The Newest Biomarker Of Aging: Breaking Down The GlycanAge Test In Detail

Lauc, PhD

Thank you for the invitation. Pleasure to be here.

Joseph M. Raffaele, M.D.

Yeah, I’m looking forward to talking to you. Dr. Lauc is a professor of biochemistry and molecular biology at the University of Zagreb and director of the National Center of Scientific Excellence in Personalized Healthcare. Honorary professor at the University of Edinburgh and the Kings College, London, and member of the Johns Hopkins Society of Scholars. In 2017, he initiated the launch of The Human Glycome Project and is one of its two co-directors. His research team is pioneering high throughput glycolic analysis, and application of glycan biomarkers in the field of precision medicine. By combining glycomic data with extensive genetic, epigenetic, and biochemical and physiological data in a systems biology approach, they are trying to understand the role of glycans in normal physiology of disease. 

Professor glycan, oh sorry, we should call you Professor Glycan. Professor Lauc has authored over 200 research articles that are cited over 5,000 times. He was PI and co-PI for four NIH and two FP6, seven FP7, and six H2020, and three ESI Funds projects, and coordinated five of them. In 2007 he founded Genos, a biotech company that is currently the global leader in high throughput glycomics. Welcome again, Gordon. I’d like to start this conversation by having you introduce to our listeners some basic glycobiology, ’cause they may not be familiar with it, as I wasn’t until about a year and a half ago.

Gordan Lauc, PhD

So glycosylation is the most elaborate and the most abundant post-translational modification. So glycans are chemical structures, complex oligosaccharides, which are being added to proteins post-translational. So they’re not encoded in a single gene like the polypeptide part. They’re encoded in the network of hundreds of genes, which enable proteins to like immunoglobulins to acquire mobile functions, even after the gene for a specific immunoglobulin has already been defined. And I work in the field of glycobiology for I think over 30 years now. And we established a field called high throughput glycomics, where we started to analyze thousands and thousands of glycans from different people. 

So kind of similar to personalized medicine, we are trying to do personalized glycomics. And we already analyzed over 150,000 people. And by analyzing so many people from many really well-characterized cohorts from all around the world, we learned that glycans attached to immunoglobulins are highly correlated with aging. 

And other people also work on IgG glycosylation, and immunoglobulins are the best selling drugs in the world for a decade already. And we know that these glycans have many regulatory roles on immunoglobulins. And one of these roles is the regulation of low-grade chronic inflammation. So if there is a specific type of glycans, which usually we find in young people on immunoglobulins, these immunoglobulins actually suppress inflammation. They do not allow this low-grade chronic inflammation to be present everywhere. 

But if glycans are changed, if different glycans are added to immunoglobulins, the pro-inflammatory glycans, which are usually shorter, they don’t have a galactose and a sialic acid on the end, they become pro-inflammatory. And this is something that we usually see in old people. We see that people have glycans, which are pro-inflammatory. So they’re actually promoting low-grade chronic inflammation. And in this way they are significantly contributing to the inflamm-aging So they’re doing damage to the tissues, which is then manifested as aging, but also as age-related disease.

Joseph M. Raffaele, M.D.

Yeah. So it’s a whole new area of biology that’s really fascinating. As a biomarker of aging, sort of telomeres are biomarkers of aging, you can have epigenetic DNA methylation. The correlation, is it sort of linear across from, you know, say twenties to eighties, or is there kind of, you know, an acceleration at some point? And what’s the spread on either side? In terms of years?

Gordan Lauc, PhD

It’s different in men and women. So when you look at the men, men have more or less linear increase in glycans from their kind of early twenties, when they are the most suppressing inflammation, to the old age when they’re more pro-inflammatory. In women, the curve is little bit different. So the biggest change happened around menopause. So before menopause women usually have less of these pro-inflammatory glycans than men. But then in perimenopause, it accelerates rapidly, and they quickly catch up with men, and actually go above the men average for short period of time. And then they kind of kind of look similar later. So it’s different men and women, and it does change with time a lot.

