One of the hallmarks of old age is vascular aging. Researchers found that a biomolecule, β-Hydroxybutyrate (BHB), can serve as a key to turning the time around. Apparently, BHB has anti-aging effects on the vascular system.
β-Hydroxybutyrate – a biomolecule
β-Hydroxybutyrate is a biomolecule with a chemical formula, C4H803. Many regard it as a ketone; however, under a strict definition, it would not technically fit as a ketone. That is because its carbonyl carbon binds to only one instead of two other carbon atoms. Nonetheless, BHB appears to be physiologically related to other ketone bodies (such as acetate and acetoacetate) based on the metabolic aspect. For instance, the tissue level of BHB rises during calorie restrictions, fasting, prolonged intense workout, and when following a ketogenic diet.1 Accordingly, BHB level occurs the highest among the three circulating ketones in the body.
β-Hydroxybutyrate – biological sources
The body naturally produces BHB through the process of ketogenesis. Low-carb diet and fasting lead to the rise of BHB level. Firstly, the body breaks down fatty acids to produce acetyl CoA. This precursor goes through a series of reactions leading to acetoacetate synthesis. In turn, the acetoacetate circulates via the bloodstream, and subsequently reaches the liver. The BHB-dehydrogenase enzyme in the liver reduces the acetoacetate to BHB. 1
Another biochemical pathway that leads to the synthesis of this biomolecule uses butyrate. The body metabolizes butyrate and produce D-β-hydroxybutyrate through the aid of the enzyme, hydroxybutyrate-dimer hydrolase.
β-Hydroxybutyrate – biological action
In humans, D-β-hydroxybutyric acid is one of the major endogenous agonist of hydroxycarboxylic acid receptor 2 (HCA2), a receptor protein encoded by the HCAR2 gene. It binds to and activates HCA2. Upon activation, HCA2 can inhibit the breakdown of fats and mediates niacin-induced flushing. Moreover, it induces the dilation of blood vessels.
Based on recent research, BHB might serve as a biomolecule that could help turn time around for the vascular system. Old age faces an increased risk to cancer and cardiovascular diseases since the vasculature ages as well. Dr. Ming-Hui Zou, director at Georgia State University, explains. “When people become older, the vessels that supply different organs are the most sensitive and more subject to aging damage….”2
β-Hydroxybutyrate – vascular study
Zou et al. 2, 3 conducted a study on vascular aging, exploring the link between calorie restrictions and delayed vascular aging. Accordingly, calorie restrictions averted vascular aging.
They found that BHB, the biomolecule naturally produced from the liver, has anti-aging effects, particularly on endothelial cells. The endothelial cells line the interior surface of the vascular system. Based on the results, BHB promoted mitosis of endothelial cells, thus, pre-empting vascular aging.3 Furthermore, they saw that BHB binds to a certain protein, which stimulates a series of reactions that consequently rejuvenate, thus, keep the blood vessels young.2
BHB could eventually become a biomolecular tool that promotes mitosis of endothelial cells. In being able to do so, it could help prevent endothelial cell senescence. Hence, this potential rejuvenating effect on the vascular system may soon become valuable not just in keeping the blood vessels young but also in preventing cardiovascular diseases related to old age.
— written by Maria Victoria Gonzaga
1 Martins, N. (2018 Sept. 26). Beta-hydroxybutyrate or BHB –All You Need to Know. Retrieved from https://hvmn.com/blog/exogenous-ketones/beta-hydroxybutyrate-or-bhb-all-you-need-to-know
2 Georgia State University. (2018 Sept. 10). Researchers Identify Molecule With Anti-Aging Effects On Vascular System. Retrieved from https://www.technologynetworks.com/neuroscience/news/fasting-molecule-delays-vascular-aging-309380
3 Han, Y. M., Bedarida, T., Ding, Y., Somba, B. K., Lu, Q., Wang, Q., Song, P., & Zou, M.H. (2018). β-Hydroxybutyrate Prevents Vascular Senescence through hnRNP A1-Mediated Upregulation of Oct4. Molecular Cell, 71(6):1064-1078.e5. https://doi.org/10.1016/j.molcel.2018.07.036
How do cells know when to separate during mitosis? A molecule called BubR1 was found to regulate the timing of the division of a parent cell into two progeny cells. Researchers who identified the role of BubR1 were optimistic that their discovery could lead to a potential cancer treatment by inducing cancer cells to undergo premature mitosis.
Phases of mitosis
When a cell enters the Synthesis phase (S phase) of the cell cycle, it is likely that it will subsequently go through the sequential phases of mitosis in which a single cell ultimately gives rise to two cells, each with its own copy of chromosomes. Firstly, the cell enters prophase, which is the phase of mitosis largely characterized by the condensation of chromatin (becoming distinct chromosomes), the beginning of spindle fiber formation, and the disintegration of the nucleolus, nuclear membrane, and organelles. This is then followed by a phase, called metaphase, wherein the chromosomes align along the metaphase plate and the microtubules attach to the kinetochores. Then, the chromosomes are pulled apart toward the opposite poles of the cell during anaphase. In the last phase of mitosis called telophase, the chromosomes have completely moved to the opposite poles of the cell resulting in two sets of nuclei. The cytoplasm divides ultimately giving rise to two new cells.
