Melatonin and aging: facts and artifacts.
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Aging↗
Biomedical subjects
Y Touitou
Publications and source records attributed to Y Touitou.
Endocrine functions in young men exposed for one night to a 50-Hz magnetic field. A circadian study of pituitary, thyroid and adrenocortical hormones.
In recent years, some epidemiologic studies have suggested that extremely low frequency magnetic and electric fields might affect human health, and, in particular, that the incidence of certain types of cancer, depression, and miscarriage might increase among individuals living or working in environments exposed to such fields. Work in our laboratory studies whether and how changes in the electromagnetic environment might affect human health. The study presented here was designed to look for possible effects of acute exposure to 50-Hz linearly polarized magnetic fields (10 microT) on the hormones of the hypothalamic-pituitary-thyroid and hypothalamic-pituitary-adrenal axes. Thirty-two young men (20-30 years old) were divided into two groups (sham-exposed or control group, and exposed group) of 16 subjects each. All subjects participated in two 24-hour experiments to evaluate the effects of both continuous and intermittent (one hour "off" and one hour "on" with the field switched "on" and "off" every 15 seconds) exposure to linearly polarized magnetic fields. The subjects were exposed to the magnetic field (generated by three Helmholtz coils per bed) from 2300 to 0800 while recumbent. Blood samples were collected during each session at 3 hour intervals from 1100 to 2000 and hourly from 2200 to 0800. Total urine was collected every 3 hours from 0800 to 2300 and then again at 0800. No significant differences were observed between sham-exposed and exposed men for any of the parameters measured: thyroid-stimulating hormone, follicle-stimulating hormone, luteinizing hormone, triiodothyronine, thyroxine, free triiodothyronine, free thyroxine, thyroxine-binding globulin, cortisol, 17-hydroxycorticosteroids (17-OH-CS) and TBK. These results suggest that acute exposure to either continuous or intermittent 50-Hz linearly polarized magnetic fields of 10 microT does not affect, at least under our experimental conditions, these endocrine functions or their circadian rhythmicity in healthy young men.
17-Hydroxycorticosteroids↗
Circadian rhythm period in reaction time to light signals: difference between right- and left-hand side.
The study was designed to test the hypothesis that the prominent rhythm period tau of simple reaction time (SRT) and three-choice reaction time (CRT) to light signals may vary between the dominant (DH) and non-dominant (NDH) hand. Eleven healthy subjects, 8 males (16-74 years, including two left-handed) and 3 females (18-43 years), synchronized with a diurnal activity (approximately 07.00 h to approximately 23.00 h) and a nocturnal rest, volunteered for the study. A battery-powered ambulatory device was used to self-record SRT to a yellow light signal and CRT to yellow, green and red signals. Tests were performed 4-7 times/24 h during a 12- to 15-day span. Power spectra, ANOVA, cosinor, chi2 and correlation tests were used to individually analyze time series. Tau = 24 h in SRT rhythms of DH (8/11 cases) and NDH (6/11 cases) with chi2 = 3.5 and p > 0.05. In CRT rhythms, tau = 24 h for DH (8/11 cases) while tau = 8 h for NDH (7/11 cases), a difference which was statistically significant (chi2 = 9.4 with p < 0.02). Concordant results were obtained with other statistical tests leading to the conclusion that the rather complex cognitive task (CRT) and, to a certain extent, SRT of certain individuals, were associated with tau = 24 h for DH and tau = 8 h for NDH. These findings are in favor of the hypothesis that functional clocks are present in the human brain cortex, associated with the possible expression of rhythms with a prominent period differing from the right- and left-hand side.
Adolescent↗
Ramadan diet restrictions modify the circadian time structure in humans. A study on plasma gastrin, insulin, glucose, and calcium and on gastric pH.
