Anti-aging molecule produced during fasting.

Diet trends like intermittent fasting and ketogenic diets are popular for their weight-loss effects. Han et al. now show that the β-hydroxybutyrate generated under these regimes slows aging of the vascular system, which is tied to overall body aging. It promotes vascular cell quiescence and inhibits cell senescence that accelerate aging. Here is the technical abstract:

Highlights

-β-hydroxybutyrate prevents the vascular cell senescence 

-β-hydroxybutyrate upregulates Oct4 expression via interacting with hnRNP A1 

-Oct4-mediated quiescence is able to attenuate hallmarks of senescenc 

-Circulating β-hydroxybutyrate alleviates the senescence of mouse aorta

Summary

β-hydroxybutyrate (β-HB) elevation during fasting or caloric restriction is believed to induce anti-aging effects and alleviate aging-related neurodegeneration. However, whether β-HB alters the senescence pathway in vascular cells remains unknown. Here we report that β-HB promotes vascular cell quiescence, which significantly inhibits both stress-induced premature senescence and replicative senescence through p53-independent mechanisms. Further, we identify heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) as a direct binding target of β-HB. β-HB binding to hnRNP A1 markedly enhances hnRNP A1 binding with Octamer-binding transcriptional factor (Oct) 4 mRNA, which stabilizes Oct4 mRNA and Oct4 expression. Oct4 increases Lamin B1, a key factor against DNA damage-induced senescence. Finally, fasting and intraperitoneal injection of β-HB upregulate Oct4 and Lamin B1 in both vascular smooth muscle and endothelial cells in mice in vivo. We conclude that β-HB exerts anti-aging effects in vascular cells by upregulating an hnRNP A1-induced Oct4-mediated Lamin B1 pathway.

Graphical Abstract