Ketosis & Longevity
Ketosis and Its Anti-Aging Effects
Veech RL, Bradshaw PC, Clarke K, Curtis W, Pawlosky R, King MT. 2017. Ketone Bodies Mimic the Life Span Extending Properties of Caloric Restriction. International Union of Biochemistry and Molecular Biology: Life 69(5): 305-314.
Most people go through life only experiencing glucose metabolism. [Sad face…] They eat carbohydrate, and that breeds glucose to fuel all bodily processes. But there is another metabolic state out there, as you may know. It is called “ketosis.” This is the basis of our entire philosophy, so it is pretty important to us. And if you are reading this blog, then you probably already know what it is. We like to think of it more as a therapeutic and cleansing metabolism. Let’s start with some background on that and then get into the nitty-gritty of this week’s research article.
As stated above, ketosis is a totally different metabolic state. It occurs when your body primarily uses ketone bodies for fuel instead of glucose. This can happen through three main methods: high fat diet, caloric restriction, or low insulin levels. When it occurs as an unwanted result of low insulin levels (usually type 1 diabetes), it is known as diabetic ketoacidosis. This lowers the blood pH to dangerously low levels, and can be fatal. Fatality is rare now-a-days, but it’s still something to watch out for.
Unfortunately, people still equate ketosis and ketoacidosis. They are not the same thing – although similar sounding. One is metabolically healthy, and the other is dangerous. The good news is that keeping away from ketoacidosis is easy when you follow a well-structured ketogenic diet. This induces nutritional ketosis. Again, this might be remedial information for you, but it doesn’t hurt to review, right? Nutritional ketosis arises from either caloric restriction (intermittent fasting) or a high-fat / low-carb diet. These are the styles we promote around here. The three ketone bodies are: acetoacetate, acetone, and betahydroxybutyrate (BHB).
Simple mechanistic overview
[For those of you interested in more of the “sciency” stuff, read this quick overview. If not, then feel free to skip right over it. Eating fat over carbohydrate will lower your insulin and increase your glucagon levels. This indirectly affects the metabolism of acetyl-CoA, which is supposed to go through the citric acid cycle. But when glucose and insulin are low, the first step of the cycle cannot happen right away. There is also a flood of fuel to the mitochondria, so the citric acid cycle gets clogged up. So, it means that the acetyl-CoA you make during the beta-oxidation of fat turns into acetoactyl-CoA. Your body will then turn the acetoactyle-CoA into the ketone bodies. These then go throughout the body to any tissues and cells that need energy. The brain specific loves this source of fuel. The ketone body, beta-hydroxybutyrate, is the ketone body used in respiration later when it’s needed. This is generally how you can fuel your body through ketosis.]
So, why does this different metabolic state bring about longer life? To keep it short and sweet: it is very complex… This single piece of research actually started giving me a headache. Doesn’t that just sound fun? Let’s jump in!
Summary of the article
- There are different shapes of the same class of ketone structures in the body: L- and D- betahydroxybutyrate (BHB). D-BHB is the healthy one.
- The metabolism of D-BHB brings about antioxidant effects.
- A decrease in the insulin and glucose pathways leads to a longer life. This is perhaps due to evolutionary effects: the body has a great desire to survive when food sources are low.
- Your stores of pyruvate dehydrogenase decrease as you age (PDH). PDH is essential for glucose metabolism, so when you rely on glucose at an elderly age, your body is not getting the energy it needs. However, ketone bodies do not need PDH, and they can be taken up for energy easily.
Ketones are awesome
Because caloric restriction brings about a stated of ketosis, the researchers theorized that it is ketosis specifically that causes the long-life affects of fasting. This makes pretty good sense. They observed and found through other research that D-BHB is directly linked to long life spans in bacteria and other animals. Let’s have a look as to why.
To be honest, I am frustrated they’re called “ketones.” They are definitely carboxylic acids (except for the sweet acetone on your breath)… But I think it’s because “ketones” sound less frightening than “acids.” But I digress. The first thing that jumped out while reading this article was that “D-BHB produces more ATP per oxygen molecule consumed than many other respiratory substrates.” Well, that’s pretty neat.
More energy efficient substrate
It appears as though betahydroxybutyrate is more energy efficient than any other fuel source. That would mean you need to go through less respiration to get the same amount of energy. You don’t need to eat as much! The article doesn’t mention this, but maybe that leads to less stress put on the electron transport chain – which then leads to a long life. However, seeing that they don’t mention this mechanism, I am might just be crazy…
Ignoring my side commentary, it is professionally accepted that ketones do, indeed, produce more ATP than anything else. You would think more people would be accepting of a ketogenic diet then. But nope – oh well. This happens because BHB generates a increase in the redox potential between NAD and coenzyme Q couples. This increases the Gibbs free energy change of ATP, making it more powerful. Ketones are “charging” ATP up more, so when it is used (released like a spring) more energy can come from it. Remember, it takes ATP to make ATP, so that’s why it matters.
