Oxidative Stress-Driven Cellular Senescence: Mechanistic Crosstalk and Therapeutic Horizons
Bojan Stojanović, Bojan Stojanovic, Ivan Jovanović, Milica Dimitrijevic Stojanovic, Bojana Stojanović, Bojana Stojanović, Vojin Kovačević, Ivan Radosavljević, Danijela Jovanović, Marina Miletić Kovačević, Nenad Zornić, Ana Azanjac Arsić, Stevan Eric, Nikola Mirković, Jelena Nešić, Stefan Jakovljević, Snežana Lazarević, Ivana Milivojcević Bevc, Bojan Milošević
Abstract
Cellular senescence, a state of permanent cell cycle arrest, represents a double-edged sword in biology-providing tumor-suppressive functions while contributing to tissue degeneration, chronic inflammation, and age-related diseases when senescent cells persist. A key driver of senescence is oxidative stress, primarily mediated by excessive reactive oxygen species that damage mitochondrial DNA, modulate redox-sensitive signaling pathways, and trigger the senescence-associated secretory phenotype. Emerging evidence highlights the pathogenic role of SASP in promoting local inflammation, immune evasion, and senescence propagation. This review explores the intricate interplay between redox imbalance and cellular senescence, emphasizing mitochondrial dysfunction, SASP dynamics, and their implications in aging and cancer. We discuss current senotherapeutic strategies-including senolytics, senomorphics, antioxidants, gene therapy, and immunotherapy-that aim to eliminate or modulate senescent cells to restore tissue homeostasis. Understanding the heterogeneity and context-specific behavior of senescent cells remains crucial for optimizing these therapies. Future research should focus on addressing key knowledge gaps, including the standardization of senescence biomarkers such as circulating miRNAs, refinement of predictive preclinical models, and development of composite clinical endpoints. These efforts are essential to translate mechanistic insights into effective senotherapeutic interventions and enable the safe integration of senescence-targeting strategies into routine clinical practice.