Dr Louise Newson: [01:00:00] So today on the podcast, I've got Nikolina Lauc from GlycanAge. We talk a lot about inflammation, what it means, how we need a little bit of inflammation, but we don't want lots. And actually too much inflammation is harming women. And guess what? Hormones reduce inflammation. So it's a great listen. So today we're going to just talk about inflammation. What it means, what it doesn't mean and just the whole hormone conversation because, Nikolina, we've known each other for eight, nine years, I think? [01:00:31][31.9]
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Nikolina Lauc: [01:00:32] Probably.  [01:00:32][0.0]
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Dr Louise Newson: [01:00:32] Yes and it's a very interesting space because I think people are talking more about inflammation and in my book The Power of Hormones I've written a whole chapter about inflammation but a lot of people still don't quite understand what it is so I'd really like to unpick that a bit and obviously talk about you and your background. So let's just talk a bit about when we first connected and what you do.  [01:00:56][23.6]
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Nikolina Lauc: [01:00:57] Yes, I think we were, it was during COVID or just around that time and you were, we did quite a bit of work with Tim Spector and you had a conversation with him about the differences pre-menopause, post-menopause with COVID. And we thought that was super interesting so I asked him to connect us and to do some research together. So I think that's where it originally started. And I like the whole immunology side that you brought to the conversation because that really wasn't there. We didn't see it anywhere else. And we saw this on this biomarker that we focused on and that my father [Professor Gordon Lauc] dedicated his scientific career to, the strongest influence we were seeing were actually hormones and it's an inflammatory biomarker. And then maybe talking about inflammation, a lot of times what we're measuring is more acute inflammation. So it would like CRP would go up after an infection, it can be really high one day and then the next day or when you are recovered, it goes down. So it doesn't really move with ageing and we see that this low grade, we call it sterile systemic inflammation is a marker of ageing or this immune ageing, inflammageing. And that's something that actually before we stumbled on the biomarker as a theory of why we age and how we age, it was work of Claudio Franceschi. I think you read some of his papers. I think he's 84 now, he had a great talk at our conference in June, and it's amazing how this field has evolved and how much work we have now to show that the immune system or this ageing of our immune system is connected to a lot of chronic disease. And he would also explain it as an accumulation of lifelong stress, but we see that hormones or the menopause transition would be the main ageing event in a woman's life.  [01:03:01][124.3]
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Dr Louise Newson: [01:03:01] Yes and the thing is we've known it for many many years but often in medicine people don't join the dots and they work very much in silos and often the academics and the researchers aren't clinicians so they don't see it in practice and the clinicians don't have the academic background so they don't really think deeply into what's going on with the pathophysiology and I guess I'm fairly unusual because my pathology degree involved a lot of immunology as well and although it was a long time ago, the basic principles are still there. And so a lot of people might have heard of the term inflammation and we need a bit of inflammation in the acute stages. So I always often use the example of if I cut my finger, I need my immune cells to go and work around that cut so it doesn't become infected. The last thing I want is to not have a good immune system, have an infected cut, end up with sepsis and catastrophically things happen that I wouldn't want. So we've got these, lots of white cells, they're called, these inflammatory cells that go, and they're like our sort of armour really, aren't they? They protect us, and they are always hypervigilant, working, and we've always got diseased cells in our body. We've all got the potential to have cancer every day. We've got the potential to infections every day, and so we want our immune cells to get rid of any abnormal tissue, any dead tissue, any abnormal cells, and that's what keeps us healthy basically. But if we have too much inflammation in our body, the immune cells can fight against us, can't they? So they can become pro-inflammatory. So then they actually damage our tissue, which is a bit paradoxical. And so they can damage tissue, they can cause diseases as well. And when I learned about, especially the macrophages, these types of cells, many years ago, it really blew my mind because you think, how can something that's good for us or a cell that's good for us turn against us? And then when you think about pretty much all diseases, they are inflammatory diseases, so ranging from obviously inflammatory bowel disease, it's got it, so we know what that is, but other diseases like osteoporosis, cardiovascular disease, dementia, depression, motor neurone disease, Parkinson's disease, non-alcoholic fatty liver disease and cancers, they're all diseases of inflammation aren't they? [01:05:24][142.8]
