Sleep,Hormones,Immunity,Longevity

andSuccessful Aging

ASCANIO POLIMENI M.D. NEUROENDOCRINOLOGISTCONDIRECTOR of “REGENERA RESEARCH GROUP”

Health-Disease

We are

What We:

Eat Feel

Think

BreathDrink

We are also..

How We:

SLEEPSLEEP is an essential a component as Good

Nutrition,Water,Air and Exercise toOptimal Health, to our Mental-Physical Performances

and to Quality of Life

Awake

Sta

ges

The Sleep Cycle in Adults

RE

M

RE

M

RE

M

RE

M

RE

M

1

2

3

4

0 1 2 3 4 5 6 7 8

Hours in Sleep

Functions of Sleep:

-Why do we sleep for 1/3 of our life?

-What are some of the functions of

sleep?

1.Memory Consolidation

2.Energy Conservation

3.Body-Brain Restoration

4.Immune-Endocrine System Regulation

Changes in the immune system cause changes in sleep and,

conversely, sleep

has an important role in restoring the immune system

or sleep loss alters immune s.

Relationship between sleep,

circadian rhythm,

and the neuroendocrine,

autonomic nervous

and immune systems.

MLT

GHRH-GH

PRL

TH1

CRH

ACTH

CORTISOLO

TH2

NONREM

SWS

REM

Sleep influences

circadian alternance between TH1-TH2

immune system branches

Putative pathways of immune

system involvement in sleep.

In general, pro-inflammatory cytokines induce sleep,

whereas anti-inflammatory cytokines inhibit sleep.

MLT

LEPTIN

GHRL

PRL

TEST.

GHRH-GH

SS

CRH-ACTH

CORT.

TSH

CYTOKINES

FSH-LH

SLEEP

HORMONES

SEX

HORMONES

PRL

NPY

GALANIN

ACTH-CRH

CORT.

GHRH-GH

SS

CYTOKINES

MLT

VASOPRESSIN

THYR.HORM.

Awake

Sta

ges

The Sleep Cycle in Adults

RE

M

RE

M

RE

M

RE

M

RE

M

1

2

3

4

0 1 2 3 4 5 6 7 8

Hours in Sleep

Sleep Hormonesdifferent hormones are produced mainly during Sleep

Melatonin(1 PART)

Ghrh-GH(1 PART SWS)

Leptin(1 PART)

Ghrelin(1 PART SWS)

Testosterone(1-2 PART)

Prolactin(MIDDLE-2 PART)

TH-1 Cytochynes(1 PART)

TH2 Cytochynes(2 PART)

CRH-ACTH-CORT-SOMATOSTATIN (2 PART-MORINING

HOURS)-

(x ± SEM)pg/ml

2 4 8 12 16 20 220

10

20

30

40

50

60

70

0 24 L/D

PLASMA MELATONIN CIRCADIAN RHYTHM

day night

*** p < .001%

of th

e tota

l 24

h

0

10

20

30

40

50

60

70

80

* *

*

DAY / NIGHT aMT6s URINARY EXCRETION

% Rhythm

MESOR M

(x ± SEM) (x ± SEM)

AMPLITUDE A ACROPHASE

(°)

(95% c.l.)

hours

YOUNG CONTR.

(n=15)

p

0.0002 55.54 21.12 ± 3.23 17.16 ± 2.91 - 22° 28'

(-04° 05' to - 47° 03')

01:30

(00:16 to 03:08)

Ø §Population

mean

cosinor

summary

Pineal gland

Cortisol

12 0 12h

12 0 12h

Sleep / Wakefulness

12 0 12 h

Temperature

Melatonin12 0 12h

Light / Dark

SCN

Circadian rhythms

MELATONIN RHYTHM AS ENDOGENOUS SYNCHRONIZER FOR OTHER

RHYTHMS

CIRCADIAN RHYTHM OF

MLT

CORTISOL

GH

INSULIN-ADIPONECTIN

LEPTIN-GHRELIN

FSH-LH

T4 T3

MLT

GHRH-GH

CRH

ACTH

CORTISOLO

SS

NONREM

SWS

REM

-------------

Hypothalamic NPY

LEPTIN FAT MASS

INTERACTION LEPTIN - NPY

food intake

BAT activity

insulin secretion

-

Twenty-four-hour profiles of rapidly sampled plasma ghrelin (a) and adiponectin (b) in lean (blue) and obese (red) male subjects

Yildiz B O et al. PNAS 2004;101:10434-10439

©2004 by National Academy of Sciences

TEST??

