Objectives: The purposes of this study were to identify age-related changes in objectively recorded sleep patterns across the human life span in healthy individuals and to clarify whether sleep latency and percentages of stage 1, stage 2, and rapid eye movement (REM) sleep significantly change with age. Design: Review of literature of articles published between 1960 and 2003 in peer-reviewed journals and meta-analysis. Participants: 65 studies representing 3,577 subjects aged 5 years to 102 years. Measurement: The research reports included in this meta-analysis met the following criteria: (1) included nonclinical participants aged 5 years or older; (2) included measures of sleep characteristics by “all night” polysomnography or actigraphy on sleep latency, sleep efficiency, total sleep time, stage 1 sleep, stage 2 sleep, slow-wave sleep, REM sleep, REM latency, or minutes awake after sleep onset; (3) included numeric presentation of the data; and (4) were published between 1960 and 2003 in peer-reviewed journals. Results: In children and adolescents, total sleep time decreased with age only in studies performed on school days. Percentage of slow-wave sleep was significantly negatively correlated with age. Percentages of stage 2 and REM sleep significantly changed with age. In adults, total sleep time, sleep efficiency, percentage of slow-wave sleep, percentage of REM sleep, and REM latency all significantly decreased with age, while sleep latency, percentage of stage 1 sleep, percentage of stage 2 sleep, and wake after sleep onset significantly increased with age. However, only sleep efficiency continued to significantly decrease after 60 years of age. The magnitudes of the effect sizes noted changed depending on whether or not studied participants were screened for mental disorders, organic diseases, use of drug or alcohol, obstructive sleep apnea syndrome, or other sleep disorders. Conclusions: In adults, it appeared that sleep latency, percentages of stage 1 and stage 2 significantly increased with age while percentage of REM sleep decreased. However, effect sizes for the different sleep parameters were greatly modified by the quality of subject screening, diminishing or even masking age associations with different sleep parameters. The number of studies that examined the evolution of sleep parameters with age are scant among school-aged children, adolescents, and middle-aged adults. There are also very few studies that examined the effect of race on polysomnographic sleep parameters.

https://sites.oxy.edu/clint/physio/article/MetaAnalysisofQuantitativeSleepParametersFromChildhoodtoOldAgeOhayon2004.pdf

Meta-Analysis of Quantitative Sleep Parameters From Childhood to Old Age in Healthy Individuals: Developing Normative Sleep Values Across the Human Lifespan

Three centuries ago, the French philosopher Rene Descartes described the pineal gland as “the seat of the soul,” but it was not until the late 1950s that melatonin, the principal substance secreted by the pineal gland, was identified.1 There is now evidence that melatonin may have a role in the biologic regulation of circadian rhythms, sleep, mood, and perhaps reproduction, tumor growth, and aging (Table 1). However, uncertainties and doubts still surround the role of melatonin in human physiology and pathophysiology. This review summarizes current knowledge about melatonin in humans and its clinical implications. Physiology and Pharmacology In humans, the . . .

Melatonin in humans.

Heterotrimeric G proteins are key players in transmembrane signaling by coupling a huge variety of receptors to channel proteins, enzymes, and other effector molecules. Multiple subforms of G proteins together with receptors, effectors, and various regulatory proteins represent the components of a highly versatile signal transduction system. G protein-mediated signaling is employed by virtually all cells in the mammalian organism and is centrally involved in diverse physiological functions such as perception of sensory information, modulation of synaptic transmission, hormone release and actions, regulation of cell contraction and migration, or cell growth and differentiation. In this review, some of the functions of heterotrimeric G proteins in defined cells and tissues are described.

