Review

The circadian clock and pathology of the ageing brain

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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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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.

Author information

Affiliations

  1. Department of Molecular Genetics, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA.

    • Anna A. Kondratova
  2. Department of Biological, Geological and Environmental Sciences, Center for Gene Regulation in Health and Disease, Cleveland State University, Cleveland, Ohio 44115, USA.

    • Roman V. Kondratov

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Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Roman V. Kondratov.

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.