Simon Tual-Chalot

Systemic sclerosis (SSc) is a devastating fibrosing disorder affecting the skin and internal organs, associated with the highest mortality among all rheumatic diseases. The mechanisms underlying excessive fibrogenesis in SSc are incompletely defined and treatment options are limited. N6-methyladenosine (m6A), the most abundant internal mRNA modification, is a reversible and pharmacologically tractable determinant of RNA fate. Here we mapped the m6A epitranscriptome of peripheral blood mononuclear cells (PBMCs) from patients with SSc using two orthogonal single-nucleotide-resolution platforms, a MazF-based m6A microarray and nanopore direct RNA sequencing. SSc PBMCs showed coordinated upregulation of the m6A writer complex (METTL3, METTL14, WTAP), a two-fold increase in global m6A, and redistribution of m6A marks from 3' untranslated regions toward coding sequences. Both platforms converged on TGF-b signaling as the most enriched pathway among differentially methylated transcripts, with hypermethylation of TGFB1, JUNB and KLF10 transcripts. Pharmacologic inhibition of METTL3 with STM2457 significantly reversed TGF-b-induced transcriptomic changes in skin fibroblasts preventing their transformation into pathological myofibroblasts. Together, these findings uncover an epitranscriptomic signature driving profibrotic transcriptional alterations in SSc, including enhanced TGF-b signaling, which can be effectively reversed by clinically available enzymatic m6A inhibitors. Our data suggest that targeting m6A methylation may offer a novel therapeutic strategy to mitigate fibrosis in SSc.

Most acquired cardiovascular diseases are more common in older people, and the biological mechanisms and manifestations of aging provide insight into cardiovascular pathophysiology. Measuring aging within the cardiovascular system may help to better understand risk profiles for specific individuals and direct targeted preventative therapy. In this review, we explore telomere attrition, cellular senescence, epigenetic modifications, and mitochondrial dysfunction as key molecular mechanisms of aging. These phenomena are associated with cardiovascular disease through endothelial dysfunction and systemic inflammation, which are measurable in clinical practice with a variety of clinical, laboratory, and imaging techniques. Finally, we discuss that the next tools for modelling cardiovascular aging must be capable of incorporating a vast amount of diverse data from a given patient, pointing to recent developments in artificial intelligence and machine learning.

Background: Recent evidence suggests that Alzheimer's amyloid‐beta (1‐40) (Αβ1‐40), an emerging biomarker of cardiovascular disease, may be involved in the heart‐brain‐renal axis. We aimed to comprehensively explore the association between circulating Aβ1‐40 levels and renal function and its clinical relevance.Methods: Consecutively recruited subjects in the Athens Angiometabolic Registry with measured Aβ1‐40 plasma levels (n = 811) were analysed. Αβ1‐40 was measured by enzyme‐linked immunosorbent assay and glomerular filtration rate (GFR) was calculated using the abbreviated four‐variable Modification of Diet in Renal Disease (MDRD) formula. All‐cause mortality was the main clinical endpoint across a median follow‐up of 47 months.Results: Cross‐sectionally, a bidirectional association between Αβ1‐40 [adjusted odds ratio (adjOR) = 3.67 for highest tertile of Αβ1‐40 and chronic kidney disease (CKD) stage ≥3, p < .001] and CKD stage ≥3 (adjOR = 3.52 for association with highest Aβ1‐40 tertile, p < .001) was observed. Longitudinally, increased Αβ1‐40 at baseline was associated with decline in renal function at follow‐up (adjOR for CKD stage ≥3 = 2.26, p = .033). Similarly, longitudinal changes in Aβ1‐40 were inversely associated with changes in GFR (OR = .77 per 1 SD increase in Aβ1‐40, p = .006). Aβ1‐40 was associated with all‐cause mortality, independently of traditional risk factors (hazard ratio = 1.20 per 1 SD increase in Aβ1‐40, p = .016). An indirect effect of GFR on the association between Aβ1‐40 and mortality (p < .05) with an estimated indirect‐to‐total effect ratio of .334, but not of Αβ1‐40 on GFR with mortality, was observed.Conclusions: In a population with a wide range of GFR, we found a bidirectional association between Αβ1‐40 levels and renal function. The association of Αβ1‐40 with all‐cause mortality was partly mediated by lower GFR.