https://www.physiology.org/doi/pdf/10.1152/physrev.00003.2005

Mammalian G proteins and their cell type specific functions

Data from rodent studies indicate that cumulative stress exposure may accelerate senescence and offer a theory to explain differences in the rate of aging. Cumulative exposure to glucocorticoids causes hippocampal defects, resulting in an impairment of the ability to terminate glucocorticoid secretion at the end of stress and, therefore, in increased exposure to glucocorticoids which, in turn, further decreases the ability of the hypothalamo-pituitary-adrenal axis to recover from a challenge. However, the consensus emerging from reviews of human studies is that basal corticotropic function is unaffected by aging, suggesting that the negative interaction of stress and aging does not occur in man. In the present study, a total of 177 temporal profiles of plasma cortisol from 90 normal men and 87 women, aged 18-83 yr, were collected from 7 laboratories and reanalyzed. Twelve parameters quantifying mean levels, value and timing of morning maximum and nocturnal nadir, circadian rhythm amplitude, and start and end of quiescent period were calculated for each individual profile. In both men and women, mean cortisol levels increased by 20-50% between 20-80 yr of age. Premenopausal women had slightly lower mean levels than men in the same age range, primarily because of lower morning maxima. The level of the nocturnal nadir increased progressively with aging in both sexes. An age-related elevation in the morning acrophase occurred in women, but not in men. The diurnal rhythmicity of cortisol secretion was preserved in old age, but the relative amplitude was dampened, and the timing of the circadian elevation was advanced. We conclude that there are marked gender-specific effects of aging on the levels and diurnal variation of human adrenocorticotropic activity, consistent with the hypothesis of the "wear and tear" of lifelong exposure to stress. The alterations in circadian amplitude and phase could be involved in the etiology of sleep disorders in the elderly.

Effects of gender and age on the levels and circadian rhythmicity of plasma cortisol.

Sleep spindles: an overview

To delineate the physiological effects of aging on basal levels and temporal patterns of neuroendocrine secretions, the 24-h profiles of cortisol, thyroid-stimulating hormone (TSH), melatonin, prolactin, and growth hormone (GH) levels were simultaneously obtained at frequent intervals in eight healthy, active elderly men, age 67-84 yr and in eight young male adults, age 20-27 yr. The study was preceded by an extended period of habituation to laboratory conditions, and sleep was polygraphically recorded. Mean cortisol levels in the elderly were normal, but the amplitude of the circadian rhythm was reduced. Circulating levels of daytime and nighttime levels of both TSH and GH were greatly diminished in old age. In contrast, prolactin and melatonin concentrations were decreased during the nighttime only. The circadian rises of cortisol, TSH, and melatonin occurred 1-1.5 h earlier in elderly subjects, and the distribution of rapid-eye-movement stages during sleep was similarly advanced, suggesting that circadian timekeeping is modified during normal senescence. Despite perturbations of sleep, sleep-related release of GH and prolactin occurred in all elderly men. Age-related decreases in hormonal levels were associated with a decrease in the amplitude, but not the frequency, of secretory pulses. These findings demonstrate that the normal process of aging involves alterations in the central mechanisms controlling the temporal organization of endocrine release in addition to a reduction of secretory outputs.

Neuroendocrine rhythms and sleep in aging men

Dual activation by thyrotropin of the phospholipase C and cyclic AMP cascades in human thyroid.

Iodide oxidation and binding to proteins require a thyroperoxidase and an ill defined H2O2-generating system. The NADP+ supply and, thus, NADPH oxidation are the limiting steps of the pentose phosphate pathway. The purpose of this work was to test the hypothesis that H2O2 generation is a limiting step of iodination and NADPH oxidation and, therefore, of the pentose phosphate pathway. H2O2 produced by dog thyroid slices was measured with the homovanillic fluorescence assay. Our data show that H2O2 generation is stimulated by both the cAMP cascade [as activated by TSH, forskolin and (Bu)2cAMP] and the Ca2(+)-phosphatidylinositol cascade (as activated by carbamylcholine, ionomycin, and 12-O-tetradecanoylphorbol-13-acetate). We used several physiological and pharmacological agents that modulate iodide organification. In all cases there was a strict parallelism between effects on H2O2 generation, iodide binding to proteins, and pentose phosphate pathway activity. Moreover, in TSH- or carbamylcholine-stimulated slices, glucose or Ca2+ depletion, which greatly depressed H2O2 generation, also greatly decreased iodide organification and the activity of the pentose phosphate pathway. The glutathione peroxidase-catalyzed H2O2 reduction in the cytosol, which involves NADPH oxidation and, therefore, increases the NADP supply, also enhances the activity of the pentose phosphate pathway. All of these data strongly support the hypothesis that H2O2 generation in dog thyroid controls iodination of proteins; through the NADPH oxidation resulting from H2O2 production and reduction, hydrogen peroxide also regulates the activity of the pentose phosphate pathway.

