The circadian rhythm is a natural biological process governed by a number of carefully synchronized biological clocks that each complete one cycle about every 24 hours. The term circadian comes from the Latin circa, meaning “around”, and diēm, meaning “day”.
Circadian rhythm cycles are changing the concepts of biological homeostasis and have enabled a new medical approach called circadian medicine.
Here, experts in the field Kun Hu and Peng Li, principal investigators at Harvard Medical School, delve into circadian biology’s effects on health, what happens when things go awry, challenges facing researchers, and their passion for advancing our understanding of the field.
What are key scientific developments that led to your current thinking about disturbances in circadian rhythm and its effects on age-related health?
Kun: Most human circadian studies 10 or 20 years ago focused on demonstration of the “endogenous” circadian rhythms of different biological/physiological functions and their responses to external stressors, independent of external daily behavioral cycles.
My initial thoughts about circadian rhythms and circadian disturbances were limited to their “acute” effects on system performance, such as reduced cognitive performance following shift work and sleep deprivation. Less was known about how circadian disturbances impacted long-term health outcomes. However, studies in the last one or two decades showed overwhelming evidence that chronic circadian disturbances (e.g., late night shift work) result in increased risk for obesity, digestive disorders, sleep/mood disorders, cardiometabolic diseases, stroke and other vascular events, and mortality.
Additional findings have identified a role of circadian disturbances in age-related neurodegenerative diseases. Indeed, using a longitudinal design, our recent study showed a bidirectional relationship between circadian disturbances and the development and progression of Alzheimer’s disease in older persons over a follow-up period of up to 14 years.
Peng: There is a long-standing scientific debate on whether circadian disturbances are causally linked to future age-related diseases or disorders, or are consequences of underlying pathophysiological changes during disease development.
Several prospective cohort studies, including [our own work], have shown that perturbed circadian rest–activity rhythms predicted future incident cognitive impairment and dementia, including Alzheimer’s, even among cognitively [healthy] people, and also suggested a potential bidirectional relationship since circadian rest–activity patterns dampen and become arrhythmic as people grow older, which further accelerates with Alzheimer’s progression.
However, these observational studies limit our ability to infer cause and effect. Recent studies in non-human animals have advanced our causal understanding of the role for circadian dysregulation in the development of Alzheimer’s disease. […] These results call for further studies to better understand the mechanisms underlying the link between circadian disturbances and Alzheimer’s disease and other age-related health consequences.
What do you see as the major challenges hindering research in circadian biology?
Kun: There are at least three major challenges in circadian research:
1) Quantification of circadian rhythms requires continuous monitoring of biological outputs for at least about 24 hours and even longer periods when the rhythms are not stable, which makes circadian studies time-consuming and obtrusive in humans. To address this, advances in methodology are needed. For instance, fluorescence-based technology has allowed long-term in vivo recordings of clock gene expression in animal studies, and wearable devices, such smart watches have made non-invasive assessment of daily circadian activity rhythms possible in large-scale human field studies.
2) The circadian system is a network of interacting neural and hormonal pathways and there are many external stimuli or time cues, such as light and temperature, that reset or adjust circadian rhythms. Studies of individual circadian clocks and their integrative behavior represent a major challenge in chronobiology research due to “emergent properties” that arise from interactions both among the components of the network and with external factors. Indeed, we have shown that the suprachiasmatic nucleus (SCN) is a master circadian clock that is wired directly to the retina in our eyes and, surprisingly, influences heart rate and motor activity regulations over a wide range of time scales from minutes to about 24 hours.
Such multi-scale regulatory function likely represents the interaction of circadian rhythms with many other biological and physiological processes functioning at different time scales. To understand the emergent properties of the circadian system, reductionist approaches will not be sufficient. New holistic systems-based approaches, such as complex theory and systems biology, are needed to obtain a network view of all the components and their interactions.
3) [Translating] findings in circadian biology into clinical practice and healthcare (i.e., “circadian medicine”) is another major challenge – and opportunity. The barrier is in part due to insufficient communications of circadian researchers with clinicians and healthcare providers. To address this, it is crucial to promote the education of circadian health and encourage more clinicians to know and participate in circadian research.
How is circadian rhythm and aging a great example of opportunities for early-stage investigators to engage in interdisciplinary research?
Kun: The interactions between the circadian system and age-related biological processes and functions likely occur at different levels and at different time scales. Advances of this interdisciplinary field will therefore rely on different study approaches, ranging from molecular and genetic studies to physiological and person–population studies.
It will also require new experimental technologies, mathematical theories, and modeling and analytical tools. To foster such translational research, I established the Medical Biodynamics Program within the Division of Sleep Medicine at Brigham & Women’s Hospital (BWH), Harvard Medical School, in 2010.
Funded by the National Institutes of Health and supported by BWH, the program has provided training in circadian physiology, aging research, and complex data analysis for numerous researchers from different fields. For example, in collaborations with scientists with diverse backgrounds, a number of research projects are being conducted to understand the role of circadian dysfunction in the development and progression of Alzheimer’s disease.
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The growing field of circadian biology is advancing our understanding of rhythms in biology at the cellular, organ, and whole body levels. These biological rhythms represent a new model of balance and homeostasis that will no doubt inform medical practice.
Indeed, emerging studies on the timing of medical treatment based on biological rhythms is fast giving rise to a new field: circadian medicine, and maybe even a new conceptual framework for healthy living based on attention to the rhythmic cycles in our lives.
This interview was originally published in Advanced Biology on June 15, 2022.
Access the full interview here: Monty Montano, Emerging Life Sciences Series: Q&A with the Editor Circadian Biology, Advanced Biology (2022). DOI: 10.1002/adbi.202200136
