Actigraphic sleep-wake patterns and urinary 6-sulfatoxymelatonin excretion in patients with Alzheimer's disease

Recent studies suggest melatonin, due to its antioxidant and free-radical- scavenging actions, may play a role in the neuroprotection against amyloid, which is implicated in the pathogenesis of Alzheimer's disease (AD). In this study, we determined urinary 6-sulfatoxymelatonin (aMT6s) excretion together with actigraphic sleep-wake patterns of untreated male patients with AD who lived at home. Results were compared with those obtained from normal age-matched elderly and normal young male subjects. Similar measurements were also performed in another group of patients with AD who were treated with a cholinesterase inhibitor (Donepezil, Aricept). Total 24h aMT6s values were significantly reduced in elderly controls (19.9h ± 5.2 μg/24h), in those with untreated AD (12.7 ± 4.4 μg/24h), and in patients treated for AD (12.4 ± 4.4 μ g/24h) compared with normal young men (32.8 ± 3.1 μ g/24h). A day-night difference in aMT6s was evident in all young controls, in 50% of elderly controls, in only 20% of patients with untreated AD, and in 67% of those with AD receiving Aricept. Sleep quality (expressed as sleep efficiency, wake time, and long undisturbed sleep duration) was better in young and elderly controls compared with the two groups of patients with AD. There was no significant correlation between aMT6s values or sleep patterns and the severity of cognitive impairment in patients with AD. Taken together, these data suggest that disrupted sleep, decreased melatonin production, and partial lack of day-night difference in melatonin secretion were observed equally in normal elderly and in patients with AD. Our results do not permit drawing any conclusion as to whether changes in urinary aMT6s excretion is correlated with disturbed sleep in patients with AD. (Chronobiology International, 18(3), 513-524, 2001)     

LONG-TERM ALTERATION OF DAILY MELATONIN, 6-SULFATOXYMELATONIN,CORTISOL, AND TEMPERATURE PROFILES IN BURN PATIENTS: A PRELIMINARY REPORT

Melatonin, which shows a robust nycthemeral rhythm, plays the role of an endogenous synchronizer, able to stabilize and reinforce circadian rhythms and maintain their mutual phase relationships. Additionally, melatonin is a potent antioxidant and displays immunological properties. Because free radical generation, immune dysfunction, and sleep and metabolic disorders are involved in the short- and long-term pathophysiology of the burn syndrome, we undertook the study of daily urine melatonin, 6-sulfatoxymelatonin (aMT6s, the main hepatic melatonin metabolite), and cortisol variations plus temperature profiles in burn patients using a non-invasive protocol. Eight patients (6 males, 2 females) were studied on three occasions after admission to the intensive care unit (early session: days 1 to 3; intermediate session: day 10; late session: days 20 to 30). Melatonin, aMT6s, and free cortisol levels were determined in urine samples collected at 4 h intervals over a continuous 24 h span. Core temperature was recorded daily. Controls consisted of healthy subjects in the same age range. Cosinor analysis of the data provided an evaluation of mesor, amplitude, and acrophase of circadian rhythms. Also, we calculated day (D), night (N), and 24 h hormone excretions, N/D ratio for melatonin and aMT6s, and D/N ratio for cortisol. These data were analyzed using Kruskal-Wallis test followed by multiple comparisons. Cosinor analysis did not detect a circadian rhythm in melatonin, aMT6s, or cortisol in any of the three sessions. D melatonin excretion displayed a major increase, resulting in a decreased N/D melatonin ratio, and the melatonin mesor (24 h mean) was increased in the early session, compared with controls. For aMT6s, only the early N/D ratio was decreased, and the mesor of the intermediate session increased. These results were not the consequence of hepatic and/or kidney alteration, as the patients' hepatic and renal parameters were in the normal range. The D and N melatonin/aMT6s ratios of controls and patients were similar, and the aMT6s profiles were superimposed on the melatonin ones, mainly during the day. The D, N, and 24 h cortisol values were increased in all sessions, except for the D level of the early session. The consistently increased mesors in the three sessions provided confirmation. The core temperature profiles were abnormal in all three sessions, mainly during the night, although there was a tendency toward normalization with time. The individual mesors were consistently increased compared with controls. Globally, the abnormalities we report could participate in the pathophysiology of short- and long-term alterations observed in burn syndrome, especially disturbances of sleep, metabolism, and immune function. (Author correspondence: bruno.claustrat@chu-lyon.fr).     

