Differences in cellular pathway activity flip the switch from nocturnality to diurnality and explain a major evolutionary change humans have undergone.

Early mammals were nocturnal, sleeping during the day while large predators were active. However, after the extinction of dinosaurs, several different lineages of mammals independently transitioned to become active during the day. Exactly how this dramatic change occurred has proved elusive. A new study, published in the journal Science, has revealed a cellular switch which holds the answer.

Led by researchers from the MRC Laboratory for Molecular Biology, the study looked at how cells from a range of nocturnal (active at night) and diurnal (active in the day) mammals, like humans, respond to environmental signals.

Changes in temperature or osmolarity, as happens to the body throughout the day, caused the cells to respond in opposite ways, including in fundamental cellular functions. This divergence flips the timing of cellular activity, essentially acting as a day/night ‘switch’ at a molecular level.

The researchers pinpointed these differing responses to the mechanistic Target of Rapamycin (mTOR) and With-no-lysine (WNK) kinase pathways, central signalling networks in cells responsible for regulating several key functions, including protein synthesis. This suggested that modification of their activity could enable nocturnal mammals to switch to more diurnal activity.

To explore this hypothesis, the researchers administered diet-based treatments to mice to target the mTOR pathway, as mTOR activity is highly sensitive to nutrient levels. Once mTOR function was reduced, the mice began behaving more like diurnal animals, shifting their active hours into the daytime. This underlined that mTOR signalling goes beyond influencing metabolism; it also helps dictate when an animal is active.

The researchers then looked to contextualise this finding against the backdrop of mammalian evolution. After analysing genetic data across several species, co-author Matthew Christmas from Uppsala University found that genes regulating mTOR and WNK have evolved faster in diurnal mammals. This points to the importance these pathways have played in the shift from nighttime to daytime over millennia.

This discovery helps explain one of the most important evolutionary events in mammalian history and provides a piece of the puzzle for understanding human health.

To date, most explorations of pre-clinical biomedical research have depended on the mouse model, yet this study highlights that nocturnal rodents differ from humans in key cellular pathways linked to timing and metabolism. This study also carries clear implications for circadian medicine, a growing field that examines how the timing of treatments influences their effectiveness.

“That this radically different response of cellular ‘clocks’ to the same temperature shift seemed to be broadly true across mammalian species, when comparing those that are more active at night versus those that are more active during the day,” said co-author Dr Nina Rzechorzek, from Cambridge’s Department of Engineering. “We need more research to understand exactly how and why this happens, but it could teach us a lot about how biological clocks work and how they impact health and disease.”

Several of the key external factors harnessed in this study to influence animals’ circadian rhythms are vulnerable to environmental changes. As climate change disrupts temperature levels and food production capabilities, this work suggests mammals may change the time of day they are active in response. This will disrupt the fragile balance of relationships in our ecosystems and is an impact of climate change, which has perhaps been overlooked thus far.

This work was funded by UKRI MRC, UKRI Future Leaders Fellowship, Wellcome and the Royal Society. The project was further supported by Blue Sky collaboration between AstraZeneca UK Limited and the Medical Research Council (BSF38).

Reference:
Andrew D Beale et al. ‘A cellular basis for the mammalian nocturnal-diurnal switch.’ Science (2026). DOI: 10.1126/science.ady2822

Adapted from an LMB media release.