Most biochemical reactions accelerate as temperature increases, but our daily circadian rhythms, which are underlain by gene regulatory and biochemical networks, remain constant, even as temperatures rise. Researchers led by Gen Kurosawa, PhD, at the RIKEN Center for Interdisciplinary Theoretical and Mathematical Sciences (iTHEMS) used theoretical physics to discover how our biological clock maintains this consistent 24-hour cycle as temperatures change.
The scientists found that this stability is achieved through a subtle shift in the “shape” of gene activity rhythms at higher temperatures, a process known as waveform distortion. This process not only helps keep time steady but also influences how well our internal clock synchronizes with the day-night cycle. The findings could ultimately lead to new insights into sleep mechanisms and the effects of aging on our biological clock.
“Our findings show that waveform distortion is a crucial part of how biological clocks remain accurate and synchronized, even when temperatures change,” said Kurosawa. “In the long term,” Kurosawa notes, “the degree of waveform distortion in clock genes could be a biomarker that helps us better understand sleep disorders, jet lag, and the effects of aging on our internal clocks. It might also reveal universal patterns in how rhythms work—not just in biology, but in many systems that involve repeating cycles.”
Kurosawa and colleagues reported on their findings in PLOS Computational Biology, in a paper titled, “Waveform distortion for temperature compensation and synchronization in circadian rhythms: An approach based on the renormalization group method.”
Have you ever wondered how your body knows when it’s time to sleep or wake up? The simple answer is that your body has a biological clock, which runs on a roughly 24-hour cycle. However, most chemical reactions speed up as temperatures rise, and how our bodies compensate for changing temperatures throughout the year—or even as we move back and forth between the outdoor summer heat and indoor air-conditioned rooms—has largely remained a mystery.
“Numerous biological processes accelerate as temperatures increase, but the period of circadian rhythms remains constant, known as temperature compensation, while synchronizing with the 24h light-dark cycle,” the authors wrote. “One fundamental issue that remains to be understood in circadian rhythm research is temperature compensation, in which the period keeps constant despite temperature-induced changes in reaction rates.”
Our biological clock is powered by cyclical patterns of mRNA—the molecules that code for protein production—which result from certain genes being rhythmically turned on and off. “Recent advances in genetic research through insects, molds, mammals, and plants have unveiled that genes and proteins are involved as integral components in the primary mechanism governing autonomous circadian rhythms,” the team further noted.
Just as the back and forth of a swinging pendulum over time can be described mathematically as a sine wave, so can the rhythm of mRNA production and decline. Kurosawa’s research team at RIKEN iTHEMS, together with Teiji Kunihiro, PhD, at Yukawa Institute for Theoretical Physics (YITP), Kyoto University, drew on theoretical physics to analyze the mathematical models that describe this rhythmic rise and fall of mRNA levels.
Specifically, they used the renormalization group method, a powerful approach adapted from physics, to extract critical slow-changing dynamics from the system of mRNA rhythms. “We theoretically explored the conditions for clarifying the temperature compensation of the biological clock and its synchronization to light-dark cycles with a particular focus on waveform distortion,” they explained. “To investigate these conditions, we focus on the Goodwin model, which is widely used as a mathematical model that simulates various properties of biological clocks, including temperature compensation, synchronization to temperature cycles, and phase resetting by temperature steps.”
Their analyses revealed that at higher temperatures, mRNA levels should rise more quickly and decline more slowly, but importantly, the duration of one cycle should stay constant. When graphed, this high-temperature rhythm looks like a skewed, asymmetrical waveform. “Using the renormalization group method, we analytically demonstrate that the decreasing phase of circadian protein oscillations should lengthen with increasing temperature, leading to waveform distortions to maintain a stable period,” they stated.
But does this theorized change actually happen? To test this theory in real organisms, the researchers examined experimental data from fruit flies and mice. Sure enough, at higher temperatures, these animals showed the predicted waveform distortions, confirming that the theoretical predictions align with biological reality. “Although theoretical predictions based on a model might not always be realized in real organisms, we quantified the gene activity rhythms of published experimental data using Drosophila and mice,” the team noted. “This quantification confirmed that the waveform is distorted.” The researchers conclude that waveform distortion is the key to temperature compensation in the biological clock, specifically the slowing down of mRNA level decline during each cycle.
The team also found that waveform distortion affects how well the biological clock synchronizes with environmental cues, such as light and darkness. Their analysis predicted that when the waveform becomes more distorted, the biological clock is more stable, and environmental cues have little effect on it. This theoretical prediction matches experimental observations in flies and fungi and is significant because irregular light-dark cycles are part of modern-day life for most people.
“This study also investigated the synchronization with environmental light-dark cycles at various temperatures,” they reported. “The numerical simulations and theoretical analysis predict that as the distortion of the gene activity rhythms for achieving a temperature-compensated period increases, it becomes more difficult to synchronize with the light-dark cycle. This prediction aligns with the reported temperature-dependent variation in response to light pulses in Drosophila and Neurospora, displaying smaller phase shifts at higher temperatures.”
Kurosawa suggests that future research can now focus on identifying the exact molecular mechanisms that slow down the decline in mRNA levels, which leads to the waveform distortion. Scientists also hope to explore how this distortion varies across species—or even between individuals—since age and personal differences may influence how our internal clocks behave. “Our analyses demonstrate that the fundamental role of the waveform distortions in temperature compensation from both theoretical and experimental perspectives in accordance with the previous findings,” the team concluded. “We believe that further systematic quantification of the waveforms of gene activity and/or protein activity rhythms in various circadian organisms will be essential for clarifying the importance of the waveform in circadian rhythms in the future.”