| Criteria | Stress-Induced Senescence | Replicative Senescence | Remarks |
| Definition | A premature, irreversible growth arrest triggered by cellular stressors | A state of permanent growth arrest due to telomere shortening after repeated cell divisions | Both are forms of cellular senescence but differ in cause and timing |
| Primary Cause | DNA damage, oxidative stress, oncogene activation, irradiation, or cytotoxic drugs | Progressive telomere attrition during successive rounds of cell division | Replicative senescence is telomere-dependent; stress-induced is not |
| Telomere Length | Often unaffected; cells may have long telomeres | Critically short telomeres trigger the DNA damage response | Telomere length is a key differentiating factor |
| Onset Timing | Can occur rapidly upon exposure to stress | Occurs gradually with chronological cell divisions | Stress-induced senescence can happen even in young cells |
| p53/p21 Pathway Involvement | Strongly involved in initiating cell cycle arrest | Also involves p53/p21 pathway but due to telomere dysfunction | Shared molecular mediators, but distinct upstream triggers |
| p16INK4a Pathway Involvement | Often activated depending on cell type and duration | Strongly associated with chronic replicative signals | p16 is more consistently upregulated in replicative senescence |
| Reversibility | Generally considered irreversible, but some studies suggest context-dependent reversibility | Considered irreversible under physiological conditions | Both serve as tumor-suppressive barriers |
| Cell Type Dependency | Occurs in many cell types exposed to environmental/genotoxic stress | More commonly studied in primary human fibroblasts and epithelial cells | Both phenomena observed in vitro and in vivo |
| Biological Role | Acts as a protective mechanism against malignant transformation | Limits the proliferative capacity of somatic cells | Both contribute to aging and cancer prevention |
| Senescence Markers | Elevated SA-β-gal activity, γH2AX foci, ROS, and SASP | Telomere dysfunction-induced foci (TIFs), SA-β-gal, and SASP | Some biomarkers are shared, others differ based on the initiating stimulus |