Joseph M. Raffaele, M.D.

And when you give a glycan age to, they get the test from your lab, and say a woman is 60 years old. Is that her glycan age against a untreated post-menopausal group, or it’s against no treatment? Because, and that’s how you and I sort of met, because I started ordering your test. And we saw that some of our patients, particularly men and women, but had much younger glycan ages, and everybody in my practices is on some sort of hormone optimization. There’s a big impact there, we were, you know, talking about that. I know a lot of our listeners practice hormone optimization. And so, talk a little bit about that, what happens with the hormones? ‘Cause I know there are other things that impact glycans, like lifestyle, body fat, metabolic health, hypertension, et cetera. But I think, you know, one of the biggest impacts is hormones.

Gordan Lauc, PhD

So our baseline is the general population. And in the general population, the majority of people are not doing hormone optimization. So I would say the baseline would be people who do not do hormone optimization. And the glycan age as index we have, is modeled based on these thousands of people we did in the past. So we kind of say your glycans look like an average glycans of person of 58, 75, or whatever year old. As you mentioned, we got quite puzzled with your data. And actually my statisticians were initially wondering what went wrong, and why are all the samples which we are now analyzing, coming from your labs so much younger. Until we started talking and doing more and more people, and realized actually that what you do in your practice is actually making people look younger on our glycan age test. And here I would like to stress one very important aspect. 

And this is that glycans, immunoglobulins and our glycan age, they are not only a biomarker. For example, if you talk about epigenetics, methylation on a specific CPG site is just the biomarker. We don’t know anything about its function. And people, original Steve Horvath’s epigenetic clock is something like, I think the 373 CPG marks. Glycans are functional effectors. So these are molecules which either suppress or promote inflammation. So if somebody has more of these glycans which suppress inflammation, we know that inflammation level will be lower. And if there is more of these glycans which promote inflammation, we know that they’re actually promoting inflammation. 

And now we know that this low-grade chronic inflammation is behind so many different chronic diseases. That actually we can be very confident that having a lower glycan age is something which is good. Which is associated with a lower risk of a disease, or a milder disease. And something else which is also very important. When we look longitudinally, glycans usually change first. In some diseases, they change up to 10 years before the disease is actually diagnosed. Because you know, disease, this is a name which was given by physicians for a condition when people appear to the hospital, because something does not work. 

There is pain, some organ doesn’t function, and then you get a disease name. This does not happen overnight. This is a long process where the body is first trying to compensate for a problem. And then when all the compensatory mechanisms fail, there is disease. And glycans in immunoglobulins are one of the early things which happen. So before you get ill, your immunoglobulins become pro-inflammatory. They start to do damage. And what we haven’t proven in humans, we have some evidence in animals, that if you improve glycans, disease does not happen. For humans we only have correlation, glycans change first, and then the disease appear.

Joseph M. Raffaele, M.D.

Which specific diseases are you talking about? Just out of curiosity.

Gordan Lauc, PhD

So we have one study where we have shown that by preventing these bad glycans, you can prevent hypertension. And this was done on mice. Mice were fed a high-fat diet. And on high-fat diet, they became fat and they developed hypertension, and their immunoglobulins were hyposialated. They had less sialic acid, which is this young immunoglobulins. And when mice were fed N-acetylmannosamine, which is a precursor for sialic acid, their immunoglobulin glycans preserved this good glycosylation. So they kept young immunoglobulins. Of course, they got fat on high-fat diet, but then did not develop hypertension. 

So actually, by preventing aging of immunoglobulin glycans, it’s possible to save mice, obese mice, from developing hypertension. For humans we do not know. We did study a small cohort of healthy people, where we did not see a big change after taking mannosamine, but we do not know whether actually in obese people taking mannosamine would improve glycosylation and contribute to the decrease in hypertension. 