The rule of Ramadan (1 month of food and water intakes restricted to night hours) is followed by the majority of the Moslem fraction of the human population, but the possible consequences of this long-lasting modification of food intake schedule on public health have not yet been extensively documented. Therefore, a group of healthy control subjects and a group of healed duodenal ulcer patients were studied before (controls), during (both groups), and after (both groups) the month of Ramadan. The time-restricted food and water intakes were associated with variations of gastric pH, plasma gastrin, insulin, glucose, and calcium documented on a circadian basis. All of the studied biological variables, except insulin, underwent changes in their 24-h mean concentration (e.g. decrease in gastric pH, increase in plasma gastrin), some of which were still present 1 month after the end of Ramadan. The circadian patterns of all the studied variables were altered during the month of Ramadan. Some differences between the group of healthy control subjects and the group of healed duodenal ulcer patients may suggest a greater susceptibility of the latter to the modifications of feeding and sleeping schedule, which could possibly be a risk factor for the disease.
Adult↗
Morning versus afternoon gymnastic time and diurnal and seasonal changes in psychophysiological variables of school children.
The aims of this study were to document time-related (morning versus afternoon) effects of physical activities (gymnastics) on a set of physiological and psychological variables in school children, including diurnal changes. For the study, 61 boys and 69 girls, 6 to 11 years of age, volunteered. They were considered healthy according to routine clinical criteria. They were synchronized with diurnal activity from around 07:00 to 21:00 and nocturnal rest, time of year being taken into account. Tests were performed at school during 4 weeks of 4.5 days of school at fixed clock hours: 09:00, 11:00, 14:00, and 16:00. Gym time was randomized with regard to week order and season. Four different classes (39 boys and 38 girls) were involved in psychophysiological tests, and two different classes (22 boys and 31 girls) collected saliva samples for morning free cortisol determination. Both t-test and three-factor analysis of variance (ANOVA) were used for statistical analyses. Better performances were obtained in June than in mid-winter with reference to letter cancellation and random number addition tests. As a group phenomenon, morning (09:00 to 10:00) versus afternoon (14:00 to 15:00) gym was not an influential condition with regard to sleep duration, oral temperature, self-rated fatigue and drowsiness, letter cancellation, addition tests, or salivary cortisol. However, gym-time-related differences were observed in classes of younger subjects (e.g., 6-7 years) with regard to self-rated fatigue and the letter cancellation test. Such variability among subgroups suggests that interindividual differences are likely to exist in younger children with regard to manipulation of environmental factors. In addition, gym itself (without gym time consideration) may be an influential factor with regard to diurnal patterns of some variables (e.g., the letter cancellation test).
Body Temperature↗
Serum neuron-specific enolase in patients with pituitary adenoma.
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Adenoma↗
Pharmacokinetically guided melatonin scheduling in rats with circadian system suppression.
To obtain a pharmacologic effect of melatonin in rats kept under prolonged continuous light exposure, conditions known to produce functional suppression of the circadian system, mimicking of the physiologic 24-h pattern of melatonin secretion, a hormonal signal of darkness exposure may be needed. The delivery scheme for melatonin was established in rats in the present studies. First, the plasma pharmacokinetics of [3H]melatonin were determined in rats kept under continuous light and in rats synchronized by exposure to alternating 12 h light and 12 h darkness (LD 12:12) in the early light span. The pharmacokinetics of total radioactivity were similar in both groups. Further quantitation of melatonin by thin-layer chromatography revealed differences dependent on light conditions. The mean plasma clearance and steady-state distribution volume were approximately twice as low with continuous light as with LD 12:12. Plasma protein binding of melatonin was approximately 33%, irrespective of group or sampling time. These pharmacokinetic parameters were used to devise a 24-h periodic delivery schedule consisting of a 6-h constant infusion of exogenous melatonin, followed by an 18-h melatonin-free interval. In a second study, the melatonin 24-h pattern was estimated from the measurement of 2-h fractions of urinary 6-sulfatoxymelatonin excretion for 4 days. 6 unrestrained rats kept under continuous light received melatonin for 2 days from 22:00 to 04:00 h through an indwelling jugular catheter, connected to a reservoir from a programmable pump. Only the administration of low doses (0.01 mg/kg/day) resulted in both a circadian pattern for 6-sulfatoxymelatonin excretion and normal physiological values during the infusion-free intervals. The resynchronizing efficacy of this schedule should be tested in rats with functional suppression of the circadian system.
Animals↗
Increased delta aminolevulinic acid and decreased pineal melatonin production. A common event in acute porphyria studies in the rat.
