AGING and WELLNESS

AGING: SLEEP AND INFLAMMATORY MECHANISMS IN DEPRESSION PREVENTION
PI: Michael R. Irwin
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, Univ. of South Carolina, Michael R. Irwin, 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.

SUBJECTIVE SOCIAL ISOLATION AND SLEEP DISTURBANCES: INFLAMMATORY MECHANISM IN AGING
PI: Michael R. Irwin, MD
NIA
Social isolation has significant health consequences in older adults, but it is not known how feelings of loneliness and loss of emotional connections lead to increases in disease risk. Given our evidence that social isolation is associated with sleep disturbance, and such sleep difficulties increase inflammation with consequences for a number of medical disorders including cardiovascular disorder, diabetes mellitus, and cancer, this study will examine the relationships between social isolation, sleep disturbance and inflammation in socially isolated older adults. This study will inform the development of potential treatments that target disordered sleep with possible prevention of disease outcomes in older adults who are socially isolated.

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.

RESILENCE & HEALTH WITHIN PERONS & ACROSS COMMUNITIES
PI: Michael R. Irwin, UCLA PI
NIA
The fundamental question asked in this investigation is whether measures of resilience capacity, identified from recent theoretical advances and empirical study, will predict physical and emotional functioning beyond that provided from well-established risk factors for disease and psychological ill-health for community residents from a wide range of backgrounds. A community sample of men and women aged 40 to 65 (total N = 800) will be drawn from 40 census neighborhoods that vary in average income, age, and ethnic composition. Using multi-level methods, participants and their neighborhoods will be evaluated on global indices of risk and resilience. Deeper probing of the underlying bio-behavioral mechanisms of risk and resilience will be conducted through laboratory testing and electronic diary assessments with a sub-sample (N = 200) drawn from the larger pool of participants. Current functioning and precursors of future health status of the mid-aged adults will be taken as outcomes. For those mid-aged adults with children, the outcome measures will also be assessed in one their children approaching adult life (aged 16 to 24 years; N = 160) to probe the transmission of resilience across generations.

MOTIVALA AGING: INSOMNIA TREAMENT AND ENERGY BALANCE
PI: Sarosh Motivala, PhD
NIA
Over 50% of adults older than 65 years report problems sleeping and the prevalence of persistent insomnia is estimated to be over 30% in this population, and steadily increases with age. Behavioral treatments for chronic insomnia have demonstrated consistent improvements in self-reported sleep, but outcome assessment, including polysomnography, behavioral factors such as health functioning and biologic factors impacted by sleep have not been comprehensively examined, especially in older adults. In particular, one promising area of research is the impact of interventions on energy balance. The hormones ghrelin and leptin are thought to convey information about energy balance to the brain, and dysregulation of these hormones lead to increases in appetite and lipid accumulation. Epidemiologic studies have found that poor sleep is associated with elevated ghrelin and decreased leptin, corroborated by experimental sleep restriction studies as well. Elevated ghrelin and decreased leptin levels also correlate with increased sympathetic activity; which is seen in insomnia patients. Taken together, these findings indicate that older insomnia patients may have altered energy balance. Yet few studies have measured objective sleep assessment following insomnia interventions and no study has reported its effects on energy balance. The proposed project is an ancillary study to a newly funded NIA randomized, controlled trial comparing the effects of cognitive-behavioral therapy (CBT), Tai Chi Chih (TCC), and hygiene/education control (EC) on sleep outcomes in older insomnia patients. This K23 project is an opportunity for the PI (a health-clinical psychologist) to utilize expertise in sleep and psychophysiology assessment and previous clinical training while developing expertise in behavioral insomnia treatment research and biological effects of treatment. The unique aims of this K23 project are to: 1) evaluate the effects of CBT vs. TCC vs. EC on ghrelin and leptin levels at baseline, mid- treatment, post-treatment and 3- and 12-month follow-ups; 2) determine the effects of CBT vs. TCC vs. EC on nocturnal autonomic function (power spectral analysis of heart rate variability) during sleep assessments at the UCLA GCRC at baseline and post-treatment; 3) examine whether energy balance and autonomic function are related to improvements in objective and subjective measures of sleep over the course of the treatment trial.

