[DatBtrue]

ANTI-AGING

I've tried to emphasize that Slow Wave Sleep (SW) and Growth Hormone (GH) are not merely positively correlated but are intricately bound together such that a change in one leads to a change in the other. That is why from the start I have attempted to underscore that a pre-bed dose of Growth Hormone Releasing Hormone (GHRH) & Growth Hormone Releasing Peptide 6 (GHRP-6) will increase that vital period of sleep known as Slow Wave Sleep which has restorative benefits beyond amplified GH release.

The following study is fascinating for all of us because it reveals that somatopause begins dramatically between age 25 and 35. The following study published in the prestigious Journal of the American Medical Association is well worth examining.

The chronology of aging of GH secretion follows a pattern remarkably similar to that of SW sleep. Thus, in men, the so-called "somatopause" occurs early in adulthood, between age 25 and 35 years, an age range that corresponds to the human life expectancy before the development of modern civilization and is essentially completed by the end of the fourth decade.

Our analyses further indicate that reduced amounts of SW sleep, independent of age, are partly responsible for reduced GH secretion in midlife and late life. That this correlative evidence reflects a common mechanism underlying SW sleep generation and GH release rather than an indirect association is supported by 2 studies that have shown that pharmacological enhancement of SW sleep results in increased GH release. - Age-Related Changes in Slow Wave Sleep and REM Sleep and Relationship With Growth Hormone and Cortisol Levels in Healthy Men, Eve Van Cauter, PhD; Rachel Leproult, MS; Laurence Plat, MD,JAMA. 2000;284:861-868

The objective of the study was, to determine the chronology of age-related changes in sleep duration and quality (sleep stages) in healthy men and whether concomitant alterations occur in GH and cortisol levels.

They combined data from a series of studies conducted between 1985 and 1999 at 4 laboratories which examined 149 healthy men, aged 16 to 83 years, with a mean (SD) body mass index of 24.1 (2.3) kg/m2, without sleep complaints or histories of endocrine, psychiatric, or sleep disorders.

They created twenty-four–hour profiles of plasma GH and cortisol levels and polygraphic sleep recordings and found the following results:

The mean (SEM) percentage of deep slow wave sleep decreased from 18.9% (1.3%) during early adulthood (age 16-25 years) to 3.4% (1.0%) during midlife (age 36-50 years) and was replaced by lighter sleep (stages 1 and 2) without significant increases in sleep fragmentation or decreases in rapid eye movement (REM) sleep.

The transition from midlife to late life (age 71-83 years) involved no further significant decrease in slow wave sleep but an increase in time awake of 28 minutes per decade at the expense of decreases in both light non-REM sleep (-24 minutes per decade; P<.001) and REM sleep (-10 minutes per decade; P<.001).

The decline in slow wave sleep from early adulthood to midlife was paralleled by a major decline in GH secretion (-372 µg per decade; P<.001). From midlife to late life, GH secretion further declined at a slower rate (-43 µg per decade; P<.02).

Independently of age, the amount of GH secretion was significantly associated with slow wave sleep (P<.001).

Increasing age was associated with an elevation of evening cortisol levels (+19.3 nmol/L per decade; P<.001) that became significant only after age 50 years, when sleep became more fragmented and REM sleep declined. A trend for an association between lower amounts of REM sleep and higher evening cortisol concentrations independent of age was detected (P<.10).

For a deeper read I include the following Introduction &amp; Comments which elaborate on the significance of the results. I strongly encourage any one interested in anti-aging to read it so that they can adopt the appropriate compensatory strategies.

INTRODUCTION

Decreased subjective sleep quality is one of the most common health complaints of older adults.1 The most consistent alterations associated with normal aging include increased number and duration of awakenings and decreased amounts of deep slow wave (SW) sleep (ie, stages 3 and 4 of non–rapid eye movement (non-REM) sleep).2-4 REM sleep appears to be relatively better preserved during aging.3-7 The age at which changes in amount and distribution of sleep stages appear is unclear because the majority of studies have been based on comparisons of young vs older adults. Several investigators have noticed that there are marked decreases in SW sleep in early adulthood in men but not in women.8-11

Sleep is a major modulator of endocrine function, particularly of pituitary-dependent hormonal release. Growth hormone (GH) secretion is stimulated during sleep and, in men, 60% to 70% of daily GH secretion occurs during early sleep, in association with SW sleep.12 Whether decrements in SW sleep contribute to the well-known decrease in GH secretion in normal aging is not known.13-15