Circadian Phase in Adults of Contrasting Ages

There is evidence that aging may impair phase‐shifting responses to light synchronizers, which could lead to disturbed or malsynchronized circadian rhythms. To explore this hypothesis, 62 elder participants (age, 58 to 84 years) and 25 young adults (age, 19 to 40 years) were studied, first with baseline 1‐wk wrist actigraphy at home and then by 72 h in‐laboratory study using an ultra‐short sleep‐wake cycle. Subjects were awake for 60 minutes in 50 lux followed by 30 minutes of darkness for sleep. Saliva samples were collected for melatonin, and urine samples were collected for aMT6s (a urinary metabolite of melatonin) and free cortisol every 90 minutes. Oral temperatures were also measured every 90 minutes. The timing of the circadian rhythms was not significantly more variable among the elders. The times of lights‐out and wake‐up at home and urinary free cortisol occurred earlier among elders, but the acrophases (cosinor analysis‐derived peak time) of the circadian rhythm of salivary melatonin, urinary aMT6s, and oral temperature were not significantly phase‐advanced among elders. The estimated duration of melatonin secretion was 9.9 h among elders and 8.4 h among young adults (p<0.025), though the estimated half‐life of blood melatonin was shorter among elders (p<0.025), and young adults had higher saliva melatonin and urinary aMT6s levels. In summary, there was no evidence for circadian desynchronization associated with aging, but there was evidence of some rearrangement of the internal phase‐angles among the studied circadian rhythms.     

Circadian Rhythms in 6-Sulphatoxymelatonin and Nocturnal Sleep in Blind Children

This article describes the relationship between melatonin secretion and sleep quality and subjective complaints about sleep in totally blind children. Eleven boarding-school children (mean age 15.2 years) participated. The major urinary melatonin metabolite 6-sulphatoxymelatonin (aMT6s) was measured five times a day for 48 h. Sleep-wake cycles were recorded by continuous actigraphic recordings during the same time period. Results showed that delayed secretory peaks in aMT6s were significantly associated with disturbed nocturnal sleep and with complaints about morning fatigue.     

Circadian Rhythms in 6-Sulphatoxymelatonin and Nocturnal Sleep in Blind Children

This article describes the relationship between melatonin secretion and sleep quality and subjective complaints about sleep in totally blind children. Eleven boarding-school children (mean age 15.2 years) participated. The major urinary melatonin metabolite 6-sulphatoxymelatonin (aMT6s) was measured five times a day for 48 h. Sleep-wake cycles were recorded by continuous actigraphic recordings during the same time period. Results showed that delayed secretory peaks in aMT6s were significantly associated with disturbed nocturnal sleep and with complaints about morning fatigue.     

The effects of low-dose 0.5-mg melatonin on the free-running circadian rhythms of blind subjects

