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Ben Bikman: Understanding Metabolism For Better Brain Health

By Nicholas Chan | February 3rd, 2022

Biologist Benjamin Bikman shares insights into the link between metabolic health, aging and neurodegeneration.

Glucose is one of the brain’s main sources of fuel, providing energy for our body’s cells. But the brain’s ability to metabolize glucose becomes impaired in Alzheimer’s. In fact, scientists know that one of the earliest signs of the disease is characterized by decreased consumption of glucose in the brain. Accordingly, researchers are studying whether addressing the “starving brain,” one that is need of energy, can slow Alzheimer’s progression or delay the onset of its symptoms, including through interventions like dietary changes. 

Being Patient spoke with Benjamin Bikman, professor of cell biology and physiology at Brigham Young University, about the complex processes of our metabolism, and how metabolic health plays a role in neurodegenerative diseases like Alzheimer’s.

Being Patient: In basic terms, a key source of the brain’s fuel comes from glucose within our body, is that correct?

Benjamin Bikman: Yeah, in fact, I would even preface that just by emphasizing the brain’s remarkable metabolic rate. It is in the top three of this trinity of high metabolic rate organs. Even when we’re asleep, its metabolic demands are still remarkably high. So it has a very high energetic need. That is actually helping us identify problems that we’d never really seen before, specifically with neurological disorders, not just Alzheimer’s disease, but numerous neurological disorders that appear to have a common core of a metabolic deficiency. 

Glucose is one of the two fuels that the brain primarily relies on. Unfortunately, we live in a culture and a society where the way we eat and live demands that the brain only use glucose, and that’s the energy source the brain is increasingly having a hard time using for various metabolic reasons. 

Being Patient: Our body breaks down carbohydrates and carbohydrates lead to glucose production. Is that right?

Benjamin Bikman: Yeah. Glucose is a fuel that can be used by every single cell of the body. Thankfully, it’s something we get readily in the diet, but even more thankfully, we make all that we need. Any carbohydrate that’s coming in the mouth can turn into glucose in the blood. That’s what we eat plenty of, perhaps too much. 

But even in the absence of eating any, the liver is the great giver when it comes to nutrients in the body. If it senses that blood glucose levels are starting to drop, it will simply start making glucose and sharing it with the body. The liver is capable of making up for any absence of carbohydrate in the diet. That’s why someone could go on a multi-day fast, not [eat] any carbohydrate, and yet their glucose levels stay totally normal. That’s because the liver is able to make literally all that we need.

Being Patient: What happens with our body’s ability to process glucose as we age?

Benjamin Bikman: Our ability to use glucose is compromised. While our ability to put glucose into the blood is as good as it ever was, our ability to move it out of the blood is what’s affected. Paradoxically, we have an increase in blood glucose, and yet an increasing inability to utilize it. It is that inability to move glucose from the blood into the cells where it would be used for energy that really appears to be the foundational issue in many neurological problems, even Alzheimer’s disease.

Being Patient: So problems can arise when our brain is not getting enough fuel.

Benjamin Bikman: Yes. The hippocampus is the little pocket of the brain that’s most relevant to memory and learning. Much of the glucose that’s coming into the brain to be burned for energy requires the humble hormone insulin.

Insulin’s most famous effect — not that I’m saying it’s the most important because insulin does a lot of very important things — is what it does to glucose. Insulin will essentially come and knock on a door, including the neurons in the brain, and it will open those doors and allow the glucose to come from the blood, into the cell, providing the cell with fuel. As the brain starts to become insulin resistant, now you have insulin politely knocking on the door, maybe even pounding on the door of the cell, but the cell won’t open up and allow the glucose in.

You have this demented version of The Rime of the Ancient Mariner where it’s not water everywhere, but glucose everywhere and not a drop to drink. That’s the cry of the brain where blood glucose levels may be twice as high as they should be, and yet, the brain can’t get it because insulin isn’t working well enough. That’s where the inefficiency comes in. As the brain starts to become increasingly insulin resistant, now you start to have this energetic gap. Because glucose is the only fuel available to it at the moment, although there’s another fuel, there’s this gap. 

That gap is what starts to create not only the memory learning deficits, like you see in Alzheimer’s disease, but even the reduced dopamine production that you see with Parkinson’s disease, or the seizures that you see with epilepsy, and even migraine headaches. All of these, despite being on their surface distinct disorders, share what’s called brain glucose hypometabolism, a brain that is burning less glucose than normal, [which is] known and confirmed. 

Being Patient: Ketones are an alternative source of fuel for our brain. Are they as efficient of a fuel as glucose?

Benjamin Bikman: The best available evidence suggests they’re more efficient. You literally create more chemical energy when the brain is burning a ketone than it does burning glucose. We say that ketones are an alternate fuel, but the reality might be that it’s the primary fuel. 

Case in point: If we start to increase ketones in the blood of a person, even though ketone [levels] are much lower than glucose, maybe it’s only a quarter as much in the blood, even still, the brain immediately starts relying on ketones. As ketone [levels] go higher and higher and higher, the brain continues to rely on the ketones more and more as its fuel. 

