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Disclosures Sleep-Circadian Rhythms in Aging and Women: Current research funding (Northwestern University) A Bi-directional Relationship? NIH (NHLBI, NIA) DARPA Jazz Alzheimers Association Dixon Family Foundation

  1. Disclosures Sleep-Circadian Rhythms in Aging and Women: Current research funding (Northwestern University) A Bi-directional Relationship? • NIH (NHLBI, NIA) • DARPA • Jazz • Alzheimer’s Association • Dixon Family Foundation Scientific Advisory Board (consultant) • Merck • Philips Phyllis C. Zee, MD, PhD • Wellcome Trust • Jazz Benjamin and Virginia T. Boshes Professor in Neurology • Galderma (Nestle) Director Center for Circadian and Sleep Medicine Chief, Division of Sleep Medicine Other Northwestern University Feinberg School of Medicine Stock ownership: Teva ABIM Sleep Medicine Examination and Policy Committee As the world turns…there are prominent Fundamental Basic Science Discoveries Have Changed How We Fundamental Basic Science Discoveries Have Changed How We dynamic changes in our biology, from Think About the Role of Sleep and Circadian Rhythms in Health Think About the Role of Sleep and Circadian Rhythms in Health molecules to behavior…. Sleep and Circadian Rhythms WAKE-SLEEP • Sleep is of the brain for the brain and all tissues of the body! • Sleep is cellular, molecular in tissues and organs • Circadian clock genetic machinery exits in virtually all cells-tissues Circadian rhythms and sleep are integrated into metabolic, inflammatory, neural pathways…. AND their proper alignment with each other is essential for optimal health. 1

  2. Sleep and Circadian Rhythms Functions of Sleep and Circadian Rhythm Functions of Sleep and Circadian Rhythm Implications for Aging, Health and Disease “If sleep does not serve an absolutely vital function, then it is the biggest mistake the evolutionary process ever made.” A. Rechtschaffen Muscle CNS/PNS Insulin resistance – Psychomotor performance Neurological Disorders Cancer – Learning and memory Inflammation - Breast DIABETES – Mental/emotional health -Prostate Liver Clocks- Insulin resistance Sleep – Neurological health Pancreas Abnormal insulin Heart, Vessel, Endothelium – Cardio-metabolic health Cardiovascular GI tract disease Peptic ulcer Adipose Obesity Tract Nocturia, Incontinence Sleep Markedly Increases Convective Exchange of Glymphatic ymphatic Flow is ow is Modulat Modulated b d by Sleep Sleep CSF with Interstitial Fluid (Glymphatic System) Garbage Removal for Brain During Sleep  Brain water dynamics and organized flow  CSF-ISF exchange with perivascular convective flow Eiko Oj Ei Ojala, NY NYT (Xie L, et al, Science 342:373, 2013)  Sleep stage dependence of parenchymal impedance and extracellular volume Xie et al., Science, 2013 2

  3. Functions of Sleep/Circadian Functions of Sleep/Circadian Rhythm: Brain Health Rhythm: Brain Health Neurodegenerative Disease Neurodegenerative Disease Alzheimer’s Alzheimer’s Parkinson’s Parkinson’s Traumatic Brain Injury Traumatic Brain Injury Neurotoxins Neurotoxins Inflammation Inflammation Oxidative stress Metabolic Metabolic Oxidative stress Glymphatic flow Autonomic Autonomic Glymphatic flow Glia, astrocyte etc Glia, astrocyte etc Vascular, etc Vascular, etc References Sleep/circadian Disrupted Sleep Schlosser Covell et al. 2012 References Aziz et al. 2009 dysfunction Schlosser Covell et al. 2012 Morton et al. 2005, Pallier, et al. 2007 Aziz et al. 2009 Boone et al. 2012 Morton et al. 2005, Pallier, et al. 2007 Mathias, Alvaro 2012 Boone et al. 2012 Xie et al 2013 Science, Musiek and Holtzman, Science 2016 Mathias, Alvaro 2012; Xie et al 2013 Science, Musiek and Holtzman, Science 2016 Mechanism Linking Sleep and Health Impact of Sleep Duration on Hormonal and Metabolic Profiles 4 HOURS IN BED 8 HOURS IN BED 12 HOURS IN BED • In the laboratory setting, short-term sleep restriction leads to a 3h48' OF SLEEP 6h52' OF SLEEP 8h52' OF SLEEP variety of adverse physiologic sequelae, including 5.5 – Impaired glucose control LEPTIN (ng/ml) 3.5 – Increased cortisol 1.5 – Increased blood pressure 15 CORTISOL – Sympathetic activation 10 (µg/dL) 5 – Increased markers of inflammation 0 – Decreased leptin level 40 HOMA • These data suggest that chronic sleep restriction may have (INSULIN (mU/L) * 20 GLUCOSE(mmol/L) long-term health consequences / 22.5) 0 9 13 17 21 1 5 9 9 13 17 21 1 5 9 9 13 17 21 1 5 9 CLOCK TIME CLOCK TIME CLOCK TIME Zee PC, et al. Arch Intern Med . 2006;166:1686-1688 . Modified from Spiegel et al., J Clin Endocrinol Metab, 2004 3

