Cellular senescence and stemness have long been cast as biological opposites: one process shuts cells down permanently in response to stress, the other keeps tissues young by continuously renewing them. A new review published in the journal Aging argues that this tidy dichotomy doesn’t hold up, and that the real relationship between the two is far messier, and far more clinically important, than previously appreciated.

The review, titled “The love and hate relationship between cellular senescence and stemness,” was led by first author Angelos Papaspyropoulos and corresponding author Vassilis G. Gorgoulis, both affiliated with the National and Kapodistrian University of Athens and the Biomedical Research Foundation of the Academy of Athens in Greece. As the authors put it, cellular senescence and stemness represent two biological entities with several opposing properties, at least on paper. In practice, growing evidence shows their interaction depends heavily on tissue type, physiological state, and whether disease, particularly cancer, is in the picture.

Senescent cells permanently exit the cell cycle in response to damage or stress, a mechanism that helps prevent damaged cells from replicating and spreading further harm. Stem cells, by contrast, maintain tissue repair by continuously renewing themselves and generating the specialized cell types tissues need to function. The review compiles evidence that, rather than simply opposing one another in every context, the two processes can suppress or reinforce each other depending on the biological setting.

Under normal physiological conditions, the review finds, senescence generally acts as a brake on stem cell activity. Multiple lines of evidence show that excessive senescence can impair the regenerative capacity of mesenchymal stem cells, muscle satellite cells, dental pulp stem cells, and pancreatic beta-cell progenitors. In several experimental models, dialing back senescence restored stem cell function and improved tissue regeneration, suggesting the brake, when it engages too aggressively, can genuinely impair the body’s ability to repair itself.

At the molecular level, the review traces this balance to a handful of overlapping signaling pathways, including p53/p21 and p16INK4A/RB, mTOR signaling, Wnt/beta-catenin signaling, and the senescence-associated secretory phenotype, or SASP, the cocktail of inflammatory molecules senescent cells release into their surroundings. Together, these pathways help determine whether a given cell retains its regenerative potential or settles into a stable, senescent state.

The picture shifts substantially in cancer, where the review describes senescence taking on what amounts to a darker second role. In many tumors, senescent cells can actively promote the emergence of cancer stem cells, either through inflammatory SASP signaling or through cells escaping the senescent state altogether. This dynamic has been documented across a range of malignancies, including B-cell lymphoma, liver cancer, colon cancer, lung cancer, and breast cancer, where stem cell-like properties in tumor cells have been linked to disease progression, metastasis, and resistance to treatment.

That dual identity, protective in healthy tissue, potentially dangerous in cancer, creates a genuine dilemma for anyone trying to design therapies around it. The review’s authors note that eliminating persistent senescent cells, an approach already being explored through so-called senolytic drugs, could improve tissue repair and reduce age-related disease. But indiscriminately targeting senescence carries real risk, since it could just as easily interfere with beneficial regenerative processes or disrupt stem cell function in ways researchers don’t yet fully anticipate.

As the authors write, the complex interplay between senescence and stemness may vary considerably between different cell types and physiological contexts, making it clinically important to work out both the nature of the interaction and its potential effects case by case, rather than assuming a single rule applies everywhere.

The review argues that a clearer understanding of exactly when senescence suppresses stem cell function, and when it instead promotes stemness, will be essential for developing safer regenerative therapies and more effective cancer treatments going forward. The authors also urge caution around the growing enthusiasm for senolytic therapies specifically, arguing they should be evaluated using validated biomarkers and rigorous clinical studies before any widespread rollout.

Taken as a whole, the review pushes back against treating senescence and stemness as a simple binary, framing their relationship instead as highly context-dependent, shaping tissue maintenance, aging, regeneration, and cancer in different, sometimes contradictory, ways depending on the setting. Untangling that context-dependence, the authors suggest, may be the key to therapies that support healthy aging without inadvertently raising cancer risk.

Notes

1. Impact Journals LLC, news release, “Cellular senescence and stem cells share a more complex relationship than previously recognized,” published June 29, 2026, via EurekAlert.

2. Study: Papaspyropoulos, A., Gorgoulis, V.G., et al., “The love and hate relationship between cellular senescence and stemness,” Aging, Vol. 18 (2026), DOI: 10.18632/aging.206387.