2. Academic Validation
  3. Characterizing primary and secondary senescence in vivo

Characterizing primary and secondary senescence in vivo

  • Nat Aging. 2025 Aug;5(8):1568-1588. doi: 10.1038/s43587-025-00917-y.
Yuko Sogabe 1 2,  Hirofumi Shibata 1 3,  Mio Kabata 1,  Akito Tanaka 1,  Kanae Mitsunaga 1,  Kazunori Sunadome 1 4,  May Nakajima-Koyama 1,  Michitada Hirano 5,  Eisuke Nishida 6,  Knut Woltjen 1,  Hiroshi Seno 2,  Yasuhiro Yamada 7,  Takuya Yamamoto 8 9 10
Affiliations

Affiliations

  • 1 Department of Life Science Frontiers, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan.
  • 2 Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
  • 3 Department of Otolaryngology Head and Neck Surgery, Gifu University Graduate School of Medicine, Gifu, Japan.
  • 4 Institute for the Advanced Study of Human Biology (WPI-ASHBi), Kyoto University, Kyoto, Japan.
  • 5 Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
  • 6 RIKEN Center for Biosystems Dynamics Research (BDR), Kobe, Japan.
  • 7 Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. [email protected].
  • 8 Department of Life Science Frontiers, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan. [email protected].
  • 9 Institute for the Advanced Study of Human Biology (WPI-ASHBi), Kyoto University, Kyoto, Japan. [email protected].
  • 10 Medical-risk Avoidance Based on iPS Cells Team, RIKEN Center for Advanced Intelligence Project (AIP), Kyoto, Japan. [email protected].
PMID: 40646305 DOI: 10.1038/s43587-025-00917-y
Abstract

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.

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