Hormones SleepA number of hormones are known to modify sleep and sleep

propensity

Sleep inducing hormones

Delta Sleep Inducing Hormone

Vasoactive intestinal peptide

Growth Hormone Releas. Fact.

Ghrelin-Prolactin

Growth hormone

Insulin

Melatonin

Progesterone

Estradiol

Oxytocin

Th-1 cytokines

Vasopressin-NPY-Galanin

Sleep reducing hormones

ACTH-CRH

Cortisol-Catecholamines

Pregnenolone

Somatostatin

Thyreotropin releasing

hormone(t3-t4)

Endorphine

Prostaglandine E

Th2-cytokines

Melatonin&

Sleep

MLT in the elderly people

Elderly people who are good sleepers had higher mlt levels

than those with insomnia.

Elderly produce less mlt and present altered mlt rhythm

(begin produce it earlier at night and stop producing it earlier

in the morning.-’’PHASE –ADVANCED’’).

Older people show a disruption in the normal stage of

sleep.They get less priority sleep (REM and stage III and IV).

26

Significantly lower serum melatonin in patients

with chronic primary insomnia

0

30

60

90

120

82.5

p = 0.01

116.8Peak of

nocturnal

serum

melatonin

(pg/ml)

98.26

72,1

Chronic

insomnia

- 29 %

more

than 5 yrs

Healthy

Chronic insomnia

less

than 5 yrs

- 16%- 38%

n = 10n = 5

Hajak G, Rodenbeck A, Staedt J, Bandelow B, Huether G, Ruther E. Nocturnal plasma melatonin levels in patients suffering

from chronic primary insomnia. J Pineal Res 1995 Oct;19(3):116-22 Department of Psychiatry, University of Gottingen, Germany.

Figure: Serum melatonin levels were significantly lower in patients with chronic primary insomnia (mean

age 41.3 yrs) compared to healthy controls (mean age 27.2 yrs).

The lowest values were found in chronic primary insomnia patients with a history of sleep

disturbance lasting for longer than five years.

MLT and SLEEP

Action:

-reduction in core body temperature.

-phase-shift of the endogenous circadian pacemaker.

-direct action on somnogenic structures of the brain.

Effects:

-reduces time to fall asleep.

-lengthens REM phase

-increases quality of sleep(deep or slow wave sleep).

-reduces number of night awakening.

-even fractions of mlt(0,3 MG) enhance sleep.

-No changes seen in total sleep time or sleep architecture

-No changes seen in patients without insomnia

28

Significant beneficial effects of melatonin

on sleep in elderly insomniacs

0

30

60

90

33'

p < 0.0O1

83 %

Sleep

parameters

73'

Melatonin

Placebo

Melatonin

Melatonin

75 %

p = 0.088 (NS)

Sleep efficiency Wake time

after sleep onset

Sleep latency

19'

49'

Placebo

Placebo

p < 0.0O1

Total

sleep time

was not

affected

onset

Garfinkel D, Laudon M, Nof D, Zisapel N. Improvement of sleep quality in elderly people by controlled-release melatonin

. Lancet 1995 Aug 26;346(8974):541-4 Day Care Unit, E Wolfson Medical Center, Holon, Israel.

Figure: Sleep efficiency was significantly greater and wake time after sleep onset was significantly shorter

in 12 elderly sunjects complaining from insomnia (aged 76 (SD 8) years) with melatonin therapy

(2 mg/day of a controlled-release formulation during 3 weeks in a randomised,double-blind

placebo-controlled cross-over study).

