Sleep and Health

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.

SLEEP DISTURBANCE, INFLAMMATION, AND CELLULAR AGING IN BREAST CANCER SURVIVORS
PI: Michael R. Irwin, MD
NCI
Advances in cancer treatment have resulted in a growing number of cancer survivors in the United States. Despite the success of cancer treatments, survivors face long-term changes in health, with twice the likelihood of disability as those without a cancer history, greater risk for second primary cancers, more age-related comorbid disorders, and 28% reduction in life expectancy. This study hypothesizes that the increased risk of morbidity and mortality in cancer survivors is due to accelerated biological aging. Furthermore given that the risk for the late effects of cancer diagnosis and treatment show considerable variability, individual differences may either confer protection or promote vulnerability. Given our preliminary data that sleep disturbance leads to greater increases in inflammation and telomere erosion over a one year period, we further hypothesize that sleep disturbance and depression history serve as susceptibility factors to accelerate biological aging. To examine these questions, this study leverages an existing project (CA160245) of a Kaiser Permanente Southern California (KPSC) SEER-affiliated tumor registry-based sample of 300 (>55 years) breast cancer survivors, includes biological aging outcomes of cellular and transcriptional markers of inflammation and telomere erosion, and recruits a KPSC comparison cohort of 300 older women without a cancer history. Both KPSC groups will be examined at baseline and prospectively followed at 8, 16, 24, and 32 months to address three specific aims: 1) to examine differences at baseline and in prospective rate of change of cellular and transcriptional markers of inflammation and telomere length as a function of breast cancer survivorship; 2) to examine differences at baseline and in prospective rate of change of cellular and transcriptional markers of inflammation and telomere length as a function of sleep disturbance and breast cancer survivorship; 3) to examine differences at baseline and in prospective rate of change of cellular and transcriptional markers of inflammation and telomere length as a function of depression history and breast cancer survivorship This study will determine whether biological aging is driven by breast cancer status, by independent effects of sleep disturbance or depression history, or by the interaction of these behavioral factors with breast cancer status. Such information is necessary to define the risk population (i.e., breast cancer survivors, depression history) and/or risk factors (i.e., sleep disturbance) in the design, implementation, and delivery of treatments, which selectively target biological aging with greatest efficacy with the potential to reduce risk of age-related morbidities.

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.

SLEEP, INFLAMMATION, AND DEPRESSION OCCURRENCE IN BREAST CANCER SURVIVORS
PI: Michael R. Irwin
NCI
In 2006, there were over 11.4 million cancer survivors in the US. However for many individuals with cancer, improved survival is complicated by long-term behavioral effects including depression. Indeed, the prevalence of depression in breast cancer survivors is nearly three to five times greater than the general population. Yet, the unique clinical, behavioral, and biological factors that prospectively contribute to increased depression risk in breast cancer survivors is not known. In older adults, we have found that sleep disturbance independently contributes to depression occurrence, and this prospective risk is specific to those with a history of depression. Breast cancer status may add to that risk, as we have found that breast cancer survivors with insomnia have a prevalence of depression history that is nearly twice that in older women with insomnia; yet, other factors in the prior risk model do not generalize to breast cancer survivors. There are no published prospective data that have examined the independent contribution of sleep disturbance on depression occurrence in breast cancer survivors. Increasing evidence also implicates sleep disturbance in the activation of inflammatory signaling, which serves as a biological mechanism that contributes to depression. Hence, in this SEER-affiliated tumor registry-based study, we will evaluate 300 early stage-, older adult (>55 years) breast cancer survivors and 300 age-matched comparison women, stratified by a history of major depression. All participants will be community members of Kaiser Permanente Southern California (KPSC), a large nonprofit health plan that serves over 3 million members. In a prospective cohort study, older adult breast cancer survivors vs. comparisons, stratified by depression history will be evaluated at baseline (i.e., 1 year post- primary treatmen for breast cancer survivors) and at 6, 12, 18, and 24 months with the following aims: 1) to determine the prospective association between sleep disturbance and depression occurrence; 2) to evaluate the prospective association between sleep disturbance and cellular and genomic markers of inflammation; and 3) to examine the prospective relationships between sleep disturbance, cellular and genomic markers of inflammation, and depression occurrence. Understanding the cancer-specific clinical, behavioral, and biological factors that prospectively contribute to depression risk in breast cancer survivors vs. comparison older women will substantially alter clinical management by leading to the development of a targeted intervention for depression prevention, specific for breast cancer survivors.