Exogenous melatonin (0.5-10 mg) has been shown to entrain the free-running circadian rhythms of some blind subjects. The aim of this study was to assess further the entraining effects of a daily dose of 0.5 mg melatonin on the cortisol rhythm and its acute effects on subjective sleep in blind subjects with free-running 6-sulphatoxymelatonin (aMT6s) rhythms (circadian period [tau] 24.23-24.95 h). Ten subjects (9 males) were studied, aged 32 to 65 years, with no conscious light perception (NPL). In a placebo-controlled, single-blind design, subjects received 0.5 mg melatonin or placebo p.o. daily at 2100 h (treatment duration 26-81 days depending on individuals' circadian period). Subjective sleep was assessed from daily sleep and nap diaries. Urinary cortisol and aMT6s were assessed for 24 to 48 h weekly and measured by radioimmunoassay. Seven subjects exhibited an entrained or shortened cortisol period during melatonin treatment. Of these, 4 subjects entrained with a period indistinguishable from 24 h, 2 subjects continued to free run for up to 25 days during melatonin treatment before their cortisol rhythm became entrained, and 1 subject appeared to exhibit a shortened cortisol period throughout melatonin treatment. The subjects who entrained within 7 days did so when melatonin treatment commenced in the phase advance portion of the melatonin PRC (CT6-18). When melatonin treatment ceased, cortisol and aMT6s rhythms free ran at a similar period to before treatment. Three subjects failed to entrain with initial melatonin treatment commencing in the phase delay portion of the PRC. During melatonin treatment, there was a significant increase in nighttime sleep duration and a reduction in the number and duration of daytime naps. The positive effect of melatonin on sleep may be partly due to its acute soporific properties. The findings demonstrate that a daily dose of 0.5 mg melatonin is effective at entraining the free-running circadian systems in most of the blind subjects studied, and that circadian time (CT) of administration of melatonin may be important in determining whether a subject entrains to melatonin treatment. Optimal treatment with melatonin for this non-24-h sleep disorder should correct the underlying circadian disorder (to entrain the sleep-wake cycle) in addition to improving sleep acutely.     

Circadian phase in adults of contrasting ages

There is evidence that aging may impair phase-shifting responses to light synchronizers, which could lead to disturbed or malsynchronized circadian rhythms. To explore this hypothesis, 62 elder participants (age, 58 to 84 years) and 25 young adults (age, 19 to 40 years) were studied, first with baseline 1-wk wrist actigraphy at home and then by 72 h in-laboratory study using an ultra-short sleep-wake cycle. Subjects were awake for 60 minutes in 50 lux followed by 30 minutes of darkness for sleep. Saliva samples were collected for melatonin, and urine samples were collected for aMT6s (a urinary metabolite of melatonin) and free cortisol every 90 minutes. Oral temperatures were also measured every 90 minutes. The timing of the circadian rhythms was not significantly more variable among the elders. The times of lights-out and wake-up at home and urinary free cortisol occurred earlier among elders, but the acrophases (cosinor analysis-derived peak time) of the circadian rhythm of salivary melatonin, urinary aMT6s, and oral temperature were not significantly phase-advanced among elders. The estimated duration of melatonin secretion was 9.9 h among elders and 8.4 h among young adults (p < 0.025), though the estimated half-life of blood melatonin was shorter among elders (p < 0.025), and young adults had higher saliva melatonin and urinary aMT6s levels. In summary, there was no evidence for circadian desynchronization associated with aging, but there was evidence of some rearrangement of the internal phase-angles among the studied circadian rhythms.     

The Daily Melatonin Pattern in Djungarian Hamsters Depends on the Circadian Phenotype