Something what we published only a couple of days ago is that we were tracking 2000 twins in UK for 20 years. And then we have shown in the study, and actually there was a replication cohort in Germany, that glycans today are predictive of hypertension in the future. So maybe this could also work in humans, that if you improve your glycans, you will not develop hypertension in the future.

Joseph M. Raffaele, M.D.

And well, that’s really fascinating. Would that, I would imagine, that would probably also extend to atherosclerosis. Have you looked at, and there’s mouse models of atherosclerosis as well, particularly with the high-fat diet. I wonder whether there’s an impact there. Because, particularly women, you see women going through menopause, they’re very well protected. We thought it was from the estrogen before menopause, that from getting atherosclerosis. And then afterwards their coronary calcium scores start going up, their carotid intimal medial thickness goes up, and their events start going up, they catch up with men relatively rapidly. And I suppose that could be because of the change in the glycans that occurs with the loss of estrogen. Do we have any… Go ahead, sorry.

Gordan Lauc, PhD

Of course hypertension and all cardiovascular or all other kinds of metabolic diseases are very complex, and they’re very different in different individuals so we cannot generalize, but I guess that this is one of the important mechanisms, because we know that inflammation is important. We know that these old glycans are pro-inflammatory. And for example, in women, we definitely know that estrogen, actually in both women and men, estrogen is improving the IgG glycan composition. We had one proper randomized placebo-controlled trial where the menopause was chemically induced. 

And then in the placebo group, we saw a huge increasing in glycan age. I think average was nine years in six months. There was some woman who age for 20 plus years in a few months, while in a estrogen groups of people, where the estrogen was returned with this estrogen patch, there was no change in the glycan age. So definitely estrogen is causative. And it does improve glycans. And interestingly in men, if you give testosterone glycan age also improves, but if you block aromatase, the enzyme which converts testosterone to estrogen, there is no effect. So it’s actually estrogen which is improving IgG glycan in men too.

Joseph M. Raffaele, M.D.

Yeah. And that’s a very, you know, when I heard that, I had always been cautious with Arimidex, or anastrozole, any aromatase inhibitors in my practice. But other practitioners I think use it, because they think estrogen is a bad thing in men, but a certain level of estrogen is very important. And here’s another reason why you don’t want to block it down too much, because you’re gonna lose that benefit. And the benefit is, just turning to men for a second, the benefit is really quite significant. 

The average glycan age in my practice on men that are on testosterone replacement therapy with good youthful levels, is 25 years younger than their chronological age. And you know, that is, it’s a fit group for sure, I mean, they’re working out, but we see a change when they come in, even if they are fit and with low testosterone levels. So, you know, we’re up to about 160, 170 patients now we’re looking at, we’re gonna try to see what other factors might be involved there. But it’s interesting to me that it’s even more in men. I don’t know if you saw that in your study, whether there was a change, a bigger change in glycan age in men when they knocked out the estrogen from the testosterone.

Gordan Lauc, PhD

So definitely, so this was not, it was a different study. And in that study, we did not look glycan age specifically. It was a little bit older study when the glycan age was not, we were not able to measure it then. But what we did see is that this change from young to old glycan did happen if the gonadal hormones were blocked, and it did happen if the conversion of testosterone to estrogen was blocked. But if the testosterone was returned, and there was no inhibition of this aromatase, then the glycan age did not change. Not the glycan age. The IgG glycans did not change in the direction of older glycan age. So definitely I think just blocking the conversion of testosterone to estrogen would not be beneficial in the respect of inflammation and immunoglobulin glycans affecting inflammation.

Joseph M. Raffaele, M.D.

Yeah. I mean, I think that’s, we know in other things, for bone health and for arterial health, that it’s important to maintain a certain level of estrogen. I always tell my patients, women come in, post-menopausal women, that, you know, their husbands have three to four times the amount of estrogen circulating in their blood than they do, and that’s, you know, time to get back up to at least a man’s level of estrogen. So, I mean, I think that this test that you have available, which by the way is really great, because there’s a blood spot. 

