Distinct senotypes in p16- and p21-positive cells across human and mouse aging tissues
Senescent cells drive age-related tissue dysfunction via the induction of a chronic senescence-associated secretory phenotype (SASP). The cyclin-dependent kinase inhibitors p21<sup>Cip1</sup> and p16<sup>Ink4a</sup> have long served as markers of cellular senescence. However, their individual roles remain incompletely elucidated, particularly in vivo. Thus, we conducted a comprehensive examination of multiple single-cell RNA sequencing datasets spanning both murine and human tissues during aging. Our analysis revealed that p21<sup>Cip1</sup> and p16<sup>Ink4a</sup> transcripts demonstrate significant heterogeneity across distinct cell types and tissues, frequently exhibiting a lack of co-expression. Moreover, we identified tissue-specific variations in SASP profiles linked to p21<sup>Cip1</sup> or p16<sup>Ink4a</sup> expression. Using RNA velocity and pseudotime analyses, we discovered that p21+ and p16+ cells follow independent trajectory dynamics, with no evidence of direct transitions between these two states. Despite this heterogeneity, we identified a limited set of shared "core" SASP factors that may drive common senescence-related functions. Our study underscores the substantial diversity of cellular senescence and the SASP, emphasizing that these phenomena are inherently cell- and tissue-dependent.
Authors
- João F. Passos (ORCID: https://orcid.org/0000-0001-8765-1890)
- Diana Jurk (ORCID: https://orcid.org/0000-0003-4486-0857)
- Nathan K. LeBrasseur (ORCID: https://orcid.org/0000-0002-2002-0418)
- Sundeep Khosla (ORCID: https://orcid.org/0000-0002-2936-4372)
- Dominik Saul (ORCID: https://orcid.org/0000-0002-0673-3710)
- Paul D. Robbins (ORCID: https://orcid.org/0000-0003-1068-7099)
- Laura J. Niedernhofer (ORCID: https://orcid.org/0000-0002-1074-1385)
- Robyn Laura Kosinsky (ORCID: https://orcid.org/0000-0003-2869-7762)
- Yeaeun Han (ORCID: https://orcid.org/0000-0003-1122-3691)
- Madison L. Doolittle (ORCID: https://orcid.org/0000-0003-0912-0095)
- Sung Young Kim (ORCID: https://orcid.org/0000-0003-4702-8265)
- David G. Monroe (ORCID: https://orcid.org/0000-0002-4818-0114)
- Y. S. Prakash (ORCID: https://orcid.org/0000-0002-2968-224X)
- Saranya P. Wyles
- Xu Zhang (ORCID: https://orcid.org/0000-0002-9784-0481)
- Luigi Ferrucci
- Ana Catarina Franco (ORCID: https://orcid.org/0000-0001-6730-7021)
Institutions
- University of Minnesota (US)
- Mayo Clinic (US)
- Konkuk University (KR)
- Robert Koch Institute (DE)
- WinnMed (US)
- Robert Bosch Hospital (DE)
- Konkuk University Medical Center (KR)
- Mayo Clinic in Arizona (US)
- Institute on Aging (US)
- National Institute on Aging (US)
- Mayo Clinic in Florida (US)
- University of Tübingen (DE)
- Hankuk University of Foreign Studies (KR)
- Robert Bosch (Germany) (DE)
Publication Details
- Journal
- The EMBO Journal
- Published
- 2025-10-29
- DOI
- https://doi.org/10.1038/s44318-025-00601-2
- Citations
- 7
- Primary Topic
- Telomeres, Telomerase, and Senescence
- Type
- article
- Field-Weighted Citation Impact
- 8.15