Live to the rhythm, slave to the rhythm

Summary

Circadian rhythms in health and disease have most often been described in terms of their phases and amplitudes, and how these respond to a single exposure to stimuli denoted as zeitgebers. The present paper argues that it is also important to consider the 24-h regularity in the repeated occurrence of the zeitgebers. The effect of the regularity of stimulation by light, melatonin, physical activity, body temperature, corticosteroids and feeding on synchronization within and between the central circadian clock and peripheral oscillators is discussed. In contrast to the phase shifts that can be recorded acutely after a single zeitgeber pulse, the effects of irregularly versus regularly timed zeitgeber can be studied only in long-term protocols and may develop slowly, which is a possible reason why they have received relatively little attention. Several observations indicate a reciprocal relation between the robustness of the endogenous circadian timing system and its dependency on regularly timed zeitgebers. Especially at old age and in disease, proper functioning of the circadian timing system may become more dependent on regularly timed exposure to zeitgeber stimuli. in such conditions, regularly timed exposure to zeitgeber appears to be highly important for health. After a concise introduction on inputs to the central and peripheral oscillators of the circadian timing system, the paper discusses the responses of the circadian timing system and health to (1) a chronic lack of zeitgeber stimuli; (2) fragmented or quasi-ultradian stimuli and (3) repeated phase shifts in stimuli. Subsequently, the specific relevance to aging is discussed, followed by an overview of the effects of experimentally imposed regularly timed stimuli. Finally, a possible mechanism for the gradually evolving effects of repeated regularly timed stimuli on the circadian timing system is proposed.

Introduction

Some may associate the title of this manuscript with long forgotten times, with a dance floor, swinging to the syncopated timing of a 1985 song of singer Grace Jones. Her call to live to the rhythm was only a few years after punk rock musicians, following James Dean's adage, expressed their preference to live fast and die young. Some readers may recognize these music scenes; others may have been too young or old to remember, maybe at the age of getting pushed on a swing by their parents, or the other way around, busy pushing their own child on a swing. What does all this have to do with circadian rhythms? The answer will develop in the discourse of this manuscript, which focuses on how repeated, regular time cues may affect circadian rhythms, and their sequelae for health and well-being, with special relevance to aging.

Many excellent reviews have discussed the complex mechanisms of the central and peripheral oscillators that make up the circadian timing system (CTS) (e.g.1, 2). It is not the aim of the present paper to add another comprehensive review. Rather, the focus will here be on the specific question of what the consequences might be of a lack of input or irregular (versus regular) input impinging on the central and peripheral clocks. To explain what regular versus irregular input means, let us first consider a metaphor. Imagine a child playing on a swing (Figure 1). By stretching and contracting the legs at specific times during the oscillation, and thus systematically raising and lowering its center of mass, the child can continue swinging, i.e. sustain the oscillation, as long as he desires. This swinging behavior is known as a parametric oscillation and can be described with a mathematical function. One could regard this as comparable to a self-sustained oscillator, or an endogenous clock. Experienced children can get into such oscillation by themselves without any push. Well-timed regular pushing still does help them however. This pushing can be regarded comparable to, in circadian terminology, a zeitgeber. A child that does not master the specific leg movement yet is even completely dependent on such regular pushing. In this case, if one stops to push, the oscillation will dampen and eventually stop. One could regard this comparable to a non-self-sustained or dampened oscillator.

Now suppose that the pusher advances the timing of each push, yet keeping the same time interval. This initially disrupts the smoothness and amplitude of the swing oscillation a little, but after a while, it regains its strong amplitude, resynchronized to the phase of the new push timing. One could regard this as a phase-advance, and a similar scenario could be sketched to obtain a phase-delay. The swinging child re-entrains to an altered zeitgeber timing.

The present review focusses on the following part of the metaphor. Suppose that the pusher is really distracted by other interesting on goings in the play garden, consequently does not pay attention to the timing of the push anymore, and as a result often forgets to push, pushes too early and pushes too late. What will happen to the swing oscillation? If the child masters the systematically timed stretching and contracting of the legs very well, it will continue to swing, be it less smooth and comfortably. But if the child does not master the essential movements too well, the oscillation will become erratic, its amplitude will decrease, and possibly the swing even comes to a halt. One could regard this as a metaphor for the first hypothesis here stated; that with irregularly timed zeitgeber a robust rhythm can only be accomplished by a strong endogenous oscillator. The less strong the endogenous oscillator is, the more the vulnerable the oscillation will be to a lack of, or erratic, external stimuli, leading to erratic oscillations and damping.

Another scenario that could also lead to erratic swinging and damping is when the child makes wrongly timed leg movements. What will happen to the swing oscillation in this case? If a parent pushes adequately, this will counteract the damping effect of the erroneous leg movements, and the child will continue to swing, be it less comfortably. But if the parent does not push regularly, the oscillation will clearly become erratic, its amplitude will decrease, and possibly the swing even comes to a halt. One could regard this as a metaphor for the second hypothesis here stated; that with a weak endogenous oscillator a robust rhythm can only be accomplished by a strong and regularly timed zeitgeber. The less strong the external zeitgeber is, the more vulnerable the oscillation will be to internal disturbances, leading to erratic oscillations and damping.

Most of the experimental studies on biological rhythms have either applied a single pulse of a zeitgeber, or repeated identical pulses, to evaluate their effect on the amplitude, phase and phase synchronization of central and peripheral clocks. We here argue that it is worthwhile to also consider the effects of (1) a chronic lack of pulses, (2) multiple (ultradian) pulses and (3) pulses of variable timing, and that doing so may provide a new view on equivocal findings in diseases where involvement of a malfunctioning CTS has been proposed.

The examples that will be given in this manuscript by no means represent a comprehensive review of all relevant studies. They serve to give examples supporting the relevance of investigating prolonged exposure to unusual zeitgeber patterns—be it a lack of circadian modulation, an ultradian pattern, or a non-24 h pattern. Such patterns could have strong implications for clock functions.

After a concise introduction on inputs to the central and peripheral oscillators of the CTS, the paper discusses the responses of the CTS and health to (1) a chronic lack of zeitgeber stimuli; (2) fragmented or quasi-ultradian stimuli; and (3) repeated phase shifts in stimuli. Subsequently, the specific relevance to aging is discussed, followed by an overview of the effects of experimentally imposed regularly timed stimuli. Finally, a possible mechanism for the gradually evolving effects of repeated regularly timed stimuli on the CTS is proposed.