A natural sense of rhythm: Shifting levels of molecules in the blood provide a snapshot of internal 'body-time'

By analyzing the ionic fragments generated through the process of mass spectrometry, it becomes possible to identify the molecules contained within a complex mixture. Analysis of human blood via this technique reveals dozens of metabolites whose levels cyclically rise (purple) or fall (green) with the body’s internal clock. Credit: 2012 Takeya Kasukawa, RIKEN Center for Developmental Biology

Anybody who has worked the overnight shift will testify that sometimes the time displayed on the clock is not the same as the one in your head. This disconnect is not merely perception; many physiological functions follow an internal chronological rhythm. 'Body-time' can profoundly affect overall health and even the response to therapies for cancer and other disorders.

By charting rising and falling concentrations of molecules in the bloodstream, researchers led by Hiroki Ueda of the RIKEN Center for in Kobe and Tomoyoshi Soga of Keio University have developed a first-generation 'metabolite clock' that enables easy monitoring of the human body's internal timetable.

"The goal of our study was to develop a method that would be available for clinical situations," says Takeya Kasukawa, a researcher in Ueda's lab and lead author on the study. Doctors can track physiological rhythms via changes in levels of the , but this is a laborious procedure as subjects have to stay in the hospital for a few days and have blood taken every few hours. By using —a technique for identifying and quantifying the various components within a mixed sample—Kasukawa and his colleagues were able to characterize temporal changes in levels of metabolic by-products in the blood.

The researchers had previously generated such a metabolite timetable in mice and attempted to replicate this success with six human volunteers. For a week, these subjects lived on a 28-hour cycle that desynchronized their internal time relative to the normal sleep/waking schedule. The researchers used blood samples collected from three of these individuals prior to the desynchronization process to generate a timetable, and identified dozens of metabolites whose levels shifted cyclically (Fig. 1). They then used these metabolite signatures to determine the post-desynchronization in all six individuals.

The results proved remarkably accurate compared to conventional cortisol measurements, with a difference generally not exceeding a few hours, even with one subject whose body-time was especially disrupted relative to the others. Kasukawa expects that future iterations of this clock will achieve greater accuracy through the identification of new timetable molecules in the blood and more sensitive instrumentation.

However, even this first-generation clock allows reasonably accurate body-time estimation from only a few and the research team plans to push forward with clinical feasibility studies. "We are planning to apply our molecular timetable method to patients with sleep disorders or irregular circadian clocks," says Kasukawa.

More information: Kasukawa, T., et al. Human blood metabolite timetable indicates internal body time. Proceedings of the National Academy of Sciences 109, 15036–15041 (2012). www.pnas.org/content/early/201… /1207768109.abstract

Minami, Y., et al. H.R. Measurement of internal body time by blood metabolomics. Proceedings of the National Academy of Sciences USA 106, 9890–9895 (2009). www.pnas.org/content/early/200… /0900617106.abstract

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