MECHANISMS OF SLEEP DISRUPTION HYPERALGESIA
UCLA PI: Michael R. Irwin, MD
NIA
Twenty percent of Americans suffer from chronic pain, a poorly understood condition that is refractory to treatment, severely limits quality of life, and is a tremendous burden on the healthcare system and the economy. Sleep disturbance is an equally ubiquitous problem and among the most common and disabling comorbidities associated with chronic pain. Sleep disturbance is not simply a consequence of pain, it substantially increases the risk of transitioning from acute pain to a chronic disorder. Although it is not known how sleep disturbance increases risk, preliminary evidence suggests that even partial sleep deprivation may cause hyperalgesia, i.e., enhanced responsivity to painful stimulation. Hyperalgesia is critical to the etiology and maintenance of chronic pain syndromes, but the complex biobehavioral factors that promote hyperalgesia are poorly understood. The mechanisms by which sleep disturbance promotes hyperalgesia have yet to be studied. We propose a novel research program to study the mechanisms of sleep disruption hyperalgesia (SD_HA). Addressing this knowledge gap has critical implications for the etiology, prevention and treatment of chronic pain. Pre-clinical studies and preliminary data from our groups implicate two possibly interrelated candidate mechanisms of major clinical import: 1) inflammation and 2) opioidergic antinociceptive system impairment. We have assembled an interdisciplinary team from Johns Hopkins and UCLA to conduct a controlled experiment in healthy human subjects to determine the role of inflammation in SD_HA and study the effects of sleep disruption and inflammation on opioid analgesia. We will employ a novel sleep disruption manipulation developed by our group that uses multiple, forced awakenings to mimic the pattern of sleep loss most commonly associated with pain and insomnia. Following undisturbed sleep and sleep disruption conditions, we will assess next-day hyperalgesia and analgesic response to either: (a) morphine or (b) placebo. Our specific aims are to: 1) examine the effects of experimental sleep disruption on spinal sensitization (secondary hyperalgesia) by evaluating laboratory pain responses in the heat-capsaicin pain model; 2) examine the effects of sleep disruption on opioid analgesia and 3) determine the effects of sleep disruption on genomic, cellular, and systemic markers of inflammation and characterize the role of inflammation on laboratory pain responses and opioid analgesia. We hypothesize that SD_HA and diminished opioid analgesia will be mediated by enhanced inflammation attributable to the sleep disruption manipulation. Focusing on genomic and cellular dimensions of the inflammatory cascade, opioidergic function and their interaction will lead to a better understanding of chronic pain pathophysiology and could have tremendous impact on the development of novel pain treatment and prevention methods. Findings will also have broad implications for problems such as opioid addiction and chronic medical conditions, such as cardiovascular disease in which inflammation contributes to morbidity and sleep disturbance is common.

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.

PTSD, SLEEP, AND RISK FOR INCIDENT HYPERTENSION
PI: Matthew Burg, Phd / Steve Cole, PhD, UCLA Co-I
NHLBI
The purpose of this study is to test the prospective relationship of post-traumatic stress disorder (PTSD) to day and night time ambulatory blood pressure (ABP) and thus, risk for hypertension and incident cardiovascular disease (CVD). PTSD occurs consequent to trauma and is characterized in part by hyperarousal, emotional dysregulation, and poor sleep, with a 50% greater risk for CVD, independent of traditional risk factors. Large cohort studies report greater prevalence of hypertension, including our n=200,000 pilot analyses, which also show that PTSD treatment may attenuate this risk. Critical questions concern early detection of hypertension risk, and whether PTSD treatment reduces this risk. Ambulatory blood pressure (ABP) is a better predictor of CVD risk than is the clinic blood pressure of 140/90mmHg on which a diagnosis of hypertension is made. ABP monitoring combined with ecological momentary assessment (EMA) by electronic diary creates a powerful tool, and using this we have found that momentary ratings of anger and anxiety are highly correlated with momentary elevations in blood pressure (BP). When combined with night time actigraphy, another powerful tool is created whereby the effects of sleep on ABP can be determined. These tools together may be particularly useful for testing the prospective relationship of PTSD to ABP and thus CVD risk, since among the hallmarks of PTSD are heightened emotional reactivity to daily events, and disrupted sleep. Leveraging the resources of our recently funded Women Veterans Cohort Study-Wave 2 and our National Center for PTSD, we propose to study 300 recent military veterans with and without a PTSD diagnosis (N=150 each) on 2 occasions, 2-years apart. We hypothesize that, 1) those with vs. without PTSD at baseline will show a greater 2-year increase in day and night time ABP, and 2a) will have a greater ABP response to both momentary negative emotion and PTSD symptoms, and poorer actigraphy-assessed sleep; 2b) negative emotions/PTSD symptoms and poor sleep will in part mediate the prospective association of PTSD to day and night time ABP; 3) improvement in PTSD from baseline to follow-up (e.g., due to PTSD treatment or natural trajectory), will be associated with a decrease or smaller increase in ABP over the 2 years. Upon completion of baseline assessments we will evaluate the cross-sectional relationships of PTSD status and symptom severity to: 1) day and night time ABP, 2) the proportion of EMA reports with PTSD symptoms endorsed 3) mean levels of EMA-reported negative affect, and 4) poor sleep. We will also analyze the effect of poor sleep - short duration, efficiency - on, 1) momentary negative emotions and PTSD symptoms, and 2) the relationship of momentary negative emotions and PTSD symptoms to ABP. Significance. The proposed study will point the way toward risk mitigation clinical trials, whether they test the targeted use of ABPM according to threshold PTSD symptoms, aggressive PTSD treatment, and/or early intervention with pharmaceutical, behavioral, or combined strategies for treating elevated day or night time ABP among individuals with PTSD.