0:00:04 – 0:00:45
VO Victoria
Welcome to Beyond Lab Walls, a podcast from the Salk Institute, a nonprofit foundational research institute bound by collaboration and curiosity where scientists come together to ask what if. The Salk Institute stands as a landmark monument to science overlooking the Pacific Ocean. Within the iconic Louis Kahn-designed architecture, scientists tackle global questions in aging, agriculture, disease, nutrition, sleep, memory, and so much more. Here at Salk, we’re unlocking the secrets of life itself and sharing them beyond lab walls.
0:00:45 – 0:03:19
Gerald
Hello everyone and welcome to this special episode of Beyond Lab Walls, a Salk podcast series. I’m Salk President Gerald Joyce, and this is actually one of a set of special podcasts within the broader series having to do with Salk’s Year of Brain Health. We’ve declared 2026 the year of cognitive brain health. And throughout this year, we’ve been speaking with various experts, scientists here at the Salk Institute and beyond about what is brain health and and how to maximize our brain health through our lifetime. And you know, we live a long time. We’re very fortunate to live in a in a time when the average life expectancy in the US is more than 78 years, thanks to good medicine and a safe environment and a more or less healthy diet. We live a long time. But what’s of course important to us is that we live a long time in a healthy state and and nothing seems more important than than our own brain health. You know, that’s us in in there. And so that’s what this series is about, is what what can we do over the course of our life to maintain good cognitive strength, good cognitive health. So we’ve had a series of conversations, another one today, on the different aspects that feed into cognitive brain health and in particular what we can do. So for example, we’ve talked about immune health. We’ve talked about the importance of good sleep. We talked about exercise. Today we’re going to talk about metabolic health. We’re going to talk about socialization and interaction and and mental stimulation. We’re even going to talk about gum disease. All these things that you can do to maintain cognitive brain health through a long lifespan. So today, as I say, we’re going to focus on metabolic health. And my guest today is Salk scientist Christian Metallo, a renowned expert on metabolism, the way in which the various nutrients that we take in fuel ourselves, fuel our brain, and so we’re going to get into that but specifically focus on the relationship between metabolism and the cognitive health of our brain. So you know this phrase, metabolic health. You hear it all the time and I think you know most commonly people think weight control and glucose levels and cholesterol, but can you give us more of a a feeling for, as a scientist and and a metabolic engineer – I’ve heard you call yourself that before – a bioengineer who thinks about metabolism. What is metabolic health? What does it really entail?
0:03:19 – 0:03:58.
Christian
So the best way to start is with the definition of metabolism. This to me is the set of biochemical reactions that are occurring in our cells, in our tissues throughout our body. This also encompasses physiology and it basically drives how nutrients get from the food we eat to the different tissues, as a chemical engineer, which I am by training. Okay, we apply the same tools that you use to study how a chemical process plant works to the human body to understand that physiology. And of course the brain is one of the most nutrient hungry tissues in the whole body.
0:03:58 – 0:04:08
Gerald
So understand. But we’re human bodies you know biological organisms but especially humans are so much more complicated than machines. I mean can we really think about it in just just engineering mechanical terms?
0:04:08 – 0:04:30
Christian
Well we’re not building it up. This is why it’s a beautiful thing. We’re using the tools to break things down into smaller parts and understand it because in order to do that and to design a chemical process plant that won’t explode on you, you really need to use these refined techniques to quantify things properly and quantify those chemical interconversions which are metabolism.
0:04:30 – 0:04:42
Gerald
Yeah. Now, you’ve already touched on the point that the brain is such an important consumer of of fuel and you hear this phrase that it’s an energy hungry organ. Now what does that actually mean in metabolic terms?
0:04:42 – 0:04:53
Christian
So it consumes a lot of nutrients. If we track how glucose is metabolized throughout the body, the brain uses more glucose than almost any other tissue. It requires a lot of energy.
0:04:53 – 0:04:58
Gerald
So the brain uses more glucose than muscles even though muscles are much larger part of our body.
0:04:58 – 0:05:05
Christian
It’s hard to say one is more than the other, but they are the two most nutrient heavy requirement tissues.