GH& sleep

GROWTH HORMONE Deficiency => SLEEP in GH deficient young adults

Figure: growth hormone-deficient young adults have deep & REM sleep (study with 60 patients). (Aström C et

Lindholm J, Neuroendocrinology, 1990; 51: 82-84)

0

100

200

300

400

500

600

8 h

4 h

(+ 53 ‘)

(+ 2 h)

(- 24 ‘) (- 22’)(1 h 38) (1 h 34)

nl GH deficient

REM SLEEP corrected within the first 390 min sleep (the shortest total sleep time in controls)

(stages 1 + 2)

(delta)(stages 3 + 4)

479

534

246

368

98 7494 72

Light sleep

Deep sleep

REM sleep

Total sleep

nlnlnlGH

deficientGH

deficient

GH deficient

total time (minutes)

GROWTH HORMONE THERAPY + SLEEP in growth deficient young adults

total time (mi-nutes)

Figure: improvement of sleep efficiency after 6 months of growth hormone treatment (2 IU/M2/day) of growth hormone-deficient young adults. (Aström C et Lindholm J, Neuroendocrinology, 1990; 33: 495-500)

0

100

200

300

400

500

600

TOTAL SLEEP

0

0

0

(- 39’)

(- 41’)

(+ 15’ )

(+ 27’)

+ GH

+ GH

REM SLEEPLIGHT

SLEEP

DEEP SLEEP558

518

350

309

64 79111 138

+ GH

+ GH

+ GH

Cortisol&

insomnia

24-hr Cortisol rhythm & sleep

Figure :24 hours plasma cortisol and ACTH-levels in a normal subject in baseline conditions. These rhythms are poorly altered by sleep deprivation or a shift in bedtime hour. (Rev Prat (Paris), 1992, 42(5): 594)

© T. Hertoghe, 02-2000,

Brussels

ACTH

cortisolnight

morningafternoon

evening

0

20

40

60

80

100

Night serum cortisol Sleep

duration-Sleep distruption

Night

serum

cortisol

µg/dl

figure : healthy young men (aged 20-34 yrs) w/ shorter total sleep time (7h57’) have higher mean nocturnal serum cortisol than men w/ longer total sleep time (9h57’).

(Späth-Schwalbe E, J Clin Endocrinol Metab, 1992, 75: 1431-1435)

© T. Hertoghe, 02-2000, Brussels

healthy men w/

shorter sleep

56

(210)

76

(nmol/l)

healthy men w/

longer sleep

(155)

0

20

40

60

80

100

Cushing syndrome deep sleep

% of

total

sleep

time

figure : in patients w/ Cushing’s Syndrome delta-or deep sleep (as total sleep time) is by 59 % compared to controls, total sleep time is & stage II of superficial sleep is . (Friedman TC, Neuroendocrinology, 1994, 60: 626-634)

Cushing

© T. Hertoghe, 02-2000, Brussels

Stage II Delta-sleep

(stages III +

IV)

Cushing :

• total sleep time (-31’= 11%)

• REM, stage I

63.8% 74%

14%5.8%

p < 0.05 p < 0.01

Cushing

-59%

+10%

Testosterone&

insomnia

SERUM TESTOSTERONE SLEEP

figure : serum testosterone levels peak generally in proximity to the initiation of the REM periods in a young normal male.

(Roffwarg HP et al, Psychosomatic Med, 1982, 44(1): 73-84)

© T. Hertoghe, 02-2000, Brussels

REM REMREM REM

testosterone

DHEA &

insomnia

DHEA sleepPLACEBO

DHEATOTAL

SLEEP LIGHT

SLEEP

DEEP

SLEEP

500mg DHEA

+ 27 %EEG sigma activity first 2 h. GABA acid co-receptor complex

slee

p

time

figure : 500 mg oral DHEA duration of REM sleep & EEG activity

in the sigma frequency range activity during REM sleep in

the first 2 h. sleep period in 10 healthy young men (mean age

of 24.9 yrs (21-30)).

