Age-related Changes In Circadian Rhythms Research Articles

Age-Related Changes in Circadian Rhythm and Association with Nutrition.

Considering the increase in life expectancy, there is a time-related decline in biological functions. Age-related changes are also observed in the circadian clock which directly leads to appropriate rhythms in the endocrine and metabolic pathways required for organism homeostasis. Circadian rhythms are affected by the sleep/wake cycle, environmental changes, and nutrition. The aim of this review is to show the relationship between age-related changes in circadian rhythms of physiological and molecular processes and nutritional differences in the elderly. Nutrition is an environmental factor that is particularly effective on peripheral clocks. Age-related physiological changes have an impact on nutrient intake and circadian processes. Considering the known effects of amino acid and energy intakes on peripheral and circadian clocks, it is thought that the change in circadian clocks in aging may occur due to anorexia due to physiological changes.

Age-Related Changes in Circadian Rhythms and Their Effects on Cognition and Psychological Well-Being: A Literature Review

Introduction: Circadian rhythms, the internal “clocks” that control a variety of physiological processes, have been found to change considerably throughout one’s lifetime. Young adults tend to be more “evening” people, while older adults tend to be more “morning” people due to age-related changes in their sleep-wake cycles. This review aims to discuss the corresponding physiological and psychological changes that occur due to the changing circadian rhythms that come with age. Methods: A literature search was conducted using the databases PubMed, PsycINFO, and AgeLine. Keywords included variations of “circadian rhythms”, “aging”, “chronotype”, “cognition”, “depression”, “mood”, “bipolar disorder”, and “anxiety”. Studies were selected and findings regarding the physiological and psychological changes due to circadian rhythms and aging were reviewed. Results: Research shows that age-related disruptions in circadian rhythms are associated with cognitive and psychological decline. Diminished sleep quality is associated with older age, due to the aforementioned underlying dysregulated circadian rhythms. Sleep deprivation is associated with increased levels of fatigue, stress, and overall mood disturbances. Moreover, circadian rhythm abnormalities associated with old age are related to greater mood disturbances, depression, and anxiety. Discussion: Poor sleep and older age are important factors that can negatively affect one’s mood and emotional well-being. It is imperative that healthcare providers consider these factors when consulting and treating patients. Populations such as shift workers have been found to have impaired levels of alertness, mood, memory, and cognitive performance due to their dysregulated circadian rhythms. Furthermore, time of day plays a crucial role in the educational success of children and adolescents. Young individuals with an evening chronotype are put at a disadvantage for early school start times due to their opposing optimal times of performance. Conclusion: Circadian rhythm dysfunction that is commonly associated with aging has the potential to contribute to adverse outcomes in human health, including cognitive deficits and pathological conditions. Future research efforts should concentrate on further clarifying the relationship between changing circadian rhythms and its impact on psychological well-being.

The Peripheral Circadian Clock and Exercise: Lessons from Young and Old Mice.

Critical biological processes are under control of the circadian clock. Disruption of this clock, e.g. during aging, results in increased risk for development of chronic disease. Exercise is a protective intervention that elicits changes in both age and circadian pathologies, yet its role in regulating circadian gene expression in peripheral tissues is unknown. We hypothesized that voluntary wheel running would restore disrupted circadian rhythm in aged mice. We analyzed wheel running patterns and expression of circadian regulators in male and female C57Bl/6J mice in adult (~4 months) and old (~18 months) ages. As expected, young female mice ran further than male mice, and old mice ran significantly less than young mice. Older mice of both sexes had a delayed start time in activity which likely points to a disrupted diurnal running pattern and circadian disruption. Voluntary wheel running rescued some circadian dysfunction in older females. This effect was not present in older males, and whether this was due to low wheel running distance or circadian output is not clear and warrants a future study. Overall, we show that voluntary wheel running can rescue some circadian dysfunction in older female but not male mice; and these changes are tissue dependent. While voluntary running was not sufficient to fully rescue age-related changes in circadian rhythm, ongoing studies will determine if forced exercise (e.g. treadmill) and/or chrono-timed exercise can improve age-related cardiovascular, skeletal muscle, and circadian dysfunction.

Napping in Older Adults: A Review of Current Literature.