0:05:05 – 0:05:21
Gerald
Okay. I guess pound-for-pound the brain uses the most, right? Because it’s really cranking away all the time. At least at least we hope it is. But as we age, what goes wrong? It seems like something goes wrong in the way we
0:05:21 – 0:05:38
Christian
So function as such a nutrient hungry tissue, you need flexibility. It’s not just one nutrient, but as you go into a fed and fasted state and those circadian cycles that we experience, the flexibility in switching to ketone bodies versus glucose is…
0:05:38 – 0:05:53
Gerald
I got to stop you there. And we’ve talked about this in another podcast, but explain. So I think when people think of the fuel, the one they think of first is glucose, right? Because everything sort of transacts through glucose. But you talked about something else called ketone bodies. Ketone bodies. So, what are ketone bodies?
0:05:53 – 0:06:05
Christian
Ketone bodies are what the body uses to fuel the heart and the brain when we’re in the fasted state. Since we’re not constantly eating, since most of us aren’t constantly downing sugar, and.
0:06:05 – 0:06:07
Gerald
Hopefully we’re not.
0:06:07 – 0:06:20
Christian
Some of us do. When you’re fasting, your body has to switch and that is the process by which fat is converted to these ketone bodies which are particularly important nutrients for the heart and the brain.
0:06:20 – 0:06:31
Gerald
When they say ketone body, they don’t mean our body. They mean that’s just the name of the molecule. It’s a a bunch of different molecules. Just like when we say glucose, we really mean different sugars.
0:06:31 – 0:06:33
Christian
Dihydroxybutyrate and…
0:06:36 – 0:06:50
Gerald
But so the brain can use either sugars like glucose or ketones like this this set of ketone bodies depending on whether it’s in a fasting state or recently fed state. But it needs fuel and it it never doesn’t need fuel, right?
0:06:50 – 0:06:51
Christian
Absolutely.
0:06:51 – 0:06:52
Gerald
Even when we’re asleep, it still burns.
0:06:52 – 0:07:22
Christian
So it’s that switching process which I think often goes awry during aging because this is the human body, it’s a beautifully designed machine, designed by evolution, that has this exquisite flexibility and can sense different nutritional environments and change the way it fuels. But it’s that changing of the guard, changing of those processes, which often goes awry in metabolic disease and in the aging process.
0:07:22 – 0:07:32
Gerald
So that ability to kind of switch hit on the fuel, that’s good. That protects the brain, let’s it keep thriving. But you’re saying that the switch off gets worse and worse over as we.
0:07:32 – 0:07:44
Christian
It’s essentially what diabetes is, where you become insulin resistant. The ability to control how much glucose you use through insulin sensitivity or insulin resistance deteriorated.
0:07:44 – 0:08:17
Gerald
So there’s obviously very strong signals of a relationship between Alzheimer’s and related dementias and metabolism. Right. So if people have poor, as you just said, if people have poor glucose control, bad hemoglobin, A1C, especially over the years, or people have bad cholesterol levels and hyperlipidemia, as it’s called, there’s clear correlation between those things going wrong and the risk of Alzheimer’s disease. Now why is that? Why do those things connect to Alzheimer’s disease?
0:08:17 – 0:09:22
Christian
So the brain and the spinal cord and the central nervous system, they’re somewhat segregated from the rest of our body, but they they’re also interconnected with the peripheral tissues like the liver, muscle, heart because they require constant oxygen transport and nutrient transport. And those metabolic signals that we often see that are starting to go awry, the metabolic deterioration that we experience with age or with diabetes or other chronic diseases that ultimately will feed back and compromise some of the nutrient sources that the brain relies on. So you’ll start to see this compromised metabolic state in our peripheral tissues can actually actually transfer to the brain function. And at night, the brain also has to transfer waste products out to the rest of the body that can be cleared as well. So these systems are intertwined and that’s kind of the essence of studying these systems as an engineer, taking a systems approach and looking at not just one tissue in isolation but the whole sum of its parts working together.
