Ping Song
Georgia State University, USA
Title: β-Hydroxybutyrate prevents vascular cell senescence through heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1)-upregulated octamer-binding transcriptional factor 4
Biography
Biography: Ping Song
Abstract
Statement of the Problem: Vascular aging is considered as a main risk factor for cardiovascular diseases. β-hydroxybutyrate (β-HB), one of three human ketone bodies, usually functions as an alternative source of energy during nutrient deprivation. Elevation of ketone bodies, including β-HB, during fasting or caloric restriction is believed to induce anti-inflammation effects and alleviate aging-related neurodegeneration. However, whether β-HB regulates molecular signaling in the aging process, specifically the senescence pathway in vascular cells, has not been previously studied. The objective of this study is to investigate the effect of β-HB on vascular cell senescence and the underlying molecular mechanisms. Methodology and Results: Vascular cells treated with β-HB and a ligand fishing pull-down approach were employed as an in vitro model. Mouse treated with β-HB was used as an in vivo animal model. β-HB stimulates cellular quiescence in vascular cells, which significantly inhibits both replicative senescence and stress-induced premature senescence via p53-independent mechanisms. Further, we identified heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) as a direct binding target of β-HB. The binding of β-HB with hnRNP A1 profoundly enforces hnRNP A1 binding to Octamer-binding transcriptional factor (Oct) 4 mRNA. The binding of hnRNP A1 with Oct4 mRNA stabilizes Oct 4 mRNA and Oct4 expression. Moreover, Oct4 increases Lamin B1, a key factor in maintaining chromosome stability against DNA damage-induced senescence. Finally, either fasting or intraperitoneal injection of β-HB in vivo elevates Oct4 and Lamin B1 in both endothelial and vascular smooth muscle cells in mice in vivo. Conclusions: Ketone body β-HB exerts anti-aging function in vascular cells by upregulating an hnRNP A1-controlled Oct4-mediated Lamin B1 pathway.