Author: Shelley Schlender

Low Carb Diets and Longevity – Ron Rosedale, MD – Extended Version  Dr. Ron Rosedale, MD, gives a “second opinion” about a widely publicized report in the prominent medical journal The Lancet.  The Lancet report contends that low carb diets (40% carbs or less) shorten lifespan, and moderate carb diets (roughly 55% carbs) promote longer lifespans. The study is being hailed as proof for why people should “eat carbs in moderation.” But what if the Lancet study didn’t go low enough on carbs to reveal potential benefits of a VERY low carb diet?  Dr. Rosedale advocates a very low carb, adequate protein, high fat diet, meaning roughly 15% of calories from carbohydrates, 15% from protein and 70% from fat.  – Producer – Shelley Schlender

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TRANSCRIPT

Shelley – Ron Rosedale what is it about your background that means that you can be somebody who speaks to the idea of low carb diet and longevity.

Ron Rosedale – For the vast majority of my professional career, that’s what I’ve been studying. And I believe at least in the U.S. I was the first person to actually recommend and utilize a high fat low carbohydrate diet to treat a multitude of the chronic diseases of aging and have been studying the biology of aging for my entire adult life.  So what my interest has been has been in the dietary connection to the hormones and pathways that are known to influence, if not regulate, the biology of aging teeth.  That’s really what one has to look at if one is going to evaluate the health of any particular dietary or interventional regime–how does it affect aging and mortality.

Shelley –  Here is a study that came out recently from the Lancet the journal Lancet about just that topic. That longevity study seems to show that people who eat a low carbohydrate diet die sooner than people who eat moderate carbohydrate diet.

“The problem is, they didn’t study a low carbohydrate diet!” — Ron Rosedale

Ron Rosedale –  Well first of all ,had they stuck to the title of the study, where it’s different amounts of carbohydrates versus mortality, if they had if they had not used, later in the study, the word “low carbohydrate” it would have been a better study because the problem is that they didn’t study a low carbohydrate diet.  So here they are then making conclusions about a low carbohydrate diet, which is you know, picked up everywhere about low carbohydrate diet. And they didn’t study a low carbohydrate diet. Not at all.

Shelley Schlender – In the Lancet study the amount of low carbohydrate that they were looking at was 40 percent or less. You say that that’s not a low carbohydrate diet?

Ron Rosedale – No. They lumped it all into — I think the the lowest quartile was 37 percent. That’s not low carbohydrate at all. In fact that’s probably the worst diet, and that’s what their studies showed. I think the worst diet is one where you mix, kind of, an equal amount of carbohydrate and fat. And the reason it’s the worst is because carbohydrates turn to sugar, then the sugar goes up, and it raises insulin and when you raise insulin, your body can’t burn fat.   If you summarize all of nutritional science you can do it in a single sentence. And that is that, one’s health and lifespan is going to be more determined by the proportion of fat versus sugar that a person burns in a lifetime than anything else. The key is to burn fat. And if you eat 40 percent, or 37 percent carbohydrates, you will not be able to burn fat. That’s why people are getting so fat—people get fat not because they eat fat but because they can’t burn it.

Shelley – What stops them from burning the fat?

Ron Rosedale – When you eat a bunch of carbohydrates, and a bunch to me it would be 37 percent. That’s a lot of carbohydrate. Really. This will raise specific nutritional pathways and hormones. People have heard about insulin and I first started talking about the connection with insulin and disease many many decades ago and now it’s becoming more commonplace. Still, we knew even a quarter of a century ago that when you raise insulin it prevents the burning of fat. And so when you eat carbohydrates, the carbs turn into glucose, you raise insulin and you can burn fat. It’s as simple as that. But you also you also raise leptin and you also raise another even more critical pathway called the target of rapamycin that hardly anybody knows about right now. All of these conspired to make a person store fat and not burn it. And that’s always a awful and that’s where you can run into higher mortality and that’s what this study found.

So what this study really showed was that a medium carbohydrate diet, so a diet that consists of high fat and high carbohydrate or you might say medium-fat, medium-carbohydrate, however you want to say it– there was no low involved anywhere that will be unhealthy. And they found also who they should use for them to eat a very high carbohydrate diet. That’s also very bad. So they found two bad groups. One was a medium carbohydrate kind of medium fat diet that’s bad lead to higher mortality and if you eat a very high carbohydrate diet that’s also bad. It’s basically what they found there was no there was no low anywhere, other than the very high carbohydrate diet was what you might call a very low fat diet. And that they found to be very detrimental and lead to higher mortality.

