Modifications of circadian and circannual rhythms with aging.

Whereas biological rhythms are now fairly well documented in young healthy adults, reports in elderly are relatively few for obvious reasons, including the difficulty of setting groups matched in age, sociological and professional background, medical history, and not in need of specific medication. Aging may modify one or several parameters characterizing biological rhythms. The modifications are different from one function to the next, and great care should be given not to mistake changes attributable to the aging process with those resulting from physical and physiological impairment caused by passed environmental aggressions and diseases. Nevertheless, the increasing number of subjects reaching the age of 65 or older, thanks to medical progress, makes necessary establishing time-qualified references values in the aged, as this kind of investigation should lead to an improvement of the conditions and quality of life of elderly subjects.

[Chronobiological approach of aging]. / Approche chronobiologique du vieillissement.

Ageing is a complex, multifactorial phenomenon. The existence of biologic rhythms as well as the study of their modifications or their alteration in the aged are useful and pertinent to understand the biologic age. These modifications, if any, may be interpreted as a change in the adaptability of aged subjects to environmental factors. The loss or decrease of adaptation capacity with ageing is worth quantifying. This paper rounds up the question.

Effects of a two-hour early awakening and of bright light exposure on plasma patterns of cortisol, melatonin, prolactin and testosterone in man.

Bright light is a synchronizing agent that entrains human circadian rhythms and modifies various endocrine and neuroendocrine functions. The aim of the present study was to determine whether and how the exposure to a bright light stimulus during the 2 h following a 2 h earlier awakening could modify the disturbance induced by the the sleep deprivation on the plasma patterns of hormones whose secretion is sensitive to light and/or sleep, namely melatonin, prolactin, cortisol and testosterone. Six healthy and synchronized (lights on: 07.00-23.00) male students (22.5 +/- 1.1 years) with normal psychological profiles volunteered for the study in winter. The protocol consisted of a baseline control night (customary sleep schedule) followed by three shortened nights with a rising at 05.00 and a 2 h exposure to either dim light (50 lux; one week) or bright light (2000 lux; other week). Our study showed a phase advance of the circadian rhythm of plasma cortisol without significant modifications of the hormone mean or peak concentration. Plasma melatonin concentration decreased following bright light exposure, whereas no obvious modifications of plasma testosterone or prolactin patterns could be observed in this protocol.

Effect of shift work on the night-time secretory patterns of melatonin, prolactin, cortisol and testosterone.

In a study of the internal desynchronization of circadian rhythms in 12 shift workers, 4 of them, aged 25-34 years, agreed to be sampled every 2 h during their night shift (0000 hours to 0800 hours). They were oil refinery operators with a fast rotating shift system (every 3-4 days). We found marked changes in the secretory profiles of melatonin, prolactin and testosterone. Melatonin had higher peak-values resulting in a four-times higher amplitude than in controls. With respect to prolactin and testosterone, peak and trough times were erratic and the serum concentrations were significantly decreased in shift workers. Serum cortisol presented a decreased rhythm amplitude together with higher concentrations at 0000 hours in shift workers. This study clearly shows that fast rotating shift-work modifies peak or trough values and rhythm amplitudes of melatonin, prolactin, testosterone and cortisol without any apparent phase shift of these hormones. Whether the large rhythm amplitude of melatonin may be considered as a marker of tolerance to shift work, as reported for body temperature and hand grip strength, since it would help the subjects to maintain their internal synchronization, needs further investigation.

Psychophysiological effects of early morning bright light exposure in young adults.

The effects of bright light on circadian rhythms in man are well documented. Nevertheless the theoretical basis and the rules for the practical utilization of light exposure as therapy need still to be better defined. The present study determined to what extent a 2-hr bright light exposure (0500-0700 h) improved the adjustment to an early rising in normal adults. Phase changes were assessed in subjective alertness, performance in several search tasks, time estimation, and a visual discrimination task, as well as in body motility, plasma cortisol concentrations, and body temperature. In comparison with a dim light exposure, the bright light resulted in increased motor activity during waking, in earlier peak of subjective alertness, and an improvement in performance speed in three out of five tasks in the morning. Cortisol and body temperature also were phase-advanced. In summary, light applied to a portion of the circadian cycle sensitive to phase advance shifts influenced rhythms with strong endogenous components (temperature and cortisol), while other rhythms with strong exogenous components were more sensitive to sleep deprivation caused by the early rising time.

