Glaucoma is a chronic optic neuropathy characterized by progressive vision loss. A previous study from our group showed that glaucoma-induced retinal degeneration disrupts photic signaling to the suprachiasmatic nucleus (SCN), altering the molecular components of the central circadian clock. Through its hypothalamic projections, the SCN entrains the hypothalamic–pituitary–adrenal (HPA) axis and drives the rhythmic secretion of corticosterone. In this study, we investigated whether central circadian clock disruption in glaucoma impacts the HPA axis and its downstream physiological rhythms. We analyzed the temporal profiles of key genes controlling the HPA axis in mice with glaucoma. The Crh gene expression was reduced in the paraventricular nucleus, while Crh-r1 exhibited a 10-h phase delay in the pituitary in response to glaucoma. Additionally, Pomc in the pituitary and Mc2r in the adrenal lost rhythmicity. The modulation of the daily rhythms of these key genes was associated with alterations in the diurnal rhythms of clock genes in the PVN, pituitary and adrenal gland. Glaucoma-induced phase shifts and amplitude alterations in the rhythmic expression of Per1, Per2, Nr1d1, and Bmal1 in the pituitary and adrenal gland, resulted in a temporal misalignment between the pituitary and adrenal rhythms. These molecular changes were associated with reduced corticosterone amplitude, suggesting impaired communication between central and peripheral clocks. Together, these findings demonstrate that glaucoma alters the temporal coordination of the HPA axis, highlighting how retinal dysfunction can propagate beyond the visual system to disturb systemic circadian and neuroendocrine regulation.

The circadian clock synchronizes physiological processes with the 24-hour light–dark cycle. Clock disruption contributes to metabolic disorders, including metabolic dysfunction–associated steatohepatitis. We investigated the role of the hepatocyte clock in metabolic dysfunction–associated steatohepatitis using hepatocyte-specific Bmal1 deletion (Hep-Bmal1KO) mice. Hep-Bmal1KO mice showed faster metabolic dysfunction–associated steatohepatitis progression with increased hepatic cholesterol, inflammation, and fibrosis. Transcriptomic and lipidomic analyses revealed dysregulated cholesterol metabolism in Hep-Bmal1KO mice, marked by reduced expression and disrupted rhythmicity of key cholesterol-related genes. Bioinformatic analyses identified Chrebp as a potential coregulator of these transcriptional changes. In an in vitro model with palmitate exposure and gene silencing, we found that Bmal1, but not Chrebp, regulated cholesterol accumulation, indicating Bmal1’s specific role in hepatic cholesterol metabolism. Translating our findings to a human patient cohort revealed a significantly shifted circadian phase, despite no marked effect on hepatic cholesterol levels in the livers of patients with more advanced liver disease (ie, metabolic dysfunction–associated steatohepatitis) compared with simple steatosis. Taken altogether, our findings offer a roadmap to understand the hepatocyte clock’s role in metabolic dysfunction–associated steatohepatitis and its potential as a therapeutic target.

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Digital biomarkers—objective, quantifiable physiological and behavioral measures collected through digital tools—enable continuous health assessment and hold promise for precision medicine. With non-communicable diseases (NCDs) being the leading cause of morbidity and mortality worldwide, digital biomarkers can provide early detection, continuous monitoring, and individualized care. This review examines advances in digital biomarkers across NCD domains, including endocrinology, cardiology, respiratory medicine, neurology, and mental health, with a focus on wearable technologies that continuously capture real-world behavior and physiology. Continuous glucose monitoring in diabetes exemplifies successful clinical translation, while digital biomarkers in cardiology, respiratory medicine, and neurology are at varying stages of validation and adoption. Most digital biomarkers across internal medicine, neurology, and mental health remain in early validation stages. Critical barriers to implementation include limited validation in diverse populations, lack of interoperability, insufficient integration with electronic health records, challenges in multimodal data synthesis, and underdeveloped regulatory pathways. Equity concerns persist as infrastructure, affordability, and capacity-building needs vary globally.Bridging the gap between consumer self-tracking and clinically validated, guideline-compatible digital biomarkers requires rigorous multicenter validation, standardized interfaces, open data models, secure and ethical data infrastructures, and equitable design. Coordinated efforts addressing these challenges are essential to enable digital biomarkers to improve prevention, diagnosis, and management of NCDs.

