Could your body’s hidden 12-hour clock hold the secret to metabolic health and disease? New research links our internal rhythms to ancient ocean tides.
Review: Biological rhythms: Living your life, one half-day at a time. Image Credit: izzuanroslan / Shutterstock
In a recent review published in the journal npj Biological Timing and Sleep, researchers Patrick Emery and Frédéric Gachon explored the mechanisms, physiological significance, and potential evolutionary origins of 12-hour biological rhythms in mammals, including humans, and determined whether these rhythms represent a distinct timing system or are derived from circadian or circatidal clocks.
Background
Why do many human genes become active not once, but twice daily? This intriguing pattern reflects 12-hour biological rhythms, also called ultradian or circasemidian cycles. These rhythms are well known in marine animals that respond to tidal cycles. However, similar 12-hour patterns have been observed in recent studies in terrestrial animals, such as mice and humans. Some scientists propose these rhythms evolved from ancient tidal clocks, while others see them as distinct and necessary for managing feeding and stress. Since they regulate key processes like metabolism and immune responses, understanding them could offer insights into disorders such as obesity and mental illness. Further research is needed to identify their underlying mechanisms.
Circadian and Circatidal Rhythms: Similar Clocks or Separate Systems?
Biological clocks help organisms adapt to recurring environmental changes. Circadian rhythms follow a 24-hour cycle, controlling sleep, hormone release, and other daily behaviors. These rhythms are regulated by proteins, including Circadian Locomotor Output Cycles Kaput (CLOCK), Brain and Muscle ARNT-like 1 (Bmal1), Period (PER), Cryptochrome (CRY), and Timeless (TIM).
Circatidal rhythms, seen in marine animals, occur about every 12.4 hours. These rhythms align with tidal movements, helping species such as crabs, worms, and crustaceans survive in coastal habitats. For example, the marine crustacean Eurydice pulchra and the amphipod Parhyale hawaiensis continue to exhibit 12.4-hour behavioral patterns even when circadian genes, such as per, are disrupted. This suggests the existence of a separate 12.4-hour oscillator, though with some mechanistic overlap through Bmal1. However, in other crustaceans like Eurydice pulchra, RNAi studies show that circatidal rhythms are independent of core circadian genes such as per and Clock, suggesting a complex relationship. These findings highlight how circadian and circatidal mechanisms may intersect or operate independently depending on the organism and context.
12-Hour Gene Rhythms in Mice: Beyond the Circadian Clock
The discovery of 12-hour gene expression patterns in mouse liver revealed a distinct rhythmic cycle separate from the 24-hour circadian clock. These ultradian rhythms persist even in constant darkness and isolated cells, suggesting control by largely cell-autonomous mechanisms rather than light or brain signals. Many of the genes involved are linked to stress response, mitochondrial activity, and the Unfolded Protein Response (UPR). X-box Binding Protein 1 (XBP1), a transcription factor activated during endoplasmic reticulum stress, plays a major, but not exclusive, role in regulating these rhythms. However, when Xbp1 was deleted in mouse liver, some 12-hour rhythms persisted or intensified, indicating that other regulatory elements are involved. This has led researchers to question whether these rhythms arise from a dedicated 12-hour oscillator or through interactions between feeding, stress, and circadian signals and are modulated by feeding rhythms and systemic cues. Current evidence suggests that multiple overlapping systems may collaborate to generate and maintain 12-hour gene expression patterns in mammals.
Are 12-Hour Rhythms Present in Humans?
Human studies have confirmed 12-hour gene expression patterns. In a 48-hour study of three individuals, 653 genes followed a 12-hour cycle, distinct from those showing 24-hour circadian rhythms. These ultradian genes were involved in stress, metabolism, and immune function, and closely resembled patterns seen in mice, particularly those regulated by XBP1. Although participants controlled their own lighting and meals, which could have affected results, the original research highlights that this is a significant limitation and that environmental or behavioral cues may have contributed to the observed patterns. However, the overlap with mouse data supports the biological relevance of these rhythms. The timing of gene peaks varied among individuals, likely influenced by personal habits or internal biological differences.
Could 12-Hour Rhythms Have Tidal Origins?
Some scientists believe that 12-hour rhythms in mammals may have evolved from marine circatidal clocks. This idea is supported by overlapping gene expression patterns between mammals and marine organisms, including cnidarians and limpets, with the limpet study being particularly notable because it involved tidal entrainment.
However, this evolutionary link remains uncertain. Many marine studies were conducted under light-dark cycles rather than tidal conditions, making it unclear whether the observed 12-hour rhythms are truly tidal or are influenced by light. Furthermore, key pathways such as the Unfolded Protein Response and lipid metabolism are fundamental to cell function across species. The similarity in rhythmic expression could result from independent evolution rather than shared ancestry. The study in the limpet C. rota, which was conducted under tidal conditions, provides a stronger link. Overall, the review urges caution in drawing direct evolutionary connections, as convergent evolution may explain the similarities observed across species.
Nonetheless, the repeated observation of 12-hour rhythms across diverse organisms supports their functional importance. These rhythms may help cells prepare for predictable metabolic or environmental changes, such as feeding times or shifts in body temperature, as proposed in the "rush hour" hypothesis for metabolic readiness.
Clinical Implications of Disrupted 12-Hour Rhythms
Emerging evidence suggests that altered 12-hour rhythms may contribute to human disease. In one study, brain samples from people with schizophrenia showed disrupted 12-hour gene expression, especially in pathways linked to neuronal maintenance and protein folding (Unfolded Protein Response). Although it is unclear whether this disruption contributes to the disorder or results from it, the findings suggest a connection worth exploring.
In mice, 12-hour rhythms are sensitive to metabolic status. Obesity and irregular feeding schedules dampen these cycles. This raises the possibility that maintaining healthy ultradian rhythms could help protect against metabolic and cognitive disorders. Just as circadian medicine has transformed approaches to sleep and hormone disorders, ultradian chronobiology has the potential to inform future treatment strategies for psychiatric and metabolic diseases, although further research is needed.
Conclusions
Twelve-hour rhythms are now recognized as a key layer of biological timing, regulating critical processes such as metabolism, stress response, and immune function. While some 12-hour cycles appear to stem from the circadian system, others may be driven by distinct mechanisms involving transcription factors, such as XBP1. Evidence from marine species, mice, and humans highlights the widespread presence and potential importance of these rhythms. Their disruption has been observed in conditions such as schizophrenia and obesity. Understanding how these ultradian rhythms are generated and maintained could lead to innovative strategies for disease prevention and personalized medical care.