Biology subjects

Segers, P.

Publications and source records attributed to Segers, P..

3 recordsLinked to original sources

bioRxiv2026

Longitudinal dynamics of organ-specific proteomic aging clocks over a decade of midlife

Organ-specific proteomic clocks are promising tools for quantifying heterogeneity in biological aging, but their longitudinal behavior remains largely unexplored. Here, we analyzed paired plasma proteomic profiles with 10-year follow-up in middle-aged adults (n= 1,250) to evaluate their longitudinal properties. Cross-sectional associations of protein concentrations with age mirrored average longitudinal trajectories, validating the common cross-sectional training of clocks. Organ-specific age acceleration was moderately stable over the decade, and aging across organs progressed in parallel, with the immune and adipose systems acting as central hubs and early cardiorespiratory aging predicting downstream metabolic aging. Critically, longitudinal changes in predicted age tracked subclinical risk factor alterations. In women, the menopausal transition dominated the aging landscape and was associated with multi-organ age acceleration. Medication initiation altered clocks through specific drug-targeted proteins (such as renin and APOB) rather than generalized organ aging. Together, these findings position organ-specific proteomic clocks as interpretable, dynamic indicators of aging and organ health.

systems biology↗

bioRxiv2025

Systematic disruption of zebrafish fibrillin genes identifies a translational zebrafish model for Marfan syndrome

BackgroundFibrillins are essential components of the extracellular matrix. Marfan syndrome (MFS), the most common fibrillinopathy, is characterized by severe cardiovascular complications, including cardiac valve abnormalities, myocardial dysfunction, arrhythmias, and, most commonly, thoracic aortic disease. Unfortunately, no definitive medical cure is available. ObjectivesTo establish a zebrafish model of MFS, to enhance understanding of the cardiovascular consequences of fibrillin impairment and identify novel therapeutic targets. MethodsCRISPR/Cas9 technology was used to systematically target all zebrafish fibrillin genes. The cardiovascular phenotype was investigated using fluorescent microscopy at embryonic stages and cardiac ultrasound, histology, and synchrotron X-ray imaging in adults. RNA sequencing and drug testing were performed during early development. ResultsFibrillin-2b mutant (fbn2b-/-) zebrafish had a reproducible phenotype, with a subset of embryos showing endocardial detachment leading to early mortality. Interestingly, the remaining fbn2b-/- zebrafish developed dilation of the bulbus arteriosus, a structure analogous to the aortic root in humans, and survived normally to adulthood. Adult fbn2b-/- zebrafish displayed cardiac valve abnormalities. Transcriptomic analysis of fbn2b-/-embryos suggested the involvement of extracellular matrix remodeling and immune-related pathways. Administration of nebivolol and losartan did not improve the phenotype of fbn2b-/- larvae. Zebrafish lacking fibrillin-1 and/or fibrillin-2a did not show any phenotype. ConclusionOur fbn2b-/- zebrafish model recapitulates key aspects of human cardiovascular manifestations of MFS and can therefore be considered a novel relevant animal model for MFS. Studying this model allows us to broaden the knowledge of the underlying mechanisms of the disease and discover much-needed disease-specific treatment options. CONDENSED ABSTRACTFibrillin defects lead to severe cardiovascular complications in Marfan syndrome (MFS), including aortic dilation, dissection, and rupture. To model MFS, we generated zebrafish mutants lacking various fibrillin genes. Among these mutant lines, only fibrillin-2b-deficient zebrafish exhibited cardiovascular phenotypes mimicking human disease. Multimodal imaging revealed early cardiac defects, bulbus arteriosus dilation, and valve abnormalities. Transcriptomic analysis identified altered regulation of pathways related to extracellular matrix homeostasis and immune system activation. Compound testing demonstrated the models potential for drug discovery. This zebrafish model, recapitulating key cardiovascular features of MFS, provides a valuable platform to investigate disease mechanisms and identify novel treatment strategies.

genetics↗

bioRxiv2024

Early mechanisms of aortic failure in a zebrafish model for thoracic aortic dissection and rupture

Thoracic aortic aneurysm and dissection (TAAD) associates with a high mortality rate. Despite the existence of different mouse models for TAAD, the underlying disease mechanisms remain elusive. Treatment options are limited and mainly consist of surgical repair at critical aortic diameters as current pharmacological interventions are unable to stop disease progression. In humans, loss of function (LOF) of SMAD3 and SMAD6 impairs vascular homeostasis, increasing the risk for TAAD. We developed a zebrafish model for thoracic aortic dissection/rupture by targeting both ohnologs of smad3 and smad6. At 10 days post fertilization, we found an increased diameter of the ventral aorta in smad3a-/-;smad3b-/- double knockout zebrafish, while smad6a-/-;smad6b-/- double knockout zebrafish have a reduced aortic diameter associated with early mortality. We discovered that a smad3a-/-;smad3b-/-;smad6a-/-;smad6b-/- quadruple knockout (qKO) zebrafish model is viable and survives to adulthood, although exposure to stress leads to sudden death. Histological analysis of the adult ventral aorta shows medial elastolysis, aortic dissections and ruptures at sites exposed to high biomechanical stress. RNA-sequencing of 5 days post fertilization qKO zebrafish indicates a profile of reduced negative regulation of proteolysis and upregulation of melanogenesis, a previously unaddressed pathway in this pathology. We confirm that pharmacological modulation of tyrosinase, the enzyme responsible for the production of melanin, influences aortic morphology. Overall, the qKO mutant, thus far the only known zebrafish model of thoracic aortic dissection and rupture, reveals novel SMAD3/6-dependent pathways that impact thoracic aortic homeostasis, in this way opening avenues for the development of novel treatments in TAAD.

developmental biology↗