(Frien E et al, Am J Physiol. 1995; 268 (1 Rt 1) : 107-13)

15.7% 19.3%of sleep of sleep

409.1423.2

261.1(stage

2 230.6)

258.7(stage

2 228.3)

67.9 68.4 69.6 88.4

REM

SLEEP

Estrogens&

insomnia

0

100

200

300

400

500

ESTROGEN THERAPY IMPROVES SLEEP

sleep

para-

meters

(minutes)

Figure : 0.625 mg daily conjugated estrogens the duration of REM-sleep and sleep latency in 16 hypogonadal women (aged 31-65 yrs).

(Schiff I, JAMA, 1979, 242: 2405-2407)

total sleep time

placebo

19’

CE

12’

REMsleep

latency

CE

CE

+25’

placebo

7h18’

7h6’

70.4’ 95.4’

placebo

Progesterone&

insomnia

0

10

20

30

40

50

PROGESTERONE REM, AWAKE TIME (SLEEP)

% of

total

sleep

time

Figure : 300mg to 10 healthy menopausal women their REM sleep, but their awake time without impairing cognitive functions during daytime. As possible mechanisms of progesterone a Gaba agonistic effect and the regulation of gene expression via the progesterone receptor are discussed. Progesterone might be useful in the treatment of sleep disturbances of postmenopausal women.(Psychoneuroendocrinology. 2008 Sep)

PGREM

13.5%13.7%

18%

+15’

30.4%

AWAKE

TIME

-26’

PG

Sleep:

What

happens

with Aging ?

Normal Sleep and Normal Aging:Sleep Efficiency

The ability to get

sufficient,continuous quality sleep may

become more

difficult as we age

Sleep among older adults

--Many older adults don’t get enough sleep:

-Little deep sleep(3-4-SWS) and more lighter sleep(STAGE 1,2

Variable).Decreased Sleep efficiency.Fewer cycles.

-Decreased REM Sleep.

-Dozens of awakenings and arousal during the night.

-Falling asleep takes longer.

-Many older adults go to bed earlier at night and wake up earlier in the morning (Phase Advancement)

-Older adults are more likely to nap during the day and have a decrease of psychomotor performance ,sleepness

Normal Sleep and Normal Aging:Less Deep Sleep

Sleep Problems/DisordersPrevalent Among Older Persons

SYMPTOMS OF SLEEP PROBLEMS BY AGE

Symptoms: a few nights

a week or more 55-64 65-74 75-84

Insomnia 49% 46% 50%

Snoring 41% 28% 22%

Sleep Apnea 9% 6% 7%

Restless Legs Syndrome (RLS) 15% 17% 21%

Sleep of the average 70-yr-oldThe average 70-year-old :

sleeps only 6 hrs a night,

may obtain 1 or 2 hrs more during daytime naps

number of sleep disruptions

incidence of chronic diseases or drugs that alter sleep=> poorer

sleep

the 2 most common geriatric sleep disorders =

-obstructive sleep apnea syndrome

restless legs syndrome

Left untreated, sleep disorders =>

serious patient's health & morbidity & mortality.

Barthlen GM. Sleep disorders. Obstructive sleep apnea syndrome, restless legs syndrome, andinsomnia in geriatric patients. Geriatrics. 2002 Nov;57(11):34-9; quiz

40. Center for Sleep Medicine, Department of Neurology, Weill Cornell Medical College, New York, NY, USA

SLEEP

DISORDERS

AGING

AGING RELATED DISEASES

Sleep 2009

Chronic Insomnia

CVD

DIABETES-OBESITY

METABOLIC SYNDROME

MOOD DISORDERS

NEURODEGENERATIVE DISEASES

INFLAMMAGING-IMMUNESEN.-CANCER

UNSUCCESSFULL AGING

Sleep

Disorders

Aging related

Hormones

Deficiencies

/Imbalances

Sleep Deprivation

Six days of restricted sleep (4 hours per 24-hour period) caused changes to the sleep architecture similar to the changes seen in people suffering from depression.

changes in several natural body rhythms of hormone secretion.