Daytime napping-frequently reported among older populations-has attracted increasing attention in geriatric research due to its association with multiple health conditions. This review aims to integrate the latest knowledge about napping in older adults to provide implications for future research. The prevalence of napping in older adults ranges from 20% to 60% in different studies, but has been consistently reported to be higher than in other age groups. Age-related changes in circadian rhythm and sleep patterns, cultural beliefs, chronic conditions, medications, and lifestyle changes contribute to the high prevalence of napping in older adults. Daytime napping has been associated with multiple health conditions in older adults. Naps of short duration (e.g., 30 minutes) are reported in adults with better health; naps with longer durations (e.g., >90 minutes) have been linked to adverse cardiovascular and diabetes outcomes, declining cognitive function, and increased mortality. Current evidence in the literature, however, is not enough for us to determine the exact role of napping in the health of older adults. Longitudinal and interventional studies are needed to investigate the influence of napping and the critical parameters such as duration, timing, and frequency on health in older adults and the underlying mechanisms. A combination of objective and self-reported measurements of napping are recommended instead of self-reported data only.

Phase‐shifting response to light in older adults

Age-related changes in circadian rhythms may contribute to the sleep disruption observed in older adults. A reduction in responsiveness to photic stimuli in the circadian timing system has been hypothesized as a possible reason for the advanced circadian phase in older adults. This project compared phase-shifting responses to 2 h of broad-spectrum white light at moderate and high intensities in younger and older adults. Subjects included 29 healthy young (25.1 ± 4.1 years; male to female ratio: 8: 21) and 16 healthy older (66.5 ± 6.0 years; male to female ratio: 5: 11) subjects, who participated in two 4-night and 3-day laboratory stays, separated by at least 3 weeks. Subjects were randomly assigned to one of three different time-points, 8 h before (-8), 3 h before (-3) or 3 h after (+3) the core body temperature minimum (CBTmin) measured on the baseline night. For each condition, subjects were exposed in a randomized order to 2 h light pulses of two intensities (2000 lux and 8000 lux) during the two different laboratory stays. Phase shifts were analysed according to the time of melatonin midpoint on the nights before and after light exposure. Older subjects in this study showed an earlier baseline phase and lower amplitude of melatonin rhythm compared to younger subjects, but there was no evidence of age-related changes in the magnitude or direction of phase shifts of melatonin midpoint in response to 2 h of light at either 2000 lux or 8000 lux. These results indicate that the acute phase-shifting response to moderate- or high-intensity broad spectrum light is not significantly affected by age.

Circadian clocks of faster developing fruit fly populations also age faster

Age-related changes in circadian rhythms have been studied in several model organisms including fruit flies Drosophila melanogaster. Although a general trend of period (τ) lengthening, reduction in rhythm strength and eventual arrhythmicity with increasing age has been reported, age-related changes in circadian rhythms have seldom been examined in the light of differences in the rate of ageing of the organism. We used four populations of fruit flies D. melanogaster which were selected to develop faster (as pre-adults) to ask if circadian clocks of these flies age faster than their controls. After 55 generations, the selected populations (FD) started developing ~29-h (~12%) faster than the controls (BD) while their circadian clocks exhibited τ ~0.5-h shorter than the controls. We assayed the activity/rest behaviour and adult lifespan of virgin males from the FD and BD populations under constant dark (DD) conditions. The results revealed that FD flies live significantly shorter, and markers of ageing of circadian rhythms set-in earlier in the FD flies compared to the BD controls, which suggests that circadian clocks of faster developing flies age faster than controls. These results can be taken to suggest that ageing of circadian clocks in fruit flies D. melanogaster is a function of its physiological rather than chronological age.

The effects of aging and chronic fluoxetine treatment on circadian rhythms and suprachiasmatic nucleus expression of neuropeptide genes and 5‐HT1B receptors

