Targeting the circadian clock in personalized disease prevention

Virtually every cell of our body follows the 24-hr ‘circadian’ rhythm of a hypothalamic master pacemaker that evolved in the natural light-dark cycle. Decoding this circadian clock culminated in the Nobel Prize in Physiology or Medicine 2017 for the discovery of molecular mechanisms controlling the circadian rhythm. It is now recognized that a strong, unperturbed circadian clock is a hallmark of healthy aging. The introduction of electric light, however, presents unique challenges: today, 20% of the global work force engages in alternate working hours associated with light in unnatural times. Increases in the risk of major chronic disease and mortality have been associated with night work. Further, night-activity is widespread also outside of work, implicating potential risk for many. This project targets the urgency of alleviating adverse health consequences of a perturbed clock. It does so by aiming to decipher individual risk and related mechanisms 1) using a cutting-edge multi-polygenic score approach; 2) employing transgenerational, deeply phenotyped cohort approaches; and 3) carrying out interventions using genetic risk stratification. This epidemiological project builds on pioneering work of the applicant who conducted the first prospective study to demonstrate significant health effects of chronic clock dysregulation, leading WHO to classify night work as a probable carcinogen. Using transdisciplinary approaches, she implemented field and genetic studies and developed circadian biomarkers, establishing the field circadian epidemiology. Tying the transformative body of her work together, she proposes to take the next ground-breaking leap: To 1) identify the night-active individual who develops disease, 2) profile mechanisms involved, and 3) optimize effectiveness of interventions to improve sleep and shift work disorder, facilitating immediate implementation of risk-based prevention strategies aimed at promoting healthy aging in spite of clock perturbations.