Measuring the Age of Your Immune System

In this episode I chat with Nikolina Lauc, CEO and co-founder of Glycanage. 

Glycanage is a biological age test paired with expert advice to help guide your wellness. It is a test that I am starting to use more and more in my patients' long term health strategy.

 The Glycange test measures Glycans, important structural molecules (made up of sugars) that play a variety of cellular and protective roles. Glycans are directly involved in the pathophysiology of every major disease and are well recognised in the scientific literature to be part of the ageing process of your immune system. 

For those interested in longevity and preventative health, this is a podcast episode not to be missed. 

Links mentioned in this episode:

Glycanage 

Olshanskey 

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Transcript

SUMMARY KEYWORDS

Glycanage, biological age, inflammation, immune system, chronic disease, glycans, predictive test, menopause, hormone levels, stress, personalized medicine, longevity, cardiovascular disease, estrogen, metabolic health.

SPEAKERS

Nikolina Lauc, Peter Williams

Peter Williams  00:02

So welcome everybody. Welcome to our new functional medicine bite size podcast. If you've been reading quite a bit of my stuff at the moment, I've been doing quite a few things around longevity. It's obviously something I'm hugely interested in, because I certainly read in the research. And just let me introduce we've got Nikolina, I can't even, Nikolina pronounce your second name because I'm never going to get it, (don't worry about, it's Lauc). And Nkcoline is the CEO and co founder of Glycanage. It is, well, I'll get her to to explain what it is, but it is one of the, I'm going to say one of the predictive tests that we use within a bigger patch package of when we're dealing with individuals on a personal basis. Because number one, I think this is actually a product that has very significant science on it with lots of ongoing research. And so I feel as though that the test is one that has has done its time. From a point of view of this isn't a flash test that won't be will be gone in a couple of years. This does look like some real solid science that's been going on for very long time. So, Nikolina, you're in New York. Thank you so much for coming on. I appreciate the time of day. We always like to have a little bit of an understanding about who we're speaking to from a point of view of what's yours and maybe what's your family's story. And maybe a good time to introduce glycanage as a test,

Nikolina Lauc  01:35

sure. So we certainly have some history. So my father is the main researcher behind the well, even behind this biomarker as a field. He pioneered the space almost 17 years ago, but 15 years ago, he told me that he can measure aging on the molecular level. And I didn't think that was exciting at the time, because I was 19, so he had to wait a few years until that became relevant. If anything, I want to be older, not younger, and I think you still want to be chronologically older, not younger. But the biological sign is really exciting, because we get to control how fast our health deteriorates, and it's something that will happen at different times throughout life, but it's malleable, and it can explain some of the differences of why certain people live longer and certain people live shorter than we would think they would. So

Peter Williams  02:32

could you just break that down, because obviously there'll be a lot of people listening to here will be clinician clinicians and people in healthcare, but also the majority of the people listening in are general public, who may have very little understanding of this. So in a sense, we've got two measures, haven't we? We've got our chronological age and we've got our biological age. So can you just give us a little bit more about what you're looking at and what the glycan age is telling and really the background to what your dad and your company is fundamental well, has developed and continues to sort of expand where where, what we're understanding from your test and how that fits into overall aging as well.

Nikolina Lauc  03:14

So with chronological age, it's fixed. It's how we calculate time. It's the date on your passport. You can't change it to that wouldn't be biological age is something that's more relevant to a health outcome, and there's many biological, biological ages. There's actually not one, but it's something that should give us a better proxy on how long you're going to be healthy, and then how long you're going to live as well. We measure it by looking at the immune system. And the immune system is one of the key systems that keeps us alive, not just from infectious disease, but from cancer. It's also one of the key causes we get ill because of this background, chronic inflammation that's created in theimmune system. So it's one of those big mortality risk factors. And if we would look at the whole burden of chronic disease, so all the reasons, all the conditions that lead to to mortality, three out of five are related to chronic inflammation.

Peter Williams  04:15

Sure. And in fact, one of, one of the key things for us from systems thinking, is we're not looking at trying to come to a we're not trying to diagnose, we're trying to understand the major mechanisms that are driving chronic disease. And of course, inflammation is a key player in that. And of course, how the immune system chooses to respond to whatever it's trying to respond to will do that from it from an inflammatory perspective. So continue,

Nikolina Lauc  04:41

sure, if you if you like. I think the most exciting thing about the space is that we look at glycans, yep, and that's something that hasn't historically been done, because they're horribly hard to analyze, to analyze from a lab perspective. But they're also this top layer we have that that changes how our biology works, beyond genetics and epigenetics, but taking influence from genetics and epigenetics. So there's sugar molecules, and that's the confusion. The confusing part, you know, it's like to do with the sugar in your coffee. I have a lot of sugar in my coffee this morning, so it's nothing to do with the sugar you eat and how your body responds to it. It's sugars that you manufacture and that we've created to enable, enable multi Cell Life. All communication and biology happens through the sugar language. All of our cells are coated in glycans. Majority of our molecules, proteins and lipids. All proteins and lipids since we've been multi cell are glycoproteins and glycolipids so they have this sugar part so they can actually add function on top of them and communicate with the rest of the body. So actually, we've only scratched the surface in this space by looking at the adaptive immune system, where we see aging, but it's relevant to everything from conception, maybe one of the ways that 150 years ago, we knew glycans were relevant was blood groups. Glycans and blood cells would give you a specific blood group. And if we don't match these blood groups correctly, that can lead to mortality in a transfusion case. So that's a field that's super exciting, because instead of what we do now, either we look at the genetic blueprint, or we're measuring different levels of molecules in our blood, proteins and lipids. Now we're looking at the function of these molecules. Yeah, yeah. So that's, I think that's the most exciting part about the biomarker.

