Division of Diabetes, Endocrinology and Metabolism, Vanderbilt University Medical Center, Nashville, TN, United States.
Joslin Diabetes Center, Harvard Medical School, Boston, MA, United States.
Front Endocrinol (Lausanne). 2023 Aug 31;14:1212716. doi: 10.3389/fendo.2023.1212716. eCollection 2023.
Cellular senescence is a response to a wide variety of stressors, including DNA damage, oncogene activation and physiologic aging, and pathologically accelerated senescence contributes to human disease, including diabetes mellitus. Indeed, recent work in this field has demonstrated a role for pancreatic β-cell senescence in the pathogenesis of Type 1 Diabetes, Type 2 Diabetes and monogenic diabetes. Small molecule or genetic targeting of senescent β-cells has shown promise as a novel therapeutic approach for preventing and treating diabetes. Despite these advances, major questions remain around the molecular mechanisms driving senescence in the β-cell, identification of molecular markers that distinguish senescent from non-senescent β-cell subpopulations, and translation of proof-of-concept therapies into novel treatments for diabetes in humans. Here, we summarize the current state of the field of β-cell senescence, highlighting insights from mouse models as well as studies on human islets and β-cells. We identify markers that have been used to detect β-cell senescence to unify future research efforts in this field. We discuss emerging concepts of the natural history of senescence in β-cells, heterogeneity of senescent β-cells subpopulations, role of sex differences in senescent responses, and the consequences of senescence on integrated islet function and microenvironment. As a young and developing field, there remain many open research questions which need to be addressed to move senescence-targeted approaches towards clinical investigation.
细胞衰老（Cellular senescence）是对多种应激源的反应，包括 DNA 损伤、癌基因激活和生理衰老，病理性加速衰老导致了人类疾病，包括糖尿病。事实上，该领域最近的研究表明，胰岛β细胞衰老在 1 型糖尿病、2 型糖尿病和单基因糖尿病的发病机制中起作用。衰老β细胞的小分子或基因靶向治疗已显示出作为预防和治疗糖尿病的新治疗方法的潜力。尽管取得了这些进展，但围绕驱动β细胞衰老的分子机制、鉴定区分衰老和非衰老β细胞亚群的分子标记以及将概念验证疗法转化为人类糖尿病的新疗法等主要问题仍未得到解决。在这里，我们总结了β细胞衰老领域的当前状态，强调了来自小鼠模型以及人类胰岛和β细胞研究的见解。我们确定了用于检测β细胞衰老的标记物，以统一该领域未来的研究工作。我们讨论了β细胞衰老的自然史、衰老β细胞亚群的异质性、性别差异在衰老反应中的作用以及衰老对胰岛功能和微环境的综合影响等新兴概念。作为一个年轻且不断发展的领域，仍有许多悬而未决的研究问题需要解决，以便将针对衰老的方法推向临床研究。
