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  • Review Article
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The circadian clock and pathology of the ageing brain

Key Points

  • Recent data suggest that the circadian clock regulates cognitive functions such as memory and mood in a sleep-dependent and sleep-independent manner.

  • Some circadian clock proteins are important regulators of longevity; for example, BMAL1, NPAS2, CRY and PER.

  • Circadian rhythms in sleep and behaviour are significantly affected by ageing; this impairment can contribute to the cognitive decline of the ageing brain.

  • Circadian rhythms in sleep and behaviour are markedly disturbed in patients with Alzheimer's disease, Parkinson's disease and Huntington's disease.

  • Circadian clock disruption can serve as a biomarker of progression in a neurodegenerative disease.

  • Circadian-clock-dependent control of metabolism, oxidative stress response, DNA repair and autophagy can contribute to brain ageing and neurodegeneration.

  • Restoration of circadian clock function in animal models of neurodegeneration improves cognitive performance and increases the lifespan of these animals.

  • Restoration of circadian rhythms with combined light and melatonin therapy improves sleep quality in humans.

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.

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Figure 1: The circadian clock in mammals.
Figure 2: The circadian clock, ageing and cognitive functions.
Figure 3: Potential mechanisms of circadian clock-dependent regulation of neurodegeneration.

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Acknowledgements

We thank the three anonymous referees for critical reading of the manuscript and for suggestions. We thank W. Samsa for editorial help. This work was supported by grants 1R03AG033881 and 1R01AG039547 to R.V.K.

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Glossary

Circadian clock

A complex of genetically determined molecular, cellular and physiological processes that result in the generation of 24-hour rhythms (known as circadian rhythms) in organism behaviour, metabolism and other functions.

Advanced sleep phase syndrome

(ASPS). A circadian rhythm sleep disorder that causes a few hours advanced phase in circadian rhythms and the sleep–wake cycle. Familial ASPS is a genetically determined syndrome associated with a mutation in the circadian clock gene period 2 (PER2) or in casein kinase 1 delta (CSNK1D).

Delayed sleep phase syndrome

Also known as delayed sleep phase disorder, this syndrome is a circadian rhythm sleep disorder that causes a few hours delayed phase in circadian rhythms and the sleep–wake cycle. Treatments include light therapy, sleep-phase chronotherapy and melatonin administration.

Long-term potentiation

(LTP). LTP is an enhancement in synaptic strength and a candidate cellular mechanism of learning and memory.

Synaptic rewiring

Also known as synaptic plasticity, this is a process of formation and elimination of synapses in the nervous system.

Mitophagy

Mitophagy is a process of removing mitochondria through macroautophagic pathways.

Light therapy

An experimental therapy that has been used to treat disorders associated with disrupted circadian rhythms. Patients are exposed to light (daylight or artificial light) of defined intensity at specific times of the day.

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Kondratova, A., Kondratov, R. The circadian clock and pathology of the ageing brain. Nat Rev Neurosci 13, 325–335 (2012). https://doi.org/10.1038/nrn3208

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