Peter Williams  06:35

And I mean, what's your view with regards to so when we're looking at glycans, what? What is it that? What can we understand that? What are we measuring with it? I think is probably a good on in simple terms, because, you know, we've got these various different companies with the aging and biological clocks that you can do some, I think, reasonably well validated. I'm not too sure on some others And again, I think that was the exciting thing about yours, the research papers. There's hundreds of papers on from your group, which makes it kind of exciting that we can't really argue with the scientific literature over the last 20 years that you produced. So

Nikolina Lauc  07:15

that's sort of been ignored for a period of time. Well, look,

Peter Williams  07:18

but the reality is, everything has its time, doesn't it? This is the key thing, is that everything has its time. And I think the reason why a lot of it does is because most, most medicine isn't good yet at being able to systems, think and think about the bigger picture. And you know, that's just the way it is. So I think your time is coming. I think more and more, more and more on that side. But what are we actually measuring them? Of course, we're looking at these glycans. We know that these are these very special sugars that are part of the immune system. What is it that it's actually doing then? Is it that we're what we're showing is these glycans have an effect of how you immune Chris system communicates or controls things. Is it that actually their main role and what we're looking at is whether we are looking at an immune system that is hyper responding and creating inflammation, or whether is it the capacity, genetically or just environmentally, the control of that immune inflammatory response

Nikolina Lauc  08:25

so specifically. So first of all, we don't know what glycans do on majority of molecules, because it hasn't yet been studied. We know what they do on antibodies or immunoglobulins, because of this whole space of monoclonal antibody drugs. So work has been done to exactly understand what are these molecules doing, and they're activating or suppressing chronic inflammation, and we look at them on immunoglobulins, which are the most abundant antibody we have in blood, and they're part of our adaptive immune system. So it's the learning, the aging, the experienced immune system, and what we would see through time is the discomposition of them shifts. So it's the abundance is always the same, because they have to be in a certain amount in a certain location, but their composition is different. When you're young, you have more of these anti inflammatory structures, and then as we age, we have more and more of these pro inflammatory structures, meaning we overreact to something, we create a background level of inflammation. We don't suppress it fast enough after a legitimate threat. So it's complex. Of course, the immune system is complex, but the theory behind it is inflammation, or this continuous damage to our immune system throughout life that accumulates and then leads to disease and mortality risk.

Peter Williams  09:44

So here's how I was trying to think about how I could summarize this this morning, when I was thinking about what we're going to talk about, are we looking at a a predict, potentially predictive test, because I think about this story that we learnt about detection of antibodies 15 years so when we're looking at autoimmunity, autoimmune disease can start to progress maybe 15 years before you actually have the diagnosis, because your body is producing antibodies and responding to the threat. I sort of feel as though that's what this feels like to me. Would that be a good analogy to use? Is that we're starting to predict future problems, or we can see future problems with what the guy can result to telling us? Would that be? Would that be fair enough?

Nikolina Lauc  10:39

That's a good analogy, and it is relevant to some parts of like, it is relevant to autoimmunity to big degree, but also other things. And we've proven this in studies. So it's kind of like, I like to say that this is usually when we're measuring inflammatory markers. We're measuring acute responses to diseases already there. In this case, we're looking at a very low grade level of inflammation and predicting where is it going to end up in 10 years time. And because these sugars have a language certain like cardiovascular disease has a certain language, autoimmunity has a certain language, and we can quite accurately predict where this inflammation will go within the individual. So for example, with rheumatoid arthritis, we see a certain we call them like glycosylation patterns, or glycan pattern, change 10 years before a diagnosis with 92% accuracy. Or with hypertension, you have a certain signature shift six years prior to a clinical diagnosis with 98% accuracy in predicting it in this certain study. So we're able to map where your health concerns will go in 10 years. At a period, you can still do something about it, because we know that, for example, the cardio signatures respond to physical activity Sure, or the diabetes predictive signatures respond to weight loss. So it gives you this early warning while there's still something to do to to prevent it. So,

Peter Williams  12:06

so what I really like about this, there's a couple of things I'd like to jump on with this. One, I think this is why we're getting more interested in it, is that a lot of people are coming to us for, you know, optimal health. They want to optim you know, they've made their money. They want to get into her 80s and 90s with absolute minimal, if you like intervention, pharmaceutically, or anything wrong with them. And I feel as though what this one does, because we we extensively test our patients depending on what we're doing. And of course, as you say a lot of the time, what we find is that basic biomarkers through blood are absolutely spot on. So you know, something like CRP as an inflammatory mark is absolutely perfect, less than one on most people that we're seeing, and yet, we're starting to see just some signatures on the glycan age measure that says maybe there are underlying mechanisms and processes that we just need to pay more attention to, to make sure we bring these down. So one of this so I just wanted to go through because when you get your results, it gives you a it gives you an age score, which can be a bit, as we talked about, can be a bit frightening when you see it. You know your chronological age, maybe is 55 and your your glycan age score is, is at 65 if you're like 10 years older, which I've had one, I've had one of your tests, and I was five years older and kicked up a bit of a fuss with you guys as well, because I was sort of, I sort of feel as though I know what I'm talking about. But the reality of this is that I'm pretty clear, going back, that I was probably quite over trained at the time and and it's sort of nudging me into that maybe you should be taking a little bit more care with regards to not over training anyway. That's the story for another day. But how do you predict and is that something that you're going to change? Because I know, you know, again, a lot of the problems sometimes with testing is that you you make an amazing you have an amazing product, you do an amazing service, and then you can frighten the pants off the patient experience, because suddenly, you know, patients are always sort of, they view the world in a certain way. And some of them will be like, Look, I know your score is 10 years older, but that doesn't mean to say that you're 10 years older. It's giving you a predictive score. So can you take us through how you've how your your team have got to that point where you can say this is the predictive nature of what the test is telling us?