Shelley – What would you consider to be a true low carb diet.   If 30 percent or excuse me if 37 percent is not a low carb diet what is what is?

Ron Rosedale:  You’d have to get down to about 15 percent. Up considerably lower than what they were testing at. George Cahill at Harvard showed this — that if you don’t get down that low you’re not going to efficiently burn fat. You’re really not going to burn fat as your primary fuel unless you get down that far. And the reason for that is the reason we stated about the effects on hormones. So you really have to get down there.  A major problem with this study is that, first of all I mean there are a lot of things, there’s so many problems with it. Not the least of which is what we talked about there when there was no low carbohydrate diet group to begin with.

Challenges with Food-Recall — from the 1980s

And the reason for that is, what they studied, it was an epidemiologic study. It was a population study. Epidemiologic studies are difficult to begin with because they have so many variables that you have to account for if you can.   The problem is you can never account for all the variables because you don’t know all variables nor do you typically get data on all the variables. In this particular study it was a questionnaire. And so number one is an epidemiologic study. Number two they used questionnaires and many studies have shown that when you ask people what they’ve eaten, especially when they have to reflect on it, if you ask the question, “What did you eat last week; what did you eat yesterday?” They’re notoriously wrong. And you can speculate as to why they’re wrong.   Many people feel guilty for instance if they ate two milkshakes yesterday and french fries, they’re not going to report that–they might report one milkshake. They didn’t report that they ate too much. There’s kind of a guilt and especially when it pertains to higher fat. You know that the fat has been so vilified that people are just reluctant to admit that. So anyway whatever the reason we know that food questionnaires are fraught with inaccuracies. So that’s another problem with this study. It began in the 1980s and in the 1980s there was there was no such thing as low carb–that it wasn’t even a phrase. So virtually nobody was eating low carb because everybody was told that that you should eat high carbs. And that’s a major major problem then with an epidemiologic study.  Also, we mentioned that there’s a lot of confounding variables, and in this study there were at least at least one major one. Actually are two major ones. One you can’t blame them too much for, because in the days when this data was collected, they just didn’t know anything about TOR (the target of rapamycin), but they did know about Ferritin. 

Facing up to Ferritin (and Foods High in Iron)

Ferritin–too much iron is very bad for a person. If it accumulates we know that iron rusts, for instance and it actually literally rests inside your body too and it can kind of rust the lining of your arteries and burn the lining of your arteries. It stores in tissues such as the pancreas and we know that high ferritin is very associated with diabetes.   Ferritin is a reflection of how much iron a person eats. I knew when I was seeing diabetics every now and then you’d find a diabetic with a very high Ferritin levels and you could literally reverse that person’s diabetes if they did nothing else, just by lowering their ferritin. And so ferritin is also very highly correlated with mortality.

Shelley – What is there diet that tends to lead to higher iron levels, high ferritin levels.

Ron Rosedale – Great question. The major factor, really about the only food that can really shoot up ferritin levels and iron levels, and this can be a an additional factor that causes a greater rate of death i.e. mortality, is red meat. And so people who eat a high red meat diet have to really measure their ferritin, but it’s just rarely done. There’s no money in it for anybody. There’s no drug that really lowers your ferritin, and so it’s not paid attention to.   But it’s a really simple variable that can be accounted for, certainly in a study like this — it’s there but only indirectly — the study conclusions did point out that people who got their protein from plant-based sources tended to live significantly longer than people who got their protein from animal sources.  A lot of animal based protein comes from red meat which contains high ferritin.  And that’s really the point that we’re making–the researchers came to the conclusion that animal-based protein is more hazardous,  because in their statistics they did not account for ferritin.   That’s even though the association with ferritin and mortality is well known.  In other words had they corrected for ferritin levels I think they would have it would have negated the difference in results they had with mortality in a plant based versus animal based diet, because there’s such a high correlation of mortality and ferritin. They came to the conclusion that animal protein was bad as opposed to plant protein, but that was a false conclusion I believe. Ferritin, they didn’t account for that.  Had they accounted for that I think it would have eliminated the vast majority of their (negative) results (regarding animal versus plant protein).  It would not have been the protein source that led to higher mortality–it would have been the iron.   The animal protein consumed was mostly red meat which is lamb, beef even chicken to some extent has red from blood. And that raises ferritin, but they didn’t measure ferritin, and they didn’t compensate for that ferritin when they came to their mortality conclusion.  ((NOTE – For someone who has high ferritin levels, Ron Rosedale recommends giving blood to reduce high iron levels)

