The human body runs on a finely tuned clock synchronized to the 24-hour cycle of Earth’s rotation, known as the circadian clock, which controls various physiological processes such as the sleep-wake cycle, hormone production, and metabolism.
In a new study, researchers led by Felix Naef at EPFL were able to uncover the organization of tissue-specific gene expression rhythms in humans, and shed light on how our body clocks depend on sex and age.
In model organisms, analyzing molecular rhythms is usually done using time-stamped measurements – but such data are not readily available in humans. To work around this, the researchers used existing measurements from a large cohort of post-mortem donors, combined with a novel computer algorithm that was designed to assign internal clock times to nearly one thousand donors.
“Interestingly, the data-science algorithm we developed turned out to resemble models from magnetic systems, which are well studied in statistical physics,” says Felix Naef. Using this innovative approach, the researchers obtained the first comprehensive and accurate whole-organism view of 24-hour gene expression rhythms in 46 human tissues.
The study found that the core clock machinery properties are conserved across the body and do not change significantly with sex and age. On the other hand, the analysis revealed extensive programs of gene expression rhythms across major compartments of metabolism, stress response pathways and immune function, and these programs peaked twice a day.
In fact, the emerging whole-body organization of circadian timing shows that rhythmic gene expression occurs as morning and evening waves, with the timing in the adrenal gland peaking first, while brain regions displayed much lower rhythmicity compared to metabolic tissues.
Dividing the donors by sex and age revealed a previously unknown richness of sex- and age- specific gene expression rhythms spread across biological functions. Strikingly, gene expression rhythms were sex-dimorphic (different in males and females) and more sustained in females, while rhythmic programs were generally reduced with age across the body.
Sex-dimorphic rhythms – referring to the differences between males and females – were particularly noticeable in the liver’s "xenobiotic detoxification", the process by which liver breaks down harmful substances. Additionally, the study found that as people grow older, the rhythm of gene expression decreases in the heart's arteries, which may explain why older people are more susceptible to heart disease. This information could be useful in the field of "chronopharmacology," which is the study of how a person's internal clock affects the effectiveness and side effects of medication.
The study provides new insights into the complex interplay between our body clock, sex, and age. By understanding these rhythms, we might find new ways of diagnosing and treating pathologies such as sleep disorders and metabolic diseases.