Dr Rupy: Stuart, so glad that you can make it to the studio. We're really, really privileged to have you in. I thought maybe we could start by just going into your background and how you got into the science and a bit about your academic career.
Dr Stuart: Cool, yeah, well, to be honest, I always wanted to be an archaeologist. An archaeologist. So I just put that out there. But I guess it was all about discovery. So yeah, I think in my teens I really got interested in genetics. I think it's quite a fashionable time, fashionable to be a scientist, I'm not sure. That's probably a large extrapolation, but you know, really good time to get in genetics because then 2000 was the sequencing of the human genome. So I did my undergrad in genetics, and then did a masters in something called functional genomics. So that is how do we take our knowledge in genetics and then learn about how an organism functions, but also how that function can go wrong and that's obviously linked to disease. After my masters, I went to Oxford and did a PhD where I studied a genetic disease called spinal muscular atrophy. So this is a childhood disease where the neuromuscular junction breaks down and it's fatal and in the most severe cases children can die by the age of two or three. It's quite a severe disease. I then expanded through the nervous system. I really got into neuroscience, worked on a lot of neuropathy, also autism spectrum disorder, thinking about developmental neurological disorders, and then sort of gravitated towards then neurodegeneration. So, myotrophic lateral sclerosis, which is motor neuron disease, it's got a lot of coverage in relation to the ice bucket challenge and stuff. But then into the sort of more classically well-known neurodegenerative diseases, Alzheimer's and Parkinson's. So I was part of a consortium there that looked at genetic modifiers, so are there genes that can make the models of these conditions more severe or less severe, and then they got passed on to drug discovery units within the Oxford University ecosystem. So they can go, okay, well this particular gene increases or decreases the severity of the phenotypic readout, so how we're modelling the dementia in our models, then can we find a compound that can mimic that process or do the reverse of that process and can these be used within the drug discovery pipelines to help cure these diseases.
Dr Rupy: And did you do your undergraduate at Oxford or was that your masters?
Dr Stuart: So, undergraduate at Birmingham, very promiscuous. Masters at York, PhD at Oxford.
Dr Rupy: Okay, wow.
Dr Stuart: So three very nice universities. Very different in terms of heritage and and sort of feel, but really good universities, all very good research universities.
Dr Rupy: I'm glad you mentioned the sort of fashionability or like the heyday of genetics in the 2000s because I think now people think of that era and just think, so 2000s. Why should we be caring about our genes today given that there was so much promise around, I remember when there was a baby on the front of Time magazine and like this this sort of like air of we'll be able to figure out everything because we now know our genetic code. Why should we still be interested?
Dr Stuart: Yeah, I I remember that I think it was something along the lines of within 10 years human health is going to be solved and we're all we're all going to be out of a job. I think like with most science is it's always more complicated. So the fact that we haven't solved every genetic condition, identified every genetic mutation that's associated with disease or been able to predict every every sort of syndrome doesn't mean genetics is not important. It means biology is complicated. And I think if you talk to the scientists behind the PR pieces, they would have been telling you that in 2000. So I guess in terms of genetics, the first point you can think about genetics is in terms of genetic disease and we probably won't go into that much detail, but they're the one of the diseases I described such as spinal muscular atrophy. People have heard of cystic fibrosis. In terms of nutrition, you're probably this is probably digging back to your medical training but phenylketonuria. So which is a mutation in phenylalanine hydroxylase, that's going back to my A levels I think, so hopefully I got that right. And that's a mutation that actually means you can't convert one protein into another, it builds up and you can get intellectual disability if you do not reduce the amount of food in the diet. So these conditions exist, they're driven through genetics and they'll continue to exist. There's many, many more what we call rare diseases where people, usually children or young people present with symptoms in the clinic and then we will have to then identify potentially what mutations those individuals have and they can be very, when they say rare, it can be a mutation that only exists in that individual or their family. So you've got to do a lot of analysis. So it's not like there's going to be 20, 30 mutations that explain all human disease. There are there are hundreds of thousands. So it's actually understanding the interplay with those mutations in some of these diseases within these genetic diseases. So I think we'll put that aside. That's kind of the the monogenic, the more Mendelian, as in inherited through your family, very easily traceable genetic disease. The second point is
Dr Rupy: Would you call, sorry to interrupt, would you call these like determinist genes as in like they determine your
Dr Stuart: Yes, so so so you you can map so for example, if you have the mutation, it is going to cause disease. There can be variability in that disease, but it's going to cause the disease. It is very highly deterministic.