Circadian and seasonal variations of electrolytes in aging humans.

The circadian and seasonal variations of a set of routinely determined variables (chloride, sodium, potassium, calcium, inorganic phosphorus, magnesium, creatinine, urea and urate) were documented in young men (mean age +/- SD: 24.0 +/- 3.9 yr) and in healthy elderly men (75.3 +/- 6.6) and women (78.2 +/- 9.1). The same urinary variables, except magnesium, were studied in young men. The circadian variability of serum variables was between 2 and 11% except for serum inorganic phosphorus (12-22% according to the group). By contrast, urinary chloride, sodium and potassium revealed large peak-trough differences (55-75%) and the variability of urinary creatinine, urate and urea was also not negligible (20-30%). ANOVA validated seasonal variations for most of the plasma variables and for urinary calcium, phosphorus and uric acid. No age or sex difference in either 24 h means or amplitudes could be observed. These data are of interest for the concept of reference values, for the diagnosis of certain bone and renal disease as well as for chronooptimization in treatment of potential electrolytes deficiency states.

Activity of melatonin and other pineal indoles on the in vitro synthesis of cortisol, cortisone, and adrenal androgens.

The in vitro effects of 13 indole compounds on the synthesis of glucocorticoids and of adrenal androgens in sheep adrenal glands has been studied from 11-deoxycortisol as a precursor. This work demonstrates the activating effect of some indole compounds on 11 beta-hydroxylase and 17,20-desmolase and the inhibitory effect of most of them on 11 beta-hydroxysteroid dehydrogenase. Three categories could be distinguished: 1) compounds without any effect (5-hydroxytryptophan, 5-hydroxytryptamine); 2) compounds moderately increasing (10-30% as compared with controls) cortisol yields (tryptamine, melatonin, 6-hydroxymelatonin, 5-methoxytryptophol, indomethacin); and 3) compounds markedly increasing (80-100%) cortisol yields (5-methoxyindole acetic acid, 5-hydroxyindole acetic acid, 2-methylindole, 5-hydroxytryptophol, N-acetyl-5-hydroxytryptamine). In fact, since most of the studied indoles reduced 11 beta-hydroxysteroid dehydrogenase activity, the actual activation of cortisol synthesis was four to five times less. Lastly, all the studied compounds, but melatonin, increased the activity of 17,20 desmolase as seen from 11 beta-hydroxyandrostenedione and 11-ketoandrostenedione yields. The possible in vivo effects of the indoles for therapeutic use needs further studying.

Prevalence of magnesium and potassium deficiencies in the elderly.

Concentrations of magnesium and potassium in erythrocytes and plasma were determined in a population of 381 unselected elderly men and women, most of them in their eighties. The effects of biological factors (age, sex, weight) and a large set of pathological conditions, malignant or not, were examined. Analyses of variance showed a relation between age and concentrations of plasma potassium and between weight and concentrations of plasma magnesium. The chi-square test showed correlations between low concentrations of plasma magnesium and diabetes, abuse of alcohol and tobacco, and also between low values for erythrocyte magnesium and hypertension. Low values for plasma potassium were correlated with hypertension whereas high values were correlated with cardiovascular disease. Although some of the differences in the mean concentrations observed were statistically significant, these differences were always small. Most interesting was the distribution of the concentrations of the cations. This study shows that assays of both of these cations in erythrocytes were better than assays in plasma to evidence a deficiency. Indeed, about 20% of the studied population had low concentrations of both erythrocyte potassium and magnesium, whereas 2 and 10% had low values for plasma potassium and magnesium, respectively. This study underlines the large prevalence of magnesium and potassium deficiencies in the elderly, an observation we could not attribute to pathology or treatment. Routine electrolyte studies therefore appear to be justified in aged human subjects.

Decreased nocturnal plasma melatonin peak in patients with a functional alteration of the retina in relation with uveitis.