The Target of Rapamycin (TOR) and the problem of high protein consumption

The other major confounding variable that was not accounted for and this is probably because they didn’t know anything about it. And that’s again a problem with epidemiologic studies that you can’t account for things you don’t even know about. It had to do with a pathway called the mammalian or sometimes now it’s called mechanistic, and you should even forget about the I think.  It should be called the target of rapamycin.  That’s a newer pathway that is now extensively being studied. It’s a pathway that now has been attributed to the longevity and health benefits of calorie restriction diet, for instance. So it’s an extremely important pathway. It’s a very ancient pathway that regulates almost all life metabolism.  The pathway is influenced by all sorts of different nutritional inputs, such as the amount of energy, the amount of ATP which is kind of an energy battery, insulin, leptin but it’s also influenced by nutrients.  The most powerful stimulant of Tor is protein. The most powerful stimulants within protein are the branch chain amino acids and particularly something called leucine, which is a particular amino acid that is found much higher in animal protein.  Animal protein has long been considered a much higher so-called quality protein — that’s how it’s described in scientific journals. In contrast, plant proteins are deficient in many essential amino acids  ((Vegetarians get complete proteins by eating complimenting foods together)). But the relevance here is that plant proteins don’t elevate the target of rapamycin near as much as animal proteins.

Shelley – Is  it good or bad to have high TOR?

Ron Rosedale — Well it’s probably good early in life. This would get us into probably a longer talk than we have time for as far as the biology of aging. But prior to reproductive years it’s good to have higher TOR because you need it you need to grow.  You need to grow muscles and you need it just to grow up, so that you can become an adult.   But after reproduction — basically after middle age, then an elevated TOR starts causing lots of problems and we know elevated TOR can increase risk of cancer and an increased risk of death from other causes as well, which is why lowering the Target of Rapamycin is more known today.   There is even a drug that lowers it. And we know that that is the first drug that actually has been shown to lower TOR also very convincingly reduces the rate of aging in laboratory animals. That’s pretty cool. So in other words TOR really is a powerful pathway, and it high TOR raises its ugly head after middle age. If you raise TOR after middle age, it increases the risk of cancer, and it increases risk of mortality.

Shelley – What I hear you saying is that if someone is eating a lot of protein after middle age, they increase the likelihood that their TOR levels will be high. And if somebody wants longevity they might want to have moderate but not too much protein–ie, less than most Americans eat, in order to give them a better chance at longevity.

Ron Rosedale – That’s exactly correct. But in this study what is particularly relevant is you can eat more plant protein without raising TOR, compared to eating the same number of ounces of animal protein.  That’s because plant protein is “lower quality”  it’s less usable, and so you can eat more of it because eating more plant protein is like eating less animal protein.

Shelley – The Lancet study does seem to indicate that people who ate plant based proteins were more likely to live longer than people who ate animal based proteins.

“Rather than saying that animal protein leads to higher mortality, they could have just said that eating too many much branch chain amino acids, for instance, will lead to higher mortality, and that’s probably true.” – Ron Rosedale

Ron Rosedale – That’s correct.   But the confounding variable that they did not account for was the quality of the protein, in terms of them measuring the “amount” of usable protein in plant versus animal protein.   To figure that out, they could have just measured the amount of leucine–it’s actually quite easy to measure in a food-based analysis.   And rather than saying that animal protein leads to higher mortality they could have just said that eating too many much branch chain amino acids, for instance, will lead to higher mortality, and that’s probably true. In other words, it’s not the fact that it is an animal or a plant.  It is the fact that you have more usable protein in the animal protein.

Shelley – And people in the United States tend to eat an excess amount of protein compared to what their body actually needs?

Ron Rosedale – Exactly. And that will lead to higher mortality. In the same vein, the other reason that, calorie for calorie, a plant based diet can show greater benefits than an animal based diet is because a plant based diet is much higher in cellulose.  Cellulose is the stringy part of, let’s say celery.  Cellulose is fiber.  It’s not digested. So you hear the adage you are what you eat. But that’s not really true. What is much more true is that you are what you don’t excrete, and when you eat a bunch of plants, basically some “calories” are actually fiber, and they go right through you. You basically poop most of it out and so you don’t really eat it; you don’t absorb it. And so it’s a way to eat less without it being counted as eating less.

