Sleep and Energy Homeostasis Phyllis C Zee MD

Sleep and Energy Homeostasis Phyllis C. Zee, MD, Ph. D Northwestern University Feinberg School of Medicine Idiopathic Fatigue of Aging

Physiologic Determinants of Sleep and Wake Sleep Homeostasis Wake Propensity Wake Sleep Circadian Drive for Wakefulness 9 a. m. 3 p. m. Awake 9 p. m. 3 a. m. 9 a. m. Asleep Kryger MH et al. (2000), Principles and Practices of Sleep Medicine, 3 rd ed. Philadelphia: W. B. Saunders

Circadian Sleep-Wake Cycle 24 24 REM sleep Stage 1 -2 sleep 6 6 18 Stage 3 -4 sleep Wakefulness Courtesy of R. Ristanovic, MD. 12 Sleep stage MT REM Sleep W REM 1 2 3/4 18. 00 20. 00 22. 00 24. 00 02. 00 04. 00 06. 00 Time of day Adapted from Rogers et al. Sleep. 1994; 17: 590. 08. 00 10. 00 12. 00 14. 00 16. 00

What Can We Expect with Aging? • • • Sleep Decreased total sleep time Decreased sleep efficiency Decreased slow wave sleep Increase in wake after sleep onset Increase in daytime sleepiness Circadian Rhythms • Decrease in amplitude • Increase in variability • Advance in the phase of circadian rhythms Ohayon et al. , Sleep, 2004 Naylor and Zee, Sleep Med Clin, 2006

Prevalence of chronic sleep complaints among elderly men and women 60 57 57 Men 50 Percent Women 40 31 30 28 27 22 20 21 22 16 15 12 13 10 0 Trouble falling asleep Awakes during night Awakes too early Source: Foley, Monjan, Brown et al. SLEEP 18: 425 -432, 1995 Naps during day Awakes not rested Any chronic complaint

SLEEP CIRCADIAN RHYTHMS FUEL METABOLISM FROM THE BEGINNING Interacting Networks Regulating Feeding, Sleep and Physical Activity

Sleep: Energy Conservation Relative glucose metabolism Wake—NREM Sleep T value Nofzinger EA, et al. Psychiatry Res Neuroimag. 1999; 91: 59– 78; Brain. 2002; 125: 1094– 1104.

Obesity and Metabolic Syndrome in Circadian Clock Mutant Mice Activity and Energy Balance Turek et al. , Science 308, 13 May 2005

Sleep Loss: Implications for Metabolic Health • In the laboratory setting, short-term sleep restriction leads to a variety of adverse physiologic sequelae, including – – – Impaired glucose control Decreased leptin Increased ghrelin Alterations in HPA (increase cortisol) Sympathetic activation Increased markers of inflammation • These data suggest that chronic sleep restriction may have longterm health consequences Zee and Turek, Arch Intern Med, 2006

Heart Rate Variability: Six-Day Sleep Restriction 4 Hours in Bed r. RR 12 Hours in Bed 0. 80 0. 75 0. 70 0. 65 0. 60 9 13 17 21 Clock Time 1 5 9 9 13 17 21 1 Clock Time High r. RR = Decreased Heart Rate Variability = Increased Sympathetic Nervous Activity and/or Decreased Parasympathetic Nervous Activity Spiegel K, et al. J Clin Endocrinol Metab 2004; 89: 5762 -5771. 5 9

Impact of Sleep Duration on Hormonal and Metabolic Profiles 4 Hours in Bed 3 h 48' of Sleep 8 Hours in Bed 6 h 52' of Sleep 12 Hours in Bed 8 h 52' of Sleep 15 CORTISOL (µg/d. L) 10 5 0 40 HOMA (INSULIN (m. U/L) * 20 GLUCOSE(mmol/L) / 22. 5) 0 9 13 17 21 1 Clock Time 5 9 9 13 17 21 1 5 9 9 Clock Time HOMA = homeostasis model assessment Spiegel K, et al. J Clin Endocrinol Metab 2004; 89: 5762 -5771. 13 17 21 1 Clock Time 5 9