It can be sent to the patient and readily done, is I think gonna transform menopausal and andropausal medicine to a certain degree. I know you’re working with Louise Newson in the UK, you’re doing a trial looking at the effect of estrogen replacement therapy or hormone replacement therapy on glycans. You know, it seems to me that all the benefits that we thought estrogen had prior to the women’s health initiative, you know, have been turned around with a reanalysis of that data, and looking at it with a better lens and the timing hypothesis, et cetera, but having this tool to know whether or not a woman has gotten back her anti-inflammatory glycans, I think would be pretty revolutionary. You’re looking at it as a marker for perimenopause, and for even potentially adequacy of therapy in menopause.

Gordan Lauc, PhD

So we haven’t published anything on that yet. We only have this study, which was where menopause was chemically induced, but we have some initial data. And something which seems fascinating to me is that glycan age can deteriorate rapidly in women in perimenopause, especially in women who had very good glycan age before. So we have seen patients changing for 30 years within a year. And interestingly glycans change before any other symptoms appear. So we had a situation where women were shocked with what happened to their glycan age. And they said that “But I have no symptoms. I have no problems. Everything is okay.” And then couple of months later, all the symptoms of menopause appeared. 

And this is why, the reason why we see that, is that estrogen really directly regulates IgG glycosylation. And it regulates it in a kind of a long-term manner, because IgG we measure today is made in the last couple of weeks. So all the alterations in the hormone levels, which happen at that period are kind of integrated in a glycan age. You can still have spikes of hormones, you can keep other things functioning, but the glycan age, each immunoglobulin glycans will be changed. And I think this is very similar to way HbA1C, the glycated hemoglobin, can be used to track the average level of glucose in the past weeks. In the same way, glycan age can be used to track the level of estrogen in the past weeks. 

So it could be a very early warning signal that somebody’s entering the menopause. And of course, we still have to do a lot of research. We have no ideas whether it’s better to start therapy early, whether you get the same result after couple of months without hormones, there are many questions which we are interested to address, and we are trying to do as properly designed studies as possible. And of course, we are extremely interested to collaborate. Especially if somebody already has, you know, hundreds of samples in the fridge, we can do a very quick study to see what happens with IgG glycosylation in women, in this very sensitive period, where there are so many changes happening in the body.

Joseph M. Raffaele, M.D.

So I’m just curious about the change of, if you get a big increase in glycan age at the loss of estrogen. I don’t know if you’ve looked at this, but prepuberty does a young girl get a change in her IgG glycosylation when she goes into menarche?

Gordan Lauc, PhD

So we, you know, working with kids, it’s a little bit more difficult. So we haven’t done so many children, but we have done a couple of hundred. And for example, boys and girls look very similar before puberty. And then with the onset of puberty, girls start to change very rapidly. And it’s a little bit strange, because actually kids, before they develop this hormonal status of an adult, actually have very pro-inflammatory IgG. So young kids look like much older adults in their IgG glycan composition. And we know from experience there, kids are actually extremely pro pro-inflammatory. 

Their immune response can be very explosive when there is some kind of inflammation going on. And then this is suppressed with the hormones for the reproductive period of their lives. And then they go back as old into the older individuals to be more pro-inflammatory. So I’m actually very enthusiastic about what you do with the hormone optimization. And I think this could actually help alleviate many problems related to inflammation, which should link to all these diseases, which are now burden for the planet, because we are all getting old.

Joseph M. Raffaele, M.D.

Yeah, I mean, we see with testosterone for instance, and as well with with estrogen, that things like insulin sensitivity improve, you know, you lose body fat, and so all these metabolic changes that occur. There may be some kind of a mechanism through the IgG glycans, which is how this is taking place. So, you know, I think it’s revalidating this concept that humans, both males and females, need a certain level of estrogen to have an optimal aging, particularly from an inflammatory standpoint. Are there any other genetic factors that figure into this? I mean, we’ve been talking a lot about hormones. I mean, what percent of is heritable, do you know?