0:09:22 – 0:09:40
Gerald
Well, let’s talk a bit more about about sugar though. So if someone’s pre- diabetic or type two diabetes, why is the high sugar levels and the low insulin sensitivity, why does that connect to losing cognitive capacity?
0:09:40 – 0:09:56
Christian
Well, there’s a number of reasons. Glucose is an important nutrient for the brain, but it’s also used to line some of the myelin sheets when the glucose is metabolized, sort of insulating the wires of the brain when it’s converted into certain glycolipid structures.
0:09:56 – 0:10:02
Gerald
But if you have diabetes, you have more glucose. Isn’t that good? Because you have high sugar.
0:10:02 – 0:10:12
Christian
So that’s it as well. You can’t use it as efficiently. And that’s where it comes into measuring flux and tracing how molecules are used as opposed to just not how much are they.
0:10:12 – 0:10:24
Gerald
Yeah. I see. So because over many years people have too high glucose level, they sort of become maladaptive in the way they can even take in glucose, right? And that’s the lack of insulin sensitivity.
0:10:24 – 0:10:33
Christian
But some of our research is trying to question as to whether hypoglycemia and high glucose is the cause of all these diabetes associated maladies, right?
0:10:33 – 0:10:47
Gerald
Yeah. A lot of this stuff goes together what’s called the metabolic syndrome as as you know, right? So but type 1 diabetes patients, right? Are they also at risk for Alzheimer’s disease or is this really more a type two diabetes risk?
0:10:47 – 0:10:52
Christian
I haven’t seen definitive evidence on whether or not type 1 diabetics have.
0:10:52 – 0:11:25
Gerald
Because type 1 diabetes isn’t part of the so-called metabolic syndrome, as we know is lots of things, right? It’s it’s high cholesterol and it’s high fasting glucose and it’s weight, overweight, especially abdominal obesity. It’s it’s all these things together, right? So it’s more a metabolic disease than an autoimmune type disease, which is what type 1 diabetes is. Okay. And then why is high cholesterol and what’s called hyperlipidemia, why is that bad for the brain?
0:11:25 – 0:11:35
Christian
Well, we’re still trying to understand exactly what dysregulation occurs. The brain actually tends to make most of its own cholesterol, whereas the liver makes cholesterol for the rest of the body.
0:11:35 – 0:11:37
Gerald
The brain makes its own cholesterol.
0:11:37 – 0:11:38
Christian
Absolutely.
0:11:38 – 0:11:44
Gerald
No matter what your cholesterol level is in the periphery, the brain just does its own thing or is it somehow connected?
0:11:44 – 0:11:54
Christian
I wouldn’t say they’re completely disconnected and there’s definitely an outflow, but the brain uniquely synthesizes cholesterol on-site where the liver does it for the rest of…
0:11:54 – 0:12:12
Gerald
I bet people didn’t know that. So, and and obviously another bad thing about having high cholesterol and hyperlipidemia is atherosclerosis, right? Then people get atherosclerosis, which is bad for cardiovascular blood flow to the brain and the brain really needs blood flow because the blood flow brings the nutrients.
0:12:12 – 0:12:23
Christian
It starts from there, getting those nutrients to where they need to be from the periphery to those sites of tissues where they can oxygenate and provide amino acids and glucose and other nutrients.
0:12:23 – 0:12:48
Gerald
So let’s talk more about that. Let’s play follow the nutrient, right? So this, as a metabolic engineer and metabolism scientist, what are the most important nutrients to track as they come in food, they get to your your digestive system, they get to your bloodstream, they get to your brain. From the point of view of cognitive brain health, what are the most important nutrients?
0:12:48 – 0:13:21
Christian
I got to punt on that answer a little bit because that answer is different for every single person because of the redundancies that we have in the system. We all tend to age differently and that’s one of the things we’re trying to answer in the lab when you have a different genetic background or a different disease state. Does that mean one nutrient or the other becomes compromised? And part of how we do that is by tracing molecules, as you were alluding to before, where we’ll take isotopes and label specific nutrients with those isotopes and feed them to cells, feed them to people.