Melatonin

cortisol

thyroid-stimulating hormone

leptin

Prolactin

growth hormone.

PCR-IL6-TNF

WHAT HAPPENS

DURING AGING?

Alterations of Circadian

Rhythmicity and Sleep in Aging:

Endocrine Consequences

Horm res-1998-

Because sleep loss in young subjects results

in endocrine disturbances which mimic those

observed in aging, it is conceivable that the

decrease in sleep quality which characterizes

aging may contribute to age-related

alterations in hormonal function and their metabolic consequences.

SLEEP DISORDERS-AGING

HORMONAL IMBALANCES

GH-

GHRH TESTO

ANAB.H(IGF-

1-DHEAS

TEST.)/CATAB

H(CORT)

CRH

CORT.CAT.VASO.

PRL

MELATONIN

TNF-IL6

INSULIN - LEPTIN GHRL

Sleep

disorders

Hormones

Deficiencies

/Imbalances

Unsuccessfull Aging

Aging related

Diseases

Nrem Sleep GH (35-50 yrs) JAMA -2000-

---Normal aging leads to ↓ sleep spindles and

SWS,concurrent with a: reduced nocturnal GH

release and of Th1 cytokines • decrease of deep-restorative sleep (3-4 SWS) with increase

of 1-2,no change on REM,on WAKE TIME and SLEEP TIME.

• ↑ truncal,abdominal obesity and ↓ lean body mass

• ↓ exercise response

• ↓ Declarative (Semantic)memory(hippocampal atrophy )

Immunological memories-Immunesenescence

MLT

GHRH-GH

TH1

CRH

ACTH

CORTISOLO

TH2

NONREM

3-4 SWS

REM IL6

Sex

hormones

Rem Sleep Cort.-IL6 ( >50 yrs)-JAMA 2000-

- Normal aging leads to an ↑ evening-night cortisol

and day-night time IL6 with a Th2 -TH17cytokine shift

---sleep fragmentation,night awakenings REM WAKE

TIME, SLEEP TIME, 1-2 NREM,3-4 NREM not significant.

• insulin-resistance ,metab.sy,diabetes, CV

risk,Osteoporosis,Sarcopenia,Immunesenescence

DAY-NIGHT TIME IL6,INFLAMMAGING,daytime fatigue-

decreased performance, disability,morbility for age related

diseases,mortality.

Emotional Declarative(Episodic memory,amigdala

dep),Procedural memory

MLT

GHRH-GH

TH1

CRH

ACTH

CORTISOLO

TH2

NONREM

3-4 SWS

REM IL6

Sex

hormones

SLEEP DISORDERS & AGING RELATED DISEASES

-Cardio-Metabolic Risk Factors

• Obesity/body fat distribution

• Type 2 Diabetes Mellitus

• Hypertension

• Coronary Heart Diseas

• Cognitive disorders

• Immunesenescence-Autoimmune Diseases-Cancer

• Total and Cause-Specific Mortality

Chronic Sleep Loss,

Behavioral or Sleep

Disorder Related

Weight gain,

Insulin resistance,

and Type 2

Diabetes.

Sleep and Diabetes

Sleep problems: risk factors for Diabetes

Sleep problems worsen Diabetes

Sleep deprivation worsens insulin resistance

and glucose intolerance

Sleep apnea does the same

Control of sleep problems improves DM

CPAP improves Diabetes control

Acute Sleep Loss Causes InsulinResistance

4 hours of acute sleep loss for 6 days:

40% reduction in rate of glucose clearance

30% reduction in insulin effectiveness

Decreased thyroid hormone

Increased evening cortisol

Increased sympathetic nervous system activity

(CATECOLAMIN)

(similar changes to that seen in obesity & aging)

Spiegel K, Leproult R, Van Cauter E. Lancet 354:1435-9, 1999

Chronically Short Sleepers HaveInsulin Resistance

Chronically short sleepers (306 vs 486 min/nt)