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Nikolina Lauc: [01:05:27] Yes they are, but there is a difference, as you pointed out, This acute response is something that keeps us alive, but then when it turns into chronic, that's when it leads to chronic disease. And that's the difference we see because we're not measuring, looking at the acute markers, we're looking at something you can think of as a type of HbA1c for inflammation, this kind of cumulative effect. So what they do on a daily basis, even if because I've just come off an overnight flight, won't change this marker. But in the long term, if I'm accumulating this damage, that will lead to problems.  [01:06:04][37.2]
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Dr Louise Newson: [01:06:04] And that's really important. So with your tests, glycanAge, there's various tests that seem to be coming out. But when you look at the immunology and inflammation, you want to look at them longer term. You don't want to just think, oh, well, I have just cut my finger. I don't know what's happening today. It's sort of longer. Because like you say, this term, inflammageing, I think is really interesting because as we age, we're more likely to have diseases, that's just fact. And for many years, and even now, the way doctors get trained, the way we get taught, is often to wait for the disease to come and then we treat it. But certainly over here in the UK, our NHS is sadly falling apart, and other healthcare systems, and we shouldn't really be waiting for the disease, we should be trying to reduce it. And a lot of the diseases of ageing are inflammatory diseases. And so some of the times we can't prevent them, but we might be able to delay them, which is actually really good because we're living so much longer. But as you say, menopause is a complete car crash when it comes to inflammation because we have this accelerated ageing, this increased inflammation in our body. And for many years, it's been spoken about and I read some minutes from a conference that was held here in London in 1972 on ageing and menopause. And it's really interesting because they didn't have the knowledge that we have now, but they were still, it was all men in the conference, of course, but when you read their lectures and their notes, it was about heart disease, osteoporosis, and dementia. But what was really amazing was that they were all writing how taking hormone treatments can reduce the incidence of those diseases, which makes sense, actually even though back then the hormones they were prescribing were different to what we prescribe now. They were still seeing the women and noticing how much healthier they were.   [01:08:04][120.0]
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Nikolina Lauc: [01:08:06] It's incredible and maybe I can explain a bit what we see and what we measure. So the biomarker is based on antibodies and we look at these sugars that would regulate how the antibody functions if it's acting pro-inflammatory or anti-inflammatory and this is our adaptive learning immune system. And we see that women prior to menopause they're in a way protected against this inflammation. When we compare them to men, their immune system looks much, much younger. And this is also why a lot of this chronic disease, cardiovascular disease, diabetes, all of it happens postmenopause. And we see that this transition, this actually a study we did together with Tim Spector on his twins. We see that this rate of inflammageing by looking at this, it's called IDG glycosylation, would be double to any other period from perimenopause to menopause, even while women are still cycling. And if you introduce estrogen, we had the other studies where you can completely prevent acceleration or even recently with the cohort we looked at in your clinic, reverse the inflammageing with the hormone replacement. So we do have the tools and we are, and there is data now on hormone replacement reducing all-cause mortality. So we look at the drugs which are actually extending healthspan and reducing long-term risk. There was this recent review they did on UK Biobank, and out of 14 drugs, they identified as potential life extending drugs. Four of them were estrogens. So I think this information is there, but if I go to our spaces, which is very obsessed with these kind of new drugs they're going to, and GLP-1s, we just came from a conference in Boston where everybody was talking about GLP-1s being potentially anti-ageing or longevity medicine, but actually everybody's ignoring the data we already have for estrogen because it's not a new drug. It's generic. [01:10:06][120.1]
