Designed By Nature

I am almost finished with the book “Lifespan: Why we age – and why we don’t have to” from David Sinclair. In this book he explains the result of his research in a very readable way, avoiding much of the scientific language so that it is accessible to everybody. While reading the book, I recognized a lot of effects that can be obtained in a different way. Namely through a ketogenic diet.

So I’ll be going through the points raised in the book where I saw the ketogenic diet having a similar effect. The first point is the uncoupled metabolism.

Uncoupling

One of the reasons why uncoupling would be health promoting and life extending is because it would be protective against oxidative damage by reducing ROS production. This is also what the ketone body beta-hydroxybutyrate (BHB) does. It stimulates the expression of the uncoupling protein.

“Mitochondrial uncoupling and longevity – A role for mitokines?”, Klaus S, Ost M, 2019, https://www.ncbi.nlm.nih.gov/pubmed/31786315

“Ketones drive mitochondrial uncoupling in adipose tissue”, Chase Walton, and Benjamin T. Bikman, 2018, https://www.fasebj.org/doi/abs/10.1096/fasebj.2018.32.1_supplement.41.1

“Mitochondrial biogenesis and increased uncoupling protein 1 in brown adipose tissue of mice fed a ketone ester diet”, Shireesh Srivastava, Yoshihiro Kashiwaya, M. Todd King, Ulrich Baxa, Joseph Tam, Gang Niu, Xiaoyuan Chen, Kieran Clarke, and Richard L. Veech, 2012, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3360149/

So ketones may promote longevity by the same mechanisms. This could make sense as it is a molecule associated with long-term fasting and starvation. Plenty of discussion on what exactly is fasting versus starvation because starvation has a negative connotation but what I mean here is going without food long enough so that your level of BHB rises significantly to support energy requirements while not eating.

But that definition doesn’t really matter.

What I want to get to is, to understand the effect, how much BHB do you have circulating and where is it used? Because, even if you have sufficient quantities of it circulating around, only where it is used as fuel it will be able to exert its effect.

For example the liver is unable to use BHB as fuel. Curiously, the liver is the only organ that can recover fully despite tremendous damage.

In order for BHB to reach the cells in the organs, it has to be carried across the endothelial cells. BHB is transferred using MCT1.

Now also keep in mind that there is an inverse correlation between BHB and blood glucose in part due to the suppressing effect BHB has on the release of glucose from the liver. The brain is a huge consumer of glucose so it must be able to obtain BHB more easily when glucose goes down. And for that we see an 8-fold (!) increase of MCT1 in the endothelial cells in the blood-brain-barrier. The same effect in humans can be expected as shown by starvation experiments.

“Diet-induced ketosis increases monocarboxylate transporter (MCT1) levels in rat brain.”, Leino RL, Gerhart DZ, Duelli R, Enerson BE, Drewes LR, 2001, https://www.ncbi.nlm.nih.gov/pubmed/11248400

So can we expect all of this uncoupling to take place in the brain? Probably, but I want to cast some doubt here. Uncoupling results in heat production. In the past I have raised a question to professor Thomas Seyfried asking why fatty acids are not used as fuel in the brain. He suspect it is because of the heat production. A skull is a closed area making it difficult to cool off. It is not proof uncoupling doesn’t take place but I would be careful to take that assumption for true without any research.

What is already available is mRNA that indicates uncoupling does take place to some degree. We don’t know by how much though but the following research tells us it is even vital for health, and I would say maximum healthspan of the central nervous system (cns). The uncoupling proteins in the CNS are not the UCP1 version which is important for thermogenesis. Instead, it are different versions that have health improving aspects. Sounds good but… UCP1 was stimulated by ketones, is the same true for these other versions (UCP2, UCP4, BMCP1/UCP5)?

“Mitochondrial uncoupling proteins in the cns: in support of function and survival”, Zane B. Andrews, Sabrina Diano & Tamas L. Horvath, 2005, https://www.nature.com/articles/nrn1767

The little evidence that I could find seems to suggest it is the case for at least UCP4 and UCP5.

“A Ketone Ester Diet Increases Brain Malonyl-CoA and Uncoupling Proteins 4 and 5 while Decreasing Food Intake in the Normal Wistar Rat”, Yoshihiro Kashiwaya, Robert Pawlosky, William Markis, M. Todd King, Christian Bergman, Shireesh Srivastava, Andrew Murray, Kieran Clarke and Richard L. Veech, 2010, http://www.jbc.org/content/285/34/25950.full

So we’ve seen an effect in brown fat and CNS. It is reasonable to suspect that the brain will be the main consumer of BHB due to its energy requirements and evidenced by the upregulation of MCT1 so I don’t think other organs will make increased use of BHB and instead rely more on fatty acids for fuel. Perhaps there are some other mechanisms that the rest of the body can benefit from. We’ll explore them in the next posts.