COMPLICATED GRIEF IN OLDER ADULTS: PHYSIOLOGICAL SUBSTRATES OF EMOTION REGULATION
PI: Mary-Frances O’Connor, PhD
NIA
Complicated Grief in Older Adults: Physiological Substrates of Emotion Regulation This application for a Career Development Award in Aging describes an integrated training plan and research project to allow the candidate to become an expert in the physiological underpinnings of emotion regulation in older adults. Conjugal bereavement is highly prevalent in older adults, with more than 900,000 people widowed each year in the U.S. Although most adjust gradually to widow(er)hood, others experience a complicated course. Complicated grief, which persists despite anti-depressant treatment, has been found to be an independent predictor of cognitive decline, poor health, depression and suicidality in older adults, making it a major public health concern. Cognitive factors, such as the inability to shift attention away from intrusive thoughts of the deceased are hypothesized to impair adjusting to a life as a widow(er). Furthermore, physiological mechanisms, such as low-grade inflammatory processes, may contribute to emotional dysregulation found in this population. The proposed research will assess neural activation, immune markers, and neuropsychological tests of attention and emotion regulation in older adults. We will recruit 135 older adults (45 with complicated grief, 45 with uncomplicated grief and 45 non-bereaved, determined by a structured interview with new consensus criteria). The specific aims are: Aim 1) To examine attentional deficits in older adults with complicated grief as measured by the e-Stroop as compared to controls (uncomplicated grief and non-bereaved); Aim 2) To examine the neural substrates of attentional deficits in a subsample of 36 older adults with fMRI in these three groups; Aim 3) To evaluate circulating markers of inflammation (e.g., sTNF-RII, IL-6, slL-6R and IL-1Ra) in older adults with complicated grief as compared to controls (uncomplicated grief and non-bereaved). The long-term goal of the project is to explore whether neural activity mediates the relationship between circulating markers of inflammation and attentional deficits. The Cousins Center for Psychoneuroimmunology at UCLA has both excellent resources (e.g. 3T imaging scanner) and excellent mentors (including Dr. Michael Irwin, MD) necessary for advanced training in bereavement, immunology, and neuroimaging research that will facilitate development of the candidate, Dr. Mary-Frances O'Connor, into an independent investigator and allow her to develop an R01 proposal to evaluate treatment for complicated grief, based on both physiological and psychological mechanisms. 

Relevant Publications

Complementary use of tai chi chih augments escitalopram treatment of geriatric depression: a randomized controlled trial. Lavretsky H, Alstein LL, Olmstead RE, Ercoli LM, Riparetti-Brown M, Cyr NS, Irwin MR. Am J Geriatr Psychiatry. 2011 Oct;19(10):839-50. doi: 10.1097/JGP.0b013e31820ee9ef. PMID: 21358389

Diurnal cortisol in Complicated and Non-Complicated Grief: Slope differences across the day. O'Connor MF, Wellisch DK, Stanton AL, Olmstead R, Irwin MR. Psychoneuroendocrinology. 2011 Sep 16. [Epub ahead of print] PMID: 21925795

An evaluation of a biopsychosocial framework for health-related quality of life and disability in rheumatoid arthritis. Nicassio PM, Kay MA, Custodio MK, Irwin MR, Olmstead R, Weisman MH. J Psychosom Res. 2011 Aug;71(2):79-85. Epub 2011 May 14. PMID: 21767687

When grief heats up: pro-inflammatory cytokines predict regional brain activation. O'Connor MF, Irwin MR, Wellisch DK. Neuroimage. 2009 Sep;47(3):891-6. Epub 2009 May 27. PMID: 19481155 Free PMC Article

Mitigating Cellular Inflammation in Older Adults: A Randomized Controlled Trial of Tai Chi Chih. Irwin MR, Olmstead R. Am J Geriatr Psychiatry. 2011 Sep 19. [Epub ahead of print] PMID: 21934474

Reciprocal regulation of the neural and innate immune systems. Irwin MR, Cole SW. Nat Rev Immunol. 2011 Aug 5;11(9):625-32. doi: 10.1038/nri3042. PMID: 21818124

Major depressive disorder and immunity to varicella-zoster virus in the elderly. Irwin MR, Levin MJ, Carrillo C, Olmstead R, Lucko A, Lang N, Caulfield MJ, Weinberg A, Chan IS, Clair J, Smith JG, Marchese RD, Williams HM, Beck DJ, McCook PT, Johnson G, Oxman MN. Brain Behav Immun. 2011 May;25(4):759-66. Epub 2011 Feb 15. PMID: 21329753

Prior depression history and deterioration of physical health in community-dwelling older adults--a prospective cohort study. Cho HJ, Lavretsky H, Olmstead R, Levin M, Oxman MN, Irwin MR. Am J Geriatr Psychiatry. 2010 May;18(5):442-51. PMID: 20220581 Free PMC Article

Improving depression and enhancing resilience in family dementia caregivers: a pilot randomized placebo-controlled trial of escitalopram. Lavretsky H, Siddarth P, Irwin MR. Am J Geriatr Psychiatry. 2010 Feb;18(2):154-62. PMID: 20104071 Free PMC Article