Nikolina Lauc  14:38

Yes, well of course, we can remove the age and call it chronic inflammation, and in some clinical settings, we do that, because both the patient and clinician can struggle with the age component, although it is inflammation related to age and aging, and even if we look at the things that most are associated with age, I. Um, there was a nice study that looked at all the molecular traits. We did it with Wade, Cornell and Doha, about 400 people, over 6500 molecular traits. 20 had the strongest association with age. Nine of these were glycans, and the rest were pretty much hormones. So they are an aging marker. Now, sometimes it's useful to have the age because it helps you motivate a person, yeah, something. It's just that the action steps they have to follow have to be very clear, yeah. So you have to be working with a specialist, a clinician. You we have to present, think, we have to figure out what the problem is in the individual and motivate them to do something about it. So I think the age component is really powerful, and it is a strong proxy for health outcomes. Now it can be both predicting that you are ill, and you can have a young person with an autoimmune condition who looks like it's 50 or 60 years old. Yeah, what the test is saying is their level of inflammation is same of an average 50 or six year old in our data set, and that's over 200,000 people to date for trials, but they already know why, because there isn't present onto immune disease that's creating that chronic inflammation, and it's inflammation can both be a cause of aging because of an early onset of a disease, like an autoimmune disease, we know that patients have a reduced health span, and it can be a consequence of aging. So we can look at the healthy old person that has a high level of inflammation,maging but don't have a chronic condition yet. So it's both a cause and the consequence of aging, and I think this is where the confusion is. But if we look at the predictive power now we we're just about to publish a nice trial with twins in Karolinska Institute in Sweden, okay, at this great bio bank where they followed them over 30 years, and they can look at this before all the studies were large cohort correlation studies on a cohort basis. This is an individual basis. So the twins that had accelerated inflammaging had an increased risk of mortality, dementia and some other health outcomes, and the hazard ratio was quite high. It was 0.74 which is significant. So we know that on an individual basis, this is relevant for for health outcome, and it's malleable, so it shouldn't be scary information. If you have it as early as possible, it's something you can influence and then change the outcome.

Peter Williams  17:39

So question on that, then, how much of this glycan science is genetically led from a point of view of, are we going to have, because I can think of one of our patients were we've got a result that we don't like. We seem to be doing everything optimally. And we did some work with your group, and we came up that maybe because of his Irish background, that that might be an issue with some of the genetics so So, and I know on your test results that to some degree, the way glycans perform over a lifetime, there's a there's a genetic component to it is, how much is genes and how much is environment? Or is, is that? Is that going to be always a fluid conversation with regards to the time frame that that patient is in,

Nikolina Lauc  18:42

it varies. So we know that for individual structures, heritability is being 30 and 70% for example, there's a cardio glycan signature that's 70% heritable specifically to women. So men and women have different signatures for cardio disease. On an aging perspective in twins, we showed that the overall heritability of the clock is about 40% so we can say about 40% on average, is due to your genes. But now that also doesn't mean that that's the case for you as an individual. This is what we saw on a cohort basis. So we're developing a calculator in the background to be able to tell individuals how much of their score is due to genetics. And that's going to take some years. This is scientific development, so no, but

Peter Williams  19:29

I think, I think that's a really interesting question, because the reality of this is that, you know, I think about that patient we've got at the moment, I'm just not quite sure what the next step is, because we seem to be covering all of our bases and, and, you know, I don't know whether how much he he might be right up at the 70% and it's like, you know, we're doing, we're doing our absolute best. And yes, his markers are still not as good as we would like.

Nikolina Lauc  19:55

So sometimes there's some things which are difficult to eliminate for and you had a question on what mostly influenced the clock? Or that's one topic you want to talk about. And there's three things I would say we see the strongest impact on the clock. And one is very obvious, it's weight loss and weight gain. Yeah. So losing weight to different modalities of weight loss, weight loss, drugs, surgery, natural diet and caloric restriction, all of that very proven out. But if you have patient who's now overweight, then that you don't care about. Second is hormones, both in men and women, related to estrogen. So estrogen depletion for menopause, but also as you're losing testosterone throughout time as a man, because it converts to estrogen. Can,

Peter Williams  20:43

can I just, can I just pick on that? Because I actually went on your podcast a few months ago with some of the research you doing on menopause, and we are increasingly doing a lot of work around menopause. I mean, we've got a specialization in cardiovascular disease, but also in risk of dementia. And of course, I think what we're looking at in the literature, the menopause transition for women, is a big time when things change. And so can you talk about what your research is starting to show with regards to how glycans and the glycan scores change when women hit menopause,

Nikolina Lauc  21:24

absolutely. But I just want to focus in on your patient and put a third point. It's usually the most.  With menopause we see 10 years acceleration on the clock on average, as women transition into menopause, there are glycan changes connected to dementia. We haven't yet connected the changes in menopause to dementia, just because we haven't studied the type of cohort, sure, but we know that it's a whole majority of chronic disease in women happens post menopause. They usually have delays and men start earlier in terms of chronic disease diagnosis. Third thing that has the strongest impact of a clock, stronger than menopause and weight is stress. So we have a history of work that goes all the way back to 30 years ago, when my father started in the field, because he's Croatian, and at the time we had the Yugoslavian Civil War, and we were looking at glycans and stress, and there was a very high correlation. Then there was a study on PTSD over 10 years ago where we showed that the clinical diagnosis of PTSD gives you an average of 15 years acceleration on the clock and then milder trauma exposure, less and no trauma none.

Peter Williams  22:36

So So is that because, well, it's interesting, isn't it? Because I look at some of the work we do with regards to some of the cytokines, and IL6, IL1 Beta. And you know what is clear in the literature is psychosocial stressors ramp up those cytokine signals, and so you're going to have a pro inflammatory response from psychosocial stressors, for sure. So is that, is that the mechanism that's that's driving the glycans or or is it independent?

