Sogabe Yuko, Shibata Hirofumi, Kabata Mio, Tanaka Akito, Mitsunaga Kanae, Sunadome Kazunori, Nakajima-Koyama May, Hirano Michitada, Nishida Eisuke, Woltjen Knut, Seno Hiroshi, Yamada Yasuhiro, Yamamoto Takuya
Department of Life Science Frontiers, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan.
Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Nat Aging. 2025 Jul 11. doi: 10.1038/s43587-025-00917-y.
There is robust evidence that senescence can be propagated in vitro through mechanisms including the senescence-associated secretory phenotype, resulting in the non-cell-autonomous induction of secondary senescence. However, the induction, regulation and physiological role of secondary senescence in vivo remain largely unclear. Here we generated senescence-inducible mouse models expressing either the constitutively active form of MEK1 or MKK6 and mCherry, to map primary and secondary senescent cells. Our models recapitulate characteristic features of senescence and demonstrate that primary and secondary phenotypes are highly tissue- and inducer-dependent. Spatially resolved RNA expression analyses at the single-cell level reveal that each senescence induction results in a unique transcriptional profile-even within cells of the same cell type-explaining the heterogeneity of senescent cells in vivo. Furthermore, we show that interleukin-1β, primarily derived from macrophages, induces secondary phenotypes. Our findings provide insight into secondary senescence in vivo and useful tools for understanding and manipulating senescence during aging.
有充分的证据表明，衰老可以通过包括衰老相关分泌表型在内的机制在体外传播，从而导致非细胞自主性的继发性衰老诱导。然而，继发性衰老在体内的诱导、调控和生理作用在很大程度上仍不清楚。在这里，我们构建了表达持续激活形式的MEK1或MKK6以及mCherry的衰老诱导小鼠模型，以绘制原发性和继发性衰老细胞图谱。我们的模型重现了衰老的特征，并证明原发性和继发性表型高度依赖于组织和诱导剂。单细胞水平的空间分辨RNA表达分析表明，每次衰老诱导都会导致独特的转录谱——即使在同一细胞类型的细胞内——这解释了体内衰老细胞的异质性。此外，我们表明，主要来源于巨噬细胞的白细胞介素-1β可诱导继发性表型。我们的研究结果为体内继发性衰老提供了见解，并为理解和调控衰老过程中的衰老提供了有用的工具。
