-term modest sleep restriction has benefits or negative effects in older adults. A modest amount of sleep restriction might reduce the number of interruption of sleep and help older adults sleep better. This experiment will examine 100 older long sleepers and 100 older average-duration sleepers over 5 years in 4 difference sites: Columbia, SC, Brooklyn, NY, Tucson, AZ, and Los Angeles. Subjects will spend 1 hour less in bed for 12 weeks and we will examine many potential negative and positive effects, including depression, sleepiness, and blood sugar levels.

LATE LIFE SLEEP DISTURBANCES: EFFECTS ON CELL STRESS, TELOMERASE, INFLAMMATION
PI: Judith E. Carroll, PhD
NIA
Insufficient sleep in later life is thought to contribute to declines in physical and mental functioning, and increase risk for morbidity and mortality. A yet unanswered question is: how does poor sleep contributes to worse health, particularly in aging. Both inflammation and cellular stress, which contribute to aging of cells, are proposed biological pathways through which sleep loss influences disease. I propose that sleep deprivation in older adults will alter the intracellular environment, decrease telomerase, and increase gene expression patterns consistent with cellular stress responses, inflammatory activity, and senescent signal expression. The over-arching objective of this proposal is to apply a biobehavioral framework to study the sleep-health relationship in older adults. Aims. To do this I will: 1) obtain training in sleep, aging, and gene expression, 2) test biobehavioral mechanisms of sleep loss on health by conducting analyses using the Multi-Ethnic Study of Atherosclerosis (MESA), examining the contribution of sleep disturbances, sleep quantity, and sleep depth to rates of telomere attrition over 10 years, and 3) experimentally test the inflammatory, cellular stress, and cell senescence gene expression pathways that are disrupted from one night (Study 2) and 12 weeks (Study 3) of partial sleep deprivation in older adults (ages 60+). Significance. This unique interdisciplinary work will advance the field of biomedical sleep research by better defining one of the biological mechanisms through which sleep influences disease vulnerability in late life.

A RANDOMIZED TRIAL FOR SLEEP DISTURBANCES TO REVERSE CELLULAR AGING
PI: Judith E. Carroll, PhD
NIA
Research is needed to bridge the continuum from behavioral factors to molecular stress, define the role of cellular aging in age related rises in inflammation, and identify interventional strategies that may alter the course of aging and ultimately improve the number of healthy years of living. The current proposal seeks to address this need by targeting sleep, a modifiable behavior that has been linked to aging and age related disease. Sleep disturbances elevate risk for chronic disease, possibly by accelerating aging and age related rises in inflammation. No research to date has demonstrated a role of sleep disturbances in these pathways nor tested whether remission of sleep disturbances using highly efficacious behavioral strategies reverses the cellular aging processes. This project will leverage an ongoing randomized clinical trial (RCT; R01 AG026364; Irwin) that is testing whether treatment of sleep disturbance using cognitive behavioral therapy for sleep quality (CBT-SQ) vs. sleep seminar (SS), controls, improves sleep and reduces the risk for depression in non-depressed older adults with sleep complaints (Pittsburgh Sleep Quality Index, PSQI >5; n=305) over a 3-year follow-up with assessments at baseline, 12 months, 18 months, 24 months, 36 months. In this project, we will aim to: 1) evaluate the effects of CBT-SQ vs. SS on markers of cellular aging over 3-years. Hypothesis 1: Relative to SS, CBT-SQ for sleep disturbances will improve mitochondrial function, increase telomerase activity, lengthen PBMC telomeres, and reduce expression of key aging related genes over 3-years. 2) Evaluate the effects of sleep disturbance remission (PSQI <5) at 6 months vs. unremitted sleep disturbance on markers of cellular aging over 3 years follow-up. Hypothesis 2: Relative to remitters, those with unremitting sleep disturbances (PSQI Global >5) at 6 months will show poorer mitochondrial function, lower telomerase, shorter PBMC telomeres, and greater expression of key aging related genes over 3-years. Exploratory Aim: To address critical gaps in current knowledge, we will apply discovery science approaches using advanced bioinformatics methods to interpret whole genome gene expression arrays and age related epigenetic methylation patterns to DNA to provide novel understanding in the role of sleep disturbances to cellular biology. In addition, we will use existing inflammatory data collected from the parent R01 to examine a possible bi- directional relationship between cellular aging and inflammation (i.e., inflammaging). Impact Statement: The proposed project addresses a very significant issue in the field of biobehavioral sleep research as it will be the first study to examine whether treatment of sleep disturbances reverses processes of cellular aging, using numerous innovative molecular biomarkers of this process over 3 years, and leveraging a well powered and demonstrated RCT to treat sleep disturbances. This work has the potential to implicate late life sleep disturbances in the progression of biological aging, and to demonstrate that interventions to treat sleep disturbances in older adults may slow or even reversing cellular aging.

