Targeted clearance of senescent cells alleviates alcohol-associated liver disease by restoring cellular function and immune balance

The liver is one of the organs most affected by alcohol consumption, and its interaction with aging is particularly significant. Chronic alcohol consumption accelerates liver aging through mechanisms such as oxidative stress, inflammation, fibrosis, and impaired regeneration. It is still unknown whether senescent cell clearance orchestrates innate and adaptive immune responses during the alcohol-induced old liver damage process. To investigate this, we used INK-ATTAC transgenic mice treat with AP20187 (AP) to eliminate p16^Ink4a-positive senescent cells in chronic-plus-binge ethanol feeding model. Senescent cell clearance alleviates age-related liver oxidative stress and lipid accumulation in long-term (8wks)-plus-binges mice. Importantly, AP clears senescent cells, promoting M1/M2 macrophage polarization and reducing the expression of senescence-associated secretory phenotype (SASP) factors. In addition, senescent cell clearance mitigates liver injury by reducing CD8⁺ T cells, myeloid-derived suppressor cells (MDSCs), and neutrophil infiltration, as well as ameliorating immuno-senescence and T cell exhaustion. These findings demonstrate that the clearance of senescent cells influences immune response and contributes to inhibiting immune senescence. This work sheds light on senolytic interventions' being a potential therapeutic avenue for alleviating age-associated pathologies in alcohol related liver disease (ALD) and has the potential for clinical translation.