A functional alteration of the retina is present in patients suffering from uveitis. Because of the relation between the pineal gland and the retina we documented possible modifications of melatonin secretion in patients with uveitis. Plasma melatonin was assayed in 19 patients and 16 age-matched controls. Blood samples were drawn at the known high and low points of the circadian rhythm of the hormone, i.e. 02.00 and 11.00 h, respectively. We found that the nocturnal peak of plasma melatonin was greatly decreased (45%) in patients with uveitis. These data cannot be related to the impairment of retinal melatonin synthesis alone. The possibility exists that the decline of the nocturnal peak of melatonin we have reported is due to a pineal inflammation in patients with uveitis, as observed in the experimental autoimmune uveitis induced in rats by retinal S-antigen.

Differences between young and elderly subjects in seasonal and circadian variations of total plasma proteins and blood volume as reflected by hemoglobin, hematocrit, and erythrocyte counts.

Circadian and seasonal rhythms in total plasma proteins were documented in healthy young men (around 24 years old), and in elderly subjects (both sexes), including senile-dementia patients in their eighties. The concentration of plasma proteins within a given group changed predictably (7-13%), depending on the hour of sampling and the season. Concentrations decreased noticeably around 04:00 h, then peaked around 08:00 h (shortly after waking). The 24-h mean concentrations of total plasma proteins were lower in the elderly groups than in the young men. But the seasonal variations of the 24-h mean values were strikingly larger in the elderly groups (7-8 g/L) than in the young men (2-5 g/L). Moreover, the circadian profiles of plasma proteins differed from the profiles of hematocrit, hemoglobin, and erythrocyte counts. Evidently, circadian variations of blood volume may not be the only element accounting for the variations of plasma protein concentrations. We suggest that the rhythms in plasma protein concentrations be taken into account when reference values are set. Circadian and seasonal variations in plasma proteins may also significantly affect the transport and binding of drugs, especially in the aged.

Age-related changes in both circadian and seasonal rhythms of rectal temperature with special reference to senile dementia of Alzheimer type.

The biological rhythms of rectal temperature were documented in young (circadian variations) and elderly (circadian and seasonal variations) human subjects either in apparent good health or suffering from senile dementia of Alzheimer type (SDAT). All the subjects were synchronized. Data obtained showed a decrease of the body core temperature rhythm amplitude in the healthy elderly for each documented season but not in patients with SDAT. Seasonal variations in these rhythms were observed in these elderly groups of persons.

Patterns of plasma melatonin with ageing and mental condition: stability of nyctohemeral rhythms and differences in seasonal variations.

Effects of ageing and mental condition on the nyctohemeral and seasonal rhythms of plasma melatonin in human subjects were investigated. Four groups of subjects were formed for a transverse study: 7 healthy young men (24 years), 6 elderly women, 6 elderly men and 6 elderly patients (2 men and 4 women) suffering from senile dementia (70-80 years). The subjects were synchronized. Blood samples were taken every 4 h during 24 h in January, March, June and October. In comparison to young men, the plasma levels of melatonin were markedly decreased (by about one half) in elderly subjects without any difference according to sex or mental condition. Nyctohemeral rhythms of the hormone were validated in all groups and at all sampling sessions. The nyctohemeral acrophases were remarkably stable (around 03.00 h) whatever the season, age or sex. A seasonal variation was found in all groups (except elderly women) with differences between young and elderly subjects: plasma melatonin levels were significantly lower in January than in June in young men, whereas in elderly subjects they were significantly lower in October than in January/March. No significant difference was observed in mesor, amplitude or acrophase of nyctohemeral and seasonal rhythms of plasma melatonin in patients with senile dementia when compared with healthy elderly subjects. The stability of the nyctohemeral peak time whatever the age group or season as opposed to the differences in the seasonal pattern of plasma melatonin according to the age groups raises the problems of both outdoor photoperiod and ageing in ruling the secretion of melatonin in man.

Alterations in circadian rhythmicity in calcium oxalate renal stone formers.

