One of the interesting aspects

One of the interesting aspects of the findings in this study is the dissociation between the large phase advances/delays observed in the biochemical rhythms and the much more moderate changes in the sleep/wake cycle. We believe that this discrepancy mainly derives from the environmental/behavioral constraints placed on sleep/wake behavior with hospitalization and medications. From initial stage of hospitalization, behavioral problems, especially sleep problems, were intensively treated. If the patients had not been treated, we assume that perhaps the discrepancies would not appear so great. Like adjustments for jet lags, after environmental circadian realignment, it takes time to be adjusted in alignment of the endogenous circadian rhythm. We suggested that BD patients tend to be easily circadian phase shifted by the disturbance of sleep wake cycles and some disordered Zeitgeber (e.g., inappropriate artificial light). We observed that delays of the circadian rhythm of salivary AMG-517 to bright light exposure before bedtime is related to subthreshold bipolarity (Cho et al., 2016). From these findings, we suggest a new circadian rhythm shift model of BD (Fig. 7). Our observations indicate that the biochemical circadian phase orientations had distinct abnormalities in acute manic episodes versus mixed episodes versus depressive episodes, and that some phase disturbances resolved through advance and others through delay to recover the normal phase orientation. However, since we have no observations of the development of these abnormal states, we cannot infer with certainty whether some developed through advance or others through delay. It has been hypothesized that both bipolar depression and mania result from a tendency towards phase delay, but mania occurs when the delay is more extreme than in depression and may perhaps exceed 12h, leading to resolution by a 360 degree delay rotation of phase (Kripke et al., 2015). Moreover, differing phase excursions of distinct cell groups within the SCN may be involved, contributing to internal desynchronization of peripheral circadian rhythms. Indeed, bifurcation of circadian secretion of melatonin suggesting bifurcation of SCN circadian systems has been hypothesized (Kripke et al., 2015; Novakova et al., 2015). In this regard, we have not noted any suggestion of bifurcation of individual circadian rhythms we have observed in bipolar patients, but it is possible that some dysregulation resembling pacemaker bifurcation might be suggested by dramatic phase abnormalities in cortisol and RNA expression contrasted to no significant phase changes in sleep and gross activity.
Conflict of Interests
Author Contributions
Acknowledgements and Funding Sources This study was supported by the Korea Health 21 R&D Project funded by the Ministry of Health & Welfare, Republic of Korea (HI14C3212 and HM14C2606) and by Ministry of Science, ICT and Future Planning, Republic of Korea (NRF-2012M3A9C7050135).
Introduction Telomeres are DNA-protein structures that include a repeated nucleotide sequence at the ends of eukaryotic chromosomes, acting to prevent the degradation of functional DNA sequences during cellular replication (Olovnikov, 1973). Shortening of telomeres in human cells in vitro has been shown to lead to cellular dysfunction, senescence, and cell death (Allsopp and Harley, 1995; Blackburn, 2000). Telomere length (TL) has therefore been hypothesized to be a marker of human aging and chronic disease (Zhu et al., 2011a; Hamad et al., 2016). Observational studies in human populations have built on this molecular basis and have shown that chronic and acute stressors, including adverse socioeconomic conditions, are associated with shorter TL, suggesting that environmental factors may lead to variation in TL in later life (Chae et al., 2014; Epel et al., 2004; Needham et al., 2013). Thus, telomeres are thought to shorten with natural aging and with stress over the lifespan. It remains unclear whether these correlations are due to a causal relationship between stress and TL, or whether the association is confounded by other unobserved factors. Nevertheless, there is substantial evidence that TL acts as a marker of biological aging, even if it is not a causal relationship.