Periodic Reporting for period 1 - CLOCKrisk (Targeting the circadian clock in personalized disease prevention)
Période du rapport: 2022-10-01 au 2025-03-31
The proposal ‘CLOCKrisk’ tackles an evolutionarily ancient, yet only fairly recently discovered physiological system: the circadian clock. This central pacemaker, which is located in the hypothalamic suprachiasmatic nuclei (SCN), connects with peripheral clocks in virtually every cell and directs our lives in a roughly 24-hour (‘circadian’) fashion (Figure 1). It is a mechanism entrained by the sun and preserved in all organisms on our planet, including e.g. in flowers, as they close their buds at sunset, and open them at sunrise. Bodily functions in humans that follow a circadian rhythm include the sleep/wake cycle, blood pressure, core body temperature (lowest at night), immune system (recovering in darkness), gene expression, or hormone secretion.
This ancient system has remained fairly undisturbed over the roughly four billion years that life exists on earth; until just over a century ago, when in 1876 Thomas Edison invented the light bulb – arguably the greatest invention of all times. The subsequent race to electrify the world changed our lives in fundamental ways no one could ever have imagined. Artificial light at night has now become common in our 24/7 societies, yet with our body’s physiology hardly adapted to this evolutionarily young perturbation of our circadian system.
Today, the demands placed on our circadian clock by exposure to light at ’unnatural’ times (i.e. at night) lead to a disruption of the 24-hr rhythm of normal physiological function, with many adverse consequences for health. Night work represents the gravest perturbation of the circadian system, and is often accompanied by a variety of symptoms commonly referred to as ‘shift work disorder’, especially insomnia symptoms, often associated with excessive sleepiness, difficulty concentrating, or lack of energy. Some 30 years of research, to which the applicant contributed a substantial part, have shown that persistent circadian rhythm disruption is an important risk factor for chronic diseases, such as cardiometabolic disease, depression, or cancer, which has led the World Health Organization (WHO) to classify night work as a probable (class 2A) carcinogen.
The proposal CLOCKrisk deals with the challenge of optimizing the management of the everyday (often unavoidable) stress on the circadian clock in view of the now almost omnipresent night-time exposure to light in our 24/7 societies: it offers an immense opportunity for persevering good health, as well as for healthy aging, and, in particular for new personalized strategies to prevent important chronic (e.g. cardiometabolic) disease risk. We propose that the genetic predisposition for a resilient clock helps people to better cope with situations that challenge their clock (i.e. irregular sleeping hours, leaving the light on until late at night, or working at night). Preliminary studies support this proposition, though a comprehensive picture is still elusive. The identification of those persons who have a greater probabilistic susceptibility to illness in the case of persistent demands on their clock (e.g. in its most extreme form, night work) would be of central importance for possible preventive measures. To this day, however, it is impossible for us to know in advance whose health would most likely suffer from night work, sleep deprivation, or other circadian clock-adverse behavior patterns. The scope of the project is to address this knowledge gap in a multi-disciplinary way: by (1) exploiting large existing cohorts to unravel geno- and phenotypic determinants of resilient versus vulnerable clocks (building on the early concepts of shift work tolerance by Andlauer, Reinberg and Smolensky, later refined by Saksvik-Lehouillier and others, adding personality traits such as neuroticism, rigidity and resilience); and determine the interactions of these phenotypic traits and genetic risk with behavioral, physical, environmental, socio-economic and modifiable lifestyle factors that increase the risk of individuals who encounter repeated challenges to their biologic clock (e.g. night workers) to develop chronic diseases; (2) gaining additional mechanistic insights using transgenerational mother/child studies and deeply phenotyped data sets; and (3) using this knowledge to improve risk identification and to develop, implement, and evaluate the effectiveness of targeted interventions that can be utilized for personalized, risk-based health management, prevention strategies and policies. Implicitly, the project will also contribute to the scope of identifying genetic, physical, psychological, and environmental determinants and pathways specific to healthy and active aging.