In contrast to the enhanced activity of the GH axis during sleep, the hypothalamic-pituitary-adrenal (HPA) axis is acutely inhibited during early SW sleep.16-20 Furthermore, even partial sleep deprivation results in an elevation of cortisol levels the following evening.21 Thus, both decreased SW sleep and sleep loss resulting from increased sleep fragmentation could contribute to elevating cortisol levels. An elevation of evening cortisol levels is a hallmark of aging14-15,22 that is thought to reflect an impairment of the negative feedback control of the HPA axis and could underlie a constellation of metabolic and cognitive alterations.23-25

The present study defines the chronology of age-related changes in sleep duration and quality (ie, amounts of sleep stages), GH secretion, and cortisol levels in healthy men and examines whether decrements in sleep quality are associated with alterations of GH and cortisol levels.

...

COMMENT

The present analysis demonstrates that, in healthy men, aging affects SW sleep and GH release with a similar chronology characterized by major decrements from early adulthood to midlife. In contrast, the impact of age on REM sleep, sleep fragmentation, and HPA function does not become apparent until later in life. The analysis further suggests that age-related alterations in the somatotropic and corticotropic axes may partially reflect decreased sleep quality.

Human sleep is under the dual control of circadian rhythmicity and of a homeostatic process relating the depth of sleep to the duration of prior wakefulness.44 This homeostatic process involves a putative neural sleep factor that increases during waking and decays exponentially during sleep. Slow wave sleep is primarily controlled by the homeostatic process. Circadian rhythmicity is an oscillation with a near 24-hour period generated by a pacemaker located in the hypothalamic suprachiasmatic nucleus. Circadian rhythmicity plays an important role in sleep timing, sleep consolidation, and the distribution of REM sleep.45 The present data indicate that an alteration in sleep-wake homeostasis is an early biological marker of aging in adult men. In contrast, components of sleep that are under the control of the circadian pacemaker appear to be relatively well preserved until late in life.

The chronology of aging of GH secretion follows a pattern remarkably similar to that of SW sleep. Thus, in men, the so-called "somatopause" occurs early in adulthood, between age 25 and 35 years, an age range that corresponds to the human life expectancy before the development of modern civilization and is essentially completed by the end of the fourth decade. Our analyses further indicate that reduced amounts of SW sleep, independent of age, are partly responsible for reduced GH secretion in midlife and late life. That this correlative evidence reflects a common mechanism underlying SW sleep generation and GH release rather than an indirect association is supported by 2 studies that have shown that pharmacological enhancement of SW sleep results in increased GH release.46-47 Also supporting a causal relationship between decreased sleep quality and reduced nocturnal GH secretion are studies in patients with sleep apnea showing a marked increase in GH release following treatment with positive airway pressure.48-49 The reverse interaction between sleep and GH, ie, a deleterious impact of reduced somatotropic function on sleep, is also possible since studies in both normal and pathological conditions have shown that GH-releasing factor and GH influence sleep quality.12, 50 In the present study of nonobese men, the finding of a negative impact of BMI on both GH secretion during waking and amount of SW sleep is consistent with the hypothesis that inhibition of the GH axis may adversely affect sleep regulation.

While the clinical implications of decreased SW sleep are still unclear, the relative GH deficiency of the elderly is associated with increased fat tissue and abdominal obesity, reduced muscle mass and strength, and reduced exercise capacity.51-53 Multiple trials are currently examining the clinical usefulness and safety of replacement therapy with recombinant GH, the other hormones of the GH axis, and synthetic GH secretagogues in elderly adults without pathological GH deficiency. While the benefits of such interventions are still unproven, the present findings suggest that they should target a younger age range than currently envisioned, ie, individuals in early midlife rather than those older than 65 years, when peripheral tissues have been continuously exposed to very low levels of GH for at least 2 decades. Furthermore, since pharmacological enhancement of SW sleep in young adults has been shown to result in a simultaneous and proportional increase in GH release 46-47 and ongoing studies in our laboratory indicate that similar effects can be obtained in older subjects, drugs that reliably stimulate SW sleep may represent a novel class of GH secretagogues.