Age-related changes in circadian rhythms, including attenuation of photic phase shifts, are associated with changes in the central pacemaker in the suprachiasmatic nucleus (SCN). Aging decreases expression of mRNA for vasoactive intestinal peptide (VIP), a key neuropeptide for rhythm generation and photic phase shifts, and increases expression of serotonin transporters and 5-HT(1B) receptors, whose activation inhibits these phase shifts. Here we describe studies in hamsters showing that aging decreases SCN expression of mRNA for gastrin-releasing peptide, which also modulates photic phase resetting. Because serotonin innervation trophically supports SCN VIP mRNA expression, and serotonin transporters decrease extracellular serotonin, we predicted that chronic administration of the serotonin-selective reuptake inhibitor, fluoxetine, would attenuate the age-related changes in SCN VIP mRNA expression and 5-HT(1B) receptors. In situ hybridization studies showed that fluoxetine treatment does not alter SCN VIP mRNA expression, in either age group, at zeitgeber time (ZT)6 or 13 (ZT12 corresponds to lights off). However, receptor autoradiographic studies showed that fluoxetine prevents the age-related increase in SCN 5-HT(1B) receptors at ZT6, and decreases SCN 5-HT(1B) receptors in both ages at ZT13. Therefore, aging effects on SCN VIP mRNA and SCN 5-HT(1B) receptors are differentially regulated; the age-related increase in serotonin transporter sites mediates the latter but not the former. The studies also showed that aging and chronic fluoxetine treatment decrease total daily wheel running without altering the phase of the circadian wheel running rhythm, in contrast to previous reports of phase resetting by acute fluoxetine treatment.

Human molecular circadian rhythms and ageing

Purpose: Validation of an approach to study human circadian rhythms in vitro and investigation of the effect of ageing on period length in this model. Methods: In vitro circadian rhythms were obtained by infecting skin fibroblasts from different donors (10 sighted, 8 blind, 18 young, 18 older) with a lentivirus mBmal-1::luc. Measurements were conducted under standard experimental conditions (bovine serum) or in human serum-containing medium. In vivo circadian period length was additionally analysed in sighted and blind subjects. Results: A good correlation was observed between in vitro and in vivo period length of both sighted and blind people. Between young and older sex-matched subjects no change of the circadian period length of fibroblasts was found under standard experimental conditions. Of note, when human fibroblasts were measured in human serum-containing medium a reduction in period length was found only for cells treated with „older“ serum. Heat-inactivation of sera from older donors almost undid the reduction in the period length suggesting that protein/s is/are responsible for the circadian disturbances observed in the elderly. Conclusions: Fibroblasts are a good model to study circadian rhythms in vitro. The interplay between the molecular components of the skin fibroblasts oscillators does not change during ageing in general. However, the age-related changes in circadian rhythms in vivo and/or in vitro are possibly related to still unknown circulating factors.

Long-Term Follow-up of the Circadian Rhythm of Heart Rate and Heart Rate Variability in Healthy Elderly Patients

The long-term age-related changes in circadian rhythm of heart rate variability (HRV), that is, autonomic nervous activity, remain unknown in elderly people. Holter monitoring was conducted twice at an interval of 15 years in 15 healthy elderly patients (age: 70.0 +/- 4.1 years, at first monitoring, female: 10) and assessed the age-related changes in 24-h mean and hourly mean normal sinus R-R interval (mean NN), HRV (high frequency (HF) component, low frequency (LF) component and LF/HF) and the circadian rhythms. As a result, 24-h mean mean NN (0.976 +/- 0.115 vs 0.903 +/- 0.117 (s), p = 0.0019), LF/HF (1.681 +/- 0.731 vs 0.962 +/- 0.442, p = 0.0022), and LF (278.88 +/- 176.43 vs 179.19 +/- 132.33 (ms2), p = 0.0039) significantly decreased 15 years later, although 24-h mean HF (221.20+/-138.89 vs 310.78+/-296.73 (ms2), p = 0.1102) increased slightly. The hourly mean NN closely correlated with hourly HF and LF/HF throughout circadian rhythms both at first and second monitoring. In the morning hours, amplitude rates of all HRV indices increased significantly 15 years later. In elderly people, age-related changes in the 24-h mean heart rate (HR) were conversely dissociated from those of the 24-h mean HRV. However, the close correlation between hourly HR and HRV was preserved, even in very elderly patients. Additionally, the amplitude rates in HRV in the morning increased with age. These age-related changes of HR and HRV might be characteristic of elderly people.

