Age-associated erosion of organ-specific endothelial programs compromises tissue function and resilience
Year: 2026
Type: preprint
Abstract: Summary Endothelial cells (ECs) express organ-specific gene programs supporting tissue homeostasis and resilience. However, the mechanisms by which aging reshapes these organ-specific endothelial programs and how the resulting changes affect tissue homeostasis, resilience, and disease susceptibility remain largely unknown. Herein, we performed single-cell RNA sequencing of ECs harvested from five organs across the lifespan and found that aging progressively erodes organ-specific endothelial programs while inducing shared interferon-responsive and antigen-presentation programs across organs. Although vascular subtype identity and conserved capillary subset identity were mostly preserved, these organ-specific transcriptional programs were broadly attenuated with aging, indicating erosion of organ-specific endothelial identity to be a fundamental feature of endothelial aging. Importantly, these alterations were associated with declines in specialized EC functions, including alveolar barrier maintenance in the lung, scavenging activity in the liver, angiogenic capacity in the heart, and homeostatic programs in the kidneys and the brain, suggesting that age-related EC alterations compromise tissue homeostasis and resilience in multiple organs. Furthermore, we established a single-cell aging index for alveolar capillary ECs in mice and humans, revealing stress-associated endothelial activation to potentially be an intermediate state linking functional deterioration to cellular senescence, and also demonstrating marked heterogeneity in aging states even among ECs from animals of the same chronological age. Notably, alveolar capillary ECs exhibited progressive functional decline before reaching a senescent-like state, suggesting endothelial dysfunction to precede overt cellular senescence as the organism ages. Collectively, our findings establish progressive erosion of organ-specific endothelial programs as a central feature of vascular aging and provide a conceptual framework for elucidating how endothelial aging contributes to tissue dysfunction and reduced resilience across organs.
Authors: Haruko Watanabe-Takano, Tomohiro Ishii, Tomohisa Hayakawa, Hitoshi Iuchi, Hitomi Matsuno, Eri Oguri-Nakamura, Kunihito Arai, Kei Yura, Michiaki Hamada, Daisuke Hishikawa, Shota Toyoshima, Mashito Sakai, Shimpei Higo, Masahiro Morishita, Hirotaka Ishii, Toru Tanaka, Sayo Horibe, Yoshiyuki Rikitake, Taichi Noda, Kimi Araki, Takashi Minami, Shinya Tanaka, Shigetomo Fukuhara
Institutions: Nippon Medical School, Waseda University, Ochanomizu University, National Institute of Advanced Industrial Science and Technology, Kobe Pharmaceutical University, Institute of Resource Development and Analysis, Kumamoto University, Kumamoto University, Center for Metabolic Regulation of Healthy Aging, Kumamoto University, Kyushu University, Medical Institute of Bioregulation, Kyushu University
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Funders: Uehara Memorial Foundation, Japan Agency for Medical Research and Development, Ichiro Kanehara Foundation for the Promotion of Medical Sciences and Medical Care, University of Tokyo, Daiichi Sankyo Foundation of Life Science, Japan Society for the Promotion of Science, Japan Science and Technology Agency, Institute of Medical Science, University of Tokyo, Institute of Genetics, Daiichi Sankyo Europe
Awards: 先端モデル動物支援プラットフォーム, 血流に起因する内腔圧に着目した腫瘍血管新生による異常血管の形成機構の解明, 血管内皮細胞を基軸としたメカニカルシグナルによる肺胞形成メカニズムの解明, 肺胞形成機構における血管内皮細胞の本質的役割の解明と再生治療への応用, G4714277935, G6455943787, Elucidation of the molecular basis of the small GTPase Rap1 governing the dynamic regulation of vascular permeability, 血管内皮細胞における加齢依存的インターフェロン応答と臓器機能破綻の分子基盤解明, 自己関連疾患を制御する末梢自己反応性CD4+T細胞についての包括的理解, 末梢自己反応性B細胞の生体恒常性維持における役割の解明
OpenAlex ID: W7167607746