I don’t care whether a person eats plant or animal protein. It doesn’t make any difference really–what is important is the amount of absorbable protein, and the amount of absorbable carbohydrate. And the same can be said for fat. And so that’s what needs we can in other words what are you really eating what are you eating that’s actually getting absorbed and doing something. And yet if it just goes in and out of you it’s it shouldn’t really be counted. And so if you eliminate that portion what you’re really seeing is that if two groups eat the same so-called calories in one group is eating a bunch of cellulose from plants they’re actually eating them they’re actually eating much less. And so that wasn’t accounted. 

The Types of Fat

Ron Rosedale – Also the types of fat weren’t accounted for. And that’s easy to measure. We know the benefit for instance of fish oil and how much omega 3 someone eats, whether from plant or animal sources.   How much mono unsaturated versus polyunsaturated fat for instance.   Walter Willett ((author of this study)) he’s done a lot of great papers but this I think was not his greatest hour. 

“Einstein once said that you want to keep things as simple as possible but not too simple.  You don’t want to keep things too simple because it will make it wrong.  And what they did in this study, is they kept things too simple.” – Ron Rosedale 

Shelley – Would you like it if the researchers would make available the entire database of what they collected over 25 years in these informational interviews, to see what else could be teased out of the study from people looking through different lenses?

Ron Rosedale – My guess is they would have they would have then come to no conclusions. I think it would have shown nothing because of the the other factors.  For instance, even if they did have a very low carbohydrate branch in this study, there would probably be too few who ate that way for statistical analysis because, really nobody was eating a very high fat, very low carb, adequate protein diet in the 1980s.  And that’s the other major problem in that you know we haven’t even talked about the major problem in this study. Now Einstein once said that you want to keep things as simple as possible but not too simple and you don’t want to keep things too simple because it will make it wrong.  And what they did in this study, is they kept things too simple. You can’t just measure the amount of carbohydrate and compare it to everything else.  When I first started talking about high fat – low carbohydrate diets in the  late 80s and early 90s, nobody was talking about it then.  But I knew even back then and there were maybe four or five other people in the world that were talking writing about low carbohydrate and they were all high protein. But at the time people didn’t really pay that much attention because they were just thinking about low carbohydrate. But since we now know, and I’m very happy because I’ve been pushing a high fat instead of a high protein diet for the last quarter century, there’s a huge difference between a low carbohydrate high fat diet and a low carbohydrate high protein diet.

“There’s a huge difference between a low carbohydrate, high fat diet and a low carbohydrate, high protein diet.” – Ron Rosedale

 And the vast majority of people who were undertaking a low carbohydrate diet since they started since we started talking about it in the late 80s and beyond, they gravitated to a high protein diet because fat had been so vilified.  It’s only been very recently that the the falsity of the detriment of high fat is coming to light.  They’re not even talking about low carbohydrate diet anymore. They’re talking about ketogenic diets and that’s also a name I’m not really fond of ((because consuming excess protein can increase ketone production as well)), but they talk about it because in general, ketones are chemicals that are produced when you burn fat.  It’s not the it’s not the fact that you’re eating low carb it’s the fact that you’re allowing the burning of fat and that allowing the burning of fat is what we talked about earlier.  By regulating hormones that tell you whether you can burn fat, it regulates insulin and leptin and Tor, so you eat to regulate the hormones that tell you whether you can burn fat or not.

And so you can’t just talk about low carbohydrate and compare it to everything else which is what this study did. And that’s really the major problem with it. So not only did they not have a low carbohydrate diet, but they then lumped low carbohydrate with anything else. They didn’t tease out: Was it a low carbohydrate high fat? Was it a low carbohydrate high protein in their mortality statistics?  They didn’t tease it out. 

Shelley – Are you concerned that this kind of study and the way that it’s been reported, ie publicity asserting that you live longer you eat over half your calories is carbohydrates–this may scare a lot of people into avoiding trying a very low carb diet?

Ron Rosedale – Yes I am very concerned. I think that papers such as this are extremely dangerous because diet is so important to a person’s health. I mean everybody’s heard that you know. Yeah what they eat is important. People don’t understand how important it is.  By influencing diet in laboratory animals you affect the rate that they age.  That’s huge. You affect the most important pathways in the body that regulate cardiovascular disease and cancer such as the TOR pathway.  What you eat is extremely important.  And so people authors such as this have to show greater responsibility.