Secreted 65% more insulin

Insulin sensitivity 40% less than normal

Significantly decreased reaction times

Lower scores on the Global Affect scale

Colecchia EF, Spiegel K, Kim R, et al. Sleep

23:A253, 2000

Sleep Duration and Risk of DiabetesThe Massachusetts Male Aging Study (n=1,139)

0

1

2

3

4

5

6

<=5 6 7 8 >8

Hours of Sleep

Re

lati

ve

Ris

k

Yaggi HK et al. Diabetes Care 2006; 29:657-61

1.95 (0.95-4.01)

3.12 (1.53-6.37)

Elevation of evening cortisol levels predisposing to

insulin resistance.

Increase in sympathetic tone, inhibiting pancreatic

function and leading to increased glucose

intolerance.

Weight gain,reduction in leptin,increase of ghrelin.

Reduction of testosterone levels.

Sleep Deprivation & Diabetes:Potential Mechanisms

Type 2 Diabetes and OSA

-80% of type 2 diabetics are overweight and in

particular have central obesity

Central obesity increases the risk of OSA

12% of type 2 diabetics had moderate to

severe OSA

- 70% of moderately obese diabetics who

snored or were sleepy had OSA

Cardio-Metabolic Risk Factors:

Obesity

Obesity and Sleep Deprivation

Direct link between avoiding sleep and

obesity.

Risk of obesity rises with sleep

deprivation:

Less than 4 hours : 73% risk

Five hours : 50% risk

Six hours : 23% risk

Obesity Epidemic and Sleep Duration

7,56,8

9,0

0,0

1,0

2,0

3,0

4,0

5,0

6,0

7,0

8,0

9,0

10,0

1910 1975 2005

Sleep duration in US adults

25,2

26,9

23,0

21,0

22,0

23,0

24,0

25,0

26,0

27,0

28,0

1910 1975 2005

BMI in US adults

Chronically Short Sleepers HaveIncreased BMI

Study of 1024 subjects with chronic sleep

restriction showed an association with

reduced leptin, increased ghrelin and

elevated BMI.

Taheri S, et al, Sleep 27: A146-7, 2004.

Sleep Deprivation Causes Obesity

↓ growth hormone ↓ lean muscle mass fat mass

↓ testosterone ↓ lean muscle mass fat mass

↓ leptin and ↑ leptin resistance

↑ ghrelin

↑ insulin resistance

↑ evening cortisol

↑ sympathetic activity:

---↑ fatigue: ↓exercise

---↑eating for “energy”

Metabolic Sydrome

Early risk factor: cardiovascular disease

Affects: 50 million Americans

High waist: men >40” women >35”-OBESITY

High triglycerides: >150 mg/dl

Low HDL: men <40mg women <50mg

High blood pressure: >130/85

High fasting glucose: >100

↑ insulin levels and insulin resistance

↑ uric acid

Add: Sleep deprivation or Sleep Apnea

Similarities between SleepDeprivation, Obesity and Aging

↓ Sleep quality and quantity

↓ Growth hormone, testosterone

↑ Evening cortisol, catecholamines

↑ insulin resistance

↓ glucose tolerance

↑ Incidence of Diabetes and Cardiovascular

Diseases

Chronic Sleep

Loss, Behavioral

or Sleep Disorder

Related

CVD

Cardio-Metabolic Risk Factors:

Hypertension

Cappuccio FP et al. Hypertension 2007:50:694-701

Sleep duration and prevalent Hypertension The

Whitehall II Study

0.70

1.00,92

0.74

0,0

0,5

1,0

1,5

2,0

Re

lati

ve

Ris

k

0,86 0,921.01.12

0.88

0,0

0,5

1,0

1,5

2,0

<=5 6 7 8 >=9

Re

lati

ve

Ris

k

Hours sleep

Women, n=1,567

Men, n=4,199

1.72 (1.07-2.75)

P = 0.037

Increased BP load resulting from prolongation of higher

BP whilst awake

Truncation of the BP dip during sleep

Prolonged activation of sympathetic nervous system

Increased renal sodium retention

Decreased nocturnal peak of MLT

Increased nadir nocturnal level of Cortisol

Gender-specific effects?