0:13:21 – 0:13:23
Gerald
You you make radioactive nutrients.
0:13:23 – 0:13:27
Christian
These aren’t radioactive. They’re stable. They’re stable isotopes.
0:13:27 – 0:13:28
Gerald
Okay. Maybe people.
0:13:28 – 0:13:32
Christian
It’s just carbon 13. So 1% of your body, Jerry, is carbon 13.
0:13:32 – 0:13:33
Gerald
Okay. 1%.
0:13:33 – 0:13:41
Christian
And I know I’m not radioactive because I can pass through a detector. So you can eat these. They’re fairly safe.
0:13:41 – 0:13:48
Gerald
And so you just track the. you So it would be a food that would have a little extra carbon 13 so you can follow it. Is that that’s the kind of stuff you do?
0:13:48 – 0:14:18
Christian
Exactly. So it puts a little label on it. It’s almost like a game of like catch because we administer the nutrients either to a person or to a cell. And then we use an array of instruments in my laboratory to figure out where those nutrients go, what tissues, how they’re metabolized. And most importantly of all, how fast they’re converted to different biochemicals. And that tells us the why as to why is this important, where are they going, and what is becoming limiting in a certain situation.
0:14:18 – 0:14:21
Gerald
So what are your favorite things to track?
0:14:21 – 0:14:31
Christian
So, right now my lab is particularly focused on understanding the role of serine and the amino acid metabolism and how it’s contributed to sphingolipids. Okay.
0:14:31 – 0:14:40
Gerald
Okay. Let’s take those a step. So, serine is, serine is one of the amino acids, it’s an essential amino acid.
0:14:40 – 0:14:41
Christian
It’s a non-essential amino acid.
0:14:41 – 0:14:42
Gerald
It’s a non-essential.
0:14:42 – 0:14:44
Christian
We make it ourselves.
0:14:44 – 0:14:49
Gerald
It’s essential that we somehow have it but we can either take it as in our diet or
0:14:49 – 0:14:57
Christian
Or we can make it. It’s that important that we have figured out how to make it and our brain actually makes it from glucose and other amino acids.
0:14:57 – 0:15:12
Gerald
So the phrase essential amino acid means the amino acids you have to get in your diet. Is that right? The rest of the the 20 that we need to have our metabolism, the rest we can make and sometimes it’s a combination. Eat, eat or make. Okay.
0:15:12 – 0:15:36
Christian
But my opinion is actually flipped around, has become flipped around over the years that we think of essential amino acids as the most important ones, but they’re all around. We have all this muscle and protein around that can be broken down and recycled, right? The non-essential amino acids can ultimately become more important because the ones like serine are not only used to make protein, but they’re also used to make lipids and nucleic acids.
0:15:36 – 0:15:42
Gerald
What’s this other word you use? Sphingolipids. So serine turns into sphingolipids or helps make sphingolipids.
0:15:42 – 0:15:51
Christian
Sphingolipids are unique. They’re I think a little bit more biologically active lipids than other fats. And sphingolipids are made from serine and fats.
0:15:51 – 0:15:53
Gerald
What does sphingo mean?
0:15:53 – 0:16:00
Christian
It’s just a I think the name on Wikipedia kind of highlights they were named that because they’re enigmatic like the sphinx.
0:16:00 – 0:16:02
Gerald
Oh, that’s okay.
0:16:02 – 0:16:08
Christian
My wife my wife made a whole t-shirt that says I never joke about sphingolipids. Because she likes hearing me say it.
0:16:08 – 0:16:16
Gerald
Okay. All right. So, but but well, very good. So, you study this this sphinx-like lipid, but but what what does it actually do?
0:16:16 – 0:16:37
Christian
So, for brain health, they’re the biologically active lipids. They’re the most abundant species that are present in our myelin, sphing myelin insulating the wires of our, insulate the wires of our nerves. And they’re also enriched in a lot of the specialized cells in our bodies, stem cells, immune cells to to keep them functioning.
0:16:37 – 0:16:41
Gerald
Okay. And so sometimes this goes haywire that we don’t make.