Dr Rupy: Okay.
Dr Stuart: So that that's the area of genetic disease and that very much sits within the clinic. So I guess the second component which is, and I think of this twofold and what can genetics tell you about these two components. One, can you be walking around healthily today in your 20s and 30s and have a genetic mutation that actually could be life limiting? And the second point is, can you have a burden of genetics or genetic mutations or variants that will mean you're more likely to get a particular condition or disease. And we're really talking here about the chronic health conditions, diabetes, cardiovascular disease, dementia, also cancer as well, but again we'll put cancer aside because there's a different clinical pathway for that. So I'm going to come up with a couple of examples. First will be familial hypercholesterolemia. So this is a condition, so there's a number of mutations, but you only need to inherit one mutation.
Dr Rupy: You know what Stuart, do you mind if we, yeah, yeah, before we dive into that because I can imagine people definitely want to learn straight away about FH and how genes and the interplay with our biology leads to conditions or a high likelihood of conditions. But maybe we should take a step back and just really do it at a foundational level. Think of me as someone like is, you know, doesn't know anything about genes. What is a gene? How do we inherit from from both parents? and and yeah, and then we can jump off from there.
Dr Stuart: Sure. Well, genetics is the study of heredity. So we inherit two sets of chromosomes, one from our mother, one from our father, and the DNA within those chromosomes encodes genes. And in essence, a gene generally encodes for a protein. There are some cases where they encode for catalytic RNAs, but they encode for proteins. And proteins are the the functional molecules that are structurally sound. So if you think about the proteins in your muscle that enable it to contract, think about the proteins that cause skin colour, the proteins that metabolise all your foods, the proteins that enable you to send nerve transmissions. All the structure and function within your body, also the proteins that tell a cell to be a nerve cell or a muscle cell or a pancreatic cell. All this information is encoded in the genome that enables you to go from a single cell to a highly complex organism like ourselves, sometimes not that complex, psychologically, but generally quite complex. So the genes enable us to become who we are. Now, the genetics, the DNA also encodes for the bits that aren't necessarily encoding for proteins, but enable you to enable the proteins to be turned on at the right time, in the right place, and also in the right amount. So there'll be proteins in my body that are exclusively neuronal, so things involved with neurotransmission. But then there are going to be proteins in my body that are in every cell, so proteins associated with metabolising glucose, for example, something that every cell needs to do. So you have you need to be compartmentalising the proteins in the right places at the right times and in the right levels. So sometimes proteins can be mutated where their levels are low, this can then lead to dysfunction and then this can lead to disease. There are some examples as well actually where you can mutate a protein and you get increased levels and this can also lead to disease as well. So we've the body orchestrates this highly complex gene regulatory process where you create the proteins, you build the organism, and then you're walking around in the world and you then have to exist. So here's the second component of that. So you're wonderfully happy and you're a young baby and then you're interacting with your environment and the environment starts to offer challenges, offer opportunities, and then this can then start to impact how those genes are expressed as well.
Dr Rupy: Okay.
Dr Stuart: So I think there's a very nice quote. I think it's mildly apocryphal, but I think it's derived from one of George Orwell's diaries, but it's something along the lines of the face you're born with is from your parents and your face at 50 is the one you deserve. And I think this very much links into you're born with this set of genetics, but what you do throughout your life then very much impacts how they're expressed and how you interpret what the genetic information means. And this is what people talk about epigenetics is epigenetics in essence is changes to gene expression that do not change the DNA sequence.
Dr Rupy: Yeah.
Dr Stuart: So and and it makes perfect sense. You know, in terms of if you fast, you do not want to be churning out certain proteins for metabolising certain metabolic components. When you're interacting in environments that may be stressful, you want to respond to the stressful situation. So it's our ability, so genetics in essence creates traits and a trait can be anything from my eye colour, height to your ability to metabolise a certain food. But if you think about height, height is only you only reach your maximum height if you've got adequate nutrition. So there's a very simple example of how your environment and your genetics. So genetics is highly heritable. There's lots of genes so you can predict someone's height based on their genetics quite tightly if there's adequate nutrition. If there's not adequate nutrition, then they will not be reaching their maximum height. And you can think about that's in the majority of this the way the majority of genetic traits work. There is potential, but the environment then realises that potential. And the same with disease. You can have mutations that are linked to disease, but actually then you're it's only the poor lifestyle that will then see the manifestation of the disease. So when a lot of people say, well, you've got genetic risk but it's not causative. And that is in part correct is because it's the genetic risk, but it's not causative. It's because the genetic risk is manifested through poor lifestyle. And actually that's the power of it because you actually if you do have those risks, there is something you can generally do about it.
