Human night owls are more likely to retire early and with disabilities. Really!

This might be dubious research! I suspect other factors than the circadian cycle or chronotype.

Again Finnish people were used for this study. See also my other blog post of today involving Finnish subjects. For some reason (better data?), Finnish people seem to be preferred test subjects. 😊

"... People with evening chronotypes are 1.7 times as likely as morning chronotypes to retire early and receive a disability pension, according to research ...

To strengthen the evidence, researchers analyzed whether people classified as E-types in their mid-40s were more likely to receive a disability pension over the next 12 years than people classified as M-types.

The researchers analyzed data from an ongoing population study that began in 1966 and included 96% of all people born in two northern provinces of Finland. ...

During the 12-year follow-up, 135 of the men (5.2%) and 249 of the women (8.1%) were granted their first disability pension.

Being classified as an E-type at age 46 was linked to a 1.7-fold greater likelihood of receiving a disability pension over the following 12 years compared with being an M-type, for both men and women. ..."

From the abstract:

"Objectives

Evening chronotypes (E) generally have poorer health than morning chronotypes (M), but whether this translates into disability pensions (DPs) is poorly known. We examined whether chronotype at age 46 predicts incident DPs over a 12-year follow-up.

Methods

In 2012, we determined chronotype among the non-retired participants of the Northern Finland Birth Cohort 1966 (n=5679) using the short Morningness–Eveningness Questionnaire, further validated by comparing the participants’ survey scores at age 46 with their polygenic scores for morningness (PGSmorn) at age 31 (n=5130). We used Cox regression to calculate HRs with 95% CIs of incident DPs until age 57 (years 2012–2023), adjusting for factors related to socioeconomic status, health, sleep and working times at age 46.

Results

In total, 253 men (9.7%) and 381 women (12.4%) were E-types. The PGSmorn correlated with the chronotype (p<0.001).

During follow-up, 135 men (5.2%) and 249 women (8.1%) were granted their first DP. For E-types, the corresponding proportions were 8.3% and 12.1%, respectively. Compared with M-types, the unadjusted HRs (95% CIs) for DPs among E-types were 1.72 (1.04 to 2.83) in men and 1.73 (1.22 to 2.46) in women. Adjusting for socioeconomic factors did not attenuate the results.

Conclusions

The higher incidence of DPs among E-types in the core productive years of work careers represents a major challenge for sustainable national economies. Further research and action to support health and work ability among E-types are needed."

Night owls may struggle to continue working until official retirement age

Evening chronotype and disability pensions: 12-year register-based follow-up of middle-aged adults from the Northern Finland birth cohort 1966 Free (open access)

Restricted daily eating windows improve cognitive skills in older women

Good news! Not only in older women! I can tell from my own experience that occasional fasting or restricting eating during the day helps.

"Restricted eating windows could be linked to a reduced dementia risk, per a new pilot study presented at the American Society for Nutrition’s annual meeting, which found that cognitive skills were improved in older women who restricted their eating to an 8–9-hour window and avoided eating four hours before bed, compared with participants who spread their meals across ~12 hours. ..."

"Eating within a shorter daily window may help protect certain thinking skills as people age. In a small six-month trial, older women who limited eating to about 8 to 9 hours a day performed better on planning and problem-solving tests than those who ate over 12 hours. Both groups lost similar amounts of weight, hinting that when people eat could matter in addition to how much they eat."

From the abstract:

"Objectives: 

Circadian rhythms coordinate physiological processes with environmental cues such as meal timing and the light-dark cycle.

Most Americans consume food over prolonged periods ( >12 h/d).

Time-restricted eating (TRE) shortens the eating window and influences circadian biology that can improve cognitive performance. However, weight loss itself also improves cognition, and studies examining TRE with caloric restriction (CR) remain limited. We examined the effects of TRE+CR versus CR on cognition in postmenopausal women.

Methods:

In this trial, women (BMI ≥25 kg/m2, 50-79 years old) were randomized to six months of TRE+CR (n=26) or CR (n=21). Groups were counseled to reduce calorie intake (-500 kcal/d), and TRE+CR self-selected a ≤ 9-hour eating window, while CR maintained their eating window.

Baseline National Adult Reading Test (NART) was used to estimate premorbid levels of intelligence. The Pittsburg Sleep Quality Index (PSQI) questionnaire and Cambridge Neuropsychological Battery of Tests (CANTAB) were administered at weeks 0 and 24.

CANTAB tests included memory and learning (Paired Associate Learning; PAL), executive function (Stockings of Cambridge; SOC; and Multitasking Test) and reaction time (RTI).

Results:

The women (61±5 years, 72% white, 33±4 kg/m2) had an eating window of 12.3±0.9 h/d, which was reduced with TRE+CR (8.2±0.7 h/d), and maintained in the CR group (12.6±0.8 h/d) (p< 0.001).

Mean NART error score (13.8±5.5) was within an expected range. Global PSQI score was unchanged after 6 months and did not differ between groups. There were similar reductions in body weight (-7.5±4.6 vs -6.1±5.4 kg) after 6 months.

Spatial planning and problem-solving (SOC) improved over time with TRE (p< 0.05), but not CR and differed between groups (p< 0.05).

Total errors during the PAL test decreased over time with TRE (p< 0.01), but not CR although the changes between groups were not significant. The multitasking test and RTI were not changed by the intervention.

