Circadian clock communication during homeostasis and ageing

Maintaining homeostasis is essential for continued health, and the progressive decay of homeostatic processes is a hallmark of ageing. Daily environmental rhythms threaten homeostasis, and circadian clocks have evolved to execute physiological processes in a manner that anticipates, and thus mitigates, their effects on the organism. Clocks are active in almost all cell types; their rhythmicity and functional output are determined by a combination of tissue-intrinsic and systemic inputs. Numerous inputs for a specific tissue are produced by the activity of circadian clocks of other tissues or cell types, generating a form of crosstalk known as clock communication. In mammals, the central clock in the hypothalamus integrates signals from external light–dark cycles to align peripheral clocks elsewhere in the body. This regulation is complemented by a tissue-specific milieu of external, systemic and niche inputs that modulate and cooperate with the cellular circadian clock machinery of a tissue to tailor its functional output. These mechanisms of clock communication decay during ageing, and growing evidence suggests that this decline might drive ageing-related morbidities. Dietary, behavioural and pharmacological interventions may offer the possibility to overcome these changes and in turn improve healthspan.