Ageing of the cardiovascular system is associated with frailty and various life-threatening diseases. As global populations grow older, age-related conditions increasingly determine healthspan and lifespan. The circulatory system not only supplies nutrients and oxygen to all tissues of the human body and removes by-products but also builds the largest interorgan communication network, thereby serving as a gatekeeper for healthy ageing. Therefore, elucidating organ-specific and cell-specific ageing mechanisms that compromise circulatory system functions could have the potential to prevent or ameliorate age-related cardiovascular diseases. In support of this concept, emerging evidence suggests that targeting the circulatory system might restore organ function. In this Roadmap, we delve into the organ-specific and cell-specific mechanisms that underlie ageing-related changes in the cardiovascular system. We raise unanswered questions regarding the optimal design of clinical trials, in which markers of biological ageing in humans could be assessed. We provide guidance for the development of gerotherapeutics, which will rely on the technological progress of the diagnostic toolbox to measure residual risk in elderly individuals. A major challenge in the quest to discover interventions that delay age-related conditions in humans is to identify molecular switches that can delay the onset of ageing changes. To overcome this roadblock, future clinical trials need to provide evidence that gerotherapeutics directly affect one or several hallmarks of ageing in such a manner as to delay, prevent, alleviate or treat age-associated dysfunction and diseases.

Spatial transcriptomics (ST) has the potential to provide unprecedented insights into gene expression across tissue architecture, but existing analytical methods often overlook the full complexity of the spatial dimension. We present STExplorer, an R package that adapts well-established computational geography (CG) methods to explore the micro-geography of spatial omics data. By incorporating techniques like Geographically Weighted Principal Component Analysis (GWPCA), Fuzzy Geographically Weighted Clustering (FGWC), Geographically Weighted Regression (GWR), and analyses of observation Spatial Autocorrelation (SA), STExplorer enables the uncovering of spatially resolved patterns that capture the spatial heterogeneity of biological data. STExplorer provides a complete suite of functions for spatial analyses and visualisations, supporting deeper biological understanding and inference. Built on the Bioconductor ecosystem, the package integrates with SpatialFeatureExperiment objects, ensuring compatibility with existing pipelines. It includes preprocessing capabilities such as data import, quality control, gene count normalisation, and variable gene selection, alongside tools for downstream analysis and detailed visualisations that quantify and map spatial heterogeneity and relationships. We demonstrate the utility of STExplorer through applications to spatial transcriptomics datasets, revealing that spatially varying gene expression and relationships are often masked by standard analyses. By bridging bioinformatics and CG, STExplorer provides a novel and informed approach to spatial transcriptomics analysis, with robust tools to address spatial heterogeneity and its associated underlying biology, thereby advancing our understanding of complex tissue biology without reinventing the wheel.

With increasing chronological age, the vascular system gradually loses its functional integrity, a process known as vascular aging. This decline is a major contributor to arterial and venous thromboembolic disorders, which represent one of the leading causes of mortality and morbidity among aged individuals. However, the precise biological mechanisms linking systemic aging to thrombotic susceptibility remain poorly understood, hindering the development of effective preventive and therapeutic strategies for age-related thrombotic diseases. Aging, as a fundamental determinant of vascular health, shifts the balance between prothrombotic and antithrombotic mechanisms through cumulative molecular and cellular alterations across vascular cells, red blood cells, platelets, and immune cells. These interconnected hallmarks collectively disrupt endothelial homeostasis, enhance platelet reactivity, and impair coagulation and fibrinolytic pathways. Emerging factors, including clonal hematopoiesis of indeterminate potential and environmental exposures, further exacerbate the thrombotic risk in older populations. Clinically, thrombosis management in the elderly requires careful calibration between protection against ischemia and bleeding risk, as age-associated changes are known to affect the safety and efficacy of antiplatelet and anticoagulant therapies. The development of geroscience-guided interventions, alongside optimized antithrombotic strategies, will be essential to reduce the thrombotic burden and improve outcomes in the aging population.

Epidemiological evidence suggests the presence of common risk factors for the development and prognosis of both cardio- and cerebrovascular diseases, including stroke, Alzheimer's disease, vascular dementia, heart, and peripheral vascular diseases. Accumulation of harmful blood signals may induce organotypic endothelial dysfunction affecting blood–brain barrier function and vascular health in age-related diseases. Genetic-, age-, lifestyle- or cardiovascular therapy–associated imbalance of amyloid-beta (Aβ) peptide metabolism in the brain and periphery may be the missing link between age-related neurocardiovascular diseases. Genetic polymorphisms of genes related to Aβ metabolism, lifestyle modifications, drugs used in clinical practice, and Aβ-specific treatments may modulate Aβ levels, affecting brain, vascular, and cardiac diseases. This narrative review elaborates on the effects of interventions on Aβ metabolism in the brain, cerebrospinal fluid, blood, and peripheral heart or vascular tissues. Implications for clinical applicability, gaps in knowledge, and future perspectives of Aβ as the link among age-related neurocardiovascular diseases are also discussed.