Tryptophan (TRP) is the precursor of melatonin, the primary secretory product of the pineal gland. Hepatic heme deficiency decreases the activity of liver tryptophan pyrrolase, leading to increased plasma TRP and serotonin. As a paradox, patients with attacks of acute intermittent porphyria (AIP), exhibit low nocturnal plasma melatonin levels. This study using a rat experimental model was designed to produce a pattern of TRP and melatonin production similar to that in AIP patients. Pineal melatonin production was measured in response to: (a) a heme synthesis inhibitor, succinylacetone, (b) a heme precursor, delta-aminolevulinic acid (Ala), (c) a structural analogue of Ala, gamma-aminobutyric acid. Studies were performed in intact rats, perifused pineal glands, and pinealocyte cultures. Ala, succinylacetone, and gamma-aminobutyric acid significantly decreased plasma melatonin levels independently of blood TRP concentration. In the pineal gland, the key enzyme activities of melatonin synthesis were unchanged for hydroxyindole-O-methyltransferase and decreased for N-acetyltransferase. Our results strongly suggest that Ala overproduced by the liver acts by mimicking the effect of gamma-aminobutyric acid on pineal melatonin in AIP. They also support the view that Ala acts as a toxic element in the pathophysiology of AIP.
Acetylserotonin O-Methyltransferase↗
Acute exposure to 50 Hz magnetic field does not affect hematologic or immunologic functions in healthy young men: a circadian study.
Some epidemiological studies report a relationship between magnetic field exposure and such human diseases as leukemia and immune system disturbances. The few published studies on animals do not demonstrate field exposure-related alterations in hematologic and immune systems. The data presented here are part of a broader study designed to investigate the possible effects of acute exposure to a 50 Hz linearly polarized magnetic field (10 microT) on hematologic and immunologic functions. Thirty-two young men (20-30 years old) were divided into two groups (control group i.e., sham-exposed. 16 subjects; exposed group, 16 subjects). All subjects participated in two 24 h experiments to evaluate the effects of both continuous and intermittent (1 h "off" and 1 h with the field switched "on" and "off" every 15 s) exposure to linearly polarized magnetic fields. The subjects were exposed to the magnetic field (generated by three Helmholtz coils per bed) from 23:00 to 08:00 while lying down. Blood samples were collected during each session at 3 h intervals from 11:00 to 20:00 and hourly from 22:00 to 08:00. No significant differences were observed between sham-exposed (control) and exposed men for hemoglobin concentration, hematocrit, red blood cells, platelets, total leukocytes, monocytes, lymphocytes, eosinophils, or neutrophils. Immunologic variables [CD3, CD4, CD8, natural killer (NK) cells and B cells] were unaltered. To our knowledge, this study is the first to document the effects of a 50 Hz magnetic field on the circadian rhythm of human hematologic and immune functions, and it suggests that acute exposure to either a continuous or an intermittent 50 Hz linearly polarized magnetic field of 10 microT, at least under the conditions of our experiment, does not affect either these function or their circadian rhythms in healthy young men.
Adult↗
Magnetic fields and pineal function in humans: evaluation of nocturnal acute exposure to extremely low frequency magnetic fields on serum melatonin and urinary 6-sulfatoxymelatonin circadian rhythms.
Exposure to a 50/60-Hz electromagnetic field can decrease the nocturnal production of melatonin in rodents. Melatonin is considered to be a marker of circadian rhythms, and abnormalities in its secretion are associated with clinical disorders, including fatigue, sleep disruption, mood swings, impaired performance, and depression, which are consequences of desynchronisation. Interestingly, some epidemiological studies have been reported finding most of these clinical disorders in individuals living or working in an environment exposed to electromagnetic fields. This experiment was designed to look for the possible effects of acute exposure (9 hours) to 50-Hz linearly polarized magnetic fields (10 mu T) on the pineal function. Thirty-two young men (20-30 years old) were divided into two groups (control group, i.e., sham-exposed: 16 subjects; exposed group: 16 subjects). All subjects participated in two 24-hour experiments to evaluate the effects of both continuous and intermittent exposure to linearly polarized magnetic fields. They were synchronized with a diurnal activity from 08:00 to 23:00 and nocturnal rest. The experiment lasted two months (mid-February to mid-April). The subjects were exposed to the magnetic fields (generated by three Helmholtz coils per bed) from 23:00 to 08:00, while lying down. Blood samples were collected during each session at 3-hour intervals from 11:00 to 20:00 and hourly from 22:00 to 08:00. Total urine was collected every 3 hours from 08:00 to 23:00 and once during the night, from 23:00 to 08:00. The levels of serum melatonin and its metabolite in urine (6-sulfatoxymelatonin) in exposed men did not differ significantly from those in control (sham-exposed) subjects. This study shows that nocturnal acute exposure to either continuous or intermittent 50-Hz linearly polarized magnetic fields of 10 mu T does not affect melatonin secretion in humans.