My lab [was] able to get tissue from donors and study the difference in gene expression between those genes that are involved in glucose-burning versus ketone-burning in people who had died with Alzheimer’s disease and with no Alzheimer’s disease. It was the glucose-burning genes that were compromised, not the ketone-burning genes. That is so powerful because if a person has an energetic gap, well then let the brain eat ketones and ketones can more than fill that energetic gap and improve cognitive performance.

Being Patient: How is your lab expanding on those findings?

Benjamin Bikman: We’ve moved into rodent models, which provide very interesting comparisons for humans. Certainly, metabolically it’s a valid comparison. We’re finding that ketones are increasing energy production or rather maintaining high energy production in older animals. It’s increasing their curiosity and their exploratory behaviors. They want to be learning and exploring. 

The ketones are providing a literal increase in energy production in the hippocampus, and that is translating into observable changes in behavior. The animals are moving more. They’re exploring more and appearing to remember more.

Being Patient: The ketogenic diet aims to get the body to burn ketones. But can we use supplements for ketones, and if so, do ketone supplements have the same impact?

Benjamin Bikman: We can supplement ketones and I can state that authoritatively, because there are in fact, human studies that have been published that prove this. You take people with Alzheimer’s disease, You give them cognitive tests. You give them a ketone supplement to dramatically increase their ketone levels in their blood. You have them perform those same cognitive tests and they perform better. 

How you describe the ketogenic diet is accurate. I would simply add another layer to it. You describe the ketogenic diet as a ketone-burning diet. But you have to take the first step, which is that it’s ketone-making. 

It all boils down to insulin, and that allows me to address the other part of your question: Are exogenous or supplemental ketones the same as making your own ketones? The ketone is the same. That molecule is the same, but so much of the benefit of a ketogenic diet isn’t necessarily the ketones, although in this context, they’re very relevant because [they’re] providing the brain with fuel. But the primary benefit is lowering the insulin and improving insulin sensitivity. Remember, the root of the neurological fall is that the brain starts to become insulin resistant.

The power of a ketogenic diet, not that I ever intend to advocate, Alzheimer’s disease is probably one of the situations that would benefit the most from an explicitly ketogenic diet, one that is keeping the insulin so low, due to very low carbohydrate consumption and fasting that you’re not only improving insulin sensitivity in the body, including in the brain, allowing it to use glucose better, but you’re also making ketones. 

Ketones are simply products of fat-burning. When the body is burning fat at a very high rate, which it does when insulin is low, it’s essentially burning more fat when it needs to use for energy and it starts turning some of that burning fat into ketones. Ketones are a viable fuel in their own right, especially for the brain. 

One to one, a ketogenic diet, not that I mean to advocate it, but I will certainly defend it, will have a greater metabolic benefit even to the brain than just supplemental or exogenous ketones, as beneficial as they are. 

For people who are unwilling or unable for whatever reason to adopt a ketogenic diet, which admittedly could be difficult [for] someone with Alzheimer’s disease, knowing that you can rely on an exogenous ketone, despite the considerable expense associated with them, is nevertheless an encouraging note.

Being Patient: Is there any evidence in humans of whether interventions that addresses ketone levels can slow down the progression of Alzheimer’s?

Benjamin Bikman: There is no evidence in clinical studies that have used very tightly controlled dietary interventions. However, there are case reports that have been published showing that in early-stage cognitive decline, you can in fact, reverse it. 

There was a series of studies published by the scientist Dale Bredesen. Again, they’re not clinically controlled studies. They’re case reports, which is just to say you notice what’s happening in the patients. But he’s very explicit in noting the cognitive improvements, emphasis on improvements, not just the slowing the decay or even stopping it but actually reversing it, by encouraging the increase of ketones through fasting and low carbohydrate diets, as well as consumption of medium-chain triglycerides in the diet, like coconut oil. 

Coconut oil is enriched with a type of fat that is burned at a much much higher rate than normal fats like from meat or dairy or vegetable oils. These are burned at much higher rates and are thus more capable of increasing ketones in the blood quite fairly rapidly.

Being Patient: We’ve talked about the ketogenic diet, but more broadly, what do you think we should be eating, and what food should we avoid?

Benjamin Bikman: I believe that there are three rules: control carbohydrates, prioritize protein – good, quality protein, which is always going to be animal and it’s uncomfortable to say nowadays, but it is better than plant proteins – and then lastly, don’t be afraid of fat.

Back to the first one, because sugar falls into the control carbohydrates category. I have three kids, so I feel the pain here. I try to not present any food as illegal or off-limits. I have tried to have just very casual conversations where I say, ‘You want a little pack of gummies? Have you had any protein lately?’ We also don’t keep junk food around the house. It’s very, very uncommon. 

All my kids like different things. I swear each of them like something different just so that they can say they don’t like what any of the others like. So whatever it may be, I will just say, ‘Can you get some protein?’ These proteins always come with fat, and I want my kids, my wife and I to always be eating real natural fats that always come with proteins. Don’t be afraid of fat, but let the fat come with the protein the way nature intended it. 

The interview has been edited for length and clarity.

Contact Nicholas Chan at nicholas@beingpatient.com

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