Reductions in the eating window predicted greater improvement in SOC (p< 0.01) and PAL (p< 0.05) after adjusting for relevant covariates.

Conclusions:

TRE improved memory, learning, and problem-solving tests, independent of weight loss. Additional mechanistic analyses are warranted to explain these findings."

 

Global Health NOW: Hope and Headwinds in the HIV Fight; and Unlocking the Medical Potential of Menstrual Blood

Eating within 8 hours may help keep the aging brain sharp "Eating within a shorter daily window may give the aging brain a modest boost beyond weight loss alone."

Time-Restricted Eating and Caloric Restriction Influences Cognition in Older Women: A Randomized Controlled Trial (open access)

Too little and too much sleep associated with faster aging

Amazing stuff! The optimal sleep duration is reported between 6.4 and 7.8 hours. But what about sleep quality?

"An analysis of biological clocks throughout the human body suggests that too few hours of sleep—and too many—may speed aging in the brain, heart, lung, and immune system and is associated with a wide range of diseases. ..."

From the abstract:

"Optimal sleep has a vital role in promoting healthy ageing and enhancing longevity. Here we propose Sleep Chart to assess the relationship between self-reported sleep duration and 23 biological ageing clocks derived from in vivo imaging, plasma proteomics and metabolomics.

First, a systemic, U-shaped pattern emerges between sleep duration and biological age gaps across nine brain and body systems and three omics technologies.

The sample-specific lowest biological age gaps are achieved between 6.4 and 7.8 h of sleep duration, varying by organ and sex in the UK Biobank (aged 37–84 years).

Furthermore, short (<6 h) and long (>8 h) sleep duration, compared with a normal sleep duration (6–8 h), are associated with increased risk of systemic diseases beyond the brain and all-cause mortality, with evidence from genetic correlations and time-to-incident survival predictions, such as depression and diabetes.

Finally, the pathways by which long and short sleep duration are associated with late-life depression differ: ageing clocks may partially mediate the pathway for long sleep duration, while short sleep duration shows a more direct link. Although Mendelian randomization does not provide strong evidence that disease causally affects sleep, it cannot completely exclude such reverse causality. Our findings suggest a cross-organ, multi-omics U-shaped relationship between sleep duration and biological ageing clocks, highlighting the potential of sleep optimization to promote healthy ageing, lower disease risk and extend longevity."

Too little sleep—and too much—associated with faster aging

Too Little Sleep—and Too Much—Associated with Faster Aging (original news release)

Sleep chart of biological ageing clocks in middle and late life (open access)

For many organs, sleep duration betwen 6.4 and 7.8 hours was associated with less aging as measured by organ-specific biological clocks. The clocks in this image are created from protein data specific to each organ. Blue lines represent males; red lines represent females.

Fig. 2: Genetic evidence for a systemic landscape of abnormal sleep duration patterns compared to normal sleep duration.

The cellular switch that explains why humans aren’t nocturnal

Amazing stuff! How mammals became diurnal after nocturnality!

"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. ...

he 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. ..."

From the editor's summary and abstract:

"Editor’s summary

When ferocious dinosaurs roamed the earth, it was advantageous for mammals to be nocturnal. After these predators became extinct, many mammals (including the ancestors of humans) switched their daily rhythms to be active during the day. Beale et al. explored changes that might allow animals that retain the same fundamental clock components to make this switch. One cue that influences the timing of cellular clocks is temperature. Cells of nocturnal animals were more sensitive to temperature changes, and their clocks ran faster at higher temperatures. This appeared to reflect differential sensitivity of signaling pathways that regulate rates of protein translation through changes in protein phosphorylation. Inhibition of one pathway containing the protein kinase mTOR (mechanistic target of rapamycin) shifted nocturnal mouse cells toward more diurnal activity.  ...

Structured Abstract

INTRODUCTION

The ancestors of modern mammals were strictly nocturnal, avoiding the daytime while dinosaurs dominated. Only after the extinction of nonavian dinosaurs did mammals radiate into daytime niches, meaning that daily physiological rhythms became reversed with respect to the day and night but without any change in the brain’s master circadian clock.

Diurnality evolved multiple times, independently, but can also arise spontaneously in certain nocturnal species under conditions of very low energy balance. No specific neuroanatomical circuit has been demonstrated to function as a nocturnal-diurnal switch in any mammalian lineage, so we tested the hypothesis that this daily biological signal inverter instead has a cell-autonomous basis.

RATIONALE

Circadian timing is intrinsic to most mammalian cells. Daily hormonal cues, such as glucocorticoid and insulin signaling, potently synchronize cellular clocks with each other and the external day:night cycle, with very similar effects on the cellular clocks of diurnal and nocturnal mammals. However, the rates and equilibria of several fundamental biochemical processes were recently revealed to differ markedly between human and mouse cells. We therefore asked whether daily systemic rhythms (temperature, osmolality) that directly affect cellular biochemistry might elicit different effects on the function of diurnal versus nocturnal mammalian cells. To test this, we compared responses of cells and tissues under acute, long-term, and cyclical stimuli at the levels of circadian timing (bioluminescence reporter assays), proteins (proteome), protein modifications (phosphoproteome), and protein synthesis. We used comparative genomics to identify genes evolving with diurnal niche preference, and we perturbed candidate pathways in cells, tissues, and live mice to test causality.

