Living by the clock: The circadian pacemaker in older people

Abstract

The suprachiasmatic nucleus (SCN) of the hypothalamus is considered to be a critical component of a neural oscillator system implicated in the timing of a wide variety of biological processes. The circadian cycles established by this biological clock occur throughout nature and have a period of approximately 24 h. With advancing age, however, these daily fluctuations deteriorate, leading to disrupted cycles with a reduced amplitude. In humans, age-related changes have been described for hormonal rhythms, body core temperature, sleep–wakefulness and several other behavioral cycles. It appears that the disruption of circadian rhythms and the increased incidence of disturbed sleep during aging are paralleled by age-related alterations in the neural and temporal organization of the SCN and a decreased photic input to the clock. The many lines of evidence of age-related decrements in circadian time-keeping and the observed neuronal degeneration of the SCN in senescence strongly suggest that the circadian pacemaker in the human brain becomes progressively disturbed during aging.

Introduction

Many organisms experience circadian oscillations in various biological processes (e.g., neuroendocrine, autonomic, cardiovascular, sleep–wake cycle). Circadian rhythms enable organisms to anticipate periodic changes in the environment and are consequently important adaptive mechanisms. In mammals, these circadian cycles are regulated by an endogenous clock, the central component of which resides in the suprachiasmatic nucleus (SCN) of the hypothalamus. Since the discovery of the SCN as the site of the master circadian pacemaker, many attempts have been undertaken to unravel the mechanisms underlying its endogenous circadian rhythmicity. In particular, lesion and transplantation experiments of the SCN and in vitro slice studies have provided firm evidence for its biological clock characteristics (for reviews, see Buijs et al., 1996, Van Esseveldt et al., 2000, Panda et al., 2002). Lesioning the SCN results in a disappearance of most circadian rhythms and makes the animal arrhythmic, while transplantation of fetal SCN tissue may restore circadian rhythmicity in such lesioned animals. When the SCN is removed from the brain and maintained in a slice preparation, the neurons continue to generate circadian rhythms in electrical activity, secretion and gene expression. Consistent with its role in the temporal organization of circadian processes, investigations in rodents and non-human primates suggest that the SCN is also involved in the seasonal timing of reproduction, sexual behavior and energy metabolism (for a review, see Hofman, 2004).

Studies in humans also seem to support the notion of the SCN being the principal neural substrate that organizes and coordinates circadian rhythms. Clinically documented disruption of circadian behavior shows involvement of the SCN region (Schwartz et al., 1986, Cohen and Albers, 1991) and age-related decrements in circadian time-keeping have been attributed to the observed neuronal degeneration of the SCN in senescence (Swaab et al., 1985, Swaab et al., 1996, Moore, 1991, Hofman, 2000). It appears that photic information may have a synchronizing effect on the clock mechanism of the SCN by inducing changes in the functional activity of groups of neurons. Increasing age and a variety of diseases, however, may impair many of these functions and may have deleterious effects on the neuronal organization and biological activity of the clock. In the present review, recent data on the circadian dynamics of some major neuropeptidergic cell groups in the human SCN are discussed in relation to aging and Alzheimer's disease.