Other kind of betahydroxybutyrate
But all of this implies there is another kind of BHB: L-BHB. It is not nearly as good as the “D” version. It reduces NAD+ and the coenzyme Q without increasing the redox potential. This means there is not as much power in the ATP molecules made from it. It does not arise out of the same pathway either. It comes into the body by reversal of the beta-oxidation of fatty acids. To be honest, I do not know how this happens or anything beyond that simple point. It is a very interesting topic, however, so I am sure to get to it at some point or another.
Don’t need insulin pathways
What makes ketones especially awesome? Our body can fuel almost everything with ketone bodies. The cells that can’t (like red blood cells and liver cells) get fuel from glucose made naturally in your body. And then that gets recycled via gluconeogenesis. All parts of your body are consistently fueled without dietary carbohydrate.
That means we do not need to worry about insulin. Insulin is released when you eat carbs, and it can have some adverse affects if you over-do it. If you are interested we also wrote about all the problems associated with hyperinsulinemia in this blog post. Also, this article mentions the life-shortening effects of the insulin receptor pathway. Eating glucose and stimulating the hormonal cascade is correlated with shorter lives. They go through the mechanism for different species, but that is where I started to get a headache. It is very complex, but you can check it out in the figure below if you dare.
Anyway, they suggest this might be due to evolution. The body is not as worried about living when there is plenty of food (glucose) around. However, it kicks itself into high gear when it senses a shortage. From their point of view, the body becomes more efficient with its resources when there aren’t as many around. I actually think this makes pretty good sense. Reduced insulin signaling also plays an important role in how autophagy helps you. This is another way ketosis is linked to longer life spans. Autophagy is the process of cells cleansing themselves, and it leads to better health.
BHB’s antioxidant effects
Oxidizing agents are a pretty hot topic. Don’t bring up free radicals or the entire room might burst up in response. In all seriousness, reactive oxygen species (ROS) and free radical species are not good for you in large amounts. ROS decrease life span. They do play important roles in plenty of physiological processes, but their hazardous nature is unquestionable in large amounts. In order to make these free radical less harmful, our body needs a way to reduce them. It has to give them an electron to pair up with, otherwise the free radical will go steal one from something that is very important (like DNA or your membranes).
D-BHB plays a pretty important role here. The article suggests pathways for their ability to reduce the radicals. This is another proposal for why ketone bodies extend life span. Here is a quick over view of how this happens. (Please refer to the headache-giving figure below if you want more detail.) D-BHB goes through some metabolism, and it results in the reduction of NADP+ into NADPH. Longevity is directly correlated to having more NADPH available. The electrons given to the NADPHs go through some other processing, but they eventually get dropped of on the radical species (on the right side – in red).
The betahydroxybutyrate drops the [NADP+]/[NADPH] ratio through the first part of the mechanism above. This also increases the NAP+ / NADPH cytosolic potential energy (-0.42 V). These are all very good things to maintain your cell’s efficiency. That might have been too much of an overview to really understand what was going on. But the takeaway is that D-BHB has excellent antioxidant effects that contribute to the lowering of radical damage. This then leads directly to a longer life. Again, aren’t ketones awesome?
Other mechanisms for longevity
With aging, you start to lose your stores of pyruvate dehydrogenase (PDH). Pyruvate is a substance involved in the metabolism of glucose, and PHD is the substance that breaks it down, so we can eventually get ATP out of it. So without PDH, you ain’t gettin’ no ATP from carbohydrate consumption… That is another one of the reasons we start to deteriorate. We just aren’t getting the same levels of energy production as we used to. But if you go through ketone metabolism, you don’t need PDH to get energy! It is almost too perfect. Yet another reason ketones are awesome and help us live longer. You can see this in the figure below.
Another way ketosis promotes longer lives is through lengthening our telomeres. Telomeres hold the ends of the chromosome together, which plays a very important role in cell reproduction. Longer telomeres are correlated with longer life spans. When they are shorter, there is a limit to the number of times a cell can reproduce. They do this mainly by reducing the amount of ROS damage our DNA sees. It doesn’t directly affect our telomeres, but it does reduce the radical species so they can’t shorten them. I do not understand this mechanism as well, so I don’t give it much time. But the main takeaway from this point of the article is that D-BHB is related to longer telomeres, which is related to longer lives.
Phew! If you seriously just made it through all of that, I am impressed! I don’t even want to admit how long it took me to understand this article. But I am so glad I worked through it. It allowed me to understand it well enough to write about the general conclusions. I hope you gained some knowledge from reading this. At least you can direct your skeptical friends or family this way if they don’t trust ketosis! I really want the world to see this is not a metabolism to be feared. It is a therapeutic metabolism to be embraced!
It saves people from so many problems, so we need to fight fake science with real science. Let’s get our armory of research built up so we can fight the nay-sayers! Of course, so much more research needs to be done on ketosis. There is relatively little out there. I suspect that is because it’s hard to get funding for a diet that can solve all the world’s problems… That’s my conspiratorial side coming out. It is not a new kind of diet or metabolism by any means – but it is new to the world of scientific investigation (beyond epilepsy that is). Spread the word, and keep on ketoing on!
 Veech RL, Bradshaw PC, Clarke K, Curtis W, Pawlosky R, King MT. (2017). Ketone Bodies Mimic the Life Span Extending Properties of Caloric Restriction. International Union of Biochemistry and Molecular Biology: Life 69(5): 305-314.
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