Circadian Disturbances and Age‐Related Disorders (2023)

As an evolutionary adaptation to the light-dark cycles across solar days, circadian rhythms are present in almost all biological and physiological processes, and observed at multiple scales from gene expression to system-level behaviors such as sleep and physical activity.[1] Circadian rhythms are regulated and orchestrated by a network of internal biological clocks with a central pacemaker located in the hypothalamus—the suprachiasmatic nucleus.[2, 3] Intact circadian regulation is key for optimal body functions, and perturbed circadian regulation has been prospectively linked to various diseased conditions such as mood, cardiometabolic, and neurocognitive disorders.[4, 5] In this issue, four review articles and seven original research articles summarize and/or provide the evidence for changes in circadian rhythms with aging and the relevance of circadian disturbances to the risk for age-related diseases and disease progression. Impacts of aging and potential pathways Aging broadly affects all aspects of biological processes on the cellular and molecular levels, leading to physiological dysfunctions on the system level. In this special issue, Xu and Li reviewed studies on the impact of aging on the circadian regulatory system in mammals. These studies highlighted that the age-related degradations of circadian rhythms at the system level should be attributed not only to changes of the circadian molecular machinery within the circadian clocks but also to the downstream pathways through which the clocks regulate biological processes (article number 2200219). The review also pointed out the potential role of increased inflammatory responses in circadian degradations with aging. Relatedly, Joshi and Sundar reviewed evidence and possible pathways for the impact of circadian clock disruption on lung inflammation, a pathological mechanism underlying the association between night shift work and pulmonary disease (article number 2200292). They also discussed the potential application of chronotherapy in the treatment of chronic lung diseases. Supporting this association, Sundar et al. also presented their new data from a mice model, showing that ozone exposure impacted clock gene expression and inflammation in the lung (article number 2300045). Circadian disturbances and other diseases Circadian disturbances are linked to the development and outcomes of many different diseases. Recent studies have also provided strong evidence that circadian disturbances are linked to neurodegenerative diseases.[4] In this special issue, Keihani et al. focused their review (article number 2200237) on the differences in the circadian regulation between healthy adults and people with mild cognitive impairment (MCI). Their main conclusion indicated that altered circadian rhythms in people with MCI are more pronounced, and some aterations are consistently reported in the studies of daily rest-activity rhythms. There is certain evidence for changes in daily/circadian rhythms of core body temperature, melatonin, and cortisol rhythms in people with MCI, but more studies are required to validate these results. This review article also highlighted preliminary evidence for the possibility to prevent or halt the progress of neurodegeneration by targeting circadian intactness. Kara et al. reviewed findings related to the influences of circadian rhythms on stroke susceptibility and pathogenesis (article number 2300048). The authors also discussed the potential relevance of circadian regulated gut-microbiome, inflammation, and immune response to stroke outcome. The reviewed evidence, despite being preliminary, suggests new directions for the design of novel stroke therapies by integrating circadian rhythms and aging in clinical stroke research. Yilmaz et al. investigated the circadian regulation and its response to different light condition in spontaneously hypertensive rats (SHRs) — a commonly used animal model for hypertension (article number 2200324). Using both traditional circadian rhythmicity and nonlinear measures of the circadian motor activity regulation, the study showed that SHRs had altered circadian regulation even before the onset of hypertension, displaying more excessive rigidity and less response to light as compared to age-matched control rats. These original data strongly support the role of altered circadian regulation in the development of hypertension. Chronotype, timing of daily behaviors, and relevance to disease prevention/treatment The intrinsic properties of the circadian clocks such as the cycle length and the entrainment of circadian rhythms may vary among individuals, which can manifest as different chronotypes or preferences in sleep and wake schedules. By investigating temporal stride-to-stride fluctuations of walking at different times of the day, Vaz et al. showed that the daily variation of gait dynamics in healthy young adults is also affected by chronotype (article number 2200235). This finding supports the relevance of the circadian regulation to motor activity regulation and balance control. Antonsdottir et al. reported original results showing the associations of daily motor activity patterns with depressive symptoms and cognitive performance in individuals with memory impairment (article number 2300138).They found that “greater depressive symptomatology is associated with greater activity in midafternoon, evening, and overnight into midday, whereas better delayed recall is associated with greater late evening activity and higher global cognitive performance is associated with greater activity in the morning and afternoon.” Their findings suggest the possibility to improve mental health in patients with memory impairment though this hypothesis should be further tested in future studies. Cumulating evidence suggests that feeding during the rest phase (instead of the active phase) disturbs metabolism, which may contribute to the development of metabolic disease. Méndez-Hernández et al. used a rat model and a unique light protocol that maintained complete darkness except for two 30-min light pulses identifying the beginning and end of the subjective day. Results indicated that small shifts in the circadian rhythms of body temperature and energy expenditure and shortened active period are linked to impacts glucose intolerance and increased adiposity, even when feeding is scheduled during the active phase or not controlled (article number 2200116). These findings suggest that an “optimal” synchronization among circadian rhythms of different physiological processes is required for metabolic homeostasis, highlighting a potential circadian therapy to prevent or treat metabolic disorders by manipulating feeding time. In addition to the inter-individual differences in intrinsic circadian regulation, the manifested daily rhythms in behavioral and physiological processes (the entrainment to the daily light-dark cycle) may also be affected by many external factors. Lai et al. presented data from a randomized controlled trial but found no significant effect of vaccination time on antibody response to an inactivated vaccine against SARS-CoV-2 (article number 2300028). They pointed out in their article that reliable assessment of the time-of-day effects require consideration of accurately phenotyping the chronotypes of participants, data on sleep-wake and work schedules, and enough sample data points across a circadian cycle. Findings in these research/review articles represent certain recent advances in the emerging field of circadian medicine, which has opened a promising, new avenue for healthcare.[6, 7] We would like to thank the editor-in-chief, Monty A. Montano, for his help throughout the conception and preparation of this special issue and to acknowledge all the authors and reviewers for their vision and contributions to this special issue of circadian medicine. The authors declare no conflict of interest.