Djungarian hamsters (Phodopus sungorus) bred at the Institute of Halle reveal three different circadian phenotypes. The wild type (WT) shows normal locomotor activity patterns, whereas in hamsters of the DAO (delayed activity onset) type, the activity onset is continuously delayed. Since the activity offset in those hamsters remains coupled to “light-on,” the activity time becomes compressed. Hamsters of the AR (arrhythmic) type are episodically active throughout the 24?h. Previous studies showed that a disturbed interaction of the circadian system with the light-dark (LD) cycle contributes to the phenomenon observed in DAO hamsters. To gain better insight into the underlying mechanisms, the authors investigated the daily melatonin rhythm, as it is a reliable marker of the circadian clock. Hamsters were kept individually under standardized laboratory conditions (LD 14:10, T?=?22°C?±?2°C, food and water ad libitum). WT, DAO (with exactly 5?h delay of activity onset), and AR hamsters were used for pineal melatonin and urinary 6-sulfatoxymelatonin (aMT6s) measurement. Pineal melatonin content was determined at 3 time points: 4?h after “light-off” [D?+?4], 1?h before “light-on” [L???1], and 1?h after “light-on” [L?+?1]). The 24-h profile of melatonin secretion was investigated by transferring the animals to metabolic cages for 27?h to collect urine at 3-h intervals for aMT6s analysis. WT hamsters showed high pineal melatonin content during the dark time (D?+?4, L???1), which significantly decreased at the beginning of the light period (L?+?1). In contrast, DAO hamsters displayed low melatonin levels during the part of the dark period when animals were still resting (D?+?4). At the end of the dark period (L???1), melatonin content increased significantly and declined again when light was switched on (L?+?1). AR hamsters showed low melatonin levels, comparable to daytime values, at all 3 time points. The results were confirmed by aMT6s data. WT hamsters showed a marked circadian pattern of aMT6s excretion. The concentration started to increase 3?h after “light-off” and reached daytime values 5?h after “light-on.” In DAO hamsters, in contrast, aMT6s excretion started about 6?h later and reached significantly lower levels compared to WT hamsters. In AR animals, aMT6s excretion was low at all times. The results clearly indicate the rhythm of melatonin secretion in DAO hamsters is delayed in accord with their delayed activity onset, whereas AR hamsters display no melatonin rhythm at all. Since the regulatory pathways for the rhythms of locomotor activity and melatonin synthesis (which are downstream from the suprachiasmatic nucleus [SCN]) are different but obviously convey the same signal, we conclude that the origin of the phenomenon observed in DAO hamsters must be located upstream of the SCN, or in the SCN itself. (Author correspondence: weinert@zoologie.uni-halle.de)     

Melatonin production and light exposure of rotating night workers

Decreased melatonin production, due to acute suppression of pineal melatonin secretion by light exposure during night work, has been suggested to underlie higher cancer risks associated with prolonged experience of night work. However, the association between light exposure and melatonin production has never been measured in the field. In this study, 24-h melatonin production and ambulatory light exposure were assessed during both night-shift and day/evening-shift periods in 13 full-time rotating shiftworkers. Melatonin production was estimated with the excretion of urinary 6-sulfatoxymelatonin (aMT6s), and light exposure was measured with an ambulatory photometer. There was no difference in total 24-h aMT6s excretion between the two work periods. The night-shift period was characterized by a desynchrony between melatonin and sleep-wake rhythms, as shown by higher melatonin production during work and lower melatonin production during sleep when working night shifts than when working day/evening shifts. Light exposure during night work showed no correlation with aMT6s excreted during the night of work (p?>?.5), or with the difference in 24-h aMT6s excretion between the two work periods (p >?.1). However, light exposure during night work was negatively correlated with total 24-h aMT6s excretion over the entire night-shift period (p?相似文献   

Sex differences in the circadian profiles of melatonin and cortisol in plasma and urine matrices under constant routine conditions

