Targeted apoptosis of senescent cells by valproic acid alleviates therapy-induced cellular senescence and lung aging

Accumulation of senescent cells in tissues and their downstream effect programs have emerged as key drivers of aging and age-associated pathologies. Recent progresses in senotherapeutics indicated that either selectively killing senescent cells with senolytics or suppressing the senescence-associated secretory phenotype (SASP) secretion using senomorphics contributes to extending of the healthy lifespan and alleviating numerous age-related disorders in mice.

However, the potential side-effects and long-term cytotoxicity of the above novel compounds have not yet been determined. Therefore, it seems to be more efficient to explore new senotherapeutical functions from approved drugs.

The effects of valproic acid (VPA), a derivative of valine, in cellular senescence were evaluated by senescence-associated β galactosidase (SA-β-Gal) staining, flow cytometry and western blot (WB). The cell viability was tested using CCK-8 kits. Cell apoptosis was detected by Annexin V-EGFP/PI apoptosis detection kit. Cell autophagy was checked using GFP-RFP-LC3 ratiometric plasmid. The roles of VPA in lung aging were investigated by in vivo experiments using H&E and Masson staining, WB, as well as electronic microscope strategies.

Here we identified VPA was able to induce an over-accumulation of reactive oxygen species (ROS) (>1.5 times increasing) and apoptosis (>2 times increasing) of senescent cells. Mechanistically, VPA activated the phospholipid modifying enzyme membrane-bound O-acyltransferase domain-containing protein 1 (MBOAT1), which was repressed during senescence, then promoted mitochondrial autophagy and apoptosis. In addition, VPA was also found to alleviate therapy induced abnormal mitochondria and lung aging phenotype (>1.5 times decreasing of lung fibrosis markers and >2.5 times increasing of naïve/memory CD4+ or CD8+ T cells) in vivo.

Taken together, our study demonstrated that VPA was able to selectively kill senescent cells both in vitro and in vivo, and thus shedding light on new functions and novel potential application of VPA in anti-aging and anti-age-associated diseases.