Healthy clocks, healthy body, healthy mind

Abstract

Circadian rhythms permeate mammalian biology. They are manifested in the temporal organisation of behavioural, physiological, cellular and neuronal processes. Whereas it has been shown recently that these approximately 24-hour cycles are intrinsic to the cell and persist in vitro, internal synchrony in mammals is largely governed by the hypothalamic suprachiasmatic nuclei that facilitate anticipation of, and adaptation to, the solar cycle. Our timekeeping mechanism is deeply embedded in cell function and is modelled as a network of transcriptional and/or post-translational feedback loops. Concurrent with this, we are beginning to understand how this ancient timekeeper interacts with myriad cell systems, including signal transduction cascades and the cell cycle, and thus impacts on disease. An exemplary area where this knowledge is rapidly expanding and contributing to novel therapies is cancer, where the Period genes have been identified as tumour suppressors. In more complex disorders, where aetiology remains controversial, interactions with the clockwork are only now starting to be appreciated.

Figure 1

Clocks, cancer and the cell cycle. (A) The circadian system is linked to the cell-division cycle through circadian control of gene expression and post-translational mechanisms. Transcription of the myelocytomatosis (Myc) oncogene and of Wee1 is circadian and this appears to be a direct target of the CLOCK:BMAL1 complex. The expression of Wee1 is coregulated with that of period homologue genes (Per) and the entry of the cell cycle into M phase is suppressed during the daytime when the transcription of Per (and Wee1) is high. In addition, the PER1 protein interacts with the checkpoint proteins ataxia telangiectasia mutated (ATM) and checkpoint kinase 2 (CHK2), whereas related work has linked the timeless (TIM) and cryptochrome (CRY) proteins with CHK1. Activation of the DNA-damage pathway can also reset the phase of the circadian clock. CDC25, cell division cycle 25; CDK1, cyclin-dependant kinase 1 (adapted from Ref. [2]). (B) Treatment schedules combining oxaliplatin (Oxal), fluorouracil (FU), and leucovorin (LV) administered as a chronomodulated infusion over 4 days (chronoFLO4) or as a conventional infusion over 2 days (FOLFOX2). The abscissa represents alternating spans of 8 hours of darkness, corresponding to the average rest span at night, and 16 hours of light, corresponding to the average duration of daytime wakefulness, over the course of chemotherapy delivery. (C) Overall survival curve for men, indicating a superior survival at 5 years in the chronomodulated (chronoFLO4) chemotherapy group (adapted from Ref. [91]).

Figure 2

The clockwork and neurodegenerative disorders. (A) Representative actograms from healthy control (top) and moderately demented (bottom) patients. Data from 28 consecutive days are double-plotted on a 48-hour time base for clarity. Group daily activity profiles (plotted as means ± SEM) and moderately demented subjects are shown to the right; adapted from Ref. . (B) Progressive changes in the activity–rest cycles of control mice (left) and R6/2 mice (right) before they develop motor and/or cognitive symptoms (6–7 weeks) and after they exhibit overt signs of disease (14–15 weeks). LD, light–dark cycle; DD, constant dim red light.

Figure I

Montage showing the hierarchical nature of circadian rhythms.