Nie Tong, Nepovimova Eugenie, Wu Qinghua
College of Life Science, Yangtze University, Jingzhou, 434025, China.
Department of Chemistry, Faculty of Science, University of Hradec Králové, 500 03, Hradec Králové, Czech Republic.
Eur J Pharmacol. 2025 Mar 5;990:177290. doi: 10.1016/j.ejphar.2025.177290. Epub 2025 Jan 23.
Cellular senescence precipitates a decline in physiological activities and metabolic functions, often accompanied by heightened inflammatory responses, diminished immune function, and impaired tissue and organ performance. Despite extensive research, the mechanisms underpinning cellular senescence remain incompletely elucidated. Emerging evidence implicates circadian rhythm and hypoxia as pivotal factors in cellular senescence. Circadian proteins are central to the molecular mechanism governing circadian rhythm, which regulates homeostasis throughout the body. These proteins mediate responses to hypoxic stress and influence the progression of cellular senescence, with protein Brain and muscle arnt-like 1 (BMAL1 or Arntl) playing a prominent role. Hypoxia-inducible factor-1α (HIF-1α), a key regulator of oxygen homeostasis within the cellular microenvironment, orchestrates the transcription of genes involved in various physiological processes. HIF-1α not only impacts normal circadian rhythm functions but also can induce or inhibit cellular senescence. Notably, HIF-1α may aberrantly interact with BMAL1, forming the HIF-1α-BMAL1 heterodimer, which can instigate multiple physiological dysfunctions. This heterodimer is hypothesized to modulate cellular senescence by affecting the molecular mechanism of circadian rhythm and hypoxia signaling pathways. In this review, we elucidate the intricate relationships among circadian rhythm, hypoxia, and cellular senescence. We synthesize diverse evidence to discuss their underlying mechanisms and identify novel therapeutic targets to address cellular senescence. Additionally, we discuss current challenges and suggest potential directions for future research. This work aims to deepen our understanding of the interplay between circadian rhythm, hypoxia, and cellular senescence, ultimately facilitating the development of therapeutic strategies for aging and related diseases.
细胞衰老会导致生理活动和代谢功能下降，常伴有炎症反应加剧、免疫功能减弱以及组织和器官功能受损。尽管进行了广泛研究，但细胞衰老的潜在机制仍未完全阐明。新出现的证据表明昼夜节律和缺氧是细胞衰老的关键因素。昼夜节律蛋白是控制昼夜节律的分子机制的核心，昼夜节律调节全身的稳态。这些蛋白介导对缺氧应激的反应并影响细胞衰老的进程，其中脑和肌肉芳香烃受体核转运蛋白样1（BMAL1或Arntl）蛋白发挥着重要作用。缺氧诱导因子-1α（HIF-1α）是细胞微环境中氧稳态的关键调节因子，它协调参与各种生理过程的基因的转录。HIF-1α不仅影响正常的昼夜节律功能，还能诱导或抑制细胞衰老。值得注意的是，HIF-1α可能与BMAL1异常相互作用，形成HIF-1α-BMAL1异二聚体，这可能引发多种生理功能障碍。据推测，这种异二聚体通过影响昼夜节律和缺氧信号通路的分子机制来调节细胞衰老。在这篇综述中，我们阐明了昼夜节律、缺氧和细胞衰老之间的复杂关系。我们综合各种证据来讨论它们的潜在机制，并确定应对细胞衰老的新治疗靶点。此外，我们讨论了当前的挑战并提出了未来研究的潜在方向。这项工作旨在加深我们对昼夜节律、缺氧和细胞衰老之间相互作用的理解，最终促进衰老及相关疾病治疗策略的发展。