Effects of Ghrelin in the CNS Effects of Ghrelinin the CNS • Acts through a series of centrally-controlled changes in energy metabolism – Increase food intake – Decrease basal metabolic rate – Decrease physical activity Ghrelin circuits in the CNS are intimately intertwined with circadian and sleep regulation circuits

Sleep duration and body mass index Wisconsin Sleep Cohort Study Taheri et al, 2004 PLo. S

Sleep Quality and Energy Homeostasis Slow-wave sleep is thought to be the most "restorative" sleep stage GH release is stimulated Prolactin release is stimulated ACTH-cortisol release is inhibited Sympathetic nervous activity is decreased Vagal tone is increased Heart rate is lower Blood pressure is lower Cerebral glucose utilization is decreased

Slow Wave Sleep 25 Recording Time (%) 20 15 10 5 0 16 -25 26 -35 36 -50 Van Cauter E, et al. JAMA. 2000; 284: 861 -868. 51 -60 61 -70 71 -83

Experimental Suppression of Slow Wave Sleep Is Associated With Increased Hunger and Decreased Vigor and Mood Total sleep time (min) Slow wave sleep (min) 100 480 80 460 60 440 40 420 * * 20 400 380 0 Baseline S 1 S 2 Baseline Broussard J , Van Cauter E , Tasali E, APSS June 2008 S 1 S 2

GLUCOSE METABOLISM Glucose tolerance (Kg; %. min-1) 2 10 * p = 0. 03 Tasali E et al, PNAS, 2007 Insulin sensitivity (m. U/l-1. min-1) 8 * 6 1 p = 0. 01 4 2 0 Baseline After 3 nights of SWS suppression 0 Acute insulin response to glucose (m. U/l-1. min) 400 ns 300 1400 100 After 3 nights of SWS suppression 2800 200 Baseline 700 0 Baseline After 3 nights of SWS suppression Disposition Index * 2100 0 Baseline p = 0. 02 After 3 nights of SWS suppression

RATINGS OF GLOBAL VIGOR AND HUNGER 9. 0 GLOBAL VIGOR 7. 0 5. 0 AFTER 2 NIGHTS OF BASELINE SLEEP 3. 0 7. 0 AFTER 2 NIGHTS OF SWS SUPPRESSION 6. 0 HUNGER 5. 0 4. 0 3. 0 2. 0 16: 00 GLOBAL VIGOR HUNGER 18: 00 20: 00 CLOCK TIME 22: 00 p level < 0. 0001 0. 03 % change - 22 +19 Broussard, Van Cauter and Tasali; SLEEP 2008

Results: Food categories AFTER BASELINE SLEEP 6. 0 5. 0 AFTER SWS SUPPRESSION Carbohydrate 4. 0 rich food 3. 0 2. 0 16: 00 18: 00 20: 00 22: 00 CLOCK TIME Carbohydrate-rich food p level 0. 08 % change +18%

Consequences of Sleep-Wake Disturbances: Chronic Sleep Loss and Metabolism Acute sleep loss glucose levels insulin levels Chronic sleep loss Appetite dysregulation and risk of weight gain Insulin resistance Decreased glucose tolerance Increased risk of type 2 diabetes Spiegel K, et al. J Appl Physiology 2005; 99: 2008 -2019. © 2005 American Physiological Society. Normal glucose levels insulin levels

Aging, Sleep and Sleepiness Older Adults: A Population at High Risk for Sleep Loss and Sleep Disorders

Etiologies of Sleep-Wake Disturbances: Disorders of Sleep and Wakefulness Common sleep disorders causing disrupted nocturnal sleep – Obstructive Sleep Apnea Syndrome (OSAS) - 6% to 20% prevalence in adults – Restless Leg Syndrome (RLS) - 10% prevalence in United States – Insomnia - 10 -25% prevalence in adults Young T, et al. Am J Respir Crit Care 2002; 165: 1217 -1239. Hornyak M, et al. J Clin Psychiatry 2005; 66: 1139 -1145. Ohayon MM, Roth T. J Psychosom Res 2002; 53: 547 -554.