Nikolina Lauc  23:05

Yeah, I don't think we have that information yet. I think stress is this area going beyond PTSD, because PTSD is a clinical diagnosis, stress in its own so the first kind of stress in its own evidence that we have is a study coming out now with medical residents, where you have multiple components, so there's a sleep/night shift problem, but we did those psychological evaluation questionnaires, and the highest Association beyond anxiety and depression was stress, and there was really high acceleration in the clock up to 20 years. So stress out beyond PTSD has a huge impact on your immune system and this process overall, of course, it can be temporary. So it can be that, you know, you're a first year medical residents, so your first year, the lives are at risk. You've never done this job before. So of course, you're going to have a high impact in those couple of years. But maybe after that it goes down, maybe the the stress goes away, or maybe becomes permanent with PTSD, where you're constantly in a spider film, or you're constantly in a high stress career, or it can also be relationship, sure, and that's the things we haven't yet decoded, because we don't have as much. But if you look at entrepreneurship and entrepreneurs and executives as a group, they look highly inflammed. It's unusual for us to see someone who hasn't caused damage at a young age, and then something we completely haven't studied are the relationship stressors. But we know from diet study pilots we've done when we would see high acceleration. I remember we those were first studies we did seven years ago with kind of exposure to the individuals, because it was a pilot with 30 nutritionists. So we spoke to everyone, and they shared beyond what was in the standard questionnaires, and we had two people accelerated just under 10 years within three months, and I asked both of them what happened, because everything's going to plan with the intervention. Oh, I just went for divorce, and the ladies just went through a divorce. So I think unfortunately, beyond the blood work, beyond the kind of obvious factors, there could be stress factors that are difficult to kind of because it's so personal. You know, you can have somebody in a high stress position that doesn't have the impact of it, but it could be something to look into with your client, because it's the most non obvious, hardest one to kind of associate, but potentially the strongest impact.

Peter Williams  25:40

So my question on that one, then, is that, based on what you've said, is that are the are the predisposing genotypes that are going to have a bigger influence with regard to the glycan age score? So let me give you an example on that. So we do a lot of genetic, Single Nucleotide Polymorphism tests. We do quite a lot across the inflammatory ones, because, as I said to you, it's a major pillar of chronic disease. So all in your opinion, would you be expecting people who have strong gene variations on IL1, IL6, tumour necrosis alpha? That are you expecting that someone who who has a more pro inflammatory genotype profile is going to that's going to translate over to a higher risk from a point of view of how the glycans are going to perform, or is that, or are they separate?

Nikolina Lauc  26:34

Potentially, I actually don't know if we did that piece of work, because we did do a lot of genomic studies. So I would have to explore it a bit further. I think with some auto immunity there was, there was a strong link, but I actually need to read the papers and, okay,

Peter Williams  26:52

well, maybe that's for me and you for another time, just trying to sort of wax it lyrical, as I said to you, I'm very interested in your test now, because I think it's got, I think it's got, I think it's got a lot of scope from its predictive nature, and I think that's where I'm getting, quite, quite interested, because, because more and more people are recognizing that what we do today is what's going to help you in 30 years, and you've got to pay now to make sure that you're not paying in 30 years, or you've got less pain and suffering in 30 years. And I think more and more people are coming over to that. So I think predictively, your test makes a lot of sense, which a little bit rather said to you that sort of feeling about, look, we're already seeing antibodies, and I know they're starting to show and we need to do something about that. Now, when I was talking about the autoimmune antibodies, because the data tells us, in 10 or 15 years, if you do nothing, you're likely to progress towards the disease. Where do where do you guys stand then, from the aging, the aging world, I think a lot of social media gives, I think, a very inappropriate, in my opinion, an inappropriate picture of the fact that, you know, if you can take a couple of supplements. I was going to talk to you about that because I'm on another podcast soon, with regards to where do we stand with the literature on supplementation, because, and I've actually, and I'll send you, uh, Nicolina, because Olshanskey's just put a new paper out in Nature Aging, which is really questioning whether we really do have the capacity to live to 125 and he's basically saying, not without some very significant medical changes. So the here's here's how I've looked at the literature, and this is what I tell our patients. I said, there's going to be a very small proportion of us who are going to live over 100 and so the best that we're trying to work with you is to make sure that we get into your 80s and 90s with as minimal problems as possible. And that's going to be quite a bit of work to do, that. Where do you guys stand on, on, on how you understand that the sort of the literature with regards to aging, and I know you guys have done quite a bit work around supplements that may work, but they're not a major factor. As far as I I'm reading what your reports are telling us. Would that? Would that be correct? 

Nikolina Lauc  29:08

Correct, absolutely, absolutely not. So those three things I've listed, weight, hormones, stress, these are the strongest factor, like the signal is undisputable, everything else, more complicated story. Now, just going back to stress. We I'll share a nice paper on rats. We did to vulnerability to stress, and 20% had vulnerability to stress, and I think that might be the genetic component to explore as a connection on the aging space. Broadly, it didn't exist when we started in this field and we didn't look for aging. It was just a small disassociation. But there was no longevity space. We were even this will have a use case in forensics to tell the age of a criminal. That was the first idea for it. There was nothing beyond it. And I think aging is very complex. It's. Multi factorial. We're not going to figure it out in one go, but we know that all healthcare is designed to delay death, and we have been delaying death since we've had healthcare. So this is another modality to do the same, just a little bit earlier. So ideally, pre disease, or let's say early detection of disease also follows to that that we don't do enough of so I think this is rudimental health care. It's just how our health care system will shift throughout time. Now how far do you want to push it? I also think that from the theories of aging, there's two theories that people think compete, but I think both of them are probably true. One is that we accumulate damage through time that leads to disease and death, and the other is that we have a program that we might be able to reprogram, where the epigenetic space plays a big role. And I think both of these are true, yeah, and I think they're true also based on some recent findings from Steve Horvit, who's the so the glycan clock and the epigene clock are equally old. We invented it at the same year, even published on the same date, which was 10th of December, 2013 The only difference is, there's a lot of people looking at the epigenome, and there's a very few glycan Yeah. And what Steve did recently, Steve horvit, he was trying to correlate his clock to predict maximum lifespan, which translates to every species. So any animal species he models the clock he can expect, he can predict maximum including human maximum, lifespan. And then he had a clock to predict mortality and morbidity, so to predict disease and to predict death, and the clock that predicts maximum lifespan does not correlate with the clocks that predict disease and death, which I think supports this theory that when we can eliminate the things that cause disease and mortality, we'll still have a finite clock which has a maximum Yeah, where Maybe some reprogramming therapies play a role, yeah, and that's why I think, of course, all of these things that kill us along the way to these program will always be important, even if we reprogram this, the whole fantasy of the longevity science. But I think in terms of where science is today and what we can do in the lab, we've gone incredibly far in terms of possibilities. So if you were a complete fanatic, they wanted to experiment on themselves and try something extremely radical there are actually tools to do crazy things. There's a lab at Yale that invented the technology to keep brains alive post death, even bring them back to life, things four to five, four to six hours after it's been dead. They do it for research purposes. So they keep now human brains, keeping them alive for research purposes, and they use drugs to block function to make sure these brains are not Saint yet, but it's already technically possible to keep brains functional after after death. Technically, it's possible to in Tel Aviv, because of the open regulatory system around embryos. They are cloning mouse. Embryos. Now human embryos, It's published in Nature where they can, with stem cells, take a skin cell, with stem cells, create your own embryo and grow it in an artificial womb of some other week. So if you're thinking about, where does this field go radically. We are there, like it is completely nuts. But then there's the other element where we play in, which is the health care and compressing the time we are health that we are ill, and trying to prolong all of these mortality risk factors as much as possible. We don't do anything on the keeping your life beyond a certain point.