Shelley – If you were to start this kind of study today to get the kind of information you think would be of use to people, what would you do?

Ron Rosedale –  Well the problem is it’s very difficult to do human mortality studies because you have to wait at least a generation. You know it would be a study that would take 50 years and most people don’t want to wait that long.   Certainly most researchers don’t, because the results of the research wouldn’t come in until after most of them had died. But you can glean at least something from animal studies.  The basic pathways that regulate metabolism have been around almost since animals have evolved and the reason for that is those pathways are so important that they they weren’t mutated away.  Any type of major mutation to these major pathways would have led to death, so that species wouldn’t be around today. So the major pathways, the major metabolic hormones Tor and insulin and leptin, they’ve been around for a very long time.

“You just have to do it and then you’ll see huge benefits,” Ron Rosedale

Shelley – What do you recommend for health — 15% carbs, 15% protein, 70% fat?

Ron Rosedale – (YES — HOWEVER . . . ) if you are going to go on a low carbohydrate diet you really have to go on a low carbohydrate diet. You can’t do it. Well I don’t know if I can say this on air but you can’t do it half assed You’ve got to do it. You’ve got to go on a low very low carbohydrate diet and substitute good fats into the type of fat make a big difference. And so it has to be done properly. You can’t just do it haphazardly and you can’t do it half assed. You just have to do it and then you’ll see huge benefits. Best thing you can do.

Down syndrome and Inflammation ((EXTENDED VERSION))  Joaquin Espinosa,  executive director of the Crnic Institute for Down syndrome, discusses the inner workings of cells in people with the genetic mutation known as Down syndrome.  His findings may explain some common characteristics of Down syndrome, such as shorter stature, cognitive challenges, protection from some cancers, and increased risk of pneumonia and Alzheimer’s.   Espinosa’s lab used Boulder’s Somalogic protein analysis tool to inspect thousands of the different proteins our bodies make.  The lab discovered a few hundred proteins that are noticeably different for people with Down syndrome.  These proteins do not specifically influence height or how to take a test.  Instead, they reveal an out-of-balance immune system.     PRODUCER – Shelley Schlender

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TRANSCRIPT:  

Joaquin Espinosa PhD  Transcript of Interview with Shelley Schlender Aug 2018

Joaquin Espinosa: I’m Joaquin Espinosa. I’m a professor of pharmacology at the University of Colorado Anschutz Medical Campus. I’m also the executive director of the Linda Crnic Institute for Down Syndrome at the Anschutz Medical Campus.

Shelley Schlender: In your lab you work on cancer and Down syndrome.

Joaquin Espinosa:  Correct. I have two research teams. One of them is focused on cancer research. One of them on Down syndrome but as we may be able to talk later there are connections between these two conditions.

Shelley Schlender: Do you know some people with Down syndrome.

Joaquin Espinosa: I do.

Shelley Schlender: What are they like?

Joaquin Espinosa: Oh they are fascinating. First of all no two people are the same. With or without the syndrome, so I don’t want to generalize about people with Down Syndrome. But there are some patterns, some qualities that are common among people with Down syndrome. They’re very kind. They’re very accepting very loving. So they’re really a great presence.

Shelley Schlender:  Yes I’ve heard that many times that people with Down syndrome there’s a way that in their presence they remind all of us of some of the most magical and special parts of being alive and being with other people.

Joaquin Espinosa:  Yes they have a joy of life. They are also very emotionally intelligent. I think they can perceive even ahead of yourself your emotional state. They can sense if you’re stressed or if you are happy and they can, interact in that way with you reading you at the emotional level very well.

DOWN SYNDROME —ALZHEIMER’S—AUTOIMMUNE DISEASES—CANCER

Shelley Schlender:  And at the same time people with Down syndrome, by the age of 40, most of them will have Alzheimer’s disease; by the age of 40, most will have some kind of serious autoimmune disorder, and they’re also prone to infectious diseases, and they’re prone to some kinds of cancers but not others.