Dr Rupy: Yeah. You mentioned there a promoter gene and a corresponding suppressor gene. How does that fit within the interplay of what we just mentioned here about genes in general?
Dr Stuart: Let's think about we can talk about a condition called familial hypercholesterolemia.
Dr Rupy: Yeah, sure.
Dr Stuart: So there's an example where so there's I think there's three mutations that are generally linked to familial hypercholesterolemia. So what this is, it's basically you get high cholesterol from birth. I think if you're male, if it becomes untreated, there's a 50% chance of having a heart attack by the age of 50. So it's incredibly significant. It promotes atherosclerosis. So there are two mutations, one in the a carrier protein that carries helps carry cholesterol around the bloodstream, one in the LDL receptor that then moves it into cells. When there are mutations in those two proteins, they increase the amount of serum cholesterol, which means you can get build up of of LDL within the arteries, which can lead to atherosclerosis, which can lead to heart disease. So they're mutations that actually reduce the amount of those proteins. There's a second, so a third protein where people who have familial hypercholesterolemia is in PCSK9, which is actually a factor that increases the amount of LDL in the blood because it modifies the amount of the receptor on the cells. So actually if you overactivate that protein, it's actually worse. So you've got one example where increasing that protein which reduces the amount of receptor, which increases the amount of LDL in the blood is pathogenic. And the other one where you mutate the receptor, which basically means the the cholesterol is not taken up into cells, which increases the amount of LDL in the blood, which is pathogenic. So you've got a bidirectional effect there. So what we generally call a loss of function mutation is where you lose the function of a protein that leads to a disease. You have then a gain of function mutation. It's one where you can increase the function of that protein or even create a new function. Some work I was doing on neuropathy showed that a protein associated with protein synthesis actually did something very different at the neuron because of this one mutation and actually was affecting the way the neuron established and and continued to grow. So you can have all these different bidirectional effects. So again, going back to the the conversation around why we didn't solve the problem in 2010 is because the complexity and the interaction of biology and also as well the trade-offs between the many systems that occur.
Dr Rupy: Okay. So looking, going back to the example of familial hypercholesterolemia. Within this condition, there are all manner of different types of mutations. Am I getting that correct? There's all manner of grades because I think most people think of FH as just one thing. If you've got that, then you're likely to have a heart attack by the age of 50, whereas there does appear to be quite a big spectrum of people who naturally have higher levels of cholesterol.
Dr Stuart: That's that's a really good question. So familial hypercholesterolemia is what you call a more Mendelian disease. So you have single mutations. So if you are have mutations in the three proteins, the LDL receptor, ApoB and PCSK9, you will have the condition. And that that is considered a genetic disease, but it's not identified until later in life generally, unless you are doing LDL tests in your teens and 20s, which is quite rare. The second one then is is you can still have a genetic burden to have a higher level of LDL, but that's generally based on more mutations. So you've probably heard the term polygenic risk score before. So this is where more common variants and when I mean by common is that you know, when you look at any particular one, there may be a 20% chance of everyone in the room having that mutation. But when you look at lots of different of these mutations which have smaller effects, so they're not necessarily knocking out a protein or massively regulating the protein, but can be having small effects on lots of different pathways in the process of removing LDL from the cell, moving it around the system, using it in different organs and metabolising it, then you can have an increased risk of raised LDL. Now, these are more the risk of these are driven more through lifestyle. So I think there's an interesting triage point in the clinic here. So if you have familial hypercholesterolemia, there are dietary interventions you can do, but actually statins or PCSK9 inhibitors are the way you're probably going to have to go. Now with the polygenic,
Dr Rupy: Just just for the audience, the PCSK9 inhibitors are a relatively new class of drug that have come to the market, specifically used for familial hypercholesterolemia, but we're now using it for for folks with quite high levels of cholesterol regardless, yeah.