RESULTS

Using daily thermal or osmotic cycles as a tool, we found opposite entrainment of diurnal versus nocturnal cells, reflecting their species’ temporal niche. Mouse and human cells differed not only in the magnitude but also the direction of their response to temperature. Moreover, temperature change evoked opposite shifts in global protein synthesis and phosphorylation between human and mouse cells and implicated differential sensitivity of the mechanistic target of rapamycin (mTOR) and with-no-lysine (WNK) kinase signaling pathways as plausible mediators.

Comparative genomics validated that genes in these pathways show accelerated evolution in diurnal mammals, rendering diurnal cells more robust against perturbations of solvent thermodynamics and consistent with an energy-saving adaptation. Last, manipulation of mTOR signaling in nocturnal mouse cells and tissues and in vivo was sufficient to shift circadian timing toward being more diurnal.

CONCLUSION

We identified a cell-intrinsic, thermodynamic mechanism underlying the mammalian switch between nocturnal and diurnal activity. By linking cellular responses to thermodynamic perturbation with circadian entrainment through genetic alterations in the mTOR and WNK pathways, our findings explain how diurnality could repeatedly evolve in mammals. More broadly, they highlight that even fundamental cellular properties, such as the response to temperature, may differ systematically between species, with profound consequences for circadian biology and temporal niche."

The cellular switch that explains why humans aren’t nocturnal | University of Cambridge "Differences in cellular pathway activity flip the switch from nocturnality to diurnality and explain a major evolutionary change humans have undergone."

A cellular basis for the mammalian nocturnal-diurnal switch (no public access)

Convergent evolution of cellular clock robustness to perturbation as a route to mammalian diurnality.

Circadian cycles studied at single-cell level across the whole brain

Amazing stuff!

"Although circadian rhythms have been well studied in a few specific regions, their brain-wide organization remains poorly understood. To quantify spontaneous circadian neural activity at single-cell resolution, Yamashita et al. used tissue clearing and whole-brain immunostaining on a large number of mouse brains over two full circadian cycles. Circadian rhythmicity was present in many brain regions. The activity of most regions peaked during the animals’ active phase. However, sleep centers, visual areas, the dentate gyrus, and the cerebellum all peaked during the inactive phase. A closer look revealed distinct circadian phases even within individual regions, highlighting temporal heterogeneity. These findings will be useful for relating physiological and behavioral experimental data to the time-of-day–driven internal regulatory forces."

From the editor's summary and abstract:

"Editor’s summary

Although circadian rhythms have been well studied in a few specific regions, their brainwide organization remains poorly understood. To quantify spontaneous circadian neural activity at single-cell resolution, Yamashita et al. used tissue clearing and whole-brain immunostaining on a large number of mouse brains over two full circadian cycles. Circadian rhythmicity was present in many brain regions. The activity of most regions peaked during the animals’ active phase. However, sleep centers, visual areas, the dentate gyrus, and the cerebellum all peaked during the inactive phase. A closer look revealed distinct circadian phases even within individual regions, highlighting temporal heterogeneity. These findings will be useful for relating physiological and behavioral experimental data to the time-of-day–driven internal regulatory forces. 

Structured Abstract

INTRODUCTION

Neural activity across different brain regions underlies essential physiological and behavioral functions. These activities are coordinated in space and time, and circadian rhythms are a fundamental temporal regulator of such activity, influencing sleep, metabolism, hormone secretion, and cognition. Although the suprachiasmatic nucleus (SCN) has been extensively studied as the master pacemaker, how spontaneous neural activity is coordinated across the entire brain over the circadian cycle has remained elusive. Previous approaches, including electrophysiological recordings, in situ hybridization, immediate early gene labeling, circadian gene reporters, and calcium imaging, have typically been restricted to limited regions and lack spatial continuity, making it difficult to achieve a systematic view.

RATIONALE

To overcome these limitations, we used tissue clearing and three-dimensional whole-brain c-Fos immunostaining. c-Fos is notable for its rapid and broad induction across the brain, making it suitable for spatially comprehensive mapping of neural activity. By sampling brains every 4 hours over 2 days under constant darkness, we aimed to generate a whole-brain atlas of circadian neural activity at single-cell resolution and to identify how different regions and subregions contribute to the temporal organization of brain function.

RESULTS

Each brain contained between 0.4 and 3.0 million c-Fos–positive cells.

Time-series analysis of 144 brains revealed that 79% of 642 anatomically defined regions showed significant circadian rhythmicity. Most regions peaked during the late subjective night, corresponding to the active phase in nocturnal mice, whereas some, including sleep-promoting nuclei such as the ventrolateral preoptic area, peaked during the subjective day. Visual regions peaked during the daytime, in antiphase to auditory regions at night, highlighting functional specialization.

The hippocampal memory system showed notable internal diversity: CA1 and CA3 peaked during the active phase, whereas the dentate gyrus peaked during the inactive phase, nearly in antiphase. This inversion aligns with reports of dentate gyrus recruitment during sleep stages, suggesting phase-specific contributions to memory processing.

Voxelwise analysis further revealed distinct subregional dynamics, including heterogeneous patterns in the SCN and dorsomedial nucleus of the hypothalamus, and a gradual peak time shift along the dorsoventral axis within CA1, highlighting continuous spatiotemporal variation even within single structures. In addition, we demonstrated that whole-brain c-Fos activity patterns could accurately predict circadian time using computational approaches adapted from omics data, confirming that brain-wide rhythms collectively encode temporal information.