Age-related changes in circadian rhythm of serotonin synthesis in ring doves: Effects of increased tryptophan ingestion

Alterations in the function of the hypothalamic suprachiasmatic nucleus (SCN) with age have been reported. As serotonin is an important regulator of the circadian clock located in SCN, this work studied the changes produced in the synthesis of serotonin with age using the accumulation of 5-HTP after decarboxylase inhibition as a measure of serotonin synthesis in the brain in vivo, in young and old ring doves at the onset of lights-on and lights-off. A diurnal cycle in tryptophan hydroxylation was observed in young animals, with an increased daylight synthesis and metabolism of 5-HT in hippocampus, neostriatum and hypothalamus. A single dose of melatonin (1 mg/kg, i.p., 1 h) at lighttime produced an inhibitory effect on the synthesis of 5-HT. In contrast, differences in 5-HT synthesis and metabolism between day and night dissappeared in old animals indicating an absence of a circadian rhythm in 5-HT synthesis and metabolism. The administration of l-tryptophan (240 mg/kg, i.p.) strongly increased the 5-HT synthesis in young animals only during lights-off time while it increased in old ones irrespective of the administration time. These results suggest that the supplemental administration of tryptophan might aid to improve the descent in 5-HT that normally occurs, as animals get old.

Spontaneous fos expression in the suprachiasmatic nucleus of young and old mice

The senescence-accelerated mouse (SAMP8) is an animal model of aging that displays an array of circadian rhythm disruptions as early as 7 months of age. The present study explored the physiological basis for age-related changes in circadian rhythms by measuring c-Fos immunostaining. Cellular activity in the SCN “core” and “shell” was examined for 2-, 7-, and 12-month-old SAMP8 at circadian times (CTs) 2 and 14. Consistent with previous studies in rats, we observed higher levels of cellular activity at CT2 than at CT14, and higher levels of activity in the “shell” than in the “core” of the SCN. However, there was no effect of age on the pattern of cellular activity in either the “core” or the “shell” of the SCN. These results are discussed in the context of current research on spontaneous and light-induced c-Fos expression in the SCN of rodents.

Women's sleep in health and disease

A huge amount of knowledge about sleep has accumulated during the last 5 decades following the discovery of rapid eye movement (REM) sleep. Nevertheless, there are numerous areas of considerable ignorance. One of these concerns the particularities of sleep in women. Most basic and clinical studies have been performed in male subjects, and only very recently research groups around the world have addressed women's sleep in health and disease. In this review, we summarize the present knowledge on the influence of oestrogens on the brain and on the distinctive changes of sleep across the menstrual cycle, during pregnancy and menopause. In addition, studies in female rodents are reviewed as well as the knowledge on female peculiarities regarding the interactions between sleep regulation and age-related changes in circadian rhythms. We also address specific aspects of sleep loss and sleep disorders in women. Finally, very recent studies on the sociology of sleep are summarized and future directions in the field are discussed.

Period expression in the honey bee brain is developmentally regulated and not affected by light, flight experience, or colony type

Changes in circadian rhythms of behavior are related to age-based division of labor in honey bee colonies. The expression of the clock gene period ( per) in the bee brain is associated with age-related changes in circadian rhythms of behavior, but previous efforts to firmly associate per brain expression with division of labor or age have produced variable results. We explored whether this variability was due to differences in light and flight experience, which vary with division of labor, or differences in colony environment, which are known to affect honey bee behavioral development. Our results support the hypothesis that per mRNA expression in the bee brain is developmentally regulated. One-day-old bees had the lowest levels of expression and rarely showed evidence of diurnal fluctuation, while foragers and forager-age bees (>21 days of age) always had high levels of brain per and strong and consistent diurnal patterns. Results from laboratory and field experiments do not support the hypothesis that light, flight experience, and colony type influence per expression. Our results suggest that the rate of developmental elevation in per expression is influenced by factors other than the ones studied in our experiments, and that young bees are more sensitive to these factors than foragers.

Aging selectively suppresses vasoactive intestinal peptide messenger RNA expression in the suprachiasmatic nucleus of the Syrian hamster