The present data demonstrate that the amount of REM sleep is reduced by approximately 50% in late life vs young adulthood. However, reduced amounts of REM sleep and significant sleep fragmentation do not occur until after age 50 years. The impact of aging on cortisol levels followed the same chronology. Aging was associated with an elevation of evening cortisol levels, reflecting an impaired ability to achieve evening quiescence following morning stimulation. Studies in both animals and humans have indicated that deleterious effects of HPA hyperactivity are more pronounced at the time of the trough of the rhythm than at the time of the peak.25, 54 Thus, modest elevations in evening cortisol levels could facilitate the development of central and peripheral disturbances associated with glucocorticoid excess, such as memory deficits and insulin resistance,24-25 and further promote sleep fragmentation. Indeed, elevated cortisol levels may promote awakenings.55-56

Elevated evening cortisol levels in late life probably reflect an impairment of the negative feedback control of the HPA axis in aging. Our analyses suggest that there is a relationship between this alteration of HPA function and decreased amounts of REM sleep that is independent of age. The data generally support the concept that decreased sleep quality contributes to the allostatic load, ie, the wear and tear resulting from overactivity of stress-responsive systems.57

The present study focused on the effects of aging on the relationship between sleep and the somatotopic and corticotropic axes in men because the predominant GH secretion occurs during sleep in men but not in women11 and because there is evidence to suggest that the marked decreases in SW sleep in early adulthood occur in men but not in women.8-11 Whether conclusions similar to those obtained for men hold for women will require a separate evaluation as sex differences in sleep quality as well as 24-hour profiles of GH and cortisol secretion have been well documented in both young and older adults.11-12,22

In conclusion, in healthy men, the distinct changes in sleep quality that characterize the transitions from early adulthood to midlife, on the one hand, and from midlife to old age, on the other hand, are each associated with specific alterations in hormonal systems that are essential for metabolic regulation. Strategies to prevent or limit decrements of sleep quality in midlife and late life may therefore represent an indirect form of hormonal therapy with possible beneficial health consequences.

REFERENCES

1. Prinz PN. Sleep and sleep disorders in older adults. J Clin Neurophysiol. 1995;12:139-146.

2. Feinberg I, Koresko RL, Heller N. EEG sleep patterns as a function of normal and pathological aging in man. Psychiatry Res. 1967;5:107-144.

3. Benca RM, Obermeyer WH, Thisted RA, Gillin JC. Sleep and psychiatric disorders. Arch Gen Psychiatry. 1992;49:651-668.

4. Bliwise DL. Normal aging. In: Kryger MH, Roth T, Dement WC, eds. Principles and Practice of Sleep Medicine. Philadelphia, Pa: WB Saunders; 1994:26-39.

5. Feinberg I. Functional implications of changes in sleep physiology with age. In: Terry RD, Gershon S, eds. Neurobiology of Aging. New York, NY: Raven Press; 1976:23-41.

6. Ehlers CL, Kupfer DJ. Effects of age on delta and REM sleep parameters. Electroencephalogr Clin Neurophysiol. 1989;72:118-125.

7. Landolt HP, Dijk DJ, Achermann P, Borbely AA. Effects of age on the sleep EEG: slow-wave activity and spindle frequency in young and middle-aged men. Brain Res. 1996;738:205-212.

8. Webb WB. Sleep in older persons: sleep structures of 50- to 60-year-old men and women. J Gerontol. 1982;37:581-586.

9. Dijk DJ, Beersma DG, Bloem GM. Sex differences in the sleep EEG of young adults: visual scoring and spectral analysis. Sleep. 1989;12:500-507.

10. Mourtazaev MS, Kemp B, Zwinderman AH, Kamphuisen HA. Age and gender affect different characteristics of slow waves in the sleep EEG. Sleep. 1995;18:557-564.

11. Ehlers CL, Kupfer DJ. Slow-wave sleep: do young adult men and women age differently? J Sleep Res. 1997;6:211-215.

12. Van Cauter E, Plat L, Copinschi G. Interrelations between sleep and the somatotropic axis. Sleep. 1998;21:553-566.

13. Ho KY, Evans WS, Blizzard RM, et al. Effects of sex and age on the 24-hour profile of growth hormone secretion in man: importance of endogenous estradiol concentrations. J Clin Endocrinol Metab. 1987;64:51-58.

14. van Coevorden A, Mockel J, Laurent E, et al. Neuroendocrine rhythms and sleep in aging men. Am J Physiol. 1991;260:E651-E661.

15. Kern W, Dodt C, Born J, Fehm HL. Changes in cortisol and growth hormone secretion during nocturnal sleep in the course of aging. J Gerontol A Biol Sci Med Sci. 1996;51A:M3-M9.