0:16:41 – 0:16:52
Christian
Absolutely. And we have information from genetic diseases that cause neurodegeneration or neurodevelopmental defects that pinpoint certain sphingolipid enzymes.
0:16:52 – 0:16:52
Gerald
Yeah.
0:16:52 – 0:17:07
Christian
As causative factors for some of those rare diseases. And what we’re trying to do in the lab is understand how that flux or that flow of sphingolipids in the body changes in patients that are experiencing neurodegeneration.
0:17:07 – 0:17:25
Gerald
Okay. So all right. So serine, which we could make as well as take it in our diet helps us make sphingolipids and the sphingolipids help protect our neurons, our cognitive brain health. So should we be eating lots of serine or should we just rely on what we make or what can we do to make sure that pathway is cranking?
0:17:25 – 0:17:51
Christian
We are investigating questions along that line. How can you improve some disease outcomes by taking more serine? The problem is like any supplemental nutrient like that, you can take more of it in and a lot of it goes right out. So we’re trying to understand and track the biochemistry of serine homeostasis and how much it contributes to lipid pools versus protein pools or other nutrients.
0:17:51 – 0:17:53
Gerald
But in a normal diet, we get enough.
0:17:53 – 0:18:04
Christian
We typically carry enough. But there’s some rare diseases or some evidence that certain tissues may become limiting for serine as we age or certain …
0:18:04 – 0:18:09
Gerald
And then a serine supplement might be helpful or some way to mimic the good effect of serine
0:18:09 – 0:18:13
Christian
Potentially. So what we’re trying to do now is understand which patients might need that.
0:18:13 – 0:18:48
Gerald
Okay. Now I’m I’m putting you on the spot here because what I’m not asking is for medical advice, okay? You’re not a physician but even if you were, we’re not here to give medical advice. But you are one of the world’s experts on metabolism and its relationship to brain health. So are there any recommendations you would like to give on what we should be doing in our diet, whether it’s the diet itself or supplements, or whatever, to support not just the serine, the sphingolipid to brain health but to support brain health. Do you have do you have some metabolic recommendations?
0:18:48 – 0:19:14
Christian
The most honest and probably likely correct answer to that question is everything in moderation. Everything in moderation. Extreme things is where we sometimes apply extreme diets to cause disease as opposed to cure disease and knowing which one to do is not something that we can apply to the whole general public. So this is part of the research that we’re trying to do, to understand who might benefit from certain supplements and who might do worse on certain supplements.
0:19:14 – 0:19:22
Gerald
Okay. So it’s individually talk to your doctor, not to the person at the nutrition store. So not the scientist in the lab.
0:19:22 – 0:19:22
Christian
Yeah.
0:19:22 – 0:19:29
Gerald
And so, but that’s just the food part of it. So, I mean, what other things should we be doing to have a healthy metabolism for for brain health?
0:19:29 – 0:19:51
Christian
The usual suspects, exercise, maintain healthy body weight, support your mental health, exercise, keep blood flow. It it allows you to keep all systems operational, systems because there’s no perfect – I mean, we get infected. We need certain biological processes to be activated or in degenerative.
0:19:51 – 0:20:12
Gerald
I mean, if there’s a general lesson from the series of podcasts, it is a kind of all the above. We should be doing all these good things because individually they help for brain health, but they interact with each other, right? Is there something that we can be tracking to know we’re in good metabolic health? Either some molecule or some thing to measure?
0:20:12 – 0:20:20
Christian
I’d like to think that monitoring amino acid and serine metabolism might become more important in the next decade.
0:20:20 – 0:20:20
Gerald
So that’s not done now.
0:20:21 – 0:20:28
Christian
Not typically. I think though you can get amino acid measurements I think increasingly through lab core and and and other places.
0:20:28 – 0:20:41
Gerald
But when your doctor does the the standard metabolic panel, so-called metabolic panel, right? There’s none of that’s in there. It’s liver enzymes to know that your liver is cranking. It’s to be sure that your kidneys not.
0:20:41 – 0:20:46
Christian
There is a new ceramide assay for heart health that that is available.