The H2O2-Generating System Modulates Protein Iodination and the Activity of the Pentose Phosphate Pathway in Dog Thyroid

There are two major known regulatory pathways in human thyrocytes: the phosphatidylinositol-Ca2+ cascade (PiP2 cascade) and the cAMP cascade. We study here the regulation of the PiP2 cascade by TSH, ATP, NaF, and bradykinin. Our data show that protein iodination and, thus, the synthesis of thyroid hormones in human thyroid is under the control of both the PiP2 cascade and the cAMP cascade. Activation of the PiP2 cascade by TSH (10 mU/mL), NaF, bradykinin, ionomycin, and 12-O-tetradecanoylphorbol-13-acetate stimulates iodide organification. Conversely, activation of the cAMP cascade by forskolin, TSH (0.3 mU/mL), and dibutyryl cAMP inhibits iodide organification. These metabolic effects are correlated to activations and inhibitions of the H2O2-generating system, showing that H2O2 is a limiting factor for protein iodination in these cells. The cascades also regulate in parallel the activity of the pentose phosphate pathway. The effects of various concentrations of TSH on H2O2 generation and [1-14C]glucose oxidation were tested, showing a dual effect with an inhibition of these metabolisms for low concentrations of TSH (that stimulate the cAMP cascade) and an activation for high concentrations of TSH (that stimulate the PiP2 cascade). The control of thyroid secretion differs from that of protein iodination, in that the cAMP cascade greatly enhances secretion, whereas the PiP2 cascade has no effect on basal secretion and even an inhibitory effect on TSH-stimulated secretion (1 mU/mL). We also demonstrate here the presence of an inhibitory effect of iodide on its own organification in human thyroid (Wolff-Chaikoff effect). This effect is probably mediated through an inhibition of the inositol trisphosphate response to TSH and of the H2O2 response to Ca2+.

Role of the cyclic adenosine 3',5'-monophosphate and the phosphatidylinositol-Ca2+ cascades in mediating the effects of thyrotropin and iodide on hormone synthesis and secretion in human thyroid slices.

To delineate the effects of aging on basal and stimulated TSH secretion, we studied the 24-h profile of plasma TSH levels and the TSH response to TRH stimulation (200 μg TRH, iv) in eight healthy elderly men, aged 67–84 yr, and eight normal young men, aged 20–27 yr. Subjects with thyroid antibodies against microsomal or thyroglobulin antigens were excluded. During the 24-h study, blood was sampled at 15-min intervals. TSH levels were measured by an ultrasensitive immunoradiometric assay. Sleep was polygraphically monitored, and circadian and pulsatile TSH variations were quantified using specifically designed computer algorithms. In older men, the 24-h mean TSH concentration was approximately 50% lower than that in young men (0.78 ± 0.37 vs. 1.43 ± 0.41 μU/mL; P < 0.01), but basal T3 levels were only slightly lower (93 ± 12 vs. 115 ± 16 ng/dL; P < 0.02), while basal T4 levels were normal. The normal diurnal variation of TSH levels, with a nocturnal acrophase and an afternoon nadir, as well as the...

Eric Laurent

Papers

Neuroendocrine rhythms and sleep in aging men

Dual activation by thyrotropin of the phospholipase C and cyclic AMP cascades in human thyroid.

The H2O2-Generating System Modulates Protein Iodination and the Activity of the Pentose Phosphate Pathway in Dog Thyroid

Role of the cyclic adenosine 3',5'-monophosphate and the phosphatidylinositol-Ca2+ cascades in mediating the effects of thyrotropin and iodide on hormone synthesis and secretion in human thyroid slices.

Decreased basal and stimulated thyrotropin secretion in healthy elderly men.