- Stress-induced senescence is a cellular process in which cells enter a permanent state of growth arrest in response to various stressful stimuli, such as DNA damage, oxidative stress, oncogene activation, or exposure to chemotherapeutic agents.
- Unlike replicative senescence, which is primarily triggered by telomere shortening after many rounds of cell division, stress-induced senescence can occur independently of the cell’s replicative age and is often rapid in onset. This mechanism plays a crucial role in tumor suppression, wound healing, tissue remodeling, and aging, but can also contribute to age-related pathologies when improperly regulated.
- When a cell experiences significant stress, a cascade of molecular signaling pathways is activated—most notably the p53/p21 and p16^INK4a/Rb tumor suppressor pathways. These lead to the cessation of the cell cycle, primarily at the G1 phase, preventing damaged or potentially malignant cells from proliferating. Although senescent cells no longer divide, they remain metabolically active and often develop a characteristic senescence-associated secretory phenotype (SASP). The SASP includes the secretion of pro-inflammatory cytokines, chemokines, growth factors, and proteases, which can influence the tissue microenvironment.
- Initially, SASP can have beneficial effects, such as promoting immune surveillance to remove senescent or damaged cells, stimulating tissue regeneration, and halting tumor progression. However, chronic accumulation of senescent cells and prolonged SASP expression can have detrimental effects, including chronic inflammation, disruption of normal tissue architecture, and promotion of diseases such as fibrosis, neurodegeneration, and even cancer in adjacent cells through paracrine signaling.
- Stress-induced senescence is also relevant in cancer therapy. Many anticancer treatments, such as radiation and chemotherapy, work in part by inducing senescence in tumor cells. While this can prevent immediate tumor growth, the presence of senescent tumor cells and their SASP can also create a pro-tumorigenic environment if these cells are not cleared by the immune system. As a result, interest has grown in developing senolytic drugs—agents that selectively eliminate senescent cells—or senostatic therapies that suppress the harmful effects of the SASP.