Gordan Lauc, PhD

So we did a number of heritability studies, and for the different glycans in IgG glycan, heritability is between 30 and 75%. So on average we can say maybe approximately half of the composition is genetic. Meaning that if your parents have kind of older glycome all the time, you will be in that direction maybe. Approximately 50% of the variation can be explained by genes. And it’s extremely complex network. We have already mapped over 40 genes, which work together to regulate IgG glycosylation. And they’re not enzymes which actually put glycans, they are different genes which regulate the immune system. And another very important aspect is lifestyle and environment. 

Obesity is a very strong factor. So with increase in the body weight, glycans age faster, and we also did on the same 2000 people, which were tracked three times, which were analyzed three times over 20 years, we have noticed that, and these are mostly women, they are from the twins UK cohort, which are mostly female. 

And we noticed that the women which were gaining weight over these time points, they were aging faster than the women who were losing weight or not changing their weight. So by gaining weight, you actually accelerate this inflammatory process. And then by losing weight, you can improve it. So one of the easy things which we all can do is just take care of this extra body fat, which we don’t need. And this is also improving this IgG glycome. But interestingly, there does not seem to be a magic diet. We did a study of thousand people on five different diets, including the high glycemic index one. And each of the diets were beneficial for some people, and they were very bad for other people. 

So IgG glycome were changing in both directions on all type of diets. So actually one has to try what works for him or her. And the same goes for exercise. So we all tend to believe that, you know, you eat too much, you just have to exercise a bit more, and then you are fine. And this may be works when you are a kid, or when you are young, but as you are getting older, you cannot sweat out what you eat. And people who overtrain tend to get also pro-inflammatory, and get very bad glycan age. 

For example, initially, we were thinking that the gyms would be a good place to start working with the glycan age, and helping people improve glycan age in a gym, but then it turned out that most of the personal trainers, and most of the people who are fanatic about going to the gym, actually got worse. And if you take middle-aged people, and try to work with them intensively, they also get worse. So yes, exercise is important, but there has to be a sufficient relaxation time. And there has to be sufficient time to compensate for all this pro-inflammatory aspects of exercise. 

Because, you know, you do need some level of inflammation to start your muscle expanding. But if you do this in a chronic way, then of course you increase this low-grade chronic inflammation, which is bad. So we are now trying also, we are doing several studies to try to find a optimal way of exercising and relaxation, which would help you to improve your glycans. So it’s a very interesting field of study too.

Joseph M. Raffaele, M.D.

Ah, what’s this? Something’s popping up, sorry. Yeah. I mean, I have ultra endurance athletes in my practice, and then even like CrossFitters and people who are really going at it, and one could use it as almost a biological WHOOP. Are you familiar with the WHOOP device that you wear, it tells you about the strain on your body? Well this is sort of a molecular sort of integrator of it over a longer period of time. Like you said, three to six weeks for the glycans to change. And particularly if they’re premenopausal and you know, relatively younger, their thirties or forties, if they’re glycans are a lot higher, and they don’t have to carry a lot of body fat, and they’re probably over-training. 

And it’s a good way, I was thinking, it’d be a good way to tell them, you know, “Maybe you need to put in some more days of rest, and we could track it to see whether your glycan age is responding to that.” I think that could be another fantastic way in people who are not even on hormone optimization to see whether or not… So the opposite problem, the people that aren’t exercising enough, and are overweight and they’re eating too much. You do have the other side of it. I mean, I’d love to see people that sort of do Ironman triathlons and, you know, I saw this one guy, did one a week for a year around the globe. I mean, what do his glycans look like? This kind of stuff is probably not good for you in the long run. And it’s good information to tell patients.