Peter Williams  34:05

No, and again, I think that's what I think that's what Olshanskey's paper was trying to say, is that, you know, I think we've, you know, only a few of us are going to live over 100 regardless, unless something like what you're talking about comes in and and becomes more and more prominent. I want to ask you two things, because it's interesting that, and I might have read this wrong, but we're not sure what's the best dietary approach is that the way you, your group, is looking at this.

Nikolina Lauc  34:36

So I think what we're learning about glycans, because a big part of them, is influenced by genetics. They're told to eventually get to this personalized precision medicine, precision health approach, because there's no size fits all in any, agree, any, any exercise modality agrees, totally agree. Um, so that's what we're seeing. The the first kind of significant finding we had was with diets, because if you just reduce calories in 1000 people, we had the 800 people on seven no 700 people on 800 calories for eight weeks, everybody's glycan age goes down. It's all positive. But nobody can maintain 800 calories for a long period of time, it's pure suffering. Then they put them on different diet types, so high protein, high carb, different combinations, and in each of these groups, half people see benefit of a certain diet, half people see harm. And now we can predict in advance who will respond to which diet, but we can re measure them in a few months and tell them if that diet is positive for them or potentially negative.

Peter Williams  35:46

So do you think the reason why the reduction in calories works for a period of time is because you're ramping up sirtuin groups or AMPK pathways or what do you think is happening?

Nikolina Lauc  35:58

Nobody really knows, but I think that the populations we looked at are overweight, mildy weight. So if you look at a population that's not overweight, I think the finding will be completely different. So,

Peter Williams  36:13

so you think that might be because it's a little bit like Longo's work, Valter Longo's work, with regards to, you know, fasting for five days. I mean, essentially, sort of some degree of, you know, very restricted calorie restriction, and then you're going to get the the punch of the stem cells, or the potential stem cell influence after that. So you just think it's just the calorie restriction in over on in those overweight groups, just reduces systemic inflammation, and that's, that's the thing that works, or...

Nikolina Lauc  36:48

Potentially. So there's another study. I actually don't know what cohort it was, whether they were overweight or not, but on fasting, where you don't eat for a whole week, right? That's maybe I'll publish in a few months. We only measure them one at the beginning and then a week later, so there wouldn't be change in glycan age, because the half life is too long. Certain glycans did shift, and the ones that shifted were the ones that predict hypertension and insulin resistance. Yeah, there was potentially reduction of risk in those I think that with fasting, potentially as an acute stressor, it's positive meaning, maybe once a year or there could be like a amount which is good per long caloric restriction, significant caloric restriction, if you are not overweight. There is some data to show that for some people, it causes problems with their thyroid.

Peter Williams  37:42

Well, I would add to that, because we have quite a lot of patients in this route, and through no fault of their own, they are, and I would say they are. They don't have any health concerns. They're sort of the worried well, they overly fast, too much calorie restriction, and when we run muscle mass scores on them, after a year, they've lost so much muscle mass that we're going to spend years and years trying to get it back. So with great caution, I think all of this advice is and that's why this your test isn't sold to the general public, is it? It's only through clinicians?

Nikolina Lauc  38:18

So we have a consumer version. Okay? It has restricted information, yeah, and on the clinician version, we have that extended be the report I think you've seen where we show some association with potential concern areas we don't want to give to consumer because we don't want to scare anybody unnecessarily. As long as you have a trained, educated physician on the other side, we think that information is valuable.

Peter Williams  38:44

Totally agree? But as you said, you know, I've been in the game a long time on this 25 years, and we are, regardless of how well we're doing in medicine, we're still best guessing, even with the best data, because every day is different, and you've got to get a lot of data together, and you've got to trace it over a large amount of time, to be able to start, start to say that this might be the most appropriate way for you. That leads me on to what we were going to talk before. Because, again, this has become a huge interest area. I've had quite a few patients, female patients in the last few years where and again, because I've got an interest in cardiovascular disease and I've got an interest in neurodegeneration. Let's talk about and this is just not, I want to say on here. It's just, it's, this is not just female menopause. This is, I think this is male andropause as well. And so it almost feels like we've got these time frames in our human life, where age, age and health, gets accelerated in a positive or a negative way. For me in the last few years, again, I'm 55 now, but in the last few years, you know, you know, and I'm in good shape, but I've definitely started to feel a little bit more like. An old man. So can we talk about what your data? Because I find this really fascinating, because I think we're moving hopefully with people listening to this. As I said to you, probably the key thing you need to think about is your dodgy knees at 60, started when you were 20. You know your type two diabetes that you've got now at 50 didn't start at 50. It started at 20. And I think what we want to do with this testing is it becomes the predictor of it's not telling us what's going on, but it's predicting. This is the signature we're seeing, and you're moving along that pathway to potentially getting x and I think that is just super cool that we can do that. The most important thing that I see, and the most striking thing was that recent webinar that you guys did on what you're seeing with regards to what menopause potentially does with regards to glycan changes. So can we talk about this? Because it's super, super important for this group?