Confounding?

Sleep Deprivation & Hypertension:Potential Mechanisms

MLT and Blood Pressure

MLT reduces night blood pressure in patients with nocturnal hypertension and is a potential

antihypertensive treatment.(Am J.Med 2006-J.Pin.Res.2007).

’’ The administration of the hormone declines blood pressure to normal range. It has been observed that MLT, even in a dose 1 mg, reduced blood pressure and decreased catecholamine level after 90 min in human subjects.’’

MLT and Blood Pressure

---MLT may reduce blood pressure via the

following mechanisms:

1) by a direct effect on the hypothalamus.

2) as an antioxidant which lowers blood

pressure.

3) by decreasing the level of catecholamines.

4) by relaxing the smooth muscle in the aorta

wall.(NO release)

Paulis L.Physiol. Res. 56: 671-684, 2007

Coronary Heart Disease

Coronary Heart Disease by hours of sleepThe MONICA Study

1.401,341,05 1.0

0,0

0,5

1,0

1,5

2,0

2,5

3,0

Re

lati

ve

Ris

k

1,051,22

1,071.01.13

0,0

0,5

1,0

1,5

2,0

<=5 6 7 8 >=9

Re

lati

ve

Ris

k

Hours sleep

Women, n=3,388

Men, n=3,508

2.98 (1.48-6.03)

Meisinger C et al. Sleep 2007; 30:1121-27

Summary

Both short and long sleep duration may be associated with more detrimental effects on cardiovascular health in women than men.

The biological mechanisms underlying these associations are unclear.

High blood pressure may represent one mechanism linking short sleep duration with increased risk of CHD, at least in women

CV PROTECTION

ENDOTHELIAL

FUNCTION

LIPID-GLUCO

METABOLISM

INFLAMMATION

HOMOCYSTEINE

HORMONES

BLOOD

PRESSURE

OXIDATIVE

STRESS

MLT and CAD

Patients with coronary disease have a low Mlt

production rate, with greater decreases in

those with higher risk of cardiac infarction

and/or death.

Incidence of sudden cardiac death is high in the morning hours.

It has been shown that Mlt levels are significantly low at these times.

Low urinary 6-sulphatoxymelatonin levels in patients withCoronary Artery Disease(J.Pin. Res.2000).

02468

10121416

18

******

*

g/24h

TOTAL aMT6s EXCRETION RATE and CAD

* p < .05

*** p < .001

Healthy CAD with higher risk

of infarction and/or death

CAD

Ask all patients withhypertension, heart disease or

diabetes…

Do you snore?

Do you wake up refreshed?

Has anyone told you that you stop

breathing in your sleep?

QUALITY

SLEEP

SUCCESSFULL

AGING

Sleep and Aging

NSF 2003 Sleep in America poll

The first NSF poll to look at the sleep habits of

older Americans -- those between the ages of 55

and 84 -- and the association between their sleep

behavior, their medical and physical conditions,

their outlook and their lifestyles.

Sleep and Aging

NSF poll found that the better the health of older adults, the more likely they are to sleep well

The greater the number of diagnosed medical conditions, the more likely they are to report sleep problems.

Positive moods and outlooks as well as having more active and "engaged" lifestyles (having someone to speak with about a problem, exercise, volunteer activity, etc.) are associated with sleeping 7–9 hours and fewer sleep complaints.

Sleep and Aging

Rather than a consequence of

aging, poor sleep among older

Americans appears to be an

indicator of health status.

Sleeping well, aging well: a descriptive and cross-sectional study of sleep in "successful agers" 75 and older.

Am J Geriatr Psychiatry. 2008 Jan;16(1):74-82.

Objective:To examine diary-based, laboratory-based, and actigraphic

measures of sleep in a group of healthy older women and men (> or

=75 years of age) without sleep/wake complaints and to describe

sleep characteristics which may be correlates of health-related

quality of life in old age.