Conflicting evidence exists as to whether there are differences between males and females in circadian timing. The aim of the current study was to assess whether sex differences are present in the circadian regulation of melatonin and cortisol in plasma and urine matrices during a constant routine protocol. Thirty-two healthy individuals (16 females taking the oral contraceptive pill (OCP)), aged 23.8 ± 3.7 (mean ± SD) years, participated. Blood (hourly) and urine (4-hourly) samples were collected for measurement of plasma melatonin and cortisol, and urinary 6-sulfatoxymelatonin (aMT6s) and cortisol, respectively. Data from 28 individuals (14 females) showed no significant differences in the timing of plasma and urinary circadian phase markers between sexes. Females, however, exhibited significantly greater levels of plasma melatonin and cortisol than males (AUC melatonin: 937 ± 104 (mean ± SEM) vs. 642 ± 47 pg/ml.h; AUC cortisol: 13581 ± 1313 vs. 7340 ± 368 mmol/L.h). Females also exhibited a significantly higher amplitude rhythm in both hormones (melatonin: 43.8 ± 5.8 vs. 29.9 ± 2.3 pg/ml; cortisol: 241.7 ± 23.1 vs. 161.8 ± 15.9 mmol/L). Males excreted significantly more urinary cortisol than females during the CR (519.5 ± 63.8 vs. 349.2 ± 39.3 mol) but aMT6s levels did not differ between sexes. It was not possible to distinguish whether the elevated plasma melatonin and cortisol levels observed in females resulted from innate sex differences or the OCP affecting the synthetic and metabolic pathways of these hormones. The fact that the sex differences observed in total plasma concentrations for melatonin and cortisol were not reproduced in the urinary markers challenges their use as a proxy for plasma levels in circadian research, especially in OCP users.     

Emergence and evolution of the circadian rhythm of melatonin in children

OBJECTIVE: To assess the age at which the circadian rhythm of melatonin begins. METHODS: 55 children, divided into groups from the neonatal period to 24 months of life, were studied. Urine samples were taken from 28 newborn babies to measure 6-sulfatoxymelatonin (aMT6s). Salivary samples were collected from infants (27 cases), to measure melatonin (aMT). aMT was measured by RIA and aMT6s by ELISA using commercial kits. Changes in the levels of aMT6s and aMT were evaluated using the Friedman test and Wilcoxon matched pair test. RESULTS: The group aged 27-41 days showed statistically significant differences in daily aMT6s and aMT concentrations. The highest values were always found between 24.00 and 8.00 h. This day/night difference persisted from 2-3 to 13-24 months of age. CONCLUSION: The data indicate that the circadian melatonin rhythm appears at the end of the neonatal period and persists thereafter.     

Moderate Changes in the Circadian System of Alzheimer's Disease Patients Detected in Their Home Environment

Alzheimer''s disease (AD) is a neurodegenerative disease often accompanied with disruption of sleep-wake cycle. The sleep-wake cycle is controlled by mechanisms involving internal timekeeping (circadian) regulation. The aim of our present pilot study was to assess the circadian system in patients with mild form of AD in their home environment. In the study, 13 elderly AD patients and 13 age-matched healthy control subjects (the patient''s spouses) were enrolled. Sleep was recorded for 21 days by sleep diaries in all participants and checked by actigraphy in 4 of the AD patient/control couples. The samples of saliva and buccal mucosa were collected every 4 hours during the same 24 h-interval to detect melatonin and clock gene (PER1 and BMAL1) mRNA levels, respectively. The AD patients exhibited significantly longer inactivity interval during the 24 h and significantly higher number of daytime naps than controls. Daily profiles of melatonin levels exhibited circadian rhythms in both groups. Compared with controls, decline in amplitude of the melatonin rhythm in AD patients was not significant, however, in AD patients more melatonin profiles were dampened or had atypical waveforms. The clock genes PER1 and BMAL1 were expressed rhythmically with high amplitudes in both groups and no significant differences in phases between both groups were detected. Our results suggest moderate differences in functional state of the circadian system in patients with mild form of AD compared with healthy controls which are present in conditions of their home dwelling.     

The daily melatonin pattern in Djungarian hamsters depends on the circadian phenotype