  4. Sleep Restriction and Heart-Rate Variability RESPONSE TO INFLUENZA VACCINATION p<0.03 rRR 4 Hours in Bed 12 Hours in Bed Mean Antibody Titers (10 ) 6 1.50 •0.80 1.25 ns •0.75 1.00 •0.70 0.75 Sleep Deprived, n=11 Control, n=14 •0.65 0.50 ns 0.25 •0.60 •9 •1 •1 •2 •1 •5 •9 •9 •1 •1 •2 •1 •5 •9 0 3 7 1 3 7 1 •Clock Time •Clock Time 0 10 21 to 31 •High rRR = Decreased Heart Rate Variability = Increased Sympathetic Nervous Activity and/or Decreased Time relative to influenza vaccination Parasympathetic Nervous Activity (days) Spiegel et al, 2000 Spiegel K, et al. J Clin Endocrinol Metab. 2004;89:5762-5771. Spiegel K, et al. J Clin Endocrinol Metab. 2004;89:5762-5771. Demographics of Aging and Sleep Disturbance in America 60 Waking Not Rested 13 57 19 50 Waking Too Early 19 40 Daytime Napping 25 30 29 Insomnia 20 30 Nocturnal Waking 43 Initiating/Maintenance 10 12 0 10 20 30 40 50 0 Sleep disturbance No Sleep Complaints Percent 4

  5. Circadian Rhythms and Aging Circadian Rhythms and Aging Changes in Sleep with Age • Decreased amplitude – Advanced /delayed phase • Meta-analysis of 65 sleep studies in healthy persons – Internal desynchronization, – 3557 total subjects aged 5-102 years – Increase in variability • Most age-related sleep changes occur in early and mid- • Cellular/Molecular changes years of human life span – Expression of Clock genes • In healthy older adults: – Neurochemical changes in the SCN – Sleep remains relatively constant from age 60 to – Decreased ability of SCN to drive peripheral mid-90s oscillators • Except for sleep efficiency which decreases • Decreased light input • Wake after sleep onset increases – Age related losses in photoreception (cataracts) • Slow wave sleep decreases – Decreased exposure? Decreased response? Wang JL, Ann Neurol, 2015 Naylor E, Zee PC. Sleep Med Clin. 2006;1:187-196; Hofman MA et al (2006) Ageing Res Rev; 5:33-51; Gibson EM et al (2009) Exp Ohayon MM, et al. Sleep . 2004;27:1255-1273 Gerontol; 44:51-56; Hofman MA and Swaab DF (1994) Brain Res; 651: 134-142; Yamazaki et al (2002) PNAS; 99:10801-10806; Turner PL and Mainster MA (2008) Br J Ophthalmol; 92:1439-1444; Campbell et al (1988) Physiol Behav; 42: 141-144; Lim et al, Sleep 2012 Circadian and Sleep Disturbances Circadian and Sleep Disturbances Sleep-Wake Disturbance and Co- in Aging in Aging Morbidities X Melatonin Common Conditions SCN PG Altered Sleep Altered Sleep Altered Sleep Medical, Neurologic, RHT Psychosocial X X Activity Regulation & Regulation & Regulation & & Psychiatric Factors 2 Circadian Rhythms 1 Circadian Rhythms 1 Circadian Rhythms 1 Conditions 1 Information about the light/dark environment X Peripheral clocks Difficulty Initiating & Difficulty Initiating & Difficulty Initiating & Chronic Pain Late-Life Stressors Maintaining Sleep Maintaining Sleep Maintaining Sleep Nocturia Depression Sleep Loss Sleep Loss Pancreas Liver Adipose Heart GI tract Muscle WBCs Sleep Disorders Kidney Breast SDB (Sleep Apnea) GI, gastrointestinal; PG, pineal gland; RHT, retinohypothalamic tract; SCN, suprachiasmatic nucleus; Restless Legs WBC, white blood cell. Beckett M, Roden LC. S Afr J Sci . 2009;105(11-12):415-420; Dibner C, et al. Annu Rev Physiol . 2010;72:517-549; Barthlen GM. Geriatrics . 2002;57:34-39. Ancoli-Israel S, Cooke JR. J Am Geriatr Soc . 2005;53(suppl):S264- Young M, et al. Sleep Med . 2007;8(6):656-667. Wang JL, Ann Neurol, 2015 S271. Foley DJ et al. Sleep. 1995;18:425-432. 5

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