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Metabolic disorders are closely linked to sleep disturbances. Timerestricted eating (TRE) can improve metabolic disturbances, but its impact onsleep quality is insufficiently studied and recommendations regarding the eatingtiming in TRE are pending. Our aim was to investigate the impact of early TRE(eTRE) and late TRE (lTRE) on sleep quality in obesity. This is a secondary analysis of the randomized crossover trial, whichincluded 31 women with overweight and obesity. Following a 2–4 week baselineperiod, participants were assigned to either a two-week eTRE (eating 8a.m−4p.m.) or a two-week lTRE (eating 1 p.m.−9 p.m.), separated by a two-weekwashout phase. Sleep metrics were assessed objectively by blinded actigraphyand subjectively using Pittsburgh Sleep Quality Index (PSQI) and self-reportof sleep quality. Hunger and satiety were examined using a Visual AnalogueScale (VAS). Actigraphy revealed no between-intervention differences in changesin sleep metrics, but improvements were observed within eTRE compared withbaseline for sleep efficiency (p = 0.047), sleep fragmentation index (SFI) (p= 0.029), and awakening length (p = 0.043). Individuals with lowest sleepquality at the baseline showed its largest improvements in eTRE. PSQI scoresand self-reported sleep quality remained unchanged between and within bothinterventions. There were no differences in evening hunger and satiety scoresbetween eTRE and lTRE, and no correlations between hunger or satiety andsleep quality

Circadian clocks govern daily physiological and behavioral processes and are crucial for health; disruptions can lead to various diseases. The circadian phase of entrainment—the phase of the internal circadian clock in relation to external environmental cycles—is influenced by both genetic and environmental factors, varies between individuals, and is reflected in daily behaviors such as sleep–wake patterns, cognitive performance, and physical activity. While circadian phase may also fluctuate within individuals, the dynamics and extent of such variation in daily life remain largely unexplored. The gold standard for circadian phase assessment, dim-light melatonin onset (DLMO), is impractical for large-scale studies, and blood-based molecular biomarkers, while promising, are limited in feasibility. To address these challenges, we developed HairTime, a noninvasive assay that estimates circadian phase from a single daytime hair sample. Developed and evaluated in two steps—a training and a validation study—HairTime demonstrated strong predictive power compared to DLMO. Suitable for large-scale studies, it was assessed using over 4,000 samples. Circadian phase estimations showed a normal distribution and were associated with age, sex, and notably, work schedules, with earlier timing on workdays, suggesting that societal factors can modulate internal rhythms. Together, these findings establish HairTime as a promising tool for assessing circadian phase in research and lay the foundation for future applications in personalized chronotherapy.

Circadian clocks orchestrate metabolic processes in the whole body and their response to food. Therefore, not only what and how much, but also when we eat has a significant impact on metabolism. In this context, daytime of carbohydrate and fat intake was recently shown to alter the metabolic state and potentially affect the disease risk. However, molecular mechanisms of this regulation in humans are poorly understood. In this crossover trial, we investigated the effects of two isocaloric 4-week dietary patterns – high carbohydrate in the morning and high fat in the afternoon (HC/HF) and the reverse (HF/HC) - on the subcutaneous adipose tissue (SAT) in overweight non-diabetic men. The SAT transcriptome was assessed using microarrays. Additionally, gene expression in peripheral blood monocytes (PBMCs) was analysed by qPCRs. Analysis of SAT samples collected across the day identified 1386 genes exhibiting diurnal oscillations. In SAT, both oscillatory and non-oscillatory genes related to lipid and glucose metabolism were modulated by the timing of macronutrient intake. Notably, expression of inflammatory response genes in SAT was elevated after HC/HF compared to HF/HC, suggesting that the HC/HF diet might promote an early proinflammatory state in SAT due to higher fat intake in the afternoon. Diet-induced remodelling of the SAT transcriptome was partly reflected in PBMCs. These findings demonstrate that diurnal macronutrient distribution significantly reshapes the SAT transcriptome, underscoring the relevance of eating timing-based (chrononutritional) strategies for prevention of metabolic dysfunction and systemic inflammation associated with obesity and type 2 diabetes.