Aging leads to many changes in the expression of circadian rhythms, including reduced amplitude, altered relationship to the environmental illumination cycle, and reduced sensitivity to phase resetting signals. Neuropeptide synthesizing neurons in the suprachiasmatic nucleus (SCN), the principal circadian pacemaker in mammals, play a role in regulating pacemaker function and in coupling the pacemaker to overt circadian rhythms. Aging may alter the activity of neuropeptide neurons in the SCN, which could be reflected in changes in mRNA expression. Therefore, this study investigated whether aging alters the level or rhythm of expression of neuropeptide mRNAs in the SCN of male Syrian hamsters, a well established model for the study of age-related changes in circadian rhythms. Three age groups of hamsters ( young [3–5 months old], middle-aged [12–15 months old] and old [19–22 months old] were sacrificed at five times of day. Their brains were dissected and sections through the suprachiasmatic nucleus were prepared and used for in situ hybridization for mRNAs for vasoactive intestinal peptide (VIP), arginine vasopressin (AVP) and somatostatin (SS). Aging selectively decreased the SCN expression of VIP mRNA without affecting AVP mRNA or SS mRNA. Also, only AVP mRNA expression exhibited a robust 24-h rhythm, in contrast to previous findings in other species that VIP mRNA and SS mRNA, as well as AVP mRNA, exhibit 24-h rhythms in the SCN. The present findings suggest that age-related reductions in VIP mRNA expression may contribute to the alterations in entrainment and attenuated sensitivity to phase resetting signals that are characteristic of aging. Furthermore, the results demonstrate that neuropeptide gene expression in the SCN is differentially regulated by aging and varies among species.

CIRCADIAN RHYTHMS AND SLEEP IN HUMAN AGING

This issue of Chronobiology International is dedicated to the age-related changes in circadian rhythms as they occur in humans. It seems timely to give an overview of the knowledge and hypotheses on these changes now that we enter a century in which the number and percentage of elderly in the population will be unprecedented. Although we should take care not to follow the current tendency to think of old age as a disease—ignoring the fine aspects of being old—there is definitely an age-related increase in the risk of a number of conditions that are at least uncomfortable.Circadian rhythms have been attributed adaptive values that usually go unnoticed, but can surface painfully clear when derangements occur. Alterations in the regulation of circadian rhythms are thought to contribute to the symptoms of a number of conditions for which the risk is increased in old age (e.g., sleep disturbances, dementia, and depression). A multidisciplinary approach to investigate the mechanisms of age-related changes in circadian regulation eventually may result in treatment strategies that will improve the quality of life of the growing number of elderly.Although diverse topics are addressed in this issue, the possible mechanisms by which a deranged circadian timing system may be involved in sleep disturbances receives the most attention. This seems appropriate in view of the numerous studies that have addressed this relation in the last decade and also because of the high frequency and strong impact of sleep disturbances in the elderly. This introduction to the special issue first briefly addresses the impact of disturbed sleep in the elderly to show that the development of therapeutic methods other than the currently available pharmacological treatments should be given high priority. I believe that chronobiological insights may play an important role in the development of rational therapeutical methods.(Chronobiology International, 17(3), 233–243, 2000)

Circadian rhythm-related behavioral disturbances and structural hypothalamic changes in Alzheimer's disease.

Age-related changes in circadian rhythm (e.g., fragmented sleep-wake patterns) occur in many older persons but are particularly pronounced in patients with Alzheimer's disease. In these patients, disruptions of circadian rhythms can be severe enough to increase mental decline, agitation during the day, and restlessness at night. Moreover, patients whose nocturnal restlessness disrupts the sleep of the caregiver are more likely to be institutionalized than those who have cognitive impairment alone.

Ageing and circadian rhythm of plasma renin and aldosterone

Five men and 8 women, 60–69 yr of age, and 4 men and 5 women, 17–37 yr of age, volunteered for this exploration of possible age-related changes in circadian-rhythm (CR) characteristics of radio-immunoassayable plasma renin (PRA) and aldosterone (PA). Blood was drawn at 06.00, 08.00, 12.00, 18.00, 20.00 and 24.00 from recumbent subjects on a habitual sodium intake of 120–140 mEq/ 24 h. Time-qualified data of PRA and PA, fitted by a 24-h cosine curve, were summarized by a population mean-cosinor method. Circadian characteristics were compared by a multivariate analysis using Hotelling's t 2 test. Rhythmometry reveals in the elderly women a lower mesor ( P < 0.001) and amplitude ( P = 0.036) of the CR in PRA and a higher mesor and amplitude ( P = 0.021 and P = 0.020, respectively) of the PA-CR. The PRA acrophase is delayed ( P < 0.001) in the elderly women (04.40 vs. 08.04) while the timing of the PA acrophase is similar in the age groups of women compared (05.52 vs. 05.20). These differences found in women were not observed in the smaller groups of men. The seventh decade of life may be characterized by an internal circadian desynchronization between the major components of the renin-angiotensin-aldosterone system. A sex-dependent amplification of the extent of circadian variation in aldosterone may precede a decrease in the circadian amplitude occurring during the eighth decade of life, as a sign of the adrenopause in women.