16. Weitzman ED, Zimmerman JC, Czeisler CA, Ronda JM. Cortisol secretion is inhibited during sleep in normal man. J Clin Endocrinol Metab. 1983;56:352-358.

17. Spath-Schwalbe E, Uthgenannt D, Voget G, Kern W, Born J, Fehm HL. Corticotropin-releasing hormone-induced adrenocorticotropin and cortisol secretion depends on sleep and wakefulness. J Clin Endocrinol Metab. 1993;77:1170-1173.

18. Spath-Schwalbe E, Uthgenannt D, Korting N, Fehm HL, Born J. Sleep and wakefulness affect the responsiveness of the pituitary-adrenocortical axis to arginine vasopressin in humans. Neuroendocrinology. 1994;60:544-548.

19. Gronfier C, Luthringer R, Follenius M, et al. Temporal relationships between pulsatile cortisol secretion and electroencephalographic activity during sleep in man. Electroencephalogr Clin Neurophysiol. 1997;103:405-408.

20. Bierwolf C, Struve K, Marshall L, Fehm HL. Slow wave sleep drives inhibition of pituitary-adrenal secretion in humans. J Neuroendocrinol. 1997;9:479-484.

21. Leproult R, Copinschi G, Buxton O, Van Cauter E. Sleep loss results in an elevation of cortisol levels the next evening. Sleep. 1997;20:865-870.

22. Van Cauter E, Leproult R, Kupfer DJ. Effects of gender and age on the levels and circadian rhythmicity of plasma cortisol. J Clin Endocrinol Metab. 1996;81:2468-2473.

23. Seeman TE, Robbins RJ. Aging and hypothalamo-pituitary-adrenal response to challenge in humans. Endocr Rev. 1994;15:233-260.

24. McEwen BS, Sapolsky RM. Stress and cognitive function. Curr Opin Neurobiol. 1995;5:205-216.

25. Dallman MF, Strack AL, Akana SF, et al. Feast and famine: critical role of glucocorticoids with insulin in daily energy flow. Front Neuroendocrinol. 1993;14:303-347.

26. Linkowski P, Mendlewicz J, Leclercq R, et al. The 24-hour profile of adrenocorticotropin and cortisol in major depressive illness. J Clin Endocrinol Metab. 1985;61:429-438.

27. Copinschi G, Van Onderbergen A, L'Hermite-Balériaux M, et al. Effects of the short-acting benzodiazepine triazolam, taken at bedtime, on circadian and sleep-related hormonal profiles in normal men. Sleep. 1990;13:232-244.

28. Van Cauter E, Blackman JD, Roland D, Spire JP, Refetoff S, Polonsky KS. Modulation of glucose regulation and insulin secretion by circadian rhythmicity and sleep. J Clin Invest. 1991;88:934-942.

29. Frank S, Roland DC, Sturis J, et al. Effects of aging on glucose regulation during wakefulness and sleep. Am J Physiol. 1995;269:E1006-E1016.

30. Biston P, Van Cauter E, Ofek G, Linkowski P, Polonsky KS, Degaute JP. Diurnal variations in cardiovascular function and glucose regulation in normotensive humans. Hypertension. 1996;28:863-871.

31. Copinschi G, Leproult R, Van Onderbergen A, et al. Prolonged oral treatment with MK-677, a novel growth hormone secretagogue, improves sleep quality in man. Neuroendocrinology. 1997;66:278-286.

32. Linkowski P, Spiegel K, Kerkhofs M, et al. Genetic and environmental influences on prolactin secretion during wake and during sleep. Am J Physiol. 1998;274:E909-E919.

33. Jarrett DJ, Greenhouse JB. Circadian rhythm of cortisol secretion is not disturbed in outpatients with a major depressive disorder. In: Program of the First Meeting of the Society for Research on Biological Rhythms; May 11-14, 1988; Charleston, SC. 97.

34. Jarrett DB, Pollock B, Miewald JM, Kupfer DJ. Acute effects of intravenous clomipramine upon sleep-related hormone secretion in depressed outpatients and healthy control subjects. Biol Psychiatry. 1991;29:3-14.

35. Rubin RT, Poland RE, Lesser IM, Winston RA, Blodgett AL. Neuroendocrine aspects of primary endogenous depression, I: cortisol secretory dynamics in patients and matched controls. Arch Gen Psychiatry. 1987;44:328-336.

36. Rubin RT, Poland RE, Lesser IM. Neuroendocrine aspects of primary endogenous depression, X: serum growth hormone measures in patients and matched control subjects. Biol Psychiatry. 1990;27:1065-1082.