Nikolina Lauc  41:01

Yeah, absolutely. So we've always seen significant gender differences in the immune aging. So if we looked at these curves of men and women, women generally looked younger to men pre menopause, and then they had this rapid acceleration between the ages of 45 and 55 and sometimes earlier. And at the time, we didn't understand how menopause happened. So we're we have 60 scientists in lab, and about 65% of them are female, but nobody's above 45 so nobody realized that actually we're seeing perimenopause. But then we looked at twins, twins UK followed 2000 twins over 20 years, and we see that these this accelerated inflammation happens before they lose their final cycle, because menopause is something you diagnose retrospectively. Sure, yeah, yeah, but the criteria is one year without a cycle, plus the next day you are menopausal. But this decline in hormones, particularly estrogen, that drives the changes in glycans. Yeah, can happen to 10 years before that, and happens in different time frames for different women. It could be a few years before your menopause that your estrogen drops. It could be a decade before your menopause estrogen starts to drop, and that's it causes a certain cascade of symptoms. They're usually misdiagnosed. So you go to your doctor and you're not sleeping, you have joint pains, you have mood disturbances, and you're generally not they don't because there's no test to identify it correctly. And hormones are incredibly complicated to track, because they fluctuate, estrogen can go from 50 to 1000 in one cycle, and also the reference range is so broad, the normal range of estrogen in the first four days of your cycle is from 65 to 350 What is your normal? Normal? Nobody knows, because we don't have your estrogen from your 20s, and we don't have it longitudinally. So there's no way for a clinician to tell you that your estrogen has dropped. So it gives you, he gives you a sleeping pill or an antidepressant or something else, and a misdiagnosis up until that point that you actually enter menopause. So I think it's really important for us to catch this thing early, or to find ways how to diagnose perimenopause and also treat it early, so that you don't have to have years of suffering with symptoms. But then when we go to treatment, so we see that, on average, menopause would accelerate the clock 10 years, and on average, HRT or estrogen would decelerate the clock 10 years. But it's different dose in different women, different modalities, gel versus patch, combination of different hormones. Some women produce a lot of estrogen through testosterone, that's more PCOS, or androgen dominant type. So finding tools how to be objective about this and how to and with inflammation, we're measuring homeostasis, or perfect balance of the body. So when your individual hormones decline, you see loss of homeostasis or inflammation. And when you correctly replace those again, you see body going back to homeostasis. So it's a really nice, objective, stable tool to look at menopause in a broad space. And some things are, of course, some so estrogen, so recently, they did a study with UK Biobank where they looked at all the commonly prescribed drugs. So 406 commonly prescribed drugs, majority of them decrease lifespan or they negatively influence your health outcomes and mortality. But 14 of these drugs prolonged lifespan, and out of these 14 drugs, four were estrogens prescribed to menopausal women, interesting so we have pretty high hard scientific evidence to show that there is a lot of benefits from estrogen, but there are some small risk factors which are very, very small. Yeah, but should be carefully navigated. So we recently did the study with the estrogen the Astrazole and tamoxifen drugs in breast cancer patients, and we thought that we're going to see purely negative effect on the glycan, because we see that with loss of estrogen, you have a very inflammatory shift in your glycans. Interestingly, in some women, we saw positive effect of the estrogen suppressant drugs. So there could be that there's a subgroup of women that has really high estrogen that, for them, causes some or that has some risk factors that would benefit from the opposite. Yeah, but finding

Peter Williams  45:42

Yeah, and Nicolina., what's really interesting this in in sort of clinical practice, we had a patient who went to and again, there's no blame game. You know, trying to get people right all the time is really difficult. But she went to her GP, put her on HRT, estrogen, she didn't put her on progesterone. She was already estrogen dominant. They didn't do any testing, and, of course, so she literally blew up like a balloon. So I think what you're probably saying isn't there, there's, like, everything. There's a there's a sweet spot for how much hormones we need. And I think that's the difficulty with Well, that's why personalization, if you can, you know, if you're prepared to go down that route and you can afford, it absolutely matters. We see this time and time again. So we have a referring group that we send our people to to make sure that they are getting absolutely the appropriate doses, because they've all been tested. So, you know, that's it's been super important and super effective for us to to get that right. And I get a lot. I'm not having a crack at NHS or anything like that. It's not what we're here to do. You know, everyone's doing an amazing job, but there is a lack of personalization, which can sometimes be highly problematic. They

Nikolina Lauc  46:57

They don't have the tools. We don't have the tools. In practice, I think these tools are coming, and glycans will play a big role, yeah, but at the moment, we can play when they, you know, have nothing to go against. Do you want to touch on men?

Peter Williams  47:11

Yeah. Do you know what I was doing? Because I was trying to throw it the other way around, actually. So what I was going to say is that, is that, if you've got super lean individuals, are they who? But? But if they're, if they're optimizing their testosterone, then they're probably going to offset enough estrogen. Are they or am I overthinking that?

Nikolina Lauc  47:33

So let me talk about the study we did with men at the time that we did this study where you chemically suppressed estrogen or testosterone in men, they had two branches of the study, and the either they gave them testosterone, or they gave them testosterone plus an Astrazole, which blocked estrogen, yeah, and the ones which went on so their testosterone was low because it was chemically suppressed. If they went on testosterone, as it is, and it converts to estrogen, naturally, they saw good anti inflammatory change.

Peter Williams  48:10

So in your opinion, is the way I look at it, is that when you're using super Max, all hormones dance with each other, and they've got this, you know, communicating with each other. And you can't really have too high of one without it affecting the sort of hormonal dance. So when you give, when you give males testosterone, they have to sort of counterbalance with at least making some estrogen. That's, that's how you guys see it. Yeah. Okay, okay, so we see

Nikolina Lauc  48:39

positive effect of the transfer aromatase, so transference of testosterone to estrogen in this arm that they blocked conversion to estrogen fully. It was completely pro inflammatory, no benefit, okay? And I think that's so we have a problem on a global scale where testosterone is declining. Sure, over the years, it's dramatically declined. Yeah, in men, nobody knows why. Now there's a whole field where we are prescribing testosterone as we should, sure, because there, there's it naturally happens with aging as well. But a lot of the practice is, and this is also driven by the obesity, poor metabolic health will, yeah, absolutely, yeah, eat more estrogen, because there's a healthy level of estrogen, and you shouldn't go too high. You shouldn't go too low. So there's complication how you treat low testosterone. But a lot of times the goal is not health, it's physique, sure, then that, and this is where you have, of course, in the body building community with the steroids