SLEEP LOSS AS A VULNERABILITY FACTOR FOR INFLAMMATION INDUCED DEPRESSIVE SYMPTOMS IN OLDER WOMEN
PI: Hyong Jin Cho, MD, PhD
NIA
Late-life depression is a major public health burden due to its high prevalence and associated morbidity, suicide risk, functional decline, and mortality. Unfortunately, current antidepressant therapies have limited effectiveness; hence, biologically plausible models for new treatments are being pursued. Systemic inflammation is hypothesized to play an important role on the onset and perpetuation of depression, especially in older women. Aging processes involve a heightened inflammatory state, and both inflammatory disorders and depression are more prevalent in women than men. However, increased systemic inflammation does not necessarily lead to depression in all women. Even when robust systemic inflammation is experimentally induced (e.g. endotoxin administration), largely variable increases in depressive symptoms are found. Defining the factors that account for this variability may identify individuals at risk of developing depression when exposed to heightened inflammatory states such as aging, obesity, and chronic disease, and informs future translational studies of depression prevention. In particular, the role of sleep disturbance in explaining this variability requires further attention because it is an independent risk factor for depression and heightens systemic inflammation by increasing the production of proinflammatory cytokines. We have also discovered that women, but not men, who report sleep disturbance including short sleep duration experience significantly more depressive symptoms in response to an inflammatory challenge than women without sleep disturbance. Thus, it is hypothesized that sleep loss is a vulnerability factor for inflammation-induced depressive symptoms in women. However, to date, no experimental approach has been used to evaluate the role of sleep loss on inflammation-induced depressive symptoms. This proposal aims to examine this hypothesis by partial sleep deprivation (PSD) followed by endotoxin challenge in older women. It also aims to explore genomic and socio- emotional mechanisms underlying the association between sleep loss and depressive symptoms. In a randomized controlled factorial design, 80 healthy female volunteers aged 60 to 69 will be randomly assigned to one of 4 arms: 1) uninterrupted sleep followed by placebo; 2) uninterrupted sleep followed by endotoxin; 3) PSD followed by placebo; or 4) PSD followed by endotoxin. Subjects will be administered placebo or endotoxin in the morning after PSD or uninterrupted sleep. Depressive symptoms will be repeatedly assessed over 6 hours after placebo or endotoxin administration. This K23 integrated training and research program is designed to prepare the candidate to become an independent translational investigator in aging research with expertise in epidemiology and psychoneuroimmunology, focused on the identification of multi-level risk factors for and the prevention of late-life depression. For the achievement of this career goal and the completion of the proposed study, the candidate will obtain training in inflammatory biology of depression, aging research, experimental study design, sleep research, and gene expression analysis.

FEELING NEEDED: EFFECTS OF GENERATIVITY ON HEALTH IN LONELY OLDER ADULTS
PI: Naomi Eisenberger, PhD
NIA
The proportion of the world's population over age 60 is increasing at an unprecedented rate. Given this trend, it is imperative to study the mental and physical health of older adults. Psychosocial factors, such as loneliness, are critical in understanding the overall health of older adults, given that increased feelings of loneliness have been linked to functional decline and increased risk of mortality in older adults. Loneliness in older adults may be partially driven by disruptions in meaningful social engagement. In fact, generativity defined as concern and activity dedicated to the well-being of others, especially younger generations and its related components, such as feeling socially useful or needed, are often included in models of successful aging. Furthermore, greater perceptions of generativity have been linked to better health outcomes and longevity in older adults. Thus, lonely older adults may especially benefit from a targeted psychological intervention aimed at increasing perceptions of generativity, which may improve feelings of social connection through increased feelings of social usefulness, as well as improve health outcomes. The objective of this NIA R03 application is to investigate the relationships between social psychological processes and pro-inflammatory responses in the context of health and aging. To do so, the proposed study will investigate the effect of an intervention aimed at increasing perceptions of generativity in lonely older adults on physical and mental health outcomes. Given that pro-inflammatory activity has been linked to both loneliness and poor health outcomes, the study will also examine the effect of the intervention on biological markers of inflammation (i.e., circulating and stimulated pro-inflammatory cytokines and pro-inflammatory gene expression). Participants (n=70) will be randomly assigned to a 6-week intervention aimed at increasing perceptions of generativity or a control condition. During pre- and post-intervention sessions, all participants will complete self-report measures of physical and mental health and have blood drawn (in order to assess biological markers of inflammation). It is hypothesized that participants in the generativity intervention, compared to those in the control condition, will show: 1) improved physical and mental health outcomes and 2) decreased pro-inflammatory activity from pre- to post-intervention. Furthermore, it is hypothesized that decreases in biological pro-inflammatory activity will mediate improvements in health outcomes. The present study will help advance the understanding of the impact of generativity on the lives of older adults, including its effects on health and inflammatory activity. This may inform a low-cost and low-effort way to improve health outcomes in older adults, especially those who may be most vulnerable to poor health outcomes, such as those who are lonely.