37. Vgontzas AN, Papnicolaou DA, Bixler EO, et al. Sleep apnea and daytime sleepiness and fatigue: relation to visceral obesity, insulin resistance and hypercytokinemia. J Clin Endocrinol Metab. 2000;85:1151-1158.

38. Rechtschaffen A, Kales A. A Manual of Standardized Terminology, Techniques and Scoring System for Sleep Stages of Human Subjects. Los Angeles, Calif: UCLA Brain Information Service/Brain Research Institute; 1968.

39. Virasoro E, Copinschi G, Bruno OD, Leclercq R. Radioimmunoassay of human growth hormone using a charcoal-dextran separation procedure. Clin Chim Acta. 1971;31:294-297.

40. L'Hermite-Balériaux M, Copinschi G, Van Cauter E. Growth hormone assays: early to latest generations compared. Clin Chem. 1996;42:1789-1795.

41. Van Cauter E. Method for characterization of 24-h temporal variation of blood constituents. Am J Physiol. 1979;237:E255-E264.

42. Van Cauter E. Estimating false-positive and false-negative errors in analyses of hormonal pulsatility. Am J Physiol. 1988;254:E786-E794.

43. Van Cauter E, Kerkhofs M, Caufriez A, Van Onderbergen A, Thorner MO, Copinschi G. A quantitative estimation of GH secretion in normal man: reproducibility and relation to sleep and time of day. J Clin Endocrinol Metab. 1992;74:1441-1450.
44. Borbely AA. Processes underlying sleep regulation. Horm Res. 1998;49:114-117.

45. Dijk DJ, Czeisler CA. Contribution of the circadian pacemaker and the sleep homeostat to sleep propensity, sleep structure, electroencephalographic slow waves, and sleep spindle activity in humans. J Neurosci. 1995;15:3526-3538.

46. Van Cauter E, Plat L, Scharf M, et al. Simultaneous stimulation of slow-wave sleep and growth hormone secretion by -hydroxybutyrate in normal young men. J Clin Invest. 1997;100:745-753.

47. Gronfier C, Luthringer R, Follenius M, et al. A quantitative evaluation of the relationships between growth hormone secretion and delta wave electroencephalographic activity during normal sleep and after enrichment in delta waves. Sleep. 1996;19:817-824.

48. Saini J, Krieger J, Brandenberger G, Wittersheim G, Simon C, Follenius M. Continuous positive airway pressure treatment: effects on growth hormone, insulin and glucose profiles in obstructive sleep apnea patients. Horm Metab Res. 1993;25:375-381.

49. Cooper BG, White JE, Ashworth LA, Alberti KG, Gibson GJ. Hormonal and metabolic profiles in subjects with obstructive sleep apnea syndrome and the effects of nasal continuous positive airway pressure (CPAP) treatment. Sleep. 1995;18:172-179.

50. Aström C. Interaction between sleep and growth hormone evaluated by manual polysomnography and automatic power spectral analysis. Acta Neurol Scand. 1995;92:281-296.

51. Cuneo RC, Salomon F, McGauley GA, Sonksen PH. The growth hormone deficiency syndrome in adults. Clin Endocrinol. 1992;37:387-397.

52. Corpas E, Harman SM, Blackman MR. Human growth hormone and human aging. Endocr Rev. 1993;14:20-39.

53. Rosen T, Hansson T, Granhed H, Szucs J, Bengtsson BA. Reduced bone mineral content in adult patients with growth hormone deficiency. Acta Endocrinol. 1993;129:201-206.

54. Plat L, Féry F, L'Hermite-Balériaux M, Mockel J, Van Cauter E. Metabolic effects of short-term physiological elevations of plasma cortisol are more pronounced in the evening than in the morning. J Clin Endocrinol Metab. 1999;84:3082-3092.

55. Holsboer F, von Bardelein U, Steiger A. Effects of intravenous corticotropin-releasing hormone upon sleep-related growth hormone surge and sleep EEG in man. Neuroendocrinology. 1988;48:32-38.

56. Born J, Späth-Schwalbe E, Schwakenhofer H, Kern W, Fehm HL. Influences of corticotropin-releasing hormone, adrenocorticotropin, and cortisol on sleep in normal man. J Clin Endocrinol Metab. 1989;68:904-911.

57. McEwen BS. Stress, adaptation, and disease. Allostasis and allostatic load. Ann N Y Acad Sci. 1998;840:33-44.