Joaquin Espinosa:  Yeah — let me elaborate a little bit on that. The Alzheimer’s piece, first of all, yes people with Down syndrome are the largest population with a genetic predisposition to early onset Alzheimer’s disease. And by the age of 40 most of them had the signs of the pathology in the brain, but not necessarily the dementia–the true manifestation of the disease. It may take another 20 years or so for that dementia to develop. And they have a lot of variability, and some of them despite the fact that they had that brain pathology do not become demented until their 70s. So studying people with Down syndrome can really reveal how to modulate the progression of Alzheimer’s disease. It is also true that people with Down syndrome are highly predisposed to autoimmune conditions. Things like Hashimoto’s Hypothyroidism, when the immune system attacks the thyroid gland, celiac disease, rheumatoid arthritis, type 1 diabetes. So a whole range of conditions. The Cancer Connection is fascinating. On one hand, they are protected from most solid malignancies. And what I mean by these is tumours of solid tissues, like breast cancer, prostate cancer, colon cancer, liver cancer–much reduced rates of those.  On the other hand they have higher rates of leukemias, the malignancies of the blood cells. So there is something very interesting going on there.

Shelley Schlender: They get some kinds of cancers they don’t get other kinds. They’re more prone to the placquing of Alzheimer’s disease though some may not show signs of dementia till a later age. They are definitely more prone to autoimmune diseases. Now you did a study that involved an extensive look at proteins and how proteins expressed in the bodies of people with the genetic condition we call Down Syndrome. What is special about a protein study why would you study proteins.

5,000 PROTEINS—IMMUNE SYSTEM “HYPERACTIVATION”

Joaquin Espinosa: So we did two studies and they’re related. One was looking at the proteins in the blood. Let me remind you that our genetic information goes from DNA which is packaged in our chromosomes. It produces a molecule called RNA and then the RNA then becomes translated into proteins so more or less, for every gene in the human genome and there are like 20,000 genes you would find a protein somewhere or another in the body. So if you want to study the genetic information, the genetic makeup of an individual, or any organism, looking at collections of proteins could be very informative.

Shelley Schlender:  In studying proteins do proteins do all the jobs in the body.

Joaquin Espinosa:  Not all of them but many, if not most of them.

Shelley Schlender: So by studying proteins in the body you can get some ideas of what kind of jobs is the body doing what kind of jobs might it be doing too much and what kind of jobs might it be doing too little.

Joaquin Espinosa:  Correct.

Shelley Schlender: So you studied the proteins between people with Down syndrome and also people who don’t have Down syndrome. Where were the variations.

Joaquin Espinosa: We looked at almost 5,000 proteins in the blood of people with and without Down syndrome, and we found about 300 that were very different, meaning they were significantly elevated or significantly depleted in people with Down syndrome, and about half of those proteins had to do the immune system.

Shelley Schlender:  The immune system. Is that what people have normally thought is the area of a person with Down syndrome that is different from other people.

Joaquin Espinosa: It was noted here and there in the literature that people with Down syndrome have differences in the immune system but nobody had done this unbiased analyses of thousands of proteins that would place the immune system at the top of the chart as the top category of what is different in people with Down syndrome.

Shelley Schlender:  When people think about Down syndrome, they usually think about somebody who doesn’t do as well on standardized school tests–yet it’s the immune system that you found is different.

Joaquin Espinosa:  Correct. And everything that we talked about–the different disease spectrum, people with Down syndrome having more Alzheimer’s. less solid tumors, more leukemia but also the cognitive aspects. All of it could potentially be explained by these differences in the immune system. Let me elaborate a little bit on the role of the immune system in the brain, since you brought that up. Yes people with Down syndrome have cognitive differences. About 15 percent of the cells in our brains are immune cells that are called the microglia. These are cells that are sitting in our brains to protect the neurons and other cells in the brain from infections. In Down syndrome, the microglia, the immune cells of the brain, become hyperactive. They produce toxic compounds that will basically poison your brain. So even the cognitive aspect of Down syndrome could be explained by a hyperactivation of the immune system.

Shelley Schlender:  You just said hyperactivation, meaning that it looks like the immune system is working too hard. Working so hard that it’s doing some wrong things in people with Down syndrome.

Joaquin Espinosa:    Correct. The immune system has many branches. It’s not the same branch of the immune system that we use to fight off a virus than it is to fight off a bacterial infection. So what we’re seeing is a particular aspect of the immune system involving the viral defense and the tumor defense, called the interferon response, because it interferes with viral replication. In Down syndrome that is hyperreactive. But when you’re doing too much of something, even if it were to be a good thing, of course you can see exhaustion and you can see it eventually wear out the system. So we like to say that the Immune system of people with Down syndrome is generally out of balance.