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Dr Louise Newson: [01:10:08] And it's not an expensive drug either, and it's not just the estrogens actually, progesterone and testosterone are very anti-inflammatory as well. They all really reduce inflammation and they improve the way the macrophages work and also mitochondrial function, so they help the energy production in all our cells as well, but it's because it's so basic, it's been forgotten and it is really interesting because there are papers, immunology papers that I've read from the 1980s. Very clear talking about the immune regulating effects of these hormones, but because they've been mislabeled and misgendered actually as sex hormones or gender hormones, they're not at all because men produce progesterone and estradiol, women produce testosterone. But people are so fixated on symptoms and even now with the testosterone people are just talking all about libido and no-one's taking a step back and thinking hang on what's going on at a molecular level? Because the hormone treatments we prescribe are the same molecular structure, as you know, as our own hormones. And so when we're looking at the health of women, we want anything we can do to reduce inflammation. And it's very interesting when you look at work of women with PMDD, premenstrual dysphoric disorder. So a lot of those women have changes of their hormones in the second half of their cycle. So a lot of those women for several days, sometimes a couple of weeks, have lower levels of hormones than other women. And studies have shown that women with PMDD have a higher incidence of guess what, cardiovascular disease, osteoporosis, dementia. And that's really interesting because thinking about the whole menopause, I hate that word because it's just about periods. You know, we've got to be looking at when else do we have this hormone imbalance that can worsen inflammation and worsen our future health? [01:12:00][112.2]
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Nikolina Lauc: [01:12:01] Yes,correct. And that's, I love the work you're doing with your daughter. I work with my father. So nice to see. We did do studies on cycles. So we had that study with 70 women were tracking weekly to see if this changes within a cycle. And with a healthy regular cycle, there was only a 1% change. So there was no variability. So if we were to measure the biological age, which is one part of GlycanAge, it would be stable. But in the woman who didn't have regular cycles. It seems to behave differently. So that's something we also want to study better. And we see a lot of influence. So we know this is not just, it's not that we're seeing effect in this inflammation process just because of the health benefits of estrogen. We have done studies on animal models where it directly changes this. So for example, we did some trials which are still unpublished with rhesus monkeys where they removed the ovaries. And then they give them estrogen, or they don't give them estrogen, and they're looking at bone marrow samples, and we see this change in bone marrow. So it is something that's mechanistically involved with what we measure. Yeah, so I think that's something we want to do a lot more research in this space to understand.  [01:13:22][80.6]
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Dr Louise Newson: [01:13:23] It's crucially important because, you know, many people who are listening know that women globally are harmed by not being prescribed hormone treatments for their future health. And I think people are waking up and realising it more. But I worry a lot about younger people. I mean, I worry about all women of all ages, but younger women who have longer without their hormones are really impacting their future health. And we know that it's probably between 3 and 4% of women have menopause under the age of 40. And I remember many years now, probably about 10 years ago, I listened to Walter Rocca, who's a great professor, he's an academic at the Mayo Institute, and he was on my podcast a few years ago. And he produced data, and it's almost barbaric when you look at it, but basically, they were looking at women who had their ovaries removed at a young age and following them up and seeing the diseases that they got compared to women who hadn't had a bilateral oophorectomy at a young age. And I remembered seeing the graph, and it's this just you know, they start off as healthy as each other and then it drops. And then it's not just those diseases that we mentioned already, these inflammatory diseases. It's also chronic kidney disease. It's also lung disease. It's like chronic obstructive airways disease, but also drug abuse and mental health disorders really do increase. And when I first saw this, I was really shocked because then I was immediately thinking, but why? Well, of course, but why. The reason is those hormones have gone in the bin with the ovaries and levels of hormones have reduced in that woman's body. But what really shocks me is that every day I speak to women who've had their ovaries removed at a young age and no-one's actually given them hormone treatments back. And it, you know, it's these women, obviously, a lot of them have symptoms, but as a doctor, I worry more about their future health. And so your studies that you've done have just replicated that as well. You're not showing us anything that's surprising, but it's confirming the harms of not having hormone treatment when hormone levels are low.  [01:15:28][124.7]