Gordan Lauc, PhD

You know, this is not surprising, because the professional athletes are old in their thirties now. And you cannot put too much stress on your body and do not expect to have consequences. And one thing which I forgot to mention also the psychological stress plays a role. So it’s also important to have psychological relaxation, to feel good, and to have sufficient amount of exercise, but not too much. Healthy food, but not too much. And then things are in kind of a balance, which is, you know, there’s no magic. We all know what is good and what is not good. The problem is that we all think that we are fine. 

Now you look yourself in the mirror. You are same as yesterday, you don’t see anything. And unless you have some kind of pain, and even if you have, you can take a pill and the pain goes away, and you just go on and go on and go on. But there’s a wear and tear in your body, which you cannot see. And then usually, at least for men, you know, we stop after the first heart attack or stroke, but then it’s often too late. So ideally I want to get an early warning signal. To tell me, you know, you are not going in the right direction. And I don’t want to wait for 20 years to get the feedback.

Joseph M. Raffaele, M.D.

Right.

Gordan Lauc, PhD

I want to get feedback as soon as possible, so if I start losing my weight, I want to see an effect in a couple of months. And if it’s not working, then I can try something else. And this is where I see a huge potential of this test which we have developed, is that to help people motivate themself to do a difficult decision. Because I know skipping that extra cookie is a difficult decision. Skipping that extra beer or whatever is a difficult decision. And people need rewards. And if you get your reward after few months, you see your glycan age is going down. I think it can help people. That’s kind of an idea.

Joseph M. Raffaele, M.D.

Yeah, no question. Do you see any, ’cause I know people practice this. Do you see any relationship between intermittent fasting and glycan age, or is that going to be correlated to if there’s weight loss or not?

Gordan Lauc, PhD

So we haven’t done a proper study of intermittent fasting. My guess is that it would be beneficial. At least we know that intermittent fasting is a good for your microbiome. Then your microbiome, because now the problem with eating all the time is that in your guts there is always food, and then the most aggressive bacteria grow. While when your digestive tract is empty, then only bugs which can attach to your gut endothelium and actually graze on the glycocalyx survive. 

And this is our evolutionary symbiosis between the bacteria we like, and our glycocalyx which is feeding them. And if you do intermittent fasting, then you have these selection periods where you get rid of all the aggressive bacteria and only the ones you like you keep them. And we know if you improve your microbiome, you will improve your glycans. So we had several studies with a fecal microbiome transplant, and yes, improving the microbiome improves the glycome. So I would guess that properly executed intermittent fasting after some period would improve the IgG glycome, but we haven’t done a study yet. So if you know somebody who might have some samples in the fridge, more than happy to look at it.

Joseph M. Raffaele, M.D.

I don’t know, Valter Longo might have some, he’s done the sort of fast-mimicking diet. He’s done a lot of research on that. He’s a possible person for that. I don’t have anybody else that I know that has samples. You know, you mentioned hormones, you mentioned stress, both psychological and physical, as things that affect the IgG glycome. Those are all sort of same sorts of things that affect telomere length and telomerase activation. I’m wondering, I did a quick look and I didn’t see anything much. Is there any research on relationship between telomere biology and glycan biology?

Gordan Lauc, PhD

So we did look in a couple of cohorts. We haven’t seen a huge correlation. No, I think one of the key problem with the telomeres is that first, how you measure them. Some of the cohorts have telomere measurement which is not extremely reproducible. And the second thing is it’s heavily biased with the composition of the cells seen in the blood. So it’s, you know, telomeres are a fantastic biomarker for an individual cell, but on an organism level it’s little bit more complicated. So yes, we were talking to Bill Andrews couple of times to try to do something together with him. He’s also very enthusiastic about it, but we haven’t done anything yet. So eventually, yes, we will look whether the same intervention has the beneficial effects for both telomeres and the glycans.

Joseph M. Raffaele, M.D.