Adult↗
Day-night differences in the effects of gonadal hormones on melatonin release from perifused rat pineals. Evidence of a circadian control.
The effects of testosterone (10(-3) M, 10(-6) M, and 10(-9) M) and 17 beta-estradiol (10(-3) M and 10(-9) M) were looked for upon isoproterenol-stimulated melatonin release by perifused pineal glands removed from male rats and female rats in diestrus. Two different times of a 12/12 hour light/dark cycle, i.e., 7 and 19 hours after light onset, were documented in order to look for the existence of a circadian stage-dependence of the hormone effects. Both testosterone (45-60%) and estradiol (60-80%) markedly increased melatonin release by glands removed during the dark span and not during the light span. These results show a direct effect of gonadal hormones on pineal melatonin release and strongly suggest a time-related effect of these hormones on pineal function.
Adrenergic beta-Agonists↗
Detrimental influence of bright light exposure on alertness, performance, and mood in the early morning.
The aim of this study was to assess the effects of exposure for one night to moderate bright light (BL) on subjective and objective measures of alertness, performance, and mood. Eight subjects were exposed to either BL or dim light (DL) during one night. During the previous day, they were exposed to bright light in both experimental conditions. Nocturnal BL suppressed melatonin secretion and increased body temperature. The ability to stay awake during the night, as measured by the power density in the alpha band, was significantly improved by BL exposure. BL also improved subjective alertness and performance during the first part of the night. However, improvements in the last two variables were followed by marked disruption in early morning patterns, with deterioration of mood and motivation.
Adult↗
Disruption of the circadian patterns of serum cortisol in breast and ovarian cancer patients: relationships with tumour marker antigens.
Few data are available on the circadian rhythmicity in cancer patients. Since monitoring the disease usually implies the follow-up of blood concentrations of a number of biological variables, it would be of value to examine the profile of the circadian variations of serum cortisol and tumour marker antigens. This we did in 33 cancer patients (13 breast cancer patients and 20 ovarian cancer patients). The profiles of serum cortisol were documented, since this hormone is considered as a strong marker of circadian rhythms. This study shows that 8 out of 13 breast cancer patients and 15 out of 20 ovarian cancer patients had deeply altered cortisol circadian patterns. The modifications were either high levels along the 24 h scale and/or erratic peaks and troughs and/or flattened profiles. Within 24 h, variations of tumour marker antigens as large as 70% were observed but no typical individual circadian patterns could be found. No relationship between cortisol subgroups and concentration of tumour marker antigens at 8 h could be observed (Kolmogorov-Smirnov's test). The question thus arises as to the origin of these alterations, and whether they are related to a cause or a consequence of the disease, and their possible incidence upon therapeutic designs.
Adult↗
Exploring the EMF-Melatonin Connection: A Review of the Possible Effects of 50/60-Hz Electric and Magnetic Fields on Melatonin Secretion.
This study analyzed the experimental data about the relationship between exposure to 50/60-Hz electric and magnetic fields (EMF) and melatonin secretion by the pineal gland. The authors report their results and discuss possible health consequences, in the light of epidemiologic data suggesting that breast neoplasms and depressive disorders might be related to EMF. The nocturnal peak of melatonin has been reported to be diminished, or time-shifted, or both, in rodents exposed to electric and/or magnetic fields. Current experimental data from primates and humans are insufficient to show that this change occurs in them. Epidemiologic studies of associations between EMF exposure and breast cancer and between EMF exposure and depressive disorders suggest that modifications of melatonin secretion could be a biologic signal of these effects. Nonetheless, changes in melatonin secretion cannot yet be considered a verified biologic explanation of any such association.