Dr Stuart: Yes, no, for sure. Yeah. So that for for the familial hypercholesterolemia, there is the clinical intervention that's required. Now, for people with high higher levels and polygenic levels, it is the first port of call is definitely lifestyle. So we're talking soy protein, we're talking oat bran, we're talking psyllium husk, I always have to pronounce that. We're talking garlic. You know, and so the one thing we do with fitness genes is we actually look at the meta-analysis. So we we evaluate people on a polygenic score as well as on the single mutation scores and then we can start to say, well actually for you guys, go and speak to your clinician, but for you guys, here are the lifestyle interventions that you should be partaking. So the familial hypercholesterolemia is, as you would say, generally deterministic with variation, then the polygenic risk score, so polygenic risk scores are not, they're not deterministic, they're probabilistic.
Dr Rupy: Right.
Dr Stuart: And it's the same with anything. You could smoke and not get lung cancer, but you don't want to. And of course smoking is one of the most severe sort of probabilistic drivers of disease. But with polygenic risk scores, and I think that this is important twofold. One, because it highlights the ability to have lifestyle intervention. And two, it's the lack of stigmatisation which can come with certain having certain burdens of genetic variants.
Dr Rupy: Yeah.
Dr Stuart: So and you'll see, so we've talked about LDL. If you think about more broadly with cardiovascular risk, that's where we are, you can look at risk scores associated with blood triglycerides. So I think at the moment the atherosclerotic sort of the the understanding of atherosclerosis is around high LDL, high blood triglycerides and high inflammation. So all three of those you could have polygenic risk scores. Then you've got lipoprotein A, which you can have raised levels of. So you can start if if you don't have hypercholesterolemia but you're still worried about your heart health, you look at all these different polygenic risk scores and evaluate where you are where you are in terms of the risk of those different components. And this can then start to highlight specific risks. So I think I'm again, I'm the scientist more than the nutritionist, but I think with high lipoprotein A, I think you'd recommend, I think it's L-carnitine. I think has has a big impact. And with high LDL, it's it's more psyllium husk and garlic. So you can start to go, okay, well my I know my family has general cardiovascular risk, but with these risk scores, you can start to unpick actually, well, how do I start to personalise my interventions more specifically?
Dr Rupy: Yeah. I need to look into L-carnitine a bit more actually because that's come up a few times. As as far as I'm aware, I didn't think with LP little A that we'll go into in a little bit more detail in a sec just to keep folks on the same train that there were many evidence-based exercise or dietary interventions for that other than generally reducing your total cardiovascular risk profile with all the all the above that you just mentioned. Um, and I think just to keep everyone on the on the train here because this is this is going to get quite in the weeds. One of the big takeaways for now, correct me if I'm wrong is we have deterministic genes and we have probabilistic genes. And that's basically where we're going to be spending most of our time in this probabilistic section. And and what we've just been talking about now. And just to give folks an idea of the polygenic risk scores, what give us a sense of like a ballpark figure of the number of mutations that could contribute to that overall high risk of of of cholesterol.
Dr Stuart: So depending on the the the trait you're looking at, it could be anything from 20, 30 to 10,000.
Dr Rupy: Oh, wow.
Dr Stuart: Yeah. So it's it is very small effects in some cases. So so some are additive, so it's literally just you have a variant and you add one. And some some of the variants within the model have higher impacts. So you can have lots of small ones, but some people with only with less mutations but with a higher impact can have a higher risk profile.
Dr Rupy: And is that all validated externally by another sort of like a
Dr Stuart: So so that there's yeah, so so you you have there's the original place where things started with the Framingham heart study, then you've got the UK Biobank and you've got so a lot so the what we use internally is we we take a lot of third-party data, third-party polygenic risk scores. We have a large customer base that share data with us. So they give us readings, so LDL levels, blood glucose levels, and then we actually test within our population, we look at the distributions of the risk scores. The other thing we do as well, which is where risk scores are probabilistic, we add in and I think a very important point you described with lipoprotein A is reducing general cardiovascular risk is within our scores and within what we present to our members is we link in lifestyle data. So within our LDL risk score, we have diabetes risk, we have age, we have pre or post menopause, we have body composition. So these actually are built in to stratify the results we give to people because lifestyle, the the component from the polygenic risk scores, the genetic component is only a part of that and you need to actually put it in the context of the other context for the person.