This ancient system has remained fairly undisturbed over the roughly four billion years that life exists on earth; until just over a century ago, when in 1876 Thomas Edison invented the light bulb – arguably the greatest invention of all times. The subsequent race to electrify the world changed our lives in fundamental ways no one could ever have imagined. Artificial light at night has now become common in our 24/7 societies, yet with our body’s physiology hardly adapted to this evolutionarily young perturbation of our circadian system.
Today, the demands placed on our circadian clock by exposure to light at ’unnatural’ times (i.e. at night) lead to a disruption of the 24-hr rhythm of normal physiological function, with many adverse consequences for health. Night work represents the gravest perturbation of the circadian system, and is often accompanied by a variety of symptoms commonly referred to as ‘shift work disorder’, especially insomnia symptoms, often associated with excessive sleepiness, difficulty concentrating, or lack of energy. Some 30 years of research, to which the applicant contributed a substantial part, have shown that persistent circadian rhythm disruption is an important risk factor for chronic diseases, such as cardiometabolic disease, depression, or cancer, which has led the World Health Organization (WHO) to classify night work as a probable (class 2A) carcinogen.
The proposal CLOCKrisk deals with the challenge of optimizing the management of the everyday (often unavoidable) stress on the circadian clock in view of the now almost omnipresent night-time exposure to light in our 24/7 societies: it offers an immense opportunity for persevering good health, as well as for healthy aging, and, in particular for new personalized strategies to prevent important chronic (e.g. cardiometabolic) disease risk. We propose that the genetic predisposition for a resilient clock helps people to better cope with situations that challenge their clock (i.e. irregular sleeping hours, leaving the light on until late at night, or working at night). Preliminary studies support this proposition, though a comprehensive picture is still elusive. The identification of those persons who have a greater probabilistic susceptibility to illness in the case of persistent demands on their clock (e.g. in its most extreme form, night work) would be of central importance for possible preventive measures. To this day, however, it is impossible for us to know in advance whose health would most likely suffer from night work, sleep deprivation, or other circadian clock-adverse behavior patterns. The scope of the project is to address this knowledge gap in a multi-disciplinary way: by (1) exploiting large existing cohorts to unravel geno- and phenotypic determinants of resilient versus vulnerable clocks (building on the early concepts of shift work tolerance by Andlauer, Reinberg and Smolensky, later refined by Saksvik-Lehouillier and others, adding personality traits such as neuroticism, rigidity and resilience); and determine the interactions of these phenotypic traits and genetic risk with behavioral, physical, environmental, socio-economic and modifiable lifestyle factors that increase the risk of individuals who encounter repeated challenges to their biologic clock (e.g. night workers) to develop chronic diseases; (2) gaining additional mechanistic insights using transgenerational mother/child studies and deeply phenotyped data sets; and (3) using this knowledge to improve risk identification and to develop, implement, and evaluate the effectiveness of targeted interventions that can be utilized for personalized, risk-based health management, prevention strategies and policies. Implicitly, the project will also contribute to the scope of identifying genetic, physical, psychological, and environmental determinants and pathways specific to healthy and active aging.
Our primary activities to date focus on identifying individuals who are more likely to develop illnesses when subjected to persistent disruptions of their biological clocks. To achieve this, we are leveraging large, pre-existing cohorts to investigate the genotypic and phenotypic determinants that distinguish resilient from vulnerable biological clocks, building on early concepts of shift work tolerance. Additionally, we are analyzing how genetic risks interact with behavioral, physical, environmental, socio-economic, and modifiable lifestyle factors to heighten the likelihood of chronic disease in individuals facing repeated challenges to their biological clocks. Furthermore, we are conducting transgenerational mother-child studies to explore the impact of early-life exposures on long-term health outcomes. Our primary achievements are workshops, presentations of preliminary results at conferences, and publications, as outlined under Results.
Identifying individuals who are particularly susceptible to illness from consistently demanding work schedules, such as prolonged night shifts, is central to this project and essential for designing effective preventive measures. The knowledge gained from this project can be used for personalized, risk-based health management, prevention strategies and measures.