The circadian (circannual for oxalic acid) variations of 13 urinary variables (volume, creatinine, calcium, oxalic acid, glycolic acid, 17-ketosteroids, 17-hydroxycorticosteroids, phosphates, urea, uric acid, chloride, sodium, and potassium) have been documented in 7 calcium oxalate renal stone formers and 7 healthy men (control group). Urine was collected every 4 h over a period of 24 h. All subjects had the same synchronization: diurnal activity from 07(00) to 23(00) +/- 1 h and nocturnal rest; meals were given at fixed clock hours (08(00), 12(30) and 20(00) +/- 1 h). A statistically-significant rhythm (p less than 0.05) was validated for all variables except urea and calcium in healthy men. In renal stone formers, 6 variables (calcium, oxalic acid, and glycolic acid in particular) had no detectable circadian rhythm. However, a periodicity of c. 8 h (ultradian rhythm) was demonstrated for calcium and oxalic acid with peaks being located around 02(00), 10(00), and 18(00). No circannual variations in oxalic acid output could be observed. The present study shows an alteration of the periodicity of calcium and oxalic metabolisms, i.e. the loss of a circadian (24-h) rhythm and the occurrence of an ultradian rhythm of 8 h. The risk of calcium-oxalate crystallisation appears thus greater at 02(00), 10(00), and 18(00). Furthermore, any study dealing with oxalic acid excretion should state the season of urine collection when comparing renal stone formers and healthy subjects, as significant differences in oxaluria may appear during the summer months and not during the rest of the year.

Adrenal circadian system in young and elderly human subjects: a comparative study.

Circadian changes in plasma 18-hydroxy-11-deoxycorticosterone (18-OH-DOC), total and unbound cortisol were studied in four groups: seven healthy young men, six elderly men, six elderly women and six elderly demented patients of both sexes. The daily activities of the subjects were synchronous; blood samples were taken every 4 h and 4 hourly urine samples were collected only from the young men. A circadian rhythm was defined for plasma 18-OH-DOC, total and unbound cortisol in all groups; the secretory patterns of these steroids were parallel, as were the profiles of urinary 18-OH-DOC and unconjugated cortisol. When compared with respect to sex, the 24-h mean level of total cortisol was higher in women; that of unbound cortisol was higher in the three groups of elderly patients than in the young men. No major changes in plasma steroids were observed between elderly demented patients (mainly women) and healthy elderly women. The phasing of total and unbound cortisol showed no major modifications with age, sex or senile dementia. Acrophases of 18-OH-DOC were earlier in elderly patients than in young men. Amplitudes were not modified with sex in elderly patients but were always lower in the demented patients. A circadian rhythm was defined for 18-OH-DOC, unconjugated cortisol, 17-hydroxycorticosteroids (17-OH-CS) and 17-ketosteroids in the urine of the young men. The acrophases of 18-OH-DOC and unbound cortisol were close, as were those of 17-OH-CS and 17-ketosteroids. The lag was short between the acrophases of 18-OH-DOC in plasma and urine and between those of plasma unbound cortisol and urinary unconjugated cortisol; it was much larger between the acrophases of plasma total cortisol and 17-OH-CS. Thus, the process of ageing, and the possible alterations in the central nervous system which are often seen in normal ageing, induced no major modifications in the temporal organization of adrenocortical function, even in subjects who were very advanced in age.

Age- and mental health-related circadian rhythms of plasma levels of melatonin, prolactin, luteinizing hormone and follicle-stimulating hormone in man.

Circadian changes in plasma levels of melatonin, prolactin, LH and FSH were studied in four groups: seven healthy young men, six elderly men, six elderly women and six elderly demented patients (two men and four women). The daily activities of the subjects were synchronous and blood samples were taken every 4 h. The 24-h mean concentrations of prolactin in plasma were the same in all groups, whereas those of LH and FSh were twice as high in the elderly as in the young men and eight and 23 times higher respectively in the elderly women. The 24-h mean plasma levels of melatonin in the elderly were half those in the young, but were not influenced by the sex or mental condition of the subjects. A statistically significant circadian rhythm for melatonin was defined in the four groups, for prolactin in all groups except the elderly men and for LH only in the demented patients and in the young men. No circadian rhythm could be detected for FSH in any of the four groups. The acrophases of melatonin and prolactin ranged between 02.30 and 04.00 h, those of LH (when a rhythm was validated) clustered around 01.00 h. The circadian rhythms of plasma levels of melatonin, prolactin and LH are not modified in old age nor in dementia. A positive correlation has been demonstrated in young men between melatonin and LH and between melatonin and prolactin, but no such correlation could be found in the elderly.