Shelley Schlender:  Do you mean that there’s too many of these immune cells doing things, or do you mean the immune cells are exhausted and they’re working too hard trying to do things that they really don’t need to be so worried about.

Joaquin Espinosa:  We see both, which is some type of immune cells that people with Down syndrome have more of and they are more active. For example the cells that are involved in fighting off tumors. Now the cells that are involved in fighting off tumores are the same cells that could cause autoimmunity because rather than attacking a tumor they start attacking a healthy tissue. There you go you have an autoimmune disease.

Shelley Schlender:    Meaning that the cells started out, we hope, fighting something that needed to be fought in the body. But then it got confused and it said Well this other cell looks a little bit like the cell I was fighting. So maybe I should fight it too. And it happens to be a cell that’s part of our body that is fighting now.

Joaquin Espinosa:  Correct. When the vigilantes in your body are hyperactive the chances of making a mistake increase. And that’s what we’re seeing. But there are also other aspects of the immune system that are depleted–the immune system is out of balance. Some parts are too active. Some parts are weakened.

Shelley Schlender:  In the case of somebody with Down syndrome your research indicates that they may have the dial turned up to high on attacking cells that, to the immune system, like similar to viruses . . . including body cells that look somewhat similar to viruses. But on the other hand if somebody with Down syndrome gets a bacterial infection, they’re prone to get really sick from it.

Joaquin Espinosa:  Absolutely correct that antibacterial defenses in people with Down syndrome are diminished. In fact bacterial pneumonia of the lung, you know, lung pneumonia, is the top cause of mortality among people with Down syndrome. Few people know that. So this is a main concern for us, and an area of intensive research. How can we normalize the immune system so that we tone down the aspects that are hyperactive and at the same time we build up the antibacterial defenses that may help these individuals fight off the pneumonia.

DRUGS & OTHER INVESTIGATIONS FOR “TAMING” IMMUNE SYSTEM

Shelley Schlender:  Well how about using some of the standard immunotherapies such as using a steroid drug to just suppress the whole immune system, etc.

Joaquin Espinosa:  Steroid Drugs will not produce the type of rebalancing that we would like to achieve. But there are other approved drugs used for some auto-inflammatory conditions like rheumatoid arthritis for example. These drugs are called JAK inhibitors (Jakinibs, or Janus Kinase Inhibitors) which we think will do a better job than just a corticosteroid. So we are testing these drugs in animals models. We have mouse models of Down syndrome, that is mice that have an extra chromosome, just like people with Down syndrome do. But also we know now of some individuals with Down syndrome that have taken these drugs for some of their autoimmune conditions and they’re seeing benefits. So we are also planning on eventually doing the appropriate clinical trial to test these immune therapies that could bring back the immune system to a state of balance.

Shelley Schlender:  Are you envisioning that a course of treatment with one of these drugs could get the immune system to a place where can take care of itself. Or are you thinking that this would be a lifelong using of a drug or a nutritional approach or something, that would help rebalance the system in an ongoing way.

Joaquin Espinosa:  I don’t think it would be a treatment that you would take for only a few weeks or a few months and then you kind of stop it. This is more like a chronic inflammatory condition. So examples will be rheumatoid arthritis or autoimmune conditions like celiac disease. So you have to be on a chronic treatment. Now when you do a long term treatment of course the concern is for undesired side effects appear if you’re going to tone down the immune system. You want to make sure you don’t do it too much. Otherwise you will increase the risk of some viral infections. To give an idea we have people with rheumatoid arthritis that have been taking these immune therapies for 20 years now and they continue to take these pills everyday. So it is possible to envision that people with Down syndrome would be on some kind of immune therapy from an early age. How early. We don’t know the research will have to be done and then continue with this for lifelong benefits. You did mention something about changes in the nutrition this is something that we’re very interested in. Are there types of anti inflammatory diets that could help people with Down syndrome. We hope so. I mentioned to you that people with Down syndrome are more likely to develop celiac disease So in those with a diagnosis of celiac disease. Of course a gluten free diet will have profound benefit.

Shelley Schlender:    Are there any other nutritional interventions or exercise interventions that you think might be helpful.

