According to a study by Georgia State University scientists, a molecule called β-hydroxybutyrate has anti-aging effects on the vascular system; more specifically, the molecule appears to prevent senescence of vascular cells by promoting cellular quiescence instead [1].

Study abstract 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 Oct4 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.

What is cellular quiescence?

Our readers are probably familiar with the concept of cellular senescence—an irreversible state of arrested growth that prevents cells from further replicating. Lately, senescent cells have been making the headlines several times, as they are a very promising target for medical intervention to delay or even reverse some aspects of aging; while a certain number of senescent cells is tolerable and even beneficial, the accumulation of senescent cells in old age drives several age-related pathologies.

By contrast, cellular quiescence is a reversible state of arrested growth; quiescent cells do not divide, but under the right conditions, they can re-enter the cell cycle and divide again. This state usually occurs when nutrition or growth factors are lacking, and it is thought to be a way that cells can avoid entering a senescent state. The cellular quiescence mechanism also helps cells to preserve stemness and resist genotoxic stress.

The study







The molecular subject of the study, β-hydroxybutyrate, is a so-called ketone body. A ketone body is one of three water-soluble molecules—acetoacetate, β-hydroxybutyrate, and acetone—containing a ketone group, which is an organic molecule containing an oxygen atom double-bonded to a carbon atom that is, in turn, bonded to two other carbon-containing molecules. High levels of ketone bodies are observed as a consequence of fasting, calorie restriction, and prolonged, high-intensity exercise; they are thought to have anti-aging effects of various kinds, including alleviation of aging-related neurodegeneration.

The team discovered that β-hydroxybutyrate upregulates the expression of a transcription factor called Oct4 in vascular cells; in turn, this increases levels of the protein Lamin B1, which is an important prevention factor against senescence induced by DNA damage. This might provide an explanation as to why fasting and caloric restriction have been observed to extend the healthspans and lifespans of a variety of multicellular organisms; it might also explain why obesity appears to accelerate aging, as β-hydroxybutyrate levels might then go down.

The researchers tested the efficacy of β-hydroxybutyrate against cellular senescence in vitro on human umbilical vein endothelial cells and human aortic smooth muscle cells, and they observed the beneficial effects of this molecule in vivo: by injecting β-hydroxybutyrate into fasting mice, the scientists were able to alleviate the senescence of the animals’ aortae.

Conclusion

The authors of the study suggest that maintaining cellular quiescence in vascular tissue might be a viable strategy to prevent senescence-associated vascular aging, and they state that Oct4 is a potential therapeutic target and propose β-hydroxybutyrate as a potential treatment for age-related vascular diseases.







It is worth noting that the senior author of the study, Dr. Ming-Hui Zou, commented about how age is the most important risk factor for human disease and about how delaying and preventing aging are promising strategies for disease prevention. It is encouraging to see how more and more researchers no longer shy away from telling it as it is—namely, that aging is something that can and should be fought by applying rejuvenative interventions.

Literature

[1] Han, Y., Bedarida, T., Ding, Y., Somba, B. K., Lu, Q., Wang, Q., … Zou, M.-H. (2018). β-Hydroxybutyrate Prevents Vascular Senescence through hnRNP A1-Mediated Upregulation of Oct4. Molecular Cell.