Experts review how 12-hour biological cycles in mice work with clues in humans

Experts review how 12-hour biological cycles in mice work with clues in humans

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.

Published in a recent review in the JournalNPJ Biological timing and sleepResearchers Patrick Emery and Frédéric Gachon examined the mechanisms, physiological significance, and potential evolutionary origins of 12-hour biological rhythms in mammals, including humans, and determined whether these rhythms represent a unique timing system or are derived from circadian or circatid clocks.

background

Why do many human genes activate twice a day rather than once? This fascinating pattern reflects 12-hour biological rhythms also called ultradian or circasemidic 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 of terrestrial animals such as mice and humans. Some scientists suggest that these rhythms evolved from ancient tidal clocks, while others see them as distinct and necessary to manage feeding and stress. Because they regulate important processes such as metabolism and immune responses, they can provide 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 and control 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 every 12.4 hours. These rhythms correspond to tidal movements and help species such as crabs, worms and crustaceans survive in coastal habitats. For example, the marine crustacean Eurydice Pulchra and the amphipod Parhyale Hawaaiensis continue to exhibit 12.4-hour behavioral patterns even when circadian genes, such as B. Per, be disturbed. This suggests the existence of a separate 12.4 hour oscillator, albeit with mechanistic overlap through BMAL1. However, in other crustaceans such as Eurydice Pulchra, RNAi studies show that circadian rhythms are independent of core circadian genes such as Per and Clock, suggesting a complex relationship. These results demonstrate how circadian and circatidal mechanisms can overlap 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 ultradic rhythms also persist in constant darkness and isolated cells, suggesting control by largely cell-autonomous mechanisms rather than brain signals. Many of the genes involved are associated with the 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 an important but not exclusive role in regulating these rhythms. However, when XBP1 was deleted in mouse liver, 12-hour rhythms persisted, 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, voltage and circadian signals and are modulated by feeding rhythms and systemic cues. Current evidence suggests that multiple overlapping systems can work together 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 people, 653 genes followed a 12-hour cycle, different from those that showed 24-hour circadian rhythms. These ultradian genes were involved in stress, metabolism and immune function and were very similar in mice, particularly those regulated by XBP1. Although participants controlled their own lighting and meals, which could influence the results, the original research highlights that this is a significant limitation and that environmental or behavioral factors 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 between 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 evolved from marine circadian 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 for its tidal entrainment.

However, this evolutionary connection remains uncertain. Many marine surveys have been conducted under light-dark cycles rather than intertidal conditions, which has made it unclear whether the observed 12-hour rhythms are truly appropriate or influenced by light. Furthermore, key pathways such as the unfolded protein response and lipid metabolism are fundamental to cellular function across species. The similarity in rhythmic expression may result from independent evolution rather than common ancestry. The study in the Limpet C. Rota, conducted under tidal conditions, provides a stronger connection. Overall, the review is cautious about making direct evolutionary connections because convergent evolution can explain the similarities observed across species.

However, repeated observation of 12-hour rhythms in different organisms supports their functional significance. These rhythms can help cells prepare for predictable metabolic or environmental changes, such as: B. 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, particularly in pathways associated with neuronal maintenance and protein folding (unfolded protein response). Although it is unclear whether this interference contributes to the disorder or outcomes, the results suggest an exploration of a relationship.

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 hormonal disorders, ultradic 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 originate from the circadian system, others may be driven by different 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 disorder has been observed in conditions such as schizophrenia and obesity. Understanding how these ultradian rhythms are generated and maintained can lead to innovative strategies for disease prevention and personalized medical care.

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