Dr Rupy: Totally. Yeah. And I think, yeah, that at the moment is sort of in the realm of the clinician to sort of compute all these different inputs. But it's good to know that there is a risk stratifier based on on what you just described. In terms of like those genes that combine to create a risk profile, are there certain ones that are just weighted heavily? Like if you've got these genes out of the 10,000 potentials, let's say, that's going to massively increase your score versus some other ones that, you know, they are there, they're going to give you a higher LDL than the average in terms of population data, but it's not going to push up your score that much.
Dr Stuart: For sure. Yeah. There are some that are worse to have than others. And for some people it's just a burden of lots and lots of genetic variants.
Dr Rupy: Okay.
Dr Stuart: But again, it doesn't mean you're necessarily going to get the disease, but it means you have an increased risk of that disease.
Dr Rupy: Okay, great. Um, so we've talked a bit about FH and PCSK9, ApoB, which is a particular particle on the LDL.
Dr Stuart: LDL, that's correct, yeah, yeah.
Dr Rupy: And the LDL receptors, so on the sort of liver cell, for example, you have a receptor that draws LDL from serum. So when Stuart says serum, that's like basically circulation, brings it into the cell, so it's out, so it can cause less trouble, let's say. So it's less likely to get oxidised and cause inflammation in the arterial wall. Um, you mentioned LP little A. So this is something that um, I don't think is on many clinicians' radars, particularly in the NHS as we we don't routinely screen for this in general practice, which in combination with ApoB, which is a bit of a bugbear of mine because we have the data that it is very much aligned to a increased cardiovascular risk profile, more so than LDL C, which is something that we do routinely screen for. What is LP little A?
Dr Stuart: So it's another lipoprotein that circulates and I think the the the sort of the end point of it is it's super sticky. It's incredibly sticky protein, protein, lipoprotein. Uh, which means when you start to have build-ups, so you get inflammation in the arteries, you get mass cells, which then starts to lay down calcium deposits. This is something that actually interacts with with those components and drives the atherosclerotic process, I guess. Uh, in terms of genetic risk, uh, it's actually mutations in the protein itself that impacts the laying down of of the LPA.
Dr Rupy: Okay. And give us a sense of the number of people that might be afflicted by raised LP little A given the information that or the limited information that we have today.
Dr Stuart: So on every trait we have on the database,
Dr Rupy: So I've just put you on the spot there.
Dr Stuart: Yeah, we have we have the thing is any of our customers can go and look at this and I can't tell you the top of my head. So so so for every trait and I think this is very important because this gives you an idea of the profile. So for every trait we report on, uh, we have a percentage. So I I I could go and look online and tell you, but I'm not sure what the, but but generally I think the high risk, I think it's a matter of 2 to 3% in the high risk. So so so again, we're not looking and then there's there's going to be there's increased risk which will be in the tens. And then so so for the the people that were really triage to the high, you'll be in the low percent for sure. And that I think that'll be with the LDL as well.
Dr Rupy: Well, considering that this is the number one killer, one of the the highest killers in the UK, if not globally, you know, two to 3% have got that extra very high risk. It's something that we should be
Dr Stuart: So hypercholesterolemia, I think there's probably 250,000 to 300,000 people walking around the UK today.
Dr Rupy: Okay.
Dr Stuart: Uh, in terms of the the the allele frequency. Uh, again with the LPA, that's a polygenic score. So you're very much, uh, looking at increased risk but not causative.
Dr Rupy: Sure.
Dr Stuart: Uh, yeah, I I it's an interesting point when you said in terms of the testing because for hypercholesterolemia, the UK government has done the cost benefit analysis and they've shown that they believe they could save the NHS money and more importantly save lives if they did screening. But the reason they don't do it is because they don't have the capacity to do the aftercare. So actually if you go to the government website, they'll go they'll go through conditions like hypercholesterolemia, hemochromatosis, which is another one which is raised iron levels, which I think there's 1.2 million people probably in the UK.
Dr Rupy: 1.2 million? Wow.
Dr Stuart: Yeah, I've heard quotes that in regions of Northern Ireland, it's one in 10.
Dr Rupy: Gosh.