CONCLUSION

Our study establishes a comprehensive atlas of circadian neural activity at the whole-brain scale. By combining tissue clearing with large-scale time-series sampling and systematic quantitative analysis, we provide a global view of how neural activity rhythms are organized across hundreds of regions and subregions.

The open-access database we developed allows users to explore these rhythms by region or voxel and to upload custom regions of interest for analysis. It is designed to be compatible with gene expression, connectivity, and cell-type resources, enabling integrative analyses that link circadian activity with molecular and anatomical data.

Thus, this resource not only advances chronobiology but also provides a temporal framework across neuroscience, linking time-of-day dynamics to studies of diverse brain functions, pharmacology, and disease."

In Science Journals | Science

A whole-brain single-cell atlas of circadian neural activity in mice (no public access)

Here is an almost 17 minutes long YouTube video about this paper. (Caveat: I did not watch it)

Whole-brain single-cell atlas of circadian neural activity.

The circadian cycle of Deep-sea shrimp is based on the tides

Amazing stuff!

"... In the depths of the sea, creatures still sync their internal schedules—but they do it to the tides instead, according to a new study.

Hydrothermal vent ecosystems are full of life that never sees the light of day. Given that most animals examined to date have light-based clocks, researchers wondered if the denizens of the deep have figured out a daily schedule without light—or if they have any clock at all.

So they collected shrimp from a vent, kept them in the dark, and analyzed gene expression patterns every 4 hours for a total of 72 hours. That revealed roughly 12.4-hour cycles instead of the 24-hour ones seen in humans—timing that matches up perfectly with tidal fluctuations. ..."

From the abstract:

"Biological clocks are a ubiquitous feature of all life, enabling the use of natural environmental cycles to track time. Although studies on circadian rhythms have contributed greatly to the knowledge of chronobiology, biological rhythms in dark biospheres such as the deep sea remain poorly understood.

Here, based on a free-running experiment in the laboratory, we reveal potentially endogenous rhythms in the gene expression of the deep-sea hydrothermal vent shrimp Rimicaris leurokolos.

Oscillations with approximately 12 h periods, probably reflecting tidal influence, greatly prevail over others in the temporal transcriptome, indicating R. leurokolos probably depends on a circatidal clock consisting of at least some components independent from the circadian clocks. The tidal transcripts exhibit an antiphased expression pattern divided into two internally synchronized clusters, correlated with wide-ranging biological processes that occur in the nucleus and cytoplasm, respectively.

In addition, the tidal transcripts showed great similarities with genes in fruit flies and mice exhibiting approximately 12 h ultradian rhythms, indicating that the tide probably had a broad impact on the evolution of approximately 12 h oscillations found across the Metazoa. These findings not only provide new insights into the temporal adaptations in deep-sea organisms but also highlight hydrothermal vent organisms as intriguing models for chronobiological studies, particularly those linked to approximately 12 h ultradian rhythms."

ScienceAdviser

Circatidal control of gene expression in the deep-sea hot vent shrimp Rimicaris leurokolos

Fig. 1 Deep-sea chronobiology study on the hydrothermal vent shrimp Rimicaris leurokolos.

Ending jet lag: Scientists discover secret to regulating our body clock

Good news! Now we need hypersonic planes to travel faster!

"Scientists have discovered a revolutionary way to put an end to jet lag by uncovering the secret at the tail end of Casein Kinase 1 delta (CK1δ), a protein that regulates our body clock. This breakthrough, achieved by researchers ... offers a new approach to adjusting our circadian rhythms, the natural 24-hour cycles that influence sleep-wake patterns and overall daily functions. ...

Using advanced spectroscopy and spectrometry techniques to zoom in on the tails, the researchers found that how the proteins are tagged is determined by their distinct tail sequences. ..."

"... This discovery highlights how a small part of CK1δ can greatly influence its overall activity. This self-regulation is vital for keeping CK1δ activity balanced, which, in turn, helps regulate our circadian rhythms.

The study also addressed the wider implications of these findings. CK1δ plays a role in several important processes beyond circadian rhythms, including cell division, cancer development, and certain neurodegenerative diseases. By better understanding how CK1δ’s activity is regulated, scientists could open new avenues for treating not just circadian rhythm disorders but also a range of conditions. ..."

From the significance and abstract:

"Subtle control of kinase activity is critical to physiologic modulation of multiple physiological processes including circadian rhythms. Casein kinase 1δ (CK1δ) and the closely related Casein kinase 1 epsilon (CK1ε) regulate circadian rhythms by phosphorylation of PERIOD2 (PER2), but how kinase activity itself is controlled is not clear. Building on the prior observation that two splice isoforms of CK1δ have opposite effects on the circadian period, we show that the difference maps to three phosphorylation sites specific to δ1 in the variably spliced region [extreme C termini (XCT)] that cause feedback inhibition of the kinase domain. More broadly, the data suggest a general model where CK1 activity on diverse substrates can be controlled by signaling pathways that alter tail phosphorylation.

