🧬🩸 What if vascular aging is driven not only by inflammation, but also by a fundamental rewiring of how endothelial cells sense mechanical forces? A new study in Nature Aging introduces the Human Aging Endothelial Cell Atlas (HAECA), revealing conserved and tissue-specific molecular programs of endothelial aging across the adult human lifespan. The central discovery: Aging endothelial cells exhibit increased inflammatory and senescence-associated signaling, reduced angiogenic programs, altered extracellular matrix remodeling, and enhanced YAP/TAZ-associated mechanotransduction. 🔬 1. Building a comprehensive human endothelial aging atlas Researchers integrated: • 375,829 endothelial cells • 290 human samples • 12 tissues • 34 independent transcriptomic studies The atlas includes endothelial cells from adipose tissue, brain, breast, heart, intestine, kidney, liver, lung, skeletal muscle, ovary, skin, and uterus. Using integrated scRNA-seq and snRNA-seq data, researchers identified conserved endothelial subtypes along the vascular tree: Arterial → Capillary → Venous They also characterized angiogenic and lymphatic endothelial populations. Importantly, the atlas was constructed from healthy or nondiseased tissues, providing a reference for physiological vascular aging. 🧬 2. A conserved transcriptional signature of endothelial aging Across tissues, aged endothelial cells exhibited: Inflammatory signaling ↑ • TNF-associated pathways • Immune activation • Senescence-associated secretory phenotype (SASP) Angiogenic programs ↓ • APLNR • COL4A1 • ID3 • PLVAP Mitochondrial and proliferative programs ↓ • Oxidative phosphorylation (OXPHOS) • MYC target signatures • Endothelial proliferation Independent age-stratification analyses identified 287 age-enriched and 135 age-depleted genes with concordant patterns. These findings support a reproducible transcriptional program of human endothelial aging. ⚡ 3. Venous endothelial cells exhibit pronounced angiogenic decline One particularly interesting finding was that aging-associated changes differed across vascular compartments. Arterial endothelial cells: Increased coagulation- and immune-associated signatures. Capillary endothelial cells: Altered stress-response, inflammatory, and metabolic programs. Venous endothelial cells: Reduced angiogenesis-associated gene expression, alongside changes in extracellular matrix interactions and cytoskeletal organization. Because venous endothelial cells can contribute to angiogenic sprouting, their age-associated transcriptional changes may help explain impaired vascular regeneration. However, the study did not directly establish that these changes cause reduced angiogenesis. 🔥 4. Aging rewires the endothelial extracellular matrix Researchers identified widespread age-associated changes in genes regulating: • Extracellular matrix assembly • Cell adhesion • Basement membrane organization • Glycosylation • Glycocalyx-associated processes These alterations were particularly prominent in endothelial cells from the liver, lung, skin, and adipose tissue. Increased expression of several GALNT-family genes and sialyltransferases suggests remodeling of endothelial surface glycosylation. In liver endothelial cells, transcriptional changes were consistent with age-associated sinusoidal pseudocapillarization. This provides a potential link between extracellular matrix remodeling and vascular aging. 🧬 5. YAP/TAZ mechanotransduction emerges as an aging-associated pathway Transcription factor activity inference identified increased activity of mechanoregulatory factors across several aged endothelial populations: YAP1 | WWTR1/TAZ | TEAD1 | TEAD2 | TEAD4 The strongest evidence emerged from human skin. Spatial transcriptomics demonstrated enrichment of mechanosignaling-related genes in larger vascular endothelial populations. Immunofluorescence confirmed increased nuclear localization of YAP in aged skin endothelial cells: P = 0.0199 These findings suggest that aging alters endothelial responses to mechanical signals. Importantly, whether increased YAP activity is compensatory or pathogenic remains unresolved. 