INFLAMMATORY BIOLOGY CORE (IBC)
PI: David Reuben, MD; Michael R. Irwin, MD, Co-I
NIA
The OAIC Inflammatory Biology Core (IBC) plays an integral role in the UCLA OAIC's renewal theme Inflammation, Aging, and Independence. The IBC supports the mission of the OAIC in understanding the interactions of non-modifiable and modifiable predisposing factors on inflammation and processes of biological aging, which impact incident diseases of aging and progression of age-associated morbidity. The IBC aims to: (1) provide intellectual support for the analysis of inflammatory biology in OAIC research domains (including basic, clinical, interventional, and/or biobehavioral studies); (2) provide laboratory infrastructure for comprehensive and vertically integrated assessment of inflammatory biology dynamics at the genomic, inflammatory signaling, cellular, and systemic levels; and (3) develop and utilize cross-cutting approaches to analyses of inflammatory biology and the effect of inflammation on cellular processes in aging and age-related disease. The IBC leadership merges expertise in proteomic markers of inflammation, cellular and molecular mechanisms of inflammation, and genomic analyses of inflammatory profiles to provide an interdisciplinary breadth within a single laboratory “home”, which provides a comprehensive assessment of inflammation from genes to cells to proteins. Moreover, by including different assay methods within a single laboratory and its infrastructure, sophisticated scientific, conceptual, and technical expertise can be delivered efficiently to assure implementation of quality monitored, standard operating procedures that are maintained across studies and over time. The IBC is also positioned to synergize with the laboratory resources available across the UCLA campus. In collaboration with the UCLA OAIC Research Education Component (REC), the Pilot and Exploratory Studies Core (PESC), and the Data Acquisition and Analysis Core (DAAC), the IBC will continue to integrate assessments of inflammatory biology mechanisms into Research Project Support and Pilot Projects, foster career development in aging-related research for early career investigators, and facilitate training of investigators new to aging and inflammatory biology research. The IBC will also continue to collaborate with externally-funded projects (EPs), which include 3 NIH Career Development (K) awards to junior investigators in aging research. The EPs are relevant to the overall goals of the UCLA OAIC, addressing changes in inflammatory biomarkers with aging, and developing/testing interventions to reduce inflammatory burden and determine the effects on health and functional outcomes. These EPs have the potential to alter clinical practice guidelines within primary care and/or collaborative care models, and enhance the maintenance of independence in older adults by targeting modifiable risk factors and inflammation.

UCLA OLDER AMERICANS INDEPENDENCE CENTER (Pepper Center)
PI: David Reuben, MD; Michael R. Irwin, MD, Co-I
NIA
The UCLA Claude Pepper Older Americans Independence Center (OAIC) is designed to promote research aimed at maintaining and restoring the independence of older persons. Through its theme of Translational Research to Maintain Independence, the UCLA OAlC's research extends across the full spectrum from T1 to T2 translational research. Within this theme, an important focus of the UCLA OAIC is on developing and understanding interventions that reduce inflammation. To accomplish its goals, the UCLA OAIC has established 4 Research Cores (Recruitment and Retention, Research Operations, Analysis and Cost Effectiveness, and Inflammatory Biology) and a new Information Dissemination Core that will facilitate OAlC-related research at every step (recruitment, measurement, data management, analysis, interpretation, and adoption of findings). Research cores provide support at 4 levels: Consultation (e.g., providing up to several hours of advice, reading a paper or a proposal) Short-term (e.g., up to a couple days of consultation, performing assays) Ongoing or long-term support (e.g., ongoing, part of the project team) Partnership on new proposals In addition, the UCLA OAIC Pilot and Exploratory Studies Core and Research Career Development Core stimulate new research via a pipeline of junior investigators and pilot awards and recruit successful investigators into OAlC-related research. A specific goal of the Center is to create teams of translational researchers and to train junior faculty in the principles of conducting research that bridges basic, clinical, and health services/dissemination research. The Leadership/Administrative Core ensures that these specific activities are accomplished and the goals of the UCLA OAIC are optimally achieved. By focusing efforts and resources through the OAIC, the timeline for research to develop, test, and disseminate promising innovations to maintain independence can be accelerated. At the end ofthe 5-year cycle, the UCLA OAIC will be a model program for translational research extending from basic science to clinical practice and policy and will have created a generation of new researchers who can begin to assume leadership in this theme.