Abstract

Casein kinase 1δ (CK1δ) controls essential biological processes including circadian rhythms and wingless-related integration site (Wnt) signaling, but how its activity is regulated is not well understood. CK1δ is inhibited by autophosphorylation of its intrinsically disordered C-terminal tail. Two CK1 splice variants, δ1 and δ2, are known to have very different effects on circadian rhythms. These variants differ only in the last 16 residues of the tail, referred to as the extreme C termini (XCT), but with marked changes in potential phosphorylation sites. Here, we test whether the XCT of these variants have different effects in autoinhibition of the kinase. Using NMR and hydrogen/deuterium exchange mass spectrometry, we show that the δ1 XCT is preferentially phosphorylated by the kinase and the δ1 tail makes more extensive interactions across the kinase domain. Mutation of δ1-specific XCT phosphorylation sites increases kinase activity both in vitro and in cells and leads to changes in the circadian period, similar to what is reported in vivo. Mechanistically, loss of the phosphorylation sites in XCT disrupts tail interaction with the kinase domain. δ1 autoinhibition relies on conserved anion-binding sites around the CK1 active site, demonstrating a common mode of product inhibition of CK1δ. These findings demonstrate how a phosphorylation cycle controls the activity of this essential kinase."

Ending jet lag: Scientists discover secret to regulating our body clock

Scientists discover a secret to regulating our body clock, offering new approach to end jet lag (original news release) "A team of scientists in Singapore and the US uncovered how a protein that controls our biological clock modifies its own function, offering new ways for treating jet lag and seasonal adjustments"

Isoform-specific C-terminal phosphorylation drives autoinhibition of Casein kinase 1 (open access)

Fig. 1 CK1δ isoforms change kinase activity in vitro and regulation of XCT phosphorylation in cells.

A peptide (shown in mesh) with attached phosphate tags (red and orange spheres) blocks the active site of CK1δ. Tagging the tail end of CK1δ, a process known as auto-phosphorylation, makes the protein less active, and with that less able to fine-tune the body’s internal clocks.

Even bacteria button up for winter. Photoperiodism might have evolved before circadian clocks

Amazing stuff!

"As winter approaches ... chronobiologists have shown that at least one kind of bacterium also prepares for the cold season—the first such seasonal response known among microbial life ...

When chilled, microbes increase the proportion of unsaturated fats in their membranes to keep them from freezing. ...

Not only did they make their membranes more fluid, but they also altered gene activity, the team reports. In anticipation of winter, when photosynthesis slows, the cyanobacteria revved up genes for conserving energy. When days got longer, they increased the activity of genes that protect against damage from sunlight. ..."

"... “To me, the most exciting thing about these results are their ramifications for the evolution of biological timekeeping,” he said. “I think we ‘chronobiologists’ have always assumed that daily (circadian) clocks evolved before organisms could measure day/night-length and thereby anticipate the changing seasons. But the facts that
(1) photoperiodism evolved in such ancient and simple organisms, and
(2) our gene expression results implicate stress response pathways that probably evolved very early in life on Earth, suggest that photoperiodism might have evolved before circadian clocks. This is because either long days or long nights are differentially stressful for photoautotrophs like cyanobacteria, and therefore these conditions would be expected to trigger stress responses differentially. As a result of these selective pressures, photoperiodic time measurement might have evolved even before bona fide circadian clocks appeared. ...” ..."

From the editor's summary and abstract:

"Editor’s summary

Long-lived plants and animals clearly regulate their physiology according to seasonal changes in day length to appropriately adjust their physiology. Jabbur et al. found that cyanobacteria can do the same even though individuals only live for a few hours, a time shorter than a single daily photoperiod. Exposure to short photoperiods characteristic of winter stimulated these cyanobacteria to adjust their membrane lipids and gene expression to accommodate cold conditions. These responses required a functional circadian clock. Thus, population-based sensing of photoperiod appears to have evolved early, perhaps as a refinement of stress pathways....

Abstract

Photoperiodic time measurement is the ability of plants and animals to measure differences in day versus night length (photoperiod) and use that information to anticipate critical seasonal transformations, such as annual temperature cycles. This timekeeping phenomenon triggers adaptive responses in higher organisms, such as gonadal stimulation, flowering, and hibernation. Unexpectedly, we observed this capability in cyanobacteria—unicellular prokaryotes with generation times as short as 5 to 6 hours. Cyanobacteria exposed to short, winter-like days developed enhanced resistance to cold mediated by desaturation of membrane lipids and differential programs of gene transcription, including stress response pathways. As in eukaryotes, this photoperiodic timekeeping required an intact circadian clockwork and developed over multiple cycles of photoperiod. Therefore, photoperiodic timekeeping evolved in much simpler organisms than previously appreciated and enabled genetic responses to stresses that recur seasonally."

Researchers Discover the Evolution of Seasonal Anticipation in Cyanobacteria (original news release)

ScienceAdvisor

In a first for microbes, bacteria seem to track—and button up for—the cold

Bacteria can anticipate the seasons: Photoperiodism in cyanobacteria

Lead scientist Maria Luísa Jabbur sitting in front of petri dishes

Synced body clocks keep muscles healthy as we age

Amazing stuff! As they say Mens sana in corpore sano!

"As we age, our muscles tend to shrink and get weaker. This loss of mass and strength is a major reason for disability in older people. ... a key player in muscle health: its own internal clock.