Djungarian hamsters (Phodopus sungorus) bred at the Institute of Halle reveal three different circadian phenotypes. The wild type (WT) shows normal locomotor activity patterns, whereas in hamsters of the DAO (delayed activity onset) type, the activity onset is continuously delayed. Since the activity offset in those hamsters remains coupled to "light-on," the activity time becomes compressed. Hamsters of the AR (arrhythmic) type are episodically active throughout the 24 h. Previous studies showed that a disturbed interaction of the circadian system with the light-dark (LD) cycle contributes to the phenomenon observed in DAO hamsters. To gain better insight into the underlying mechanisms, the authors investigated the daily melatonin rhythm, as it is a reliable marker of the circadian clock. Hamsters were kept individually under standardized laboratory conditions (LD 14:10, T=22°C±2°C, food and water ad libitum). WT, DAO (with exactly 5 h delay of activity onset), and AR hamsters were used for pineal melatonin and urinary 6-sulfatoxymelatonin (aMT6s) measurement. Pineal melatonin content was determined at 3 time points: 4 h after "light-off" [D+4], 1 h before "light-on" [L-1], and 1h after "light-on" [L+1]). The 24-h profile of melatonin secretion was investigated by transferring the animals to metabolic cages for 27?h to collect urine at 3-h intervals for aMT6s analysis. WT hamsters showed high pineal melatonin content during the dark time (D+4, L-1), which significantly decreased at the beginning of the light period (L+1). In contrast, DAO hamsters displayed low melatonin levels during the part of the dark period when animals were still resting (D+4). At the end of the dark period (L-1), melatonin content increased significantly and declined again when light was switched on (L+1). AR hamsters showed low melatonin levels, comparable to daytime values, at all 3 time points. The results were confirmed by aMT6s data. WT hamsters showed a marked circadian pattern of aMT6s excretion. The concentration started to increase 3?h after "light-off" and reached daytime values 5 h after "light-on." In DAO hamsters, in contrast, aMT6s excretion started about 6?h later and reached significantly lower levels compared to WT hamsters. In AR animals, aMT6s excretion was low at all times. The results clearly indicate the rhythm of melatonin secretion in DAO hamsters is delayed in accord with their delayed activity onset, whereas AR hamsters display no melatonin rhythm at all. Since the regulatory pathways for the rhythms of locomotor activity and melatonin synthesis (which are downstream from the suprachiasmatic nucleus [SCN]) are different but obviously convey the same signal, we conclude that the origin of the phenomenon observed in DAO hamsters must be located upstream of the SCN, or in the SCN itself.     

Urinary 6-sulphatoxymelatonin excretion is increased in rats after 24 hours of exposure to vertical 50 Hz, 100 μT magnetic field

The effect of exposure to a 50 Hz, vertical magnetic field on the excretion of urinary 6-sulphatoxymelatonin (aMT6s) of rats was studied in a self-controlled experiment. Ten male Wistar rats were kept under 9:15 h light:dark conditions in metabolic cages. The rats were exposed to 1.0 or 100 μT flux density for 24 h. The excretion of aMT6s, which is the primary metabolite of melatonin in the urine, did not show a statistically significant decrease, as measured by ¹²⁵I radioimmunoassay, during or after magnetic field exposure of rats to either flux density. At 100 μT flux density, the increase of aMT6s excretion on the day after exposure was statistically significant (P < .02), compared with the value under exposure, but was not significant compared with the baseline values before exposure. Bioelectromagnetics 18:190–192, 1997. © 1997 Wiley-Liss, Inc.     

Dim Light Melatonin Onset in Alcohol-Dependent Men and Women Compared with Healthy Controls