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Nikolina Lauc: [01:15:31] Yes, and I want to also ask you about postpartum and I think this connection with mental health is huge. It's something we see more and more in the data. So if we look at this biomarker in pregnancy, there's a special estrogen that we produce in pregnancy and basically inflammation goes all the way down to the floor. And if you have an autoimmune disease, rheumatoid, MS, all of these spontaneously go into remission during pregnancy. But then postpartum, when we look at them, the inflammation skyrockets, so similar to what we would see with menopause, but there's a recovery. And we see sometimes that can be a decade or even a few decades change postpartum, and it would stay during the breastfeeding and then it would start to normalise. So I want to ask you about hormones and postpartum. Is there something that we should be doing that we're not doing?  [01:16:21][49.4]
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Dr Louise Newson: [01:16:20] Absolutely, and I think this is a great conversation because when we're pregnant, levels of hormones are very high in our body, especially progesterone, but also estradiol and estriol, another form of estrogen as well. And then overnight, literally when the baby's born, they decline. And we've known for decades that women who have this big drop, some women are more predisposed to mental health disorders. So a lot of us experience some baby blues when we have our children. You know, a lot of us incorrectly really are told it's because you're not sleeping much, it's the stress of the baby and all of that. And of course that will affect your mood, but no-one really talks about the hormonal shift. And then when you think about postnatal depression, postnatal psychosis, again that can be triggered by this change in hormone levels. And many years ago you might know this amazing pioneer doctor, Dr Katharina Dalton, used to be prescribing progesterone mainly for these women and she'd give it at a high dose as pure progesterone for these women with postnatal psychosis and postnatal depression with absolute transformational results. But it was around the same time that the synthetic hormones or contraceptives were coming into market, so they tried to silence her. And then as you know, all the antidepressants, antipsychotics really took over in this space because people treated it as a mental health disorder. But what she was doing was treating the underlying problem, which is what we should be doing in medicine. And when you really ask more questions of these women, the symptoms they have are of a hormonal imbalance. A lot of women postpartum will have joint pain. A lot them have palpitations, a lot of them have vaginal dryness, urinary symptoms. But no- one's really putting it all together. And it's a real shame, actually, because antidepressants aren't going to treat the underlying cause. Antipsychotics often block the action of hormones, so then actually induce a chemical menopause, which makes it even worse. And I see a lot of women who have got a history of postnatal depression, postnatal psychosis. They've had PMDD and it's gone on and on sometimes for 20 or 30 years. And when I've seen them, they've become perimenopausal or menopausal. But when you take a history, a lot them have been under psychiatric services for so often. And when I see them, they've got dry hair, they've got dry skin. They've got all these symptoms, they're often on a multitude of medication. And then over, it often takes time, but over a year or two of them having treatment, you can just see them transform. And you know, a lot of people, you can see their skin and hair change, and some people think, well, that's just a cosmetic thing. Well, actually, the skin is an organ. If the skin looks healthier, then the internal organs are going to look healthier too and will function. And a lot it when you look at the root cause is these low hormones increasing inflammation, but no-one is thinking about that. They're just thinking about the symptoms of a mental health disorder.  [01:19:25][184.9]
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Nikolina Lauc: [01:19:25] Yes and then going back to, so there's something that also is coming up more and more. And we're going to kind of explore this also from an academic standpoint, but we see it in clients. There's this system integrate like psychoneuroimmunoendocrine and it seems to be crucial in this inflammation story because in some of the case studies you were sharing, even at the beginning of your practise, they would have all these mental health symptoms that seem to go away with estrogen, with hormone replacement. So that's, it seems to be an integrated system where low hormones are then also triggering our psychology in a way that we're not connecting. But when we look at them, so menopause has this big acceleration inflammation, usually it's about 10 years, and then there's this deceleration with hormone replacement. And it's also estrogen in men, and we can go touch on that maybe at the end. And then when we look at what else has this strong of an effect? And first we were focused on weight loss, caloric restriction, all of these things do have an impact. Exercise, yes, moderate, like all of this have an impact, but there's something that can change it so strongly in a very short period, which is divorce, grief, all psychology-related that we never thought, you know, looking at just the the dots on the screen in academic work, you wouldn't really meet the patient and understand the full story. But we would, you know, tracking people for years, they have the same result or it's going up gradually, then they go through divorce, there's a decade change, or they go through grief, there is a decade change. And I think that the connection of this system is coming out more and more. And I this is why we need all of the puzzles to actually treat the underlying problem versus just the symptoms of it.  [01:21:22][116.7]
