“Cellular senescence and stemness represent two biological entities with several opposing properties.”

BUFFALO, NY — June 29, 2026 — A new review was published in Volume 18 of Aging on May 30, 2026, titled “The love and hate relationship between cellular senescence and stemness.”

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 and stemness have traditionally been viewed as biological opposites. Senescent cells permanently stop dividing in response to cellular stress, helping prevent the spread of damaged cells, while stem cells maintain tissue repair by continuously renewing themselves and generating specialized cells. However, growing evidence suggests that the relationship between these two biological processes is far more complex and depends on the tissue type, physiological conditions, and disease context.

In this review, the authors summarize recent research examining how senescence and stemness interact across normal tissues, aging, regeneration, and cancer. Rather than always opposing one another, the two processes can either suppress or reinforce each other depending on the biological setting.

Under normal physiological conditions, senescence often limits stem cell activity. The review highlights studies showing that excessive senescence can impair the regenerative capacity of mesenchymal stem cells, muscle satellite cells, dental pulp stem cells, and pancreatic β-cell progenitors. In several experimental models, reducing senescence restored stem cell function and improved tissue regeneration.

At the molecular level, multiple signaling pathways contribute to this balance, including the p53/p21 and p16INK4A/RB pathways, mTOR signaling, Wnt/β-catenin signaling, and the senescence-associated secretory phenotype (SASP). These pathways help determine whether cells maintain regenerative potential or enter a stable senescent state.

The review also emphasizes that the relationship changes dramatically in cancer. In many tumors, senescent cells can promote the emergence of cancer stem cells through inflammatory signals released as part of the SASP or through cells escaping from the senescent state. This interaction has been reported in several malignancies, including B-cell lymphoma, liver cancer, colon cancer, lung cancer, and breast cancer, where stem cell-like properties may contribute to tumor progression, metastasis, and resistance to therapy.

The authors discuss how this dual role creates both opportunities and challenges for future therapies. While eliminating persistent senescent cells may improve tissue repair and reduce age-related disease, indiscriminately targeting senescence could also interfere with beneficial regenerative processes or alter stem cell function in unintended ways.

“As the complex interplay between senescence and stemness may heavily vary between different cell types and physiological contexts, elucidating the nature of the interaction and the potential effects per case, is of considerable clinical importance.”

According to the authors, a better understanding of when senescence suppresses stem cell function and when it promotes stemness will be essential for developing safer regenerative therapies and more effective cancer treatments. They also emphasize that senolytic therapies should be carefully evaluated using validated biomarkers and appropriate clinical studies before widespread implementation.

Overall, this review highlights that senescence and stemness cannot simply be viewed as biological opposites. Instead, their relationship is highly context-dependent, influencing tissue maintenance, aging, regeneration, and cancer in different ways. Understanding this dynamic interplay may help guide the development of future therapies aimed at promoting healthy aging while minimizing cancer risk.

Paper DOI: https://doi.org/10.18632/aging.206387                 

Corresponding author: Vassilis G. Gorgoulis – [email protected]  

Keywords: senescence, stemness

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