The circadian clock and pathology of the ageing brain

Abstract

Ageing leads to a functional deterioration of many brain systems, including the circadian clock--an internal time-keeping system that generates ∼24-hour rhythms in physiology and behaviour. Numerous clinical studies have established a direct correlation between abnormal circadian clock functions and the severity of neurodegenerative and sleep disorders. Latest data from experiments in model organisms, gene expression studies and clinical trials imply that dysfunctions of the circadian clock contribute to ageing and age-associated pathologies, thereby suggesting a functional link between the circadian clock and age-associated decline of brain functions. Potential molecular mechanisms underlying this link include the circadian control of physiological processes such as brain metabolism, reactive oxygen species homeostasis, hormone secretion, autophagy and stem cell proliferation.

Figure 1. Circadian clock in mammals

(A) A hierarchical organization of the circadian clock. The master pacemaker is located in the SCN of the hypothalamus and generates internal circadian rhythms in gene expression, electrophysiology and hormone secretion; direct projection from the retina transfers information about light/darkness to the SCN, which synchronizes a phase of SCN rhythms with the outside world. Local circadian clocks are found in different brain regions and throughout the body (peripheral oscillators). Electrical and humoral signals from the SCN synchronize phases of local circadian clocks oscillations. Local clocks generate rhythms in gene expression, metabolism and other physiological activities. (B) The molecular circadian oscillator. For the circadian clock transcriptional-translational negative feedback loop positive elements are shown in red, negative elements in yellow, and components that stabilize the loop in grey. Basic-HLH-PAS domain containing transcriptional factors BMAL1 and CLOCK (or NPAS2) regulate the transcription of genes with circadian E box elements in the promoter and represent positive elements of the transcriptional-translational feedback loop. The BMAL1:CLOCK complex activates the expression of Per and Cry genes. PER and CRY represent negative elements of the loop; they form complexes and inhibit the activity of BMAL1:CLOCK and hence their own expression. Rev-Erb-α and RORs represent an additional loop, these transcriptional factors negatively (Rev-Erb-α) and positively (RORs) regulate the expression of BMAL1. Finally, the BMAL1:CLOCK complex regulates the expression of circadian clock controlled genes (CCGs), which provide a circadian output in physiology.

Figure 1. Circadian clock in mammals

(A) A hierarchical organization of the circadian clock. The master pacemaker is located in the SCN of the hypothalamus and generates internal circadian rhythms in gene expression, electrophysiology and hormone secretion; direct projection from the retina transfers information about light/darkness to the SCN, which synchronizes a phase of SCN rhythms with the outside world. Local circadian clocks are found in different brain regions and throughout the body (peripheral oscillators). Electrical and humoral signals from the SCN synchronize phases of local circadian clocks oscillations. Local clocks generate rhythms in gene expression, metabolism and other physiological activities. (B) The molecular circadian oscillator. For the circadian clock transcriptional-translational negative feedback loop positive elements are shown in red, negative elements in yellow, and components that stabilize the loop in grey. Basic-HLH-PAS domain containing transcriptional factors BMAL1 and CLOCK (or NPAS2) regulate the transcription of genes with circadian E box elements in the promoter and represent positive elements of the transcriptional-translational feedback loop. The BMAL1:CLOCK complex activates the expression of Per and Cry genes. PER and CRY represent negative elements of the loop; they form complexes and inhibit the activity of BMAL1:CLOCK and hence their own expression. Rev-Erb-α and RORs represent an additional loop, these transcriptional factors negatively (Rev-Erb-α) and positively (RORs) regulate the expression of BMAL1. Finally, the BMAL1:CLOCK complex regulates the expression of circadian clock controlled genes (CCGs), which provide a circadian output in physiology.

Figure 2. The circadian clock, ageing and cognitive functions

The circadian clock regulates sleep and other brain cognitive functions such as memory and mood in a sleep-dependent and sleep-independent manner. Ageing is associated with a decline in the activity of the circadian system; this decline in turn can contribute to ageing and to age-associated changes in sleep, memory and mood. Neurodegeneration is also associated with ageing and affects sleep and circadian clock functions, this disruption of sleep and circadian rhythms will affect cognitive functions. It is possible that the circadian clock is involved in control of neurodegeneration. Potential circadian clock independent effects of ageing and neurodegeneration on cognitive functions are omitted for simplicity.

Figure 3. Potential mechanisms of circadian clock-dependent regulation of neurodegeneration

The circadian clock regulates metabolism, ROS homeostasis, DNA repair and, probably, autophagy (circadian clock controlled systems and pathways are shown in green). Disruption of circadian system function will compromise the activities of these systems, which will lead to oxidative stress (shown in red) and accumulation of intra- and extra-cellular aggregates in the brain. This in turn will lead to brain cell death and degeneration of brain structures (shown in yellow). Similar mechanisms can contribute to the changes in the brain during the normal ageing.