Peter Williams  49:49

 yeah, aromatase inhibitors, yeah, absolutely always

Nikolina Lauc  49:52

Always block aromatase, because you they have consequences which you don't like. But this healthy level of estrogen in men we see is crucially important, and we have evidence on it, which is an interesting cohort. So I don't know if every other audience wants to hear about it, but the paper just came out, and I can share it. We did a study with Worcester Institute. Actually, they did their own glycan analysis, because they have a glycan lab, but we collaborate. Where they have, they have the oldest HIV biobank in the world, and they follow their patients for decades. And HIV is an accelerated aging model, so we looked at it as accelerated and we would see accelerated aging in HIV, predominantly also driven by the treatment or the drugs that are prescribed. Then there was a subgroup of patients born as male who went on estrogen as gender affirming therapy to transition to trans female, and in their case, they didn't see as much of a negative effect from the HIV drugs, so the inflammation was reduced. But they also had long term follow up, and they saw clinical outcome change, which was less coronary plaque, so in the patients who are an estrogen, okay, coronary plaque in this long longitudinal cohort. So there is potentially a very interesting link between cardiovascular disease and estrogen men that we don't fully understand, and that is the biggest killer.

Peter Williams  51:29

Well, look, let's, let's think about estrogen and cardiovascular disease in women, and it absolutely jumps as soon as they go into menopause. Here's a question for you. Then, given that most men we were talking about so the more overweight you get, the more estrogen you produce through aromatase. And of course, we can talk about environmental factors, etc, why would so my question on that. Then, given that you take get probably as as male age. Males age, they become more estrogenic to sort of androgenic. Why is it that we don't see positive changes there? So my point about this is, is it because you need to have optimal testosterone levels there are producing the estrogen. But I'm trying to work out why the other situation is different, given that the other given that estrogen is so dominant on this you know, why is it that overweight individuals who likely produce more estrogen aren't having beneficial effects? Is that, simply because we're not accounting for the basic systemic inflammatory response that you would have on people who are overweight. It's

Nikolina Lauc  52:45

probably also because there's different types of estrogen, and I think that's the complication, and the one that's produced by fat is very different to the gonadals. So maybe that is good question look at to fully understand, it's kind of like, yes, there's a theory that estrogen is an anti inflammatory, but it's probably not an anti inflammatory, because you can't treat autoimmune patients with estrogen. There are some cases. So rheumatoid does go spontaneously into remission during pregnancy, potentially driven by the special estrogen that's released in pregnancy. But we have even had some clinics try to treat some autoimmune patients with estrogen, and it didn't change the trajectory of the disease or cause a scale of symptoms that just didn't support it. So it's probably just a tool to keep homeostasis. So it's one of these that needs optimal balance. It's not too high, not too low, and that's the complexity, because these levels are different person to person. And if you Yes, if you have somebody who's overweight and metabolically unhealthy, they will aromatize a lot. They might even have low testosterone, very hard to replace it, because they will aromatize more and have more side effects. So maybe that point you need to start with the inhibitors the the block the estrogen conversion until they become metabolically healthy and fit, meaning they will be pro inflammatory in that period of time. But after that, once you've made them metabolically fit and metabolically healthy, you should stop the aroma, the inhibitors, and try and get them to a healthy inflammatory profile

Peter Williams  54:42

where, where is your group going next? What? What is it? Because your beta report really good. I think I love the way it's been updated, because, again, it's it's becoming more and more patient friendly. It's really good for clinicians, because, in a sense, it's giving you sort of the predictive aspect of what we've got to think about. And of course, if you've got a good case history, family history, you can sort of look through that as well. What's the next steps, and what we want to make sure is that we'll obviously link to the website for everyone on the podcast. What are you guys looking at now that you'll probably end up writing a new paper on what's what's next.

Nikolina Lauc  55:26

So we have two places in the website. One is the glycan age, slash publications, where you have all of our publications and we publish about 30 papers per year as a group. And then we have a research matrix, which looks at the whole industry. That's a separate link where you can look at glycans in because we don't do a lot of cancer research, but there's a lot of cancer research happening in the glycan space. So I'll share both links so you can add on. Yeah, sure. The website is very commercial, and there's these nice science areas that you have to, like dig a little bit to find. On the report side, there's so what we did with the new reports, the ones which are for practitioners, we expanded the areas for you to try and map up what's happening, what individual risk factors are driving something in a patient, and what current research we have on interventions that you can correlate with that and start to create this picture of what's going on with the patient, because if we just say their inflammation is high, that doesn't give you a lot of information, and we actually give you a lot of information, information from these glycan signatures. So hopefully that helps with understanding the drivers and the actionable points around the patient. Of course, we haven't figured out everything. I think there's lots of gaps in around stress and many drugs therapies that haven't been and lifestyle changes that haven't been studied. Yeah. And

Peter Williams  56:53

as I said to you, I think what's been great about your group is that you're very open for me getting on a call and saying, Well, I've run these genes. How does that link into this one? So I think if you keep on going like that, you can only be a success. Let me ask you one more question, because I know we're way over the hour, and I really appreciate your time again when we're talking about the longevity groups, you know, a lot of people again, sort of, I think, falsely get an impression that if you take NAD plus, you know you're going to live to 125 it's, it's based on your research, and the way I'm reading it, there's not a huge amount. As far as it's, these are really going to help you out. As far as your glycan age is that, right? There's, there's not a huge amount that may be helpful. I mean vitamin D, maybe optimizing vitamin D levels.