Sleep-Wake Disturbances: How Do Patients Present? Sleepiness - the need for sleep, or tendency to fall asleep Fatigue - the sensation of weariness, tiredness, exhaustion, loss of energy; the desire to rest “I have no energy. The smallest tasks wear me out. ”

Sleep-Wake Disturbances: Common Complaints • • Sleepiness Irritability Cognitive deficits Reduced vigilance Distractibility Anergia Malaise Tiredness • • • Decreased motivation Dysphoria Fatigue Restlessness Impaired coordination ICSD-2 -International Classification of Sleep Disorders, 2 nd ed. Diagnostic and Coding Manual. Westchester, IL: American Academy of Sleep Medicine, 2005.

Overlap of Symptoms of Fatigue and Sleepiness Excessive Sleepiness Major Depression Fatigue Chronic Fatigue Sleepiness Sleep Disorder Narcolepsy Sleep Deprivation

Targeting Treatment: Increase Homeostatic Drive and Circadian Amplitude Sleep Homeostasis Wake Propensity Wake Sleep Circadian Drive for Wakefulness 9 a. m. 3 p. m. Awake 9 p. m. 3 a. m. 9 a. m. Asleep Kryger MH et al. (2000), Principles and Practices of Sleep Medicine, 3 rd ed. Philadelphia: W. B. Saunders

How to Improve Sleep in Elderly? Bright Light 1, 2, 3, 4 Sleep Hygiene CBT Pharmacology Exercise 5 1. Campbell SS et al. J Am Geriatr Soc. 1993; 41: 829 -836. 2. Murphy PJ and Campbell SS. J Sleep Res. 1996 Sep; 5(3): 165 -72. 3. Lack L, Wright H. Sleep. 1993; 16: 436 -443. 4. Ancoli-Israel et al. J Am Geriatr Soc. 2002 Feb; 50(2): 282 -9. 5. Naylor E et al. Sleep. 2000; 23: 87 -95.

Exercise and Sleep in Older Adults § Older adults who exercise regularly exhibit better neuropsychological performance and sleep quality than sedentary controls § Participation in aerobic exercise programs (walking/jogging) improves cognitive performance, mood, subjective sleep quality, increase in vitality Kubesh et al, J Clin Psychiatry, 2003) Blumenthal et al, Arch Intern Med, 1999 Blumenthal et al, J Gerontology, 1991 King et al, JAMA, 1997 Naylor E et al, Sleep 2001

Effect of Daily Social and Physical Activity Community dwelling healthy elderly Increased slow wave sleep Improved daytime neuropsychological performance VIGOR Naylor et al. , Sleep 23: 1, 2000 Benloucif et al, Sleep 2005

Is a single session sufficient and does time of day matter? Morning Activity Evening Activity Structured activity consisted of 30 min. seated social game-playing , 20 min light stretching and mild activity, and 30 minutes of moderate activity such as rapid walking with a cool down period. Benloucif et al, 2004

Exercise: Interventions for Chronic Insomnia in Older Adults • Age 55 and older with diagnosis of insomnia • No primary sleep pathology other than insomnia • No cognitive impairment (MMSE < 25)

Effects. Subjective Measures. Sleep Quality and Sleepiness of exercise on of Sleep and Sleepiness Sleep Quality * Sleepiness * ** Unpublished data

Depressive Symptoms (CES-D) * Unpublished data

Exercise Improves Vigor and Mood in Older Insomniacs Vigor * Mood * *

Quality of Life (SF-36) SF-36 Quality of Life Measures * * * Unpublished data

Interaction of Sleep and Health Sleep Disorders Sleep fragmentation Sleep quality Circadian rhythm Physical activity Sleep Loss Appetite Inflammation Insulin resistance Autonomic function Sleepiness Fatigue HEALTH Zee and Turek, Arch Int Med, 2006 Cardiovascular Pulmonary Metabolic Immunologic Neuropsychiatric

Ramadevi Gourineni, MD Gayle Huber, Ph. D Brandon Lu, MD Kathryn Reid, Ph. D Lisa Wolfe, MD Erik Naylor, Ph. D Kelly Glaser, Ph. D Bryce Mander Rosemary Ortiz Ashley Jaksa Dylan Murray Debbie Davis Kari Sveum NCRR-00048 R 25 RR 15404 T 32 HL 07909 P 01 AG 11412 R 01 HL 67604 R 01 HL 069988 K 08 HL 18326

Worried About Growing Old and Tired? “Don’t Lose Sleep Over it. ”