... body’s central timekeeper or circadian rhythm, we actually have many internal clocks. Different parts of our bodies have their own timekeepers, and the coordination of these peripheral clocks with the central one in the brain appears to be key to maintaining health. Mice lacking the molecular timekeeping protein Bmal1 in either their brains or their muscles exhibited premature muscle aging, found the new study. Only restoring it in both places allowed the mice’s muscles to stay fit. A study of skin, concurrently published in Cell Stem Cell , came to a similar conclusion. In both studies, the researchers found that the peripheral clock played an important role in interpreting the brain’s timing signals to optimize tissue functioning.

“It is fascinating to see how synchronization between the brain and peripheral circadian clocks plays a critical role in skin and muscle health, while peripheral clocks alone are autonomous in carrying out the most basic tissue functions,” ..."

From the editor's summary and abstract:

"Editor’s summary

Mice lacking the circadian clock component Bmal1 show not only disrupted rhythms but also premature aging and muscle wasting. To explore the specific roles of the central brain clock and the peripheral clock in muscle, Kumar et al. restored clock function by targeted expression of Bmal1 in the brain, skeletal muscle, or both. Restoration of both clocks was needed to substantially inhibit premature aging and muscle dysfunction. The muscle clock alone did not restore rhythmicity but acted to filter signals from the brain clock to achieve proper muscle function. Time-restricted feeding, a behavioral timing cue, could partially substitute for loss of the central clock. Such insights should enhance our understanding of the roles of circadian disruption in aging and provide potential strategies to protect muscle function in aging individuals. ...

Abstract

A molecular clock network is crucial for daily physiology and maintaining organismal health. We examined the interactions and importance of intratissue clock networks in muscle tissue maintenance. In arrhythmic mice showing premature aging, we created a basic clock module involving a central and a peripheral (muscle) clock. Reconstituting the brain-muscle clock network is sufficient to preserve fundamental daily homeostatic functions and prevent premature muscle aging. However, achieving whole muscle physiology requires contributions from other peripheral clocks. Mechanistically, the muscle peripheral clock acts as a gatekeeper, selectively suppressing detrimental signals from the central clock while integrating important muscle homeostatic functions. Our research reveals the interplay between the central and peripheral clocks in daily muscle function and underscores the impact of eating patterns on these interactions."

ScienceAdvisor

Brain-muscle communication prevents muscle aging by maintaining daily physiology (no public access)

Circadian rhythms of the liver can influence drugs’ effectiveness

Amazing stuff! Take your pills on time or your liver will not forgive it! 😊

The influence of the circadian rhythms on all kinds of bodily function has been known for decades. Here is more about it!

"Using tiny, engineered livers derived from human patients, ... researchers found that more than 300 liver genes are under circadian control. These circadian variations affect how much of a drug is available and how effectively the body can break it down. ...

The study also revealed that the liver is more susceptible to infections such as malaria at certain points in the circadian cycle, when fewer inflammatory proteins are being produced. ...
It is estimated that about 50 percent of human genes follow a circadian cycle ...

Most of these genes clustered in two groups — about 70 percent of the genes peaked together, while the remaining 30 percent were at their lowest point when the others peaked. These included genes involved in a variety of functions, including drug metabolism, glucose and lipid metabolism, and several immune processes. ..."

From the abstract:

"Critical aspects of physiology and cell function exhibit self-sustained ~24-hour variations termed circadian rhythms. In the liver, circadian rhythms play fundamental roles in maintaining organ homeostasis. Here, we established and characterized an in vitro liver experimental system in which primary human hepatocytes display self-sustained oscillations. By generating gene expression profiles of these hepatocytes over time, we demonstrated that their transcriptional state is dynamic across 24 hours and identified a set of cycling genes with functions related to inflammation, drug metabolism, and energy homeostasis. We designed and tested a treatment protocol to minimize atorvastatin- and acetaminophen-induced hepatotoxicity. Last, we documented circadian-dependent induction of pro-inflammatory cytokines when triggered by LPS, IFN-β, or Plasmodium infection in human hepatocytes. Collectively, our findings emphasize that the phase of the circadian cycle has a robust impact on the efficacy and toxicity of drugs, and we provide a test bed to study the timing and magnitude of inflammatory responses over the course of infection in human liver."

Circadian rhythms can influence drugs’ effectiveness | MIT News | Massachusetts Institute of Technology MIT researchers find circadian variations in liver function play an important role in how drugs are broken down in the body.

Autonomous circadian rhythms in the human hepatocyte regulate hepatic drug metabolism and inflammatory responses (open access)

Fig. 1. Primary human hepatocytes display a circadian rhythm in culture.

Untangling the Mystery of Sleep: Can we live without sleep? Possibly!

You may sleep because of your gut and not because of your brain!

Eat more proteins and you sleep better!

"... Sleep is one unified state, but it seems to have multiple components that are regulated through separate mechanisms ...
Sleep is a super old behavior that we think originated in the earliest animals. These animals had no brain; they only had a very simple nervous system. ...
We found that fruit flies who slept less had shorter lifespans: We saw a correlation where the more sleep the flies lost, the faster they died. Interestingly, the mode of sleep deprivation did not matter. What mattered was the amount of sleep lost. ...
We found that in the gut, there was an increase in oxidizing molecules, and the peak of oxidation correlated with the inflection point where the flies started to die. We confirmed this finding in sleep-deprived mice. But when we gave sleep-deprived flies antioxidants or turned on antioxidant-producing genes in the gut, we found the flies could survive on little or no sleep, suggesting that the gut is a really important target of sleep. ...
However, while CCHa1 is present in both the nervous system and the gut, it was only when we depleted it in the gut that flies were roused more easily. ...
Finally, we showed that a higher protein diet also improved the quality of sleep in mice, making them more resistant to mechanical disturbances. ..."