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Dr Louise Newson: [01:21:22] Yes, and I think medicine needs to change. I think, you know, for a lot of people, medicine is failing, not just women, but men as well. And, you now, when you think about advances in medicine, what's really made the biggest difference in medicine. Well, I think everyone would agree that hand washing, even though Semmelweis, who discovered it, ended up completely ostracised from his medical establishment and ended up dying beaten to death in an asylum. I mean, his story is so awful, yes. But everyone now agrees he was right. Antibiotics have made, obviously, a huge difference. But there, and surgery, you know, my husband's a surgeon and I often say to him, like what he does is transformational. It really is and surgeons can really transform. But medical treatment, I don't think there's been much, you know, you could say statins, the biologics, for some people, but they're still overprescribing. Antipsychotics, if you're running down the street naked, then absolutely, they're brilliant. But long term, I'm really not sure. So I think there's a difference between an acute prescription and a long term prescription. And even antibiotics. If you've got an infection, you know, my daughter's had sepsis, of course it's the best thing. But you wouldn't want long term antibiotics for recurrent urinary tract infections. You would want to treat with vaginal hormones. So the other biggest advance in medicine is hormones, but the bioidentical hormone treatments that have got so confused with the synthetic hormones and confusion about the risks and benefits, it's almost put people off and people have put off prescribing for the wrong reasons. GLP-1s, we're still working them out, but for some people, obviously they have a role. The lower dose thinking about inflammation probably do, but we need more research. But I'm very simplistic as a doctor, and if we think about the basis of hormones, we can't ignore it. And it's frustrating when you look at some of the guidelines when they say there's no increased incidence of heart disease with hormones, but there's lots of evidence to show there's a reduction. And some of it is because of the whole way that insurance works, and they don't want to make menopause a disease because then they would have to insure women, which would cost money in the short term. But longer term, they could save billions of dollars and pounds, couldn't they, by getting it right early on? [01:23:56][153.4]
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Nikolina Lauc: [01:23:57] Yeah, no, I mean, similar cases now with the weight loss drugs, getting this to reimbursement and we really should have been there already with hormones looking at the data. So that's, I think that's a big missing piece.  [01:24:11][13.8]
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Dr Louise Newson: [01:24:11] Yes. And so one of the things I think that's so important is research. You know, we do publish quite a lot of research. I've got a very small but excellent team. But we need to be changing the narrative because often, and it's happened for many decades or centuries, that women aren't believed. So when women talk about their joint pain improving, their sleep improving, often it's put down to a placebo. Now, I don't think the placebo effect is really there very much at all. But people who want to just put the nail in the coffin of hormones and don't like them would always talk about placebo. Whereas I think with studies, especially looking at inflammatory markers, looking at GlycanAge, other biometric data, you can't argue, even my Oura ring, if it's telling me I sleep well, obviously you could argue it might not be as accurate, but it really does, it's objective, the same with a blood test. And putting all these together are signals. And we can't keep ignoring proper data, can we? [01:25:12][60.5]
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Nikolina Lauc: [01:25:14] Yes, correct and maybe I can also, on the study that's now in pre-print, but we should have it published in, forget if it's Nature Communications or Nature Ageing, but one Nature paper. It was a really nice review we did that we had about 20,000 people and 19 different diseases, four just healthy ageing cohorts, and then interventions like yours, caloric restriction and therapeutic plasma is something that was done in the US. And we see that these changes in our biomarker would happen with all of these different diseases. And that's from COPD to diabetes to cardiovascular disease to all different autoimmune diseases. And in some cases where we had the data where we have patients who are healthy and then we track them until they develop disease, for example, with Crohn's disease, we see these changes six years prior to a diagnosis, in some cases even 10 years prior to a diagnosis, so it's telling us on a molecular level, we're heading