Journal Article↗
Oral contraceptives alter circadian rhythm parameters of cortisol, melatonin, blood pressure, heart rate, skin blood flow, transepidermal water loss, and skin amino acids of healthy young women.
Sixteen healthy women users and nonusers of oral contraceptives (OC) volunteered to document a set of circadian rhythms. Nine were taking OC providing ethynyl estradiol (0.03-0.05 mg/24h, 21 days/month) combined with DL- or L-norgestrel or norethisterone. There was no group difference (p > 0.05) in median age (22 years), weight (57 kg), and height (162) cm). Data were obtained at fixed hours, 5 times/24h, during a 48-h span, in November. (Day activity from approximately 08:00 to approximately 23:00 h and night rest). Environmental conditions were controlled, using air-conditioned rooms of constant temperature (26 degrees +/- 0.5) and relative humidity 45% +/- 1. Both cosinor and ANOVA were used for statistical analyses. All circadian rhythms were validated with one exception: that of salivary melatonin was not detected in OC users. The 24h mean (M) exhibited group differences for certain variables: M was greater in OC than non-OC users for systolic blood pressure (p < 0.0001), heart rate (p < 0.01), skin blood flow (p < 0.04), and transepidermal water loss (p < 0.02). M was lower in OC than non-OC users in salivary cortisol (p < 0.04) and skin amino acids (p < 0.003). No group difference was detected in any other documented rhythms: diastolic blood pressure, grip strength of both hands, oral temperature, self-rated fatigue, and the skin variables of urea, lactate, triglycerides, and acid phosphatase activity.
Adult↗
The effect on body temperature and melatonin of a 39-h constant routine with two different light levels at nighttime.
Eight healthy subjects were studied during 39-h spans (from 07:00 on one day until 22:00 the second) in which they remained awake. During one experiment, subjects were exposed to 100 lux of light between 18:00 and 8:00, and during a second experiment, they were exposed to 1000 lux during the same time span. Throughout the daytime period, they were exposed to normal daylight (1500 lux or more). The nighttime 1000-lux light treatment suppressed the melatonin metabolite aMT6s, while the 100 lux treatment did not. On the treatment day, the 1000 lux, in comparison to the 100 lux, light treatment resulted in both an elevated temperature minimum and a delay in its clock-time occurrence overnight. No real circadian phase shift in the temperature, urinary melatonin, or cortisol rhythms was detected after light treatment. This study confirmed that nocturnal exposure to lower light intensities is capable of modifying circadian variables more than previously estimated. The immediate effects of all-night light treatment are essentially not different from those of evening light. This may be important if bright light is used to improve alertness of night workers. Whether subsequent daytime alertness and sleep recovery are affected by the protocol used in our study remains to be determined.
Adult↗
[Study of control of the production of melatonin by perifusion of pineal bodies in rats].
We have documented the kinetic characteristics of melatonin production in perifused pineals removed from rats sacrified at 6 circadian stages (L:D = 12:12) i.e. 3, 7, 11, 15, 19, 23 hours after light onset (HALO). The initial melatonin production levels were as expected higher in glands removed during the dark than in those removed during the light. The higher the initial level was, the more rapide it decreased. Whatever the circadian stage the melatonin production decreased during the first 3-4 hours, then remained fairly constant up to 8 hours of perifusion. The perifusion of rat pineal glands removed at different times of the light-dark cycle showed a greater, beta-adrenergic-stimulated production of melatonin in glands obtained at the beginning of either the light or the dark stage. The effect of isoproterenol was found dependent upon its enantiomeric forms (-, +/-, +). The relative order of potency was (-) > (+/-) > (+) enantiomer. These results show that the response of pineal beta-adrenergic receptors to isoproterenol is stereospecific this response is also circadian stage dependent.
Adrenergic beta-Agonists↗
[Introduction to biological rhythms in the domain of health].
This review presents the characteristics of biological rhythms and of their components. A number of points dealing with the specific needs in experimental protocols - e.g. in a circadian study - are here discussed. Last, examples in human physiopathology are given, which emphasize the need to take into account biological rhythms in health and disease.
Biological Clocks↗