🧪 6. A p21-associated endothelial senescence program Researchers investigated whether endothelial senescence could be identified using transcriptional signatures conserved across tissues. CDKN1A (p21) was broadly detectable, whereas CDKN2A (p16) transcripts were nearly absent in the atlas. CDKN1A-positive endothelial cells exhibited increased: • TNF and IL-6 signaling • Interferon-response programs • Hypoxia-associated signaling • DNA damage and stress-response signatures These changes were observed across multiple tissue contexts. However, CDKN1A expression alone is not sufficient to establish irreversible cellular senescence. 🔍 7. MAFF emerges as a candidate regulator of endothelial senescence By integrating atlas-derived signatures with replicative and doxorubicin-induced endothelial senescence models, researchers identified candidate markers including: MAFF, ADAMTS1, ADAMTS4, JUN, SRGN, KLF2, TNFRSF10D, TNFRSF10B, UGCG, and STX12. Among these, MAFF emerged as a particularly interesting candidate. Experimental validation demonstrated: • Increased MAFF expression in senescent HUVECs. • Increased MAFF-associated signatures in additional endothelial aging models. • MAFF overexpression increased p21 expression. • MAFF overexpression increased senescence-associated β-galactosidase activity. These experiments support a functional contribution of MAFF to endothelial senescence-associated phenotypes. However, MAFF loss-of-function experiments and in vivo therapeutic validation remain necessary. 🫀 8. Implications for cardiovascular and metabolic aging The findings suggest several mechanistic research directions: Endothelial mechanotransduction Investigating whether YAP/TAZ–TEAD signaling contributes to age-related vascular stiffness and inflammatory remodeling. Mitochondrial metabolism Determining whether reduced endothelial OXPHOS signatures reflect functional mitochondrial impairment and contribute to vascular dysfunction. Endothelial senescence Testing MAFF-associated transcriptional programs as potential biomarkers or intervention targets. Microvascular regeneration Investigating whether venous endothelial dysfunction contributes to age-associated capillary rarefaction. Adipose tissue aging Exploring whether endothelial ECM and glycocalyx remodeling contributes to adipose inflammation, vascular dysfunction, and metabolic deterioration. These are mechanistic hypotheses rather than therapeutic effects established by the atlas. 💻 9. An openly accessible resource for vascular aging research The investigators provide an interactive platform for exploring endothelial gene expression across tissues, vascular subtypes, and age groups. HAECA Portal: haeca.derooijlab.org Processed atlas: doi.org/10.5281/zenodo.16779… Bulk RNA-seq: GSE305900 Analysis code: github.com/deRooijLab/HAECA The resource could facilitate cross-tissue target prioritization and integration with cardiovascular, metabolic, and aging-related disease datasets. ⚠️ Important limitations The atlas integrates heterogeneous public datasets with uneven age distributions and sampling methods. Individuals aged 80 years or older were underrepresented. Clinical covariates, including medication use, metabolic status, and comorbidities, were incompletely available. Transcriptomic signatures do not necessarily establish changes in protein activity or cellular function. Although MAFF overexpression induced senescence-associated phenotypes in vitro, the study did not demonstrate that MAFF inhibition reverses vascular aging in vivo. The broader implication Vascular aging is not a uniform process affecting every endothelial cell identically. It combines conserved inflammatory and senescence-associated programs with tissue-specific alterations in angiogenesis, metabolism, extracellular matrix organization, and mechanotransduction. The HAECA resource provides a foundation for identifying endothelial aging mechanisms and prioritizing potential therapeutic targets. The next challenge is to move from transcriptional associations to causal mechanisms—and determine which endothelial aging programs can be safely reversed. 📄 Dobner S, Kleissl L, Tóth F, et al. Uncovering the transcriptional hallmarks of endothelial cell aging via integrated single-cell analysis. Nature Aging. 2026. Resource article. DOI: doi.org/10.1038/s43587-026-0… #VascularAging #EndothelialCells #SingleCellRNAseq #HAECA #Geroscience #CellularSenescence #MAFF #YAP #TAZ #Mechanotransduction #Angiogenesis #Mitochondria #CardiovascularAging #AdiposeTissue #SystemsBiology