towards a problem, but there is room to do prevention. And then when we looked at mortality, there was another, we had 5,000 patients from a chronic kidney disease mortality cohort, and they had all the blood work, all the regular risk factors, and every extra year of immune ageing, of GlycanAge was a 10% increase in all-cause mortality. And when we removed all the factors, all the blood work, CRP, LDL, smoking, history of disease, you still had a signal for every year increasing all-cause mortality. And we have patients who are 10, 20... clients, they're not patients, not all of them, who are 10, 20 years over or 10, 20 years younger. So what we're doing now, we're looking at resilience to disease, but also if you have a condition, in some cases, like in Northwestern, they're looking at a big biobank of HIV patients. And they have some clients with HIV who are actually classified as superagers. So their cognitive function is on a level of a 25-year-old, their immune function is much younger, everything they can measure is much younger despite them having a chronic condition. So that's another element we want to understand, like not just what puts us at risk, but we want to understand what makes people resilient and what interventions improve this resilience. And hormones seem to be one. The thing we have to prove now, so we see that this would associate with greater risk, this will be meaningful for an outcome, but if you change it with intervention, are you also changing an outcome? Because here we need the long-term data. So, one thing we're doing now is analysing some older cohorts, and they're not ideal because they have the old form of HRT, unfortunately. But one large cohort that we already analysed, but we haven't written a preprint, it's the Women's Health Study, not the WHI. It's a nurse's study, so it's very well controlled. And they had long-term outcomes on women on HRT or not, and then they even have interventions. Vitamin E, which didn't do much, and a baby aspirin, which did prevent some stroke. Then another cohort we managed to convince to send the samples is the KEEP study, which has on the transdermal or oral randomised. And there they don't have long outcomes, but they have certain endpoints, so we can start to show the changes we're seeing in the reduction in this inflammatory low-grade inflammation is actually changing the outcomes. So that's the work we need to do now to convince the medical community that this will also change outcomes. And we're very interested in dosing. Because there they use pretty much the low, kind of the guideline, but the guideline is quite low. And we have some practices in the US that if they don't see as much of a reduction in inflammation, they actually increase the dose. So, that's a question we have. Are we all on the right dose? Should it be higher for some, lower for others, should it be a different combination of hormones? I think that's something that you already have in practice, but if we can publish more research on it, understanding it mechanistically is going to be one day easier.  [01:29:38][264.7]
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Dr Louise Newson: [01:29:39] Yes, absolutely because, you know, prescribing hormone treatments is personalised and we need to be prescribing the right dose, the right type of hormone to reduce inflammation and improve future health. It's so important. And so there's so much we need to do. I'm very grateful for your time, especially as you're jet lagged coming into the podcast studio today. I always end on three take home tips. So thinking, three things that you would like to see some research, looking at inflammation and hormones. What are the three things that would be really exciting over the next few years to witness?  [01:30:12][32.9]
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Nikolina Lauc: [01:30:15] So one I mentioned, dosing. I really want to understand, can we personalise dose based on inflammation? That's one question we have. Staying with hormones, testosterone. We haven't spoken about men, but we see that men only benefit from testosterone therapy if you don't block conversion to estrogen fully. If you block their conversion to estrogen, we only see pro-inflammatory change, we don't see anti-inflammatory. It's the right level of estrogen for men. It seems that estrogen is acting as an anti-inflammatory. So a lot of, well, men get their estrogen from testosterone, but a lot a women also get a lot of their estrogen through testosterone. So I'm quite interested to see if testosterone would have a similar effect we see with estrogen or the combination of testosterone with it also impacted further than just estrogen and progesterone. And then the third one has nothing to do with hormones. But we have this huge effect of psychology and we're keen to find interventions.  [01:31:17][62.3]
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Dr Louise Newson: [01:31:18] So watch this space, so the more research that's done and the whole neuroinflammation is so important. So thank you so much for coming today, it's been great.  [01:31:27][8.3]
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Nikolina Lauc: [01:31:27] I really appreciate it. Thank you for having me.  [01:31:27]

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