0:20:46 – 0:20:53
Gerald
Probably not approved for reimbursement. So, I don’t know. It depends on your insurance.
0:20:53 – 0:20:54
Christian
I try to avoid the insurance.
0:20:54 – 0:21:03
Gerald
I certainly want to get you talking about medical insurance, but so this is something maybe is coming but not really there yet that there will be more metabolic things to track.
0:21:03 – 0:21:23
Christian
Absolutely. And I think what’s also more important is to just monitor the traditional health metrics and if you see a change a rapid onset or a change in weight up, good or bad, up or down, those are some of the triggers that people should look out for to say, hey let me go to my doctor and and see what’s up.
0:21:23 – 0:21:42
Gerald
Okay. Okay. So let’s let’s just end by asking, I want to ask you about your own research. So you talked about serine and sphingolipids and I know you’re engaged in many other aspects of studying metabolism. Over the next 5 to 10 year, what are you after? What’s the next big…
0:21:42 – 0:22:15
Christian
So one of the things I’d like to do is is really map how these sphingolipid pathways are operating in all the tissues of our body, and particularly in chronic disease states so we can understand how their dysregulation drives the deterioration of physiological processes. And some of the inroads we’re getting into now link serine availability and single lipid biosynthesis to learning and cognitive function.
0:22:15 – 0:22:33
Gerald
So this tightens the connection between metabolic factors the way they traffic through us and ultimately how they affect our brain health. So the idea is to look at subjects that over lifespan, but also over health span with regard to cognitive health are doing better or worse. Is that the idea?
0:22:33 – 0:22:33
Christian
Absolutely.
0:22:33 – 0:22:40
Gerald
And then correlate that with what’s up or down metabolically and in terms of the molecules of the metabolism.
0:22:40 – 0:22:52
Christian
Absolutely. Looking at it at the molecular level so we can say not just what correlates with things but actually what biochemically makes sense. Where are these nutrients coming from? Where is the serine coming from? Where is it going?
0:22:52 – 0:22:52
Gerald
Yeah. Very good.
0:22:52 – 0:22:55
Christian
And how can we stop those processes?
0:22:55 – 0:23:32
Gerald
We look forward to following what comes next because it’s so, this word metabolism is so broad, but to really figure out what the heck’s going on, not just at this moment, but through our lifespan and to protect our cognitive health. We’ve got to actually, as you just said, we’ve got to know, what are the molecules actually doing, right? Christian, thank you. I think that was very informative, folks. And although there’s not one particular recipe of what we should be eating or monitoring, staying metabolically healthy is clearly part of the bullseye of of of cognitive brain health.
0:23:32 – 0:23:32
Christian
Yep.
0:23:32 – 0:24:48
Gerald
So this is this is how we think about things at Salk, right. We hear these this good guidance, right, Protect your metabolism, get lots of exercise, good sleep cycle, don’t eat too many fatty foods, don’t eat too much high sugar foods. But at Salk, what we try to do is figure out the why behind these, like you just heard today, to understand the mechanism behind each of these sort of do good statements. Because if we can understand the mechanism, then we know the bullseye of what the do good is right then. It’s not a sort of generic platitude. It’s a more specific thing. And of course if we know the mechanism, that’s an opportunity for what could be a drug target for those that are now suffering early cognitive decline to to really get at what is going wrong in a molecular sense. Very glad to have Christian Metallo with us here today and make that connection between metabolic health and cognitive brain health. Stay tuned for for for more in this series. We’ve already had several. There’s many more to come because there’s so many parts of our our body that then interact and affect our cognitive brain health. If you’d like to know more, please go to salk.edu/brain-health. And thank you all for listening.
0:24:48 – 0:25:20
Victoria
Beyond Lab Walls is a production of the Salk Office of Communications. Subscribe to this podcast to hear more exciting Salk science stories. Our monthly newsletter and seasonal magazine, Inside Salk, can also bring the lab to you, spotlighting our staff and scientists and the discoveries that are only possible at Salk. Visit salk.edu to learn more about the world within these walls.