Sleep disturbances in alcohol-dependent (AD) individuals may persist despite abstinence from alcohol and can influence the course of the disorder. Although the mechanisms of sleep disturbances of AD are not well understood and some evidence suggests dysregulation of circadian rhythms, dim light melatonin onset (DLMO) has not previously been assessed in AD versus healthy control (HC) individuals in a sample that varied by sex and race. The authors assessed 52 AD participants (mean?±?SD age: 36.0?±?11.0 yrs of age, 10 women) who were 3–12 wks since their last drink (abstinence: 57.9?±?19.3 d) and 19 age- and sex-matched HCs (34.4?±?10.6 yrs, 5 women). Following a 23:00–06:00?h at-home sleep schedule for at least 5 d and screening/baseline nights in the sleep laboratory, participants underwent a 3-h extension of wakefulness (02:00?h bedtime) during which salivary melatonin samples were collected every 30?min beginning at 19:30?h. The time of DLMO was the primary measure of circadian physiology and was assessed with two commonly used methodologies. There was a slower rate of rise and lower maximal amplitude of the melatonin rhythm in the AD group. DLMO varied by the method used to derive it. Using 3 pg/mL as threshold, no significant differences were found between the AD and HC groups. Using 2 standard deviations above the mean of the first three samples, the DLMO in AD occurred significantly later, 21:02?±?00:41?h, than in HC, 20:44?±?00:21?h (t?=??2.4, p?=?.02). Although melatonin in the AD group appears to have a slower rate of rise, using well-established criteria to assess the salivary DLMO did not reveal differences between AD and HC participants. Only when capturing melatonin when it is already rising was DLMO found to be significantly delayed by a mean 18?min in AD participants. Future circadian analyses on alcoholics should account for these methodological caveats. (Author correspondence: daconroy@med.umich.edu)     

The Circadian Body Temperature Rhythm in the Elderly: Effect of Single Daily Melatonin Dosing

The present study is part of a more extensive investigation dedicated to the study and treatment of age‐dependent changes/disturbances in the circadian system in humans. It was performed in the Tyumen Elderly Veteran House and included 97 subjects of both genders, ranging from 63 to 91 yrs of age. They lived a self‐chosen sleep‐wake regimen to suit their personal convenience. The experiment lasted 3 wks. After 1 control week, part of the group (n=63) received 1.5 mg melatonin (Melaxen?) daily at 22:30 h for 2 wks. The other 34 subjects were given placebo. Axillary temperature was measured using calibrated mercury thermometers at 03:00, 08:00, 11:00, 14:00, 17:00, and 23:00 h each of the first and third week. Specially trained personnel took the measurements, avoiding disturbing the sleep of the subjects. To evaluate age‐dependent changes, data obtained under similar conditions on 58 young adults (both genders, 17 to 39 yrs of age) were used. Rhythm characteristics were estimated by means of cosinor analyses, and intra‐ and inter‐individual variability by analysis of variance (ANOVA). In both age groups, the body temperature underwent daily changes. The MESOR (36.38±0.19°C vs. 36.17±0.21°C) and circadian amplitude (0.33±0.01°C vs. 0.26±0.01°C) were slightly decreased in the elderly compared to the young adult subjects (p<0.001). The mean circadian acrophase was similar in both age groups (17.19±1.66 vs. 16.93±3.08 h). However, the inter‐individual differences were higher in the older group, with individual values varying between 10:00 and 23:00 h. It was mainly this phase variability that caused a decrease in the inter‐daily rhythm stability and lower group amplitude. With melatonin treatment, the MESOR was lower by 0.1°C and the amplitude increased to 0.34±0.01°C, a similar value to that found in young adults. This was probably due to the increase of the inter‐daily rhythm stability. The mean acrophase did not change (16.93 vs. 16.75 h), although the inter‐individual variability decreased considerably. The corresponding standard deviations (SD) of the group acrophases were 3.08 and 1.51 h (p<0.01). A highly significant correlation between the acrophase before treatment and the phase change under melatonin treatment indicates that this is due to a synchronizing effect of melatonin. Apart from the difference in MESOR, the body temperature rhythm in the elderly subjects undergoing melatonin treatment was not significantly different from that of young adults. The data clearly show that age‐dependent changes mainly concern rhythm stability and synchronization with the 24 h day. A single daily melatonin dose stabilizes/synchronizes the body temperature rhythm, most probably via hypothermic and sleep‐improving effects.     

