EndoAge Atlas: Non-linear dynamics of endothelial aging reveal organ-specific vascular trajectories in mice

Aging is a complex and multifactorial condition that leads to a gradual decline in organ functions and subsequent vulnerability to various diseases. Although the hallmarks of aging are well studied, the linear models developed based on these paradigms repeatedly fall short in capturing the dynamic, non-linear, and tissue-specific changes that occur because of aging. Furthermore, multi-organ level studies in humans are limited by the constraints of tissue availability and other confounding variables. This emphasises the importance of animal models in executing systemic investigations of aging. As the universal regulator of vascular function, endothelial cells (ECs) act as the initial responders to aging cues and undergo profound molecular and functional changes over time. This remodelling of the ECs is considered the central driver of multiple age-associated diseases. However, the global and tissue-specific molecular trajectories of aging in ECs are yet to be well characterised. Here, we introduce EndoAge atlas, a single-nucleus RNA-sequencing atlas comprising approximately 1.3 million ECs from 32 sex-balanced C57BL/6 mice across eight tissues and five distinct age groups. This atlas identifies tissue-specific endothelial heterogeneity, age-associated gene programs with distinct functional signatures, and uncovers non-linear gene expression trajectories across organs. Collectively, the EndoAge atlas constitutes a comprehensive reference for vascular aging across mammalian tissues, providing a foundational platform for developing targeted therapeutic strategies for age-related diseases.