Nikolina Lauc  57:45

So we did a little bit research on omegas and NAD boosters, and there was a very small positive effect in both with NAD boosters. It's one point, 26 years change. And if you ask a hard scientist, they're going to say, this is on the borderline of being significant. Yeah, they

Peter Williams  58:07

probably say, if you're prepared to pay for the money for it, and then, yeah, okay, it might be worth the chance, but it's, it's not going to put 25 years on you, but

Nikolina Lauc  58:16

it did show a bit of a positive effect. So maybe there's something to try and then see, because nothing works for everyone. Yeah, that's the challenge. You have to try different things and see what's really important for you. And I think, of course, there will be some supplements, especially linked to deficiencies. Yes, important. We just haven't yet progressed in that science. And you know, there's, there's obvious things, vitamin D, there's a bit of science, but not looking at what we look at, like certain glycans, but not the whole aging component. Of course we want to study that. We want to study deficiencies, especially linked to the brain fog, depression, kind of all the mental yeah sides of it, and then linking to dementia, where we have some links already. So there, there will be, but it's individual. You have to figure out what it is for a patient, which is your work, and you've

Peter Williams  59:12

got, you've got to find, you've got to, you've got to test for, for the nutrient patterns, and then adjust from there. So, and my question on that one is that which, again, I probably, I don't know how you would study on this, given that we're not quite sure how much do you think the microbiome plays a role with regards to glycans?

Nikolina Lauc  59:32

Huge, huge. We did some super small study with IB now, orcertainly colitis patients with microbiome transplants from a healthy donor to a diagnosed patient, and we saw significant changes in the glycans  Interesting. Okay, so I think that field needs to progress further and further, and we need to look at different interventions for the microbe. And that could be a very strong link. And it's also very linked to auto immunity, yeah, so I think all of that will end hormones, and, you know, that will be an interesting space to go after. I think the you were mentioning about the space and the claims, and I think it's challenging, because a lot of it is pure marketing, yeah, I agree,

Peter Williams  1:00:21

yeah. And look, I think that's the, that's the sad thing about, you know, we're all valuable. We all want the magic pill. We know there isn't a magic pill, but, you know, and again, look, it says, like we said about NAD, slightly positive result. Okay, so Well, you know, if you want to pay that sort of money, that's okay, but it's not gonna, it's not going to be the elixir of youth for you, but, you know, it's something that you might want to think about.  In summary then looks, we would go on for hours here, and I would love to have you back on, because again, I just think this is, you know, it's quite an really interesting test, and definitely one of my favorites at the moment. So in summary, what would be the what would you say to the man and woman on the street who is interested in preventative and predictive aspects to their health? Because this almost feels like before you do any other testing, maybe this is the first one you do first, to give us an idea of where you're sitting currently with this, because of its predictive nature across the board, and then you can sort of start doing all the other testing and find out, and then come up with a strategy, and then play that strategy out for three to six months and then re test this. What is, is that the way we're we're looking at this test, is that the way you see it, is that the future that you see it becomes more and more of a here's the starting point.

Nikolina Lauc  1:01:50

Yes, I think that in this will I with time and painful work of proving out the health economics to the healthcare system, I think this will be a screening tool that we do for very broad population, very early on, especially for the cardiometabolic risk factors. And the age starting age as healthcare is right now, probably this will be 40, if you're talking about the NHS, but ideally it should be earlier. And I think that the earlier you start, I mean, I started measuring this when I was 24 and gave me a lot of useful information throughout the almost 10 year period. Now, I think the earlier you start with it, the better. And then, if you're in a good place, once a year, if things are accelerating, there's something happening more frequently. To see what's going on, what helps doesn't help. It's, I think it's useful, all of these things that, unfortunately, the healthcare system doesn't give us now we need that information later on when we get to treatment and problems we should, we should cover by ourselves. You know, as we pay for expensive coat or laptop or phone, yeah, it's something we should invest in

Peter Williams  1:03:01

your pricing is quite reasonable. We

Nikolina Lauc  1:03:04

don't have a big margin to make it as accessible as possible,

Peter Williams  1:03:08

yeah. But I think your pricings, I don't think your pricing is, I can't remember a bit, a couple 100 quid is it? Just remind me, 200 Yeah, I think is, I think is really reasonable for the amount of data you get off it. You know, I don't feel as though you've been ripped off with that at all. And so I think it's a really reasonable cost.

Nikolina Lauc  1:03:26

And I would add to that, if you're in your early 20s, measure hormone profile as a man and woman, to know where you are in your 20s, when you get to 30s, 40s.

Peter Williams  1:03:34

So this is the exact conversation I would, you know, but no one's going to do that, because the key thing is on this is that we don't know what optimal looks like. And so if you are listening to this, I would strongly recommend, in each decade, when you're feeling amazing, that you get a whole host of testing done so that we can have a look at what amazing looks at each decade. And because that's going to give you a sort of ground zero of Well, here's what, here's what optimal looks like. As far as close as we can get. No one's ever. No one does that, of course, because they're only, they're only testing when they're not in great shape. But maybe things would change. Nicolina, thank you so much. That was really super interesting for me. As I say, I'm, I'm increasingly interested in your test. So I get quite excited when I can have conversations with people who know a damn site more than I do. It's really cool. So with that note can we have you on at a later date, whenever that is because I know I'll have done more tests, and you guys will have more information, and I would love to get into when you're having maybe some of your science, because I sort of, I've done it a little bit when some of your scientists are maybe having a sort of round table. I'd love to come in and just wax, wax about, Well, why would you do that, and why would you do that, and what would you do with this? And that would be awesome as well. I really appreciate it. Yeah,

Nikolina Lauc  1:05:00

Yeah we are starting case reviews, so one of those case reviews. That's something that I'll be up for that. Yeah. And we do have a journal club, which is purely done in our institute, which is very technical. So I don't know if you're keen on that, but we always have space in the journal club. 

Peter Williams  1:05:17

No I'll leave other people to do the technical stuff. I don't think that's my strength at all, sort of trying to work out what's going on. I've got a better chance. But no, I'm that's not the way my brain works at all. So listen, I really appreciate your time. Thank you so much. I think everyone is going to love this episode, because it's just, there's so much you can do. And this is not poo poo science again. There's a lot of stuff out there that is just, you know, I hate to be the doomer of gloom half the time saying, Well, look, you could, you could spend 150 quid, but really, actually, the science just isn't validatied on this, whereas yours has decades worth of evidence to go, to go with it. So you can be comforted that the test is the real deal, which I think is kind of exciting. Th