Delaying strategy of BubR1 during mitosis
Researchers from Institute of Cancer Research reported in their paper published in Molecular Cell the role of BubR1 in mitosis. Accordingly, the spindle assembly checkpoint (SAC) prevents the separation of sister chromatids until all chromosomes are properly attached to the spindle. It also catalyzes the formation of the Mitotic Checkpoint Complex (MCC).1 The BubR1 is part of this molecular complex that regulates the Anaphase Promoting Complex/Cyclosome (APC/C). In particular, the BubR1 is part of the molecular machinery that delays the onset of anaphase during mitosis. The delay is crucial as it ensures the chromosomes to be properly positioned before they will be segregated.2
The researchers further reported that the N-terminal half of BubR1 contains two ABBA motifs. When they mutated these BubR1motifs, the cells become unable to normally delay mitosis. Moreover, the two resulting cells following mitosis had unevenly divided chromosomes. They explained that without the normal ABBA sequences of BubR1, the MCC failed to bind to the APC/C. Consequently, mitosis progressed despite the chromosomes not yet being properly positioned.
Premature mitosis for cancer cells
The researchers made note of the importance of the ABBA sequence of BubR1. It served as a “safety catch” – preventing the machinery from progressing prematurely. Accordingly, cancer cells rely on this safety catch much more than normal cells as they usually have extra chromosomes to be put into place, and thereby need more time for mitosis.2 This could therefore be used to design cancer treatment, such as a drug that could switch off the “safety catch” of BubR1, and forcing cancer cells to divide prematurely with an unevenly divided chromosomes following mitosis.
— written by Maria Victoria Gonzaga
1 Fiore, B.D., Wurzenberger, C., Davey, N.E., & Pines, J. (2018).Molecular Cell. https://doi.org/10.1016/j.molcel.2016.11.006
2 Institute of Cancer Research. (2016, December 8). Scientists reveal ‘safety catch’ within all dividing cells: Major discovery could lead to new cancer treatments. ScienceDaily. Retrieved August 7, 2018 from www.sciencedaily.com/releases/2016/12/161208143306.htm
A recent finding by a team of researchers from European Molecular Biology Laboratory on the parental chromosomes during the first mitosis of an embryo implicates a possible revision in biology textbooks. What they observed during the first mitotic division after the supposed “union” of gametes in mouse models apparently invalidates what is currently believed. Biologists assume that there is only one spindle apparatus that works to separate the two parental chromosomes during the first cell division of a mammalian zygote. It turns out that there are two. Their finding could also help explicate the common errors occurring during the first divisions in the early embryos of mammals, and possibly of humans.
Early model of mitosis in mammalian zygote
The first mitosis in mammals occurs during the union of male and female chromosomes. Upon fertilization, the zygote holds two parental chromosomes that unite, and then separated, triggering the formation of two cells (each with own nucleus) after the first mitosis. This marks the two-cell stage embryo.
The first mitosis is thought to proceed initially by the break-down of the nuclear envelope. This enabled the two parental chromosomes to unite thereafter. A single spindle assembly then forms. The spindles attach to the chromosomes, align them at metaphase, and then pull them apart during anaphase. The first mitosis ends at telophase where the cell divides into two cells, each with its own nucleus.
Viewing first mitosis through light-sheet microscopy
Researchers from European Molecular Biology Laboratory found out that there is not one but two spindle apparatus at work during the first mitosis of the mouse embryo. Using a light-sheet microscopy approach, they were able to conduct real-time, 3D imaging of the mouse embryo.1 Without this innovative technology, capturing an image at this stage will not be feasible because embryos are sensitive to light. With it, the researchers were able to track the chromosomes during the supposed union and saw differently what has long been held. They were surprised to find out that (1) the maternal and the paternal chromosomes assembled their own autonomous spindle structure and (2) the parental chromosomes remain in separate regions and did not mix prior to and during the first mitosis.1,2
Current model of first mitosis
Based on the current mouse embryo model, what transpires at first mitosis after the nuclear envelope disintegration post-fertilization event is that both the maternal and the paternal chromosomes form their own spindle apparatus. The mitotic spindles then attach to the chromosomes. Even so, the maternal and the paternal chromosomes remain in separate regions of the spindle. The spindles align them in a way that the maternal chromosomes align juxtapose to where the paternal chromosomes align. The two spindle apparatus then autonomously pull them apart towards opposite poles. The cell finally divides into two, where each has only one nucleus. Conversely, an erroneous axis alignment of paternal chromosomes during metaphase was observed to lead to the formation of one of the cells with multiple nuclei after the first mitosis.
The recent findings could help explain certain errors (e.g. multiple-nucleated cell) following the first mitosis. If this mechanism holds true to humans as well it could lead to new targets for treatment (particularly an erring first mitotic spindle apparatus) in a developing embryo. It might also provide an insight as to when life can be assumed to first exist — is it during the first meet-up of the male and the female chromosomes that do not mix yet… or is it that point at which they unite — but apparently occurs only after the first mitosis.
— written by Maria Victoria Gonzaga
1 Reichmann, J., Nijmeijer, B., Hossain, M. J., Eguren, M., Schneider, I., Politi, A.Z., Roberti, M.J., Hufnagel, L., Hiiragi, T. & Ellenberg, J. (2018). Dual-spindle formation in zygotes keeps parental genomes apart in early mammalian embryos. Science. DOI: 10.1126/science.aar7462
2 Zielinska, A.P. & Schuh, M. (2018). Double trouble at the beginning of life. Science 361 (6398): 128-129. DOI: 10.1126/science.aau3216