Distinct senotypes in p16- and p21-positive cells across human and mouse aging tissues

Area of Science:

• Gerontology and Cellular Biology
• Molecular Mechanisms of Aging
• Biomarkers of Senescence

Background:

• Cellular senescence contributes to age-related tissue dysfunction through the senescence-associated secretory phenotype (SASP).
• Cyclin-dependent kinase inhibitors p21^Cip1 and p16^Ink4a are established markers of cellular senescence, but their distinct in vivo roles are not fully understood.

Purpose of the Study:

• To comprehensively investigate the heterogeneity and distinct roles of p21^Cip1 and p16^Ink4a in cellular senescence across different cell types and tissues in vivo.
• To characterize the senescence-associated secretory phenotype (SASP) profiles associated with p21^Cip1 and p16^Ink4a expression and their developmental trajectories.

Main Methods:

• Analysis of multiple single-cell RNA sequencing datasets from murine and human aging tissues.
• Application of RNA velocity and pseudotime analyses to infer cell state dynamics.
• Comparative analysis of SASP factor expression linked to p21^Cip1 and p16^Ink4a.

Main Results:

• p21^Cip1 and p16^Ink4a expression exhibits significant heterogeneity and lack of co-expression across diverse cell types and tissues.
• Distinct, tissue-specific SASP profiles were associated with p21^Cip1 versus p16^Ink4a expression.
• RNA velocity and pseudotime analyses revealed independent trajectory dynamics for p21+ and p16+ cells, with no direct transitions observed.

Conclusions:

• Cellular senescence and SASP are highly diverse and context-dependent, varying significantly by cell type and tissue.
• p21^Cip1 and p16^Ink4a represent distinct cellular states within senescence, each with unique SASP signatures and developmental paths.
• A conserved core set of SASP factors may mediate common senescence-related functions despite overall heterogeneity.