Is melatonin circadian rhythm a physiological feature associated with healthy longevity? A study of long-living subjects and their progeny

The study investigates the circadian rhythm (CR) of urinary 6-sulphatoxy-melatonin (aMT6s) in long-living (longevous) subjects and their progeny. The aim is to detect whether or not the melatonin CR is a physiological feature associated with healthy longevity. The aMT6s CR was investigated in 10 longevous subjects, 8 of their children and 9 of their grandchildren, all in good health. Control data were obtained respectively from 13 adult subjects and 9 young subjects, in good health, but characterized by a negative family history for longevity. All the subjects were born and living in the same city. The study was performed in the summer of 1996. The aMT6s CR was found to persist in longevous subjects, being characterized by a lower mesor and amplitude. The aMT6s CR was found not to show properties consistently different in children and grandchildren as compared respectively to their adult and young controls. Because of its preservation in longevous subjects, it can be argued that the melatonin CR is a physiological feature associated with healthy longevity. Because of the comparability of aMT6s CR in children and grandchildren, with respect to their controls without a positive family history of longevity, it can be argued that the melatonin CR is not a marker that can be used for an earlier identification of the candidates for longevity.     

Melatonin in sleep disorders and jet-lag

In elderly insomniacs, melatonin treatment decreased sleep latency and increased sleep efficiency. This is particularly marked in Alzheimer's disease (AD) patients. Melatonin is effective to reduce significantly benzodiazepine use. In addition, melatonin administration synchronizes the sleep-wake cycle in blind people and in individuals suffering from delayed sleep phase syndrome or jet lag. Urinary levels of 6-sulphatoxymelatonin decrease with age and in chronic diseases like AD or coronary heart disease. The effect of melatonin on sleep is probably the consequence of increasing sleep propensity (by inducing a fall in body temperature) and of a synchronizing effect on the circadian clock (chronobiotic effect).     

Effect of sleep deprivation on rhythms of clock gene expression and melatonin in humans

This study investigated the impact of sleep deprivation on the human circadian system. Plasma melatonin and cortisol levels and leukocyte expression levels of 12 genes were examined over 48?h (sleep vs. no-sleep nights) in 12 young males (mean?±?SD: 23?±?5 yrs). During one night of total sleep deprivation, BMAL1 expression was suppressed, the heat shock gene HSPA1B expression was induced, and the amplitude of the melatonin rhythm increased, whereas other high-amplitude clock gene rhythms (e.g., PER1-3, REV-ERBα) remained unaffected. These data suggest that the core clock mechanism in peripheral oscillators is compromised during acute sleep deprivation.     

Association of urinary levels of 6-sulfatoxymelatonin (aMT6s) with prevalent and incident hypertension

Laboratory studies indicate that melatonin has beneficial vascular effects. However, epidemiologic studies on the relationship between endogenous levels of melatonin and hypertension in humans are limited. We examined the association of quartile levels of 6-sulfatoxymelatonin (aMT6s) in first morning urines with prevalent and incident hypertension in 777 postmenopausal women who were originally part of a case–control study of breast cancer nested in the Women’s Health Initiative Observational Study. A total of 321 prevalent and 172 incident cases of hypertension were studied. In cross-sectional analyses, higher quartile level of aMT6s was associated with lower odds of hypertension (Q4 versus Q1; odds ratio = 0.57; 95% confidence interval [CI]: 0.3–0.9), after adjustment for age, body mass index and other risk factors. We also examined the association between baseline aMT6s levels and risk of incident hypertension. Compared to women in the lowest quartile of urinary aMT6s, the multivariable-adjusted hazard ratios and 95% CIs of incident hypertension for women in the second, third and highest quartile were 1.16 (0.8–1.8), 0.96 (0.6–1.5) and 1.02 (0.6–1.6), respectively. The mean change in systolic and diastolic blood pressure over 3 years also did not vary by baseline quartile levels of aMT6s. Although we found no evidence of a prospective association between urinary levels of aMT6s and risk of incident hypertension in postmenopausal women, our cross-sectional results provide some possible evidence of a role for physiologic levels of melatonin in hypertension. Additional larger studies are warranted, preferably with a wider range of ages, both genders and multiple melatonin measurements.