From the highlights and abstract:

"Highlights

• Enrichment of dietary proteins can make flies and mice less arousable from sleep

• Dietary proteins activate cells in the fly gut to secrete the peptide CCHa1

• CCHa1 signals to brain dopamine neurons to modulate sensory responsiveness

• Different sensory modalities can be gated by independent mechanisms during sleep

Summary

Suppressing sensory arousal is critical for sleep, with deeper sleep requiring stronger sensory suppression. The mechanisms that enable sleeping animals to largely ignore their surroundings are not well understood. We show that the responsiveness of sleeping flies and mice to mechanical vibrations is better suppressed when the diet is protein rich. In flies, we describe a signaling pathway through which information about ingested proteins is conveyed from the gut to the brain to help suppress arousability. Higher protein concentration in the gut leads to increased activity of enteroendocrine cells that release the peptide CCHa1. CCHa1 signals to a small group of dopamine neurons in the brain to modulate their activity; the dopaminergic activity regulates the behavioral responsiveness of animals to vibrations. The CCHa1 pathway and dietary proteins do not influence responsiveness to all sensory inputs, showing that during sleep, different information streams can be gated through independent mechanisms."

Untangling the Mystery of Sleep | Harvard Medical School Recent sleep research reveals unexpected connections between the brain and gut

A gut-secreted peptide suppresses arousability from sleep (no public access)

Graphical abstract

Daily Gene Expression Rhythms Vary with Sex and Age: Study on postmortem tissue

Amazing stuff! This may well impact e.g. the timing of medications.

"The mammalian circadian clock strongly influences when and to what extent certain genes are transcribed in each tissue throughout the day. A new study, ... shows that this daily schedule of gene expression depends partially on a person’s sex and age. Specifically, the team found that women have more genes with rhythmicity compared to men, and that these rhythms break down as people age. ...
begin to understand causal relationships between the circadian clock and human disease states, for instance, in cancer or metabolic disorders."

From the abstract:

"The circadian clock modulates human physiology. However, the organization of tissue-specific gene expression rhythms and how these depend on age and sex is not defined in humans. We combined data from the Genotype-Tissue Expression (GTEx) project with an algorithm that assigns circadian phases to 914 donors, by integrating temporal information from multiple tissues in each individual, to identify messenger RNA (mRNA) rhythms in 46 tissues. Clock transcripts showed conserved timing relationships and tight synchrony across the body. mRNA rhythms varied in breadth, covering global and tissue-specific functions, including metabolic pathways and systemic responses. The clock structure was conserved across sexes and age groups. However, overall gene expression rhythms were highly sex-dimorphic and more sustained in females. Rhythmic programs generally dampened with age across the body."

Daily Gene Expression Rhythms Vary with Sex and Age: Study | The Scientist Magazine® By studying tissues from deceased people, a team found that women have more rhythmical gene expression and that this molecular rhythmicity decreases with age.

Sex-dimorphic and age-dependent organization of 24-hour gene expression rhythms in humans (no public access)

Internal Clock Disruptions Increase Colon Cancer Risk in Mice

Recommendable! Cancer is history (soon)!

More evidence that stressful lives and/or disruptive live styles likely promote cancer especially among younger people.

"... This link between the body’s natural circadian clock and colorectal cancer, the researchers behind the study say, may explain the alarming rise in young onset colorectal cancer observed over the last two decades. “A majority of these [cases in young adults] are sporadic in nature and not actually linked to genetic predisposition,” ...
Indeed, previous research found that nurses working night shifts have higher rates of breast cancer, so Masri and her colleagues hypothesized that keeping odd hours could also play a role in colorectal cancer. ...

To find out, the researchers took healthy mice and deleted the gene Bmal1, which regulates circadian rhythms, preventing the clock from functioning properly in their intestines. They then crossed these clock-deficient mice with ones that are prone to tumors because they carry two mutated copies of their APC gene, which normally acts as a tumor suppressor in colon cancer. The cross resulted in mice with one nonfunctional APC allele and disrupted intestinal clocks.

Intestinal organoids grown from these animals’ stem cells exhibited accelerated development of intestinal tumors compared to organoids grown from animals with a functional circadian clock. ..."

From the abstract:

"An alarming rise in young onset colorectal cancer (CRC) has been reported; however, the underlying molecular mechanism remains undefined. Suspected risk factors of young onset CRC include environmental aspects, such as lifestyle and dietary factors, which are known to affect the circadian clock. We find that both genetic disruption and environmental disruption of the circadian clock accelerate Apc-driven CRC pathogenesis in vivo. Using an intestinal organoid model, we demonstrate that clock disruption promotes transformation by driving Apc loss of heterozygosity, which hyperactivates Wnt signaling. This up-regulates c-Myc, a known Wnt target, which drives heightened glycolytic metabolism. Using patient-derived organoids, we show that circadian rhythms are lost in human tumors. Last, we identify that variance between core clock and Wnt pathway genes significantly predicts the survival of patients with CRC. Overall, our findings demonstrate a previously unidentified mechanistic link between clock disruption and CRC, which has important implications for young onset cancer prevention."

