Age-associated erosion of organ-specific endothelial programs compromises tissue function and resilience
- 1Nippon Medical School
Abstract
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.
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BibTeX
@misc{watanabetakano2026ageassociated,
title = {{Age-associated erosion of organ-specific endothelial programs compromises tissue function and resilience}},
author = {H. Watanabe-Takano and T. Ishii and T. Hayakawa and H. Iuchi and H. Matsuno and E. Oguri-Nakamura and K. Arai and K. Yura and M. Hamada and D. Hishikawa and S. Toyoshima and M. Sakai and S. Higo and M. Morishita and H. Ishii and T. Tanaka and S. Horibe and Y. Rikitake and T. Noda and K. Araki and T. Minami and S. Tanaka and S. Fukuhara},
howpublished = {bioRxiv},
year = {2026},
month = jul,
doi = {10.64898/2026.07.02.735775},
url = {https://www.biorxiv.org/content/10.64898/2026.07.02.735775v2},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Age-associated erosion of organ-specific endothelial programs compromises tissue function and resilience
AU - H. Watanabe-Takano
AU - T. Ishii
AU - T. Hayakawa
AU - H. Iuchi
AU - H. Matsuno
AU - E. Oguri-Nakamura
AU - K. Arai
AU - K. Yura
AU - M. Hamada
AU - D. Hishikawa
AU - S. Toyoshima
AU - M. Sakai
AU - S. Higo
AU - M. Morishita
AU - H. Ishii
AU - T. Tanaka
AU - S. Horibe
AU - Y. Rikitake
AU - T. Noda
AU - K. Araki
AU - T. Minami
AU - S. Tanaka
AU - S. Fukuhara
PY - 2026
DA - 2026/07/02
PB - bioRxiv
DO - 10.64898/2026.07.02.735775
UR - https://www.biorxiv.org/content/10.64898/2026.07.02.735775v2
AB - 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.
ER -