Biology subjects

Klaers, M.

Publications and source records attributed to Klaers, M..

3 recordsLinked to original sources

bioRxiv2026

Cellular senescence is associated with age-related loss of liver zonation and hepatocyte function

The liver is organized into tightly regulated zones with distinct metabolic functions but zonation erodes with age. Cellular senescence contributes to aging and liver diseases, however, its impact on aging biology is ill-defined. As part of The Cellular Senescence Network Consortium, we used multiple spatial transcriptomics approaches (GeoMx, Visium, CosMx) with snRNA-seq to profile senescence signatures, zonation markers, and metabolic pathways in livers from wild-type (WT) mice of multiple ages. We observed a loss of canonical zone signatures in aged mouse livers characterized by "expansion" of midlobular (zone 2) marker gene expression, accompanied by diminished expression of zone 3 marker genes by middle-age (18 months), indicative of loss of cell identity. Multiple analytic approaches identified distinct age-, zone- and sex-specific senescence signatures, which were significantly associated with zonation markers changes. This was recapitulated in Ercc1 mutant models of accelerated senescence, supporting a causal role of senescent cells in liver aging. A "no-zone" hepatocyte-like cluster expanded with age and with the strongest Senescence-Associated Secretory Phenotype (SASP) profile. Gene expression profiles from senescent hepatocytes implicate decreased WNT signaling and increased BMP as contributing to age-related loss of zonation. Together, these data elucidate the role of senescent cells in driving aging biology in non-diseased liver through disruption of cell:cell signaling and the loss of metabolic and cell identity gene expression necessary for hepatocyte function.

cell biology↗

bioRxiv2026

Cyclin D1 regulates the hepatic response to feeding: Evidence for non-cell cycle roles in the liver

ObjectivesPrior studies have shown that cyclin D1 regulates diverse aspects of liver metabolism during cell cycle progression. Interestingly, this protein is induced in hepatocytes by feeding, but its function in modulating hepatic postprandial physiology is poorly characterized. The aim of this study was to evaluate the contribution of cyclin D1 to the hepatic response to feeding and to gain insight into its potential non-proliferative roles in other conditions. MethodsMice with or without hepatocyte cyclin D1 (D1fl/fl or D1{Delta}Hep) were fasted and refed a high-carbohydrate diet. Mouse and human liver in the setting of aging and MASLD were analyzed. The C. elegans model was used to evaluate the role of cyclin D1 (CYD-1) in response to overnutrition. ResultsCyclin D1 regulated hepatic gene networks involved in glucose and lipid metabolism, protein synthesis, immune response, and other pathways after feeding. Induction of acute phase response proteins was markedly inhibited in D1{Delta}Hep mice, which was associated with corresponding changes in histone acetylation on key genes. In aged liver, hepatocyte cyclin D1 was induced without associated proliferation; this was markedly pronounced in progeroid Ercc1-deficient mice. Cyclin D1 was upregulated in MASLD and diminished with successful treatment. CYD-1 was induced by overnutrition in the intestine of Caenorhabditis elegans (which performs metabolic functions similar to liver) and regulates key nutrient-responsive proteins. CYD-1 inhibition prolonged lifespan in this setting. ConclusionsCyclin D1 regulates nutrient-mediated physiology in the liver and C. elegans, indicating that it has unexpected and highly conserved metabolic functions. Further study is warranted to define its role in hepatic disease and aging. HighlightsO_LICyclin D1 is induced in hepatocytes with feeding and broadly regulates hepatic gene expression. C_LIO_LIAcute phase response (APR) and senescence-associated secretory phenotype (SASP) proteins are markedly regulated by cyclin D1. C_LIO_LIHepatocyte expression of cyclin D1 is substantially upregulated in aging, premature aging, and MASLD without associated proliferation. C_LIO_LICyclin D1 (CYD-1) regulates nutrient-mediated signaling and lifespan in response to overnutrition in C. elegans. C_LI

physiology↗

bioRxiv2025

Real-time simultaneous monitoring of multiple analytes in bacterial cultures

Bacterial metabolites are essential for biological processes, influencing human health, ecosystems, and industrial applications. Simultaneous real-time monitoring of these metabolites is critical in understanding microbial dynamics, particularly in bioreactors and food or drug manufacturing. Current approaches often rely on offline methods, which are labor-intensive and susceptible to contamination, or genetic engineering techniques limited to single-analyte monitoring. Here, we present a novel method utilizing engineered periplasmic binding proteins (PBPs) conjugated with fluorophores to track multiple metabolites simultaneously in Escherichia coli cultures. This system continuously monitors the levels of multiple analytes such as glucose, arabinose, ribose, glutamate, and arginine, providing high temporal resolution while maintaining sensor stability over 24 hours. Our findings confirm hierarchical substrate utilization in E. coli and demonstrate the versatility of PBP-based multi-sensor arrays. This approach offers a non-invasive, modular, and scalable tool for bacterial metabolite analysis, paving the way for advances in both fundamental discoveries and practical applications in microbiology. ImportanceReal-time monitoring of metabolites in bacterial cultures is crucial for advancing our understanding of microbial physiology, metabolic fluxes, and dynamic responses to environmental changes. This capability enables researchers to capture transient metabolic states that are often missed in endpoint measurements. The use of engineered periplasmic binding proteins as biosensors for this real-time metabolite monitoring represents a groundbreaking approach. By leveraging the natural specificity and high affinity of PBPs for small molecules, these biosensors can be engineered to detect a wide range of metabolites with exceptional sensitivity and temporal resolution. The integration of PBP-based biosensors into microbial research not only enhances our ability to study real-time metabolism but also provides a versatile tool for optimizing industrial bioprocesses and exploring bacterial infections and complex microbial ecosystems

bioengineering↗