A new review published in Volume 18 of Aging on May 30, 2026, examines how cellular senescence and stemness interact across different biological contexts. The review was led by first author Angelos Papaspyropoulos and corresponding author Vassilis G. Gorgoulis from the National and Kapodistrian University of Athens and the Biomedical Research Foundation of the Academy of Athens, Greece.
Cellular senescence refers to cells that permanently stop dividing in response to stress, which helps prevent damaged cells from proliferating. In contrast, stem cells are responsible for tissue repair by renewing themselves and generating specialized cell types. Traditionally considered biological opposites, recent research suggests their relationship is more complex than previously thought.
The authors summarize studies showing that under normal physiological conditions, senescence often limits stem cell activity. Excessive senescence can impair the regenerative capacity of various stem cell types such as mesenchymal stem cells, muscle satellite cells, dental pulp stem cells, and pancreatic β-cell progenitors. Experimental models indicate that reducing senescence can restore function to these cells and improve tissue regeneration.
Several molecular pathways are involved in regulating this balance between senescence and stemness. These include p53/p21 and p16INK4A/RB pathways, mTOR signaling, Wnt/β-catenin signaling, and the senescence-associated secretory phenotype (SASP). These mechanisms help determine whether a cell maintains its regenerative potential or enters a stable state of senescence.
The review also discusses how this relationship changes in cancer settings. In many tumors—including B-cell lymphoma, liver cancer, colon cancer, lung cancer, and breast cancer—senescent cells may promote the emergence of cancer stem cells through inflammatory signals or by escaping from their arrested state. This process may contribute to tumor progression and resistance to therapy.
"As the complex interplay between senescence and stemness may heavily vary between different cell types and physiological contexts," said the authors, . "Elucidating the nature of the interaction and the potential effects per case is of considerable clinical importance." They recommend further research into when senescence suppresses or promotes stemness for safer regenerative therapies as well as more effective cancer treatments.
