Senolysis

Senolysis refers to strategies that selectively eliminate senescent cells, a type of cell that has permanently stopped dividing in response to stress yet persists in tissues and secretes inflammatory factors (the senescence-associated secretory phenotype, SASP). Senolysis aims to counteract age-related tissue dysfunction by reducing the burden of these cells.

Most senolytic approaches target anti-apoptotic pathways that senescent cells rely on to resist death, rendering them susceptible to apoptosis when challenged. Agents include combinations such as dasatinib and quercetin, BCL-2 family inhibitors such as navitoclax, and peptides or other compounds such as FOXO4-DRI. Genetic approaches in mice use inducible systems to clear senescent cells (for example, INK-ATTAC or p16-driven suicide constructs).

Preclinical studies in mice show that senolysis reduces the burden of senescent cells, delays or ameliorates several age-related pathologies, and can improve tissue function and healthspan; effects on lifespan have been demonstrated in some models. In humans, early-phase trials have explored dasatinib plus quercetin and other regimens to reduce senescent-cell markers and improve physical function in certain chronic conditions; results are preliminary and heterogeneous.

Safety and limitations include potential off-target effects and the importance of dosing regimens to avoid impairing beneficial roles of senescent cells (e.g., in wound healing). Navitoclax can cause thrombocytopenia and other toxicities. Biomarkers of senescence are imperfect, complicating assessment. As of now, senolysis remains experimental, with ongoing research to establish efficacy, safety, and guidelines for clinical use.