Joaquin Espinosa:  In terms of nutrition where we’re paying attention to everything that people with Down syndrome have been taking. There are a number of dietary supplements that families have adopted here and there. And as part of our research we have a cohort study of the population with Down syndrome where people with Down syndrome and their relatives provide us with biological samples but also with medical information and lifestyle information. So we’re recording all these data and if any of these dietary supplements were to have a benefit on the immune system we’ll probably pick it up during the course of this study. We’re not there yet. We have almost 500 participants in this study. To do this type of research we’ll probably need thousands of participants to have enough who are taking a supplement versus enough who or not taking the supplement to be able to do that research.

Shelley Schlender:  How about things like how much carbohydrate does someone eat compared to how much fat compared to how much protein.

Joaquin Espinosa:  We’re looking at the metabolism of people with Down syndrome in fact we published a paper last year and we have another one in preparation where again we looked at the blood and the plasma, and we measured various kinds of fats, carbohydrate, amino acids. And there are some differences in metabolism. Whether those differences then can be interpreted in a modification to the diet that will help the immune system, it’s early days to get there, but there is evidence that people with Down syndrome may metabolize certain nutrients in a different way.

Shelley Schlender:  And how about hormones. Did your test look at insulin levels? Cortisol levels?

DOWN SYNDROME – HIGH LEPTIN — SLEEP APNEA

Joaquin Espinosa:   We have looked at several hormones. Not all of them. We’ve found that a hormone called leptin, which is involved in energy metabolism but also control of appetite, is disregulated in people with Down syndrome who have obstructive sleep apnea. So it turns out that about half of people with Down syndrome have a sleep disturbance where they have, basically a problem with airflow during the night and they wake up many times during the night. There are some treatments that one could do for such as C-Pap. So we have noticed in our study that those that have obstructive sleep apnea have deregulated leptin levels. It has been noted in the literature in typical people that if you have obstructive sleep apnea, your metabolism may change and you may actually put on weight. So that is just one example of how one of the co-morbidities of Down syndrome, in this case a sleep disturbance, can then impact the metabolism and body weight.

Shelley Schlender:  Or Vice versa. It’s not clear whether the disregulation of leptin is leading to more sleep apnea or the other way around. But you also said disregulation–does that mean that people tend to have higher levels of this hormone called leptin, or do they have levels of the leptin that are too low? How is leptin dis-regulated.

Joaquin Espinosa:  Leptin is elevated in the plasma of people with Down syndrome and obstructive sleep apnea. But what happens when you are constantly exposed to high levels of a hormone, you may become desensitized to it and you may acquire what is called leptin resistance. Yes you have more of it in the blood, but actually you respond less to it. You have become desensitized. So that’s why I use the word disregulation.

Shelley Schlender:  That’s similar to insulin resistance where somebody has high levels of insulin but their cells can’t hear the signal. Do people with Down syndrome tend to have high levels of insulin as well?

DOWN SYNDROME TYPE 1 DIABETES

Joaquin Espinosa:  No. What we see in down syndrome is is more of that type 1 diabetes the autoimmune juvenile diabetes, where the new system makes some mistake and attacks the beta cells in the pancreas that produce insulin. So that is why we see more of it– with that being said this is not a highly prevalent condition in Down syndrome.

Shelley Schlender:  And so the leptin is usually high but the insulin is not usually at an unusual level. Well it sounds like you’re finding out a lot of fascinating information that may also inform people about other diseases such as Alzheimer’s such as cancer formation, such as immune system activity for protecting people against pneumonia.

DOWN SYNDROME FEWER ALLERGIES

Joaquin Espinosa:    Correct. So this extra chromosome–chromosome 21 has about 200 genes that people with Down syndrome have an extra copy of — a 3rd copy — clearly it’s regulating human biology in myriad ways, predisposing to some conditions or protecting from others. So it gives us a unique discovery platform to understand human biology and human disease. And we talked about the major examples Alzheimer’s cancer autoimmune conditions but there are many other conditions that are either more elevated or less frequent in people with Down syndrome. For example, people with Down syndrome have more autism, more epilepsy, but they have less allergic sensitization–fewer allergies of a certain type and I could go on and on. So this small more chromosome is really loaded with a treasure of information about human biology or human disease.

 

Shelley Schlender talks with renowned skeptic Michael Shermer about his new book, The Moral Arc:  How Science and Reason lead humanity toward truth, justice and freedom.  This is an extended version of the interview.  (27 minutes)

Podcast: Play in new window | Download (Duration: 26:59 — 24.7MB)

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