Chronological age causes structural and functional vascular deterioration and is a well-established risk factor for the development of cardiovascular diseases, leading to more than 40% of all deaths in the elderly. The etiology of vascular aging is complex; a significant impact arises from impaired cholesterol homeostasis. Cholesterol level is balanced through synthesis, uptake, transport, and esterification, the processes executed by multiple organelles. Moreover, organelles responsible for cholesterol homeostasis are spatially and functionally coordinated instead of isolated by forming the membrane contact sites. Membrane contact, mediated by specific protein-protein interaction, pulls opposing organelles together and creates the hybrid place for cholesterol transfer and further signaling. The membrane contact-dependent cholesterol transfer, together with the vesicular transport, maintains cholesterol homeostasis and has intimate implications in a growing list of diseases, including vascular aging-related diseases. Here, we summarized the latest advances regarding cholesterol homeostasis by highlighting the membrane contact-based regulatory mechanism. We also describe the downstream signaling under cholesterol homeostasis perturbations, prominently in cholesterol-rich conditions, stimulating age-dependent organelle dysfunction and vascular aging. Finally, we discuss potential cholesterol-targeting strategies for therapists regarding vascular aging-related diseases. This article is categorized under: Cardiovascular Diseases > Molecular and Cellular Physiology.

中文翻译：

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膜接触位点协调胆固醇稳态，这对于血管老化至关重要。

实际年龄会导致血管结构和功能恶化，并且是心血管疾病发展的公认危险因素，导致 40% 以上的老年人死亡。血管老化的病因很复杂；胆固醇稳态受损会产生重大影响。胆固醇水平通过合成、摄取、运输和酯化（由多个细胞器执行的过程）来平衡。此外，负责胆固醇稳态的细胞器在空间和功能上是协调的，而不是通过形成膜接触位点而孤立的。由特定蛋白质-蛋白质相互作用介导的膜接触将相对的细胞器拉到一起，并为胆固醇转移和进一步信号传导创造了混合场所。膜接触依赖性胆固醇转移与囊泡运输一起维持胆固醇稳态，并对越来越多的疾病（包括血管老化相关疾病）产生密切影响。在这里，我们通过强调基于膜接触的调节机制总结了胆固醇稳态的最新进展。我们还描述了胆固醇稳态扰动下的下游信号传导，特别是在富含胆固醇的条件下，刺激年龄依赖性细胞器功能障碍和血管老化。最后，我们讨论了治疗师针对血管衰老相关疾病的潜在胆固醇靶向策略。本文分类为：心血管疾病>分子和细胞生理学。