Yeah, we just recently published an effect of TA65 on immunosenescence, CD28-negative cells. And it was a reduction in them. Presumably we think through telomerase activation, sort of senolytic-like effect, although we don’t know whether the cells went away, or whether they were just turned back in to CD28-positive cells. But, you know, the immunosenescence that takes place is I guess tracking along, or is there some relationship between that and the glycan change, so that it becomes more inflammatory? 

I mean, we are now collecting the samples of patients who have, we have, you know, the lymphocyte subsets with the senescent cells, and telomeres and the glycan agent, we’ll see if there’s something there as our sample size gets larger, but it’s not, you know, of course a controlled trial. But I wonder whether there’s any thought about that sort of correlation between the senescence that we know goes up because of replicative senescence, loss of telomere length, and the change in the glycans maybe in the, I mean, this is a post-translational thing, so it’s not gonna be in the senescent B cells, it’s whatever pathways are affecting that glycosylation of the IgG, and whether or not there’s an effect there.

Gordan Lauc, PhD

Something what we know, that when you have cells in culture, and when they’re getting older, they change glycosylation of immunoglobulins they produce. So definitely there, I would expect to see an effect, but, you know, cell culture, and the human body, they’re two very different things. And, you know, we cannot look, you know, we are a complicated machines. We have evolved for billions of years to compensate for all type of problems, to fight all possible threats. And I think one of the most, well, we have two very complicated systems. 

One is of course our brain, which is immensely complicated. And the other one is our immune system. Our immune system is keeping us alive against all these crazy bugs, which mutate like crazy, they mutate all the time. And we still survive. So this is a very intricate and a complicated mechanism, which has to balance fight against infectious agents, against on the other side, there are tumors which can occur, the mutations in cells. So it’s, you know, I think this is all very complicated. We cannot simplify it too much. I think yes, glycans and senescence and telomeres are correlated in a way, but I think there are still separate aspects of this whole process. So we have to look at telomeres, we have to look at methylation, we have to look at glycans, and then try to integrate all this data.

Joseph M. Raffaele, M.D.

And you get more information, you know, they measure different things. And they’re all important processes. And what’s interesting is that there are ways to impact them, different ways for different systems. And I mean, I think your glycan age marker is great because, you know, even if you have a good lab, like Repeat Diagnostics, doing the telomere lengths, and they can do also the neutrophils, which are not subject to changes because they’re really reflecting the bone marrow stem cell. It’s a longer process with glycans. I thought it was three months, but you’re saying really three to four weeks, you can get a significant change in the glycans. How often do you think people should test to see, you know, what the effect of .

Gordan Lauc, PhD

Depending what happens. So if there is no major change in the body, it’s months. They don’t change very rapidly. But for example now, we were doing lots of studies on COVID in the last year, and people who had severe COVID, we saw a lot of changes in their IgG glycome in a matter of two weeks. So they would gain, I don’t know, 10, 15, 20 years in a couple of weeks. And it was the worst. So people who died actually had the most significant changes. It’s still unpublished, but this is what we have seen so far. So when there is rapid change in the body, like a infection, and maybe hormones. So what we are doing now is just looking how quickly the glycans would change after the start of the hormone replacement therapy. Then it could be faster. So for example, we have a cohort of women, which we are tracking now every two weeks to see how rapidly does it change, but in things like weight loss or exercise, usually we don’t see anything before two months.

Joseph M. Raffaele, M.D.

And I think you also mentioned when we talked before, or maybe it was in another with the Nicolina, that there isn’t that much change across the menstrual cycle. So if you have a premenopausal woman, you don’t necessarily have to do your test at the same time of the cycle. Is that correct?

Gordan Lauc, PhD

For majority of women, there are no huge changes. Maybe a few percent. We have seen examples of some women where the changes were more significant. So it would be better to try to kind of match the similar phase of a cycle. But if it’s the longer term, it’s not so important.

Joseph M. Raffaele, M.D.

Oh, okay. So maybe try to do the luteal phase or the follicular phase, and just keep that same one. It doesn’t matter necessarily which one. Speaking of hormones, are there any other hormones that impact glycans that you think, significantly? Is there any research on, I mean, I have quite a few patients on growth hormone, IGF1 one increases. I don’t know, you know, I haven’t seen a signal yet, but.