Dr Stuart: Because of obviously the uh, the the sort of the family groups. Uh, but yeah, it's it's and and but the bottom line is that there's either, I think with hemochromatosis, so that's a condition where iron is uh, is not absorbed properly. So therefore it raises iron in the serum, it then gets loaded into your organs and actually can cause all well, you start to get fatigue to start with and then you can have organ failure. And again, it's something that you don't, you cannot realise you've got until you're 20s and 30s. And again, there's going to be that subclinical build up of iron which will be having some effect on your organs. Now, not everyone with hemochromatosis uh, will present with symptoms. Now, there's a I think I think it's four to one men, males to females that get it. And I think one of the primary drivers of that is menstruation because women actually get rid of the iron in the blood. Uh, but there's also massively diet. I guess there's not many people eating liver and a lot of the 1980s diet anymore. We used to have. But I think like the one of the big concerns if someone's having lots of vitamin D supplementation, because vitamin D is, sorry, vitamin C, sorry, vitamin C supplementation, because vitamin C is a driver of of iron uptake. There's other ones that reduce iron uptake, but I think like sort of compounds in teas, in dairy products as well. So so there are diets around it. But again, there's another there's another condition that is a simple genetic test that actually if you ignore having it and have the wrong lifestyle, you can have significant clinical implications where genetics can can be highly beneficial for lifestyle change. Uh, but yeah, back onto the the whole idea is is it's where do we do this genetic testing? Because for a lot of this preventive care and as we go with the polygenic risk scores where we're talking about the probabilistic nature of it, well, you know, clinicians are going to go, well, tell me whether they're going to have a disease or not, which I understand from their perspective. And also, well, come back in 20 years when some of these diseases may manifest. You can see why the, for example, in the UK, the NHS and obviously different uh, you know, sort of health uh, health systems around the world are not quite involved in this process yet. But there is there is a lot of opportunity for the individual to understand them about their genetics and obviously the lifestyle information that surrounds that genetics to to start to really understand particularly health issues they may have.
Dr Rupy: Yeah. Yeah, yeah. Um, we we mentioned epigenetics quite briefly. I want to go back to that because I think we we might have just gone over that a bit a bit too quickly. What what do we mean by epigenetics? I think you got a bit of a bugbear when when people are like, isn't it just all about epigenetics and you know, maybe we should just go go back to to basics and explain what what we mean by that.
Dr Stuart: So on a high level, epigenetics is a change in gene expression that does not change the sequence of the DNA. Now, uh, if you think about going from a single cell to a fully formed human being, there are many epigenetic changes that then create the identity for all the different cells in the body, the muscle cells, the liver cells, everything else. The second component of that is how does your body then respond to the world around you? So for example, we've we've mentioned fasting or if you overeat, the continue surplus or reduction of nutrients will change the expression of genes because you don't want to keep producing genes uh that are or should I say proteins, producing proteins from genes that are not required. So what your body can do is it can uh, it can methylate the DNA and repress the expression of those genes and those methylation marks can then get instilled on the on the DNA.
Dr Rupy: What's methylation?
Dr Stuart: So methylation is so so what you can do is you can add a little tag to DNA to say, do not, do not transcribe me as a gene. So therefore you don't produce the protein.
Dr Rupy: Do not pass.
Dr Stuart: Do not pass. Yeah. So it basically stops the gene. And what you can do then is look around the whole genome and there's a new sort of science which looks at methylation and this is quite cool in aging at the moment. People will say, I have the biological age of a, you know, 14 year old even though they're 75 or something. And what they're doing is looking at epigenetic marks that are indicative of being younger and older because you see methylation changes occur as you age and there are certain factions that believe aging is all about methylation. The David Sinclairs of this world and everything else. And and there is a component of methylation in aging, but it's not the be all and end all. But what what is very important and exciting is you can change, so even though you may have particular genes you're born with, you can change the expression of those genes uh via uh via your lifestyle. And and one of the great changes of gene expression is exercise and and and and good sleep and nutrition and not smoking. I think one of the, so one of the specific methylation sites, I think in the early uh methylation arrays which basically showed you how good your methylation profile was, was a site which actually could predict smoking. If you were a smoker, you would have this uh the these marks on your your DNA which would which again, so so really uh the early methylation arrays were a very early way of telling you you've been smoking, which you probably know about already. So yeah, so so it's it's fundamentally about regulating gene expression.
