Changes in Circadian Rhythms Dysregulate Inflammation in Ageing: Focus on Leukocyte Trafficking

Abstract

Leukocyte trafficking shows strong diurnal rhythmicity and is tightly regulated by circadian rhythms. As we age, leukocyte trafficking becomes dysregulated, contributing to the increased systemic, low-grade, chronic inflammation observed in older adults. Ageing is also associated with diminished circadian outputs and a dysregulation of the circadian rhythm. Despite this, there is little evidence to show the direct impact of age-associated dampening of circadian rhythms on the dysregulation of leukocyte trafficking. Here, we review the core mammalian circadian clock machinery and discuss the changes that occur in this biological system in ageing. In particular, we focus on the changes that occur to leukocyte trafficking rhythmicity with increasing age and consider how this impacts inflammation and the development of immune-mediated inflammatory disorders (IMIDs). We aim to encourage future ageing biology research to include a circadian approach in order to fully elucidate whether age-related circadian changes occur as a by-product of healthy ageing, or if they play a significant role in the development of IMIDs.

Keywords: chronotherapy; circadian rhythm; inflammation; leukocytes; trafficking.

Figure 1

Circadian regulation of leukocyte trafficking. Migration of leukocytes such as lymphocytes, neutrophils and monocytes, out of circulation and into surrounding tissues is regulated by circadian clocks. Hematopoietic stem cells (HSPCs) and mature leukocytes (except CD8⁺ T cells) peak in the circulation during the rest phase as there’s less migration out of the blood and increased migration of leukocytes and haematopoietic stem cells out of the bone marrow. Conversely, circulating HPSCs and mature leukocytes (except CD8⁺ T cells) are at their lowest during the active phase due to increased leukocyte recruitment to tissues and reduced migration out of the bone marrow. Leukocyte migration is regulated by diurnal changes in expression of chemokines and adhesion molecules, and fluctuating glucocorticoid levels and adrenergic signalling. With increasing age, leukocyte trafficking becomes dysregulated due to a multitude of factors. Senescent cells accumulate and increase secretion of pro-inflammatory cytokines, glucocorticoid levels decrease and signalling becomes dysregulated, several age-associated changes occur to cytokine and adhesion molecule expression, and circadian outputs diminish. All of these contribute to dysregulated leukocyte trafficking seen in older adults.