Internal Clock Disruptions Increase Colon Cancer Risk in Mice | The Scientist Magazine® Disturbing circadian rhythms in organoids and mice increases intestinal tumor growth, findings that may explain a recent rise in colon cancer among young adults, the researchers behind the work say.

Disruption of the circadian clock drives Apc loss of heterozygosity to accelerate colorectal cancer (open access)

Fig. 1. Disruption of circadian clock accelerates intestinal tumorigenesis in vivo

Metastatic circulating tumor cells from breast cancer spread when women sleep

Good news! Cancer is history (soon)! I hope, this will not cause women to have insomnia. Melatonin is also implicated.

By the way, yesterday I have here exposed the perverse gender identity ideology of Nature journal, because women cannot have breast cancer, only people can, but women can be scientists, because they are vulnerable and marginalized.

"... Now, a study finds that for people [women] with breast cancer, these rogue cells — called circulating tumour cells, or CTCs — are more likely to jump into the blood at night than during the day. ...
The research community has been discussing for decades how the body’s circadian rhythm influences cancer. With this study, it has become clear that “tumours wake up when patients are sleeping”... It’s a “step forward” in understanding metastasis ..."

From the abstract:

"The metastatic spread of cancer is achieved by the haematogenous dissemination of circulating tumour cells (CTCs). Generally, however, the temporal dynamics that dictate the generation of metastasis-competent CTCs are largely uncharacterized, and it is often assumed that CTCs are constantly shed from growing tumours or are shed as a consequence of mechanical insults. Here we observe a striking and unexpected pattern of CTC generation dynamics in both patients with breast cancer and mouse models, highlighting that most spontaneous CTC intravasation events occur during sleep. Further, we demonstrate that rest-phase CTCs are highly prone to metastasize, whereas CTCs generated during the active phase are devoid of metastatic ability. Mechanistically, single-cell RNA sequencing analysis of CTCs reveals a marked upregulation of mitotic genes exclusively during the rest phase in both patients and mouse models, enabling metastasis proficiency. Systemically, we find that key circadian rhythm hormones such as melatonin, testosterone and glucocorticoids dictate CTC generation dynamics, and as a consequence, that insulin directly promotes tumour cell proliferation in vivo, yet in a time-dependent manner. ..."

These cancer cells wake up when people sleep Researchers make ‘striking’ discovery that breast cancer cells are more likely to jump into the blood when people are resting.

The metastatic spread of breast cancer accelerates during sleep (no public access)

Scientists reveal how internal biological clock may suppress tumor growth

Good news! Cancer is history!

"Those who engage in long-term, rotational shift work, such as nursing or firefighting, are at increased risk of developing cancer, but the biological roots of this phenomenon have remained largely unknown.
Now, new research ... demonstrates a clear link between the circadian clock and the body’s tumor suppression system, with the potential to accelerate cancer cell growth. ...
the new research shows how mutant forms of the circadian clock gene CRY2 found in human tumors are able to dampen the activity of a key tumor suppressor gene, P53. ...
“This is the first study to investigate point mutations in a core clock gene that have been reported in human cancers,” ... “The impact of these genetic changes on P53 activity is truly remarkable and indicates a striking regulation of tumor suppression by the circadian clock.” ..."

"... The circadian repressors CRY1 and CRY2 evolved from light-activated DNA-repair enzymes, suggesting that they may be involved. Here, we demonstrate that missense mutations in CRY2 reported in The Cancer Genome Atlas suppress P53 target-gene expression and enhance the growth of MYC-transformed fibroblasts. Our identification of point mutations in CRY2 in human tumors that influence P53 activity and cell growth provides evidence for a clinically relevant molecular connection between CRYs and P53. ...
Disruption of circadian rhythms increases the risk of several types of cancer. Mammalian cryptochromes (CRY1 and CRY2) are circadian transcriptional repressors that are related to DNA-repair enzymes. While CRYs lack DNA-repair activity, they modulate the transcriptional response to DNA damage, and CRY2 can promote SKP1 cullin 1–F-box (SCF)FBXL3-mediated ubiquitination of c-MYC and other targets. Here, we characterize five mutations in CRY2 observed in human cancers in The Cancer Genome Atlas. We demonstrate that two orthologous mutations of mouse CRY2 (D325H and S510L) accelerate the growth of primary mouse fibroblasts expressing high levels of c-MYC."

Scientists reveal how internal biological clock may suppress tumor growth | Scripps Research New discovery helps explain how disruption to daily biological rhythms could lead to increased risk of cancer.

CRY2 missense mutations suppress P53 and enhance cell growth (no public access)

Discovery of Malaria Parasite’s Clock Could Pave Way to New Treatments

Good news and amazing stuff! Certain parasites have circadian rhythms too! This applies also to the parasite that causes sleeping sickness.

Just a reminder a Covid-19 pandemic reminder: Malaria kills over 400,000 people each year, among them many young children. Why have we still not eradicated this scourge of humanity?

Discovery of Malaria Parasite’s Clock Could Pave Way to New Treatments | HHMI.org The parasite that causes malaria has its own internal clock, explaining the disease’s rhythmic fevers and opening new pathways for therapeutics.

Malaria Parasites’ Biological Clocks Coordinate Cell Destruction

Two studies show that Plasmodium—the genus of protozoans that cause malaria—have an internal sense of time that synchronizes with their host’s circadian rhythms and allows the parasites to collectively attack blood cells.