Gordan Lauc, PhD

We’d don’t know.

Joseph M. Raffaele, M.D.

Cortisol? ‘Cause cortisol is the sort of the inflammatory one.

Gordan Lauc, PhD

We haven’t seen huge effects of dexamethasone.

Joseph M. Raffaele, M.D.

Oh, really?

Gordan Lauc, PhD

Yeah. So dexamethasone doesn’t do much in a short term. So in the long-term of course it does, but for example, we know that, okay, TNF is not a hormone, but it’s important signaling mechanism. So if people are taking monoclonal drugs against TNF, we can see a very strong effects. In some people, in some people not so strong. So I would guess that many of the immunomodulatory monoclonals could have a strong impact, but these are not things people take regularly. These are drugs for different conditions. So, you know, the thing is, glycans are very novel. So the technology to measure them in high throughput is here only for maybe a decade. We managed to develop this dried blood stain testing only two years ago. Because previously we had to have a frozen plasma, and this is logistically complicated. 

If you collect the sample, and then you have to freeze it and ship it frozen, it’s complicated. So once we started working with the dried blood stains, everything became much simpler. You can actually ship it anywhere in the world. People can collect sample and mail it back. And if it’s okay, we can work with the data generated from that sample. So it’s still not so many labs doing that. There are, actually, there are over a hundred labs in the world which can analyze the IgG glycosylation, but not so many of them do it in a high throughput. 

So this is why there’s no huge amount of data. It’s more and more people working. We even have the thing called the Human Glycome Project, where we are trying to integrate our activities globally, but we still have to learn a lot, because this is a very complicated part of biology, and still not so many people working. And interestingly, even at the beginning of this pandemic, the director of NIH was writing a blog about the S glycoprotein without a single glycan. He just showed the polypeptide part. 

Well there is more glycan on a surface than a peptide. And then just after that people started thinking, and saying, “Wow, there, there are so many glycans on this virus. What are these glycans doing?” And now we know that the glycans are very important, that they are integral part of not only SARS-CoV-2, but all other viruses. So, you know, there will be more and more glycan work in the future. I’m very positive about that.

Joseph M. Raffaele, M.D.

And I know you’re a very busy man, but I just want to ask one last question with regard to COVID, you brought it up in terms of testing. If a patient has had COVID recently, you would probably expect their glycan age to be older, I guess, and maybe take that into account. How long would you wait? Three months or something ?

Gordan Lauc, PhD

If the COVID was mild, we don’t see much changes. So asymptomatic COVID, nearly nothing, mild COVID, nearly nothing, severe COVID, yes, it can be over a decade. And it can take months for this to come back to the normal level. But, when I say severe, I mean hospitalized in intensive care. So even just hospitalized means moderate, not severe. So for the majority of people, I would not expect to see huge changes.

Joseph M. Raffaele, M.D.

And how about after the vaccination? Do you have any data on that?

Gordan Lauc, PhD

There is, yes, we have. We looked at some cohorts of people who were vaccinated, there we don’t see any change. So the vaccination does not induce a change.

Joseph M. Raffaele, M.D.

Well, I mean, I know that you are on vacation. I appreciate your speaking to me. And I know you have to get to your family. As always, great talking to you. Any last words you have to say to our listeners?

Gordan Lauc, PhD

It was pleasure chatting with you, and it’s pleasure to work together with you, because we are learning so much from your experience, and how you can actually improve people. And yeah, eventually I have to try something myself, but .

Joseph M. Raffaele, M.D.

You come on over. Yeah. See, I mean, it’s great to work with researchers, and sort of put the clinical and the research together to sort of move things along more rapidly, and I’m just very pleased to be working with you and glycan age. Thank you very much, Gordon.

Gordan Lauc, PhD

Thank you.