CONCLUSIONS: Sleep quality and daytime alertness in late life may be

more important aspects of successful aging than previously

appreciated. Good sleep may be a marker of good functioning

across a variety of domains in old age. Our observations suggest

the need to study interventions which protect sleep quality in older

adults to determine if doing so fosters continued successful aging.

Protecting sleep, promoting health in later life: a randomized clinical trial.

Psychosom Med. 2010 Feb;72(2):178-86

CONCLUSIONS: Although we cannot exclude a

positive effect of education in healthy nutrition, for

healthy elderly >75 years of age without sleep

complaints, reducing sleep time may be

detrimental, whereas allowing more time to sleep

(about 7.5 hours nightly) is associated with better

maintenance of physical health-related quality of

life and stability of medical illness burden over 30

months.

Total and

Cause-Specific Mortality

Chronic Sleep Loss,

Behavioral or Sleep

Disorder Related

MORTALITY

Centenarians:

Satisfying sleep

Long-living

persons:

-Regular &

satisfying sleep

(6 – 8 h)

Dan Georgekas, The Methusaleh Factors, Ed. Academy of Chicago Publishers 1995, 153-172

The majority got up early

&

liked to work outdoors.

52 Centenarians: 36 women 16 men

Humphrey GM, Young TH. On Centenarians ( 1899)

Centenarians:

A well-balanced sleep-wake cycle

ALTERED

BIOLOGICAL

RHYTHMS

AGING

ARD

What’s the

Ideal

Sleeping

Time?

7 hrs = Optimal Sleep duration => longevity

104,010 subjects (43,852 men

& 60,158 women), aged 40

to 79 years

Prospective study

(JACC Study =

Japan Collaborative Cohort Study

on Evaluation of Cancer Risk )

Mean follow-up 9.9 yrs

Tamakoshi A, Ohno Y; JACC Study Group. Self-reported sleep duration as a predictor of all-cause mortality: results from the JACC study, Japan. Sleep. 2004 Feb 1;27(1):51-4. Department of Preventive

Medicine/Biostatistics and Medical Decision Making, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan. tamaa@med.nagoya-u.ac.jp

Sleep duration of

shorter or longer than

7 hrs was assoc. w/ a

sign. risk of all-

cause mortality

Sleep duration at

night of 7 hrs was

found to show the

lowest mortality risk

All-Cause mortality by hours of sleepThe Whitehall II Study

0

1

2

3

4

< 5h

(56 deaths)7h

(256 deaths)

8h

(87 deaths)

Hazard Ratio (95% CI)

Age-adjusted

Fully adjusted

6h

(160 deaths)

> 9h

(7 deaths)

Phase 1 (1985-88) n=9,781

0

1

2

3

4

< 5h

(29 deaths)7h

(112 deaths)

8h

(74 deaths)

Hazard Ratio (95% CI)

Age-adjusted

Fully adjusted

6h

(61 deaths)

> 9h

(16 deaths)

Phase 3 (1991-93) n=7,729

Ferrie JE et al. Sleep 2007; 30:1659-66

Summary

Either a decrease in sleep duration from a regular 6, 7 or 8h per night or an increase from a regular 7 or 8h per night predict all-cause mortality

A decrease in sleep duration affects all-cause mortality via increases in cardiovascular deaths

An increase in sleep duration affects overall mortality via an increase in non-cardiovascular deaths

Sleep changes over time may represent more reliable measures to assess the impact of sleep on health

Sleep duration and all-cause mortality: a systematic review and meta-analysis of prospective studies. Cappuccio FP, D'Elia L, Strazzullo P,

Miller MA.-SLEEP-2010 University of Warwick, Warwick Medical School, Clinical Sciences Research Institute, Coventry, UK.

CONCLUSION:

Both short and long duration of sleep

are significant predictors of death in

prospective population studies.

Sleep is the golden chain that ties

health and our bodies together.Thomas Dekker, English Dramatist (1572 - 1632)