Serum factors in older individuals change cellular clock properties

Abstract

Human aging is accompanied by dramatic changes in daily sleepwake behavior: Activity shifts to an earlier phase, and the consolidation of sleep and wake is disturbed. Although this daily circadian rhythm is brain-controlled, its mechanism is encoded by cellautonomous circadian clocks functioning in nearly every cell of the body. In fact, human clock properties measured in peripheral cells such as fibroblasts closely mimic those measured physiologically and behaviorally in the same subjects. To understand better the molecular mechanisms by which human aging affects circadian clocks, we characterized the clock properties of fibroblasts cultivated from dermal biopsies of young and older subjects. Fibroblast period length, amplitude, and phase were identical in the two groups even though behavior was not, thereby suggesting that basic clock properties of peripheral cells do not change during aging. Interestingly, measurement of the same cells in the presence of human serum from older donors shortened period length and advanced the phase of cellular circadian rhythms compared with treatment with serum from young subjects, indicating that a circulating factor might alter human chronotype. Further experiments demonstrated that this effect is caused by a thermolabile factor present in serum of older individuals. Thus, even though the molecular machinery of peripheral circadian clocks does not change with age, some age-related circadian dysfunction observed in vivo might be of hormonal origin and therefore might be pharmacologically remediable.chronobiology | peripheral oscillators | human behavior C ircadian clocks possess an endogenous periodicity of about 24 h and play a key role in physiological adaptation to the solar day for all living organisms, from cyanobacteria and fungi (1) to insects (2) and mammals (3). Circadian clocks influence nearly all aspects of physiology and behavior, including sleepwake cycles, body temperature, and the function of many organs (3). During normal aging, clock function is attenuated, with consequences both for health and quality of life. Older individuals have an earlier phase of everyday activity compared with the young (4). Not only is the consolidation of sleep and wake dramatically reduced (5, 6), but overall circadian amplitude of hormones and body temperature are lower (7,8), and many agingassociated sleep-wake pathologies have been reported (9-11). As a result, one in five healthy older individuals reports taking sleep medications regularly (9). In cases of pathological aging, chronobiological disturbance is even more acute: Huntington disease, Parkinson disease, and Alzheimer's disease are all associated with profound alterations in sleeping patterns (10-12). These effects of aging on circadian rhythms-diminished circadian amplitude, earlier phase, shorter circadian period, and desynchronization of rhythms in peripheral organs-have been observed widely in several species of mammals (7,13,14). Paradoxically, however, even though the behavioral phase is earlier in aged humans, m...

Effects of aging on circadian patterns of gene expression in the human prefrontal cortex

“…Interestingly, the recognized stimulation of alertness and cognition by blue light seen in young people is diminished in older people, suggesting decreased input to the clock (22). Moreover, the addition of serum from older people to cultured cells that express a circadian reporter construct (Bmal1-luciferase) leads to a shortening of molecular rhythms and a phase advance that is not seen with serum from younger people (23). This finding suggests the presence of circulating factors that alter molecular rhythms with age.…”

Alzheimer’s amyloid-β peptide disturbs P2X7 receptor-mediated circadian oscillations of intracellular calcium

“…1). We used human primary fibroblasts since these cells are an excellent in vitro model of peripheral oscillators [10,56,57] and show a disturbed Ca 2+ homeostasis in AD patients [31,39].…”

“…Therefore the aim of this study was to deepen our understanding of the molecular mechanisms involved in AD-related circadian clock alterations, by investigating i) the clock-dependent regulation of intracellular calcium levels in a peripheral tissue, and; ii) the effect of Aβ peptides on the changes of cytosolic calcium levels around the clock. For this purpose, we used primary cultures of human fibroblasts because: i) fibroblasts coming from AD patients present a disturbed Ca 2+ homeostasis [31,39]; and ii) fibroblasts are a valuable in vitro model of peripheral oscillators [10,56,57].…”

Insomnia Symptoms, Daytime Naps And Physical Leisure Activities In The Elderly: FIBRA Study Campinas

“…At this stage of life, the sleep becomes lighter, less durable and easily interrupted by awakenings (8)(9) .…”

“…In the elderly, the alteration of circadian rhythms may have greater intensity due to other changes that occur with aging and contribute to changes in the sleep-wake cycle (8) . At this stage of life, the sleep becomes lighter, less durable and easily interrupted by awakenings (8)(9) .…”