Clinical chronopharmacology of ACTH 1-17. II. Effects on plasma testosterone, plasma aldosterone, plasma and urinary electrolytes (K, Na, Ca and Mg).

The aim of the investigation was to study the effects of ACTH 1-17 on plasma testosterone, plasma aldosterone as well as on both plasma and urinary electrolytes (K, Na, Mg and Ca) in healthy young adult males with regard to the time (clock hours) at which this polypeptide was injected. Eight healthy adults (males from 28 to 30 years) volunteered for the study. The were synchronized with a diurnal activity from 0700 to midnight and a nocturnal rest. Each week, during 6 consecutive weeks (January 19 to February 25, 1980) a 3-day test was performed on Saturday, Sunday and Monday. On Sundays 3 control-tests and the 3 ACTH-tests were programmed during which either saline or 100 microgram ACTH 1-17 were injected i.m. at respectively 0700, 1400 and 2100. During each 3 day-test period (72 h) the urinary excretion of K, Na, Mg and Ca was determined every 4 h at fixed clock hours. In addition, on Sundays, venous blood was sampled prior to control or ACTH injections at respectively 0700, 1400 and 2100 and 20, 40, 60, 90, 120, 150 and 180 min thereafter. Plasma testosterone, aldosterone (radioimmunoassays) K, Na (flame photometry), Mg and Ca (photocolorimetric methods) were determined in the collected samples. Both conventional and cosinor methods were used for statistical analyses. The injection of ACTH at 0700 was followed by a clear and statistically significant rise of plasma testosterone. No change with regard to control occurred when ACTH was injected at either 1400 or at 2100. A statistically significant rise of plasma aldosterone was observed after each of the ACTH injections. However, the highest plasma aldosterone level was reached when ACTH was administered at 1400 and the lowest level at 2100. ACTH-induced changes in plasma electrolytes were either nil (for Na and Ca) or small (for K and Mg). A more or less important increase of urinary K occurred after the ACTH injection at each of the 3 considered times. The highest values of excreted K occurred after the injection of ACTH at 0700, without shift of the acrophase. In contrast, injections of ACTH at 1400 and 2100 induced a dramatic alteration of the K rhythms. ACTH induced an important fall in the Na urinary excretion. This fall was the greatest when ACTH was injected at 1400. Na rhythm alterations also occurred, particularly after ACTH injections at 2100. However, this effect was less pronounced after ACTH injection at 0700 than at other considered time points. The urinary amount of excreted Ca did not seem to be affected by ACTH. Rhythm alterations occurred after ACTH injections at 1400 and 2100. Peaks of plasma testosterone, plasma aldosterone as well as plasma cortisol (reported in a previous paper) resulting from ACTH stimulation coincided in time with the acrophase of the physiological circadian rhythm in plasma levels of these hormones...

Serum magnesium circadian rhythm in human adults with respect to age, sex and mental status.

25 subjects volunteered to document circadian changes in serum magnesium. 4 groups were formed: 7 healthy young males (24.0 years +/- 3.9), 6 elderly males (82.5 years +/- 7.5), 6 elderly females 81.2 years +/- 10.7) and 6 elderly insame subjects of both sexes (80.5 years +/- 8.6). They were socially synchronized with a diurnal activity (07.00 to 21.00 for the old subjects; 07.00 to 23.00 for the young ones) and nocturnal rest. The subjects followed a spontaneous diet. Venous blood was sampled at 4-h intervals and fixed clock hours (07.45, 11.45, 15.45, 19.45, 23.45, 03.45) during 24 h. The single cosinor method was used for the statistical analysis of the time series. A statistically significant circadian rhythm is detected in three of the groups: young males, elderly males and elderly females (no rhythm detection in elderly insane subjects). The 24-h mean is higher in elderly subjects than in the young one. The rhythm amplitude is larger in elderly males than in young ones. The acrophase (peak time) location in the 24-h scale is 10.12 h for elderly females, 11.35 h for elderly males and 16.36 h for young males.