Dr Rupy: Yeah. And it it kind of makes sense. So if you've got, forgive my glib analogy here, if you've got your workers, so your your genes pumping out proteins all day long, right? You don't want them to continue to pump out the same protein over and over again when their environment has completely changed. So in a fasting environment, you might not want this particular gene to be working and creating this protein because we need to conserve energy from that side and actually redistribute it to energy storage, let's say. And so that's why those particular genes might be upregulated because those proteins code for better storage. So your genes are very adaptable to the environment and that's where the epigenetic signal comes in.
Dr Stuart: Exactly. And it makes totally evolutionary sense. And it's quite an interesting point in terms of we've kind of touched on fasting as well or calorie restriction and aging. And actually a lot of the pathways associated with driving these changes are are metabolic pathways. So the pathways, it's called mTOR but associated with protein synthesis. So we our foundation was actually with bodybuilders. So our company was called muscle genes in the beginning. So people that used to put food in Tupperware boxes, weigh all their food and document everything. Really useful group of individuals to start a company with because actually the data they give you is incredibly robust. So we we we we initially started with bodybuilders. So you've got mTOR which drives protein synthesis and then you've got IGF-1 and growth hormone which drives growth. Now, when you fast, you're reducing the amounts of these proteins. So what you've seen with aging is higher regulation or higher levels of mTOR signalling or higher levels of IGF-1 growth hormone signalling is great for growth, it's great for being big and muscular, but actually may not necessarily be good for the long term. And and again, a lot of health, there's not a lot of evolutionary science in health biology, but actually there should be a lot of evolutionary science in health biology because what you're really underpinning here is your ability to maintain a healthy, happy life. And I think as we start to think about the aging industry and how we think about what to do in life, uh, we we need I think we need a a frank understanding of of what being healthy is. Now I'm going to give you a quite a sort of interesting example, but being taller generally has been linked to better success in relationships. I think there's data there and also higher uh income. For every 10 centimetres taller, you increase your cancer risk. So there's an interesting view of what you could consider is when you're young, a very beneficial trade-off to when you're older, not a very beneficial trade-off. I think a lot of centenarians always within a certain height. And and the the the pathways associated with that are not well understood, but you think about growth, cancer, growth, utilisation of uh resources, you know, radical, even though I think the free radical sort of uh component of aging is is not quite as robust as we think it is. So you've got these trade-offs in biology. And I think fasting is one of these very interesting ones. So when you look at the major modifiers of disease and you start to think about it in terms of dementia, cardiovascular disease, diabetes, the the you've got one group of individuals telling you fasting is really important. And on those pathways it is at a certain time of life it might be. But when you look at papers associated with dementia and other diseases, actually grip strength is the one factor that comes up time and time again, which is which is a proxy for muscle strength. Now, if you are calorie restricting for long periods of your life, you're probably more likely to be losing muscle mass. And I think there are people that are claiming their calorie restricting diets out there which can maintain muscle mass and increase strength, but I just don't think it's valid over the long term. So what you start to see here in biology, particularly when it comes to aging, is these trade-offs. And I know in a minute we'll probably want to talk about dementia and ApoE. Now, there's evidence starting to suggest that actually in early life, ApoE increases your fertility. So in in evolutionary terms, that kind of makes sense. A number of the variants associated with cardiovascular disease have also been shown to increase fertility. So when you start to think about biology and the genes we have in our body, we have most of them have been selected for for us to be strong, healthy, fertile when we're young. And once we've procreated, there's what's called a selection shadow. So a lot of these genes that were hanging around creating benefits when we're young, actually then create more negative consequences when you're older. And they're hanging around because actually we've we've passed on our genes. There is there is no real necessity to select against the negative effects. So when we start to think about health and disease and bad and good, it starts to become more opaque. And I think this is quite important because again, we'll talk about dementia and ApoE shortly. There's very much a stigma around or at least a fear around having certain variants and certain and and and linked to certain conditions. But actually, what you're probably not realising is that they can, you know, your genetics will be giving you pros and cons. It's not that you're bad or good. And I think the anti-aging industry is coming down the line of exceptionalism where there's this perfect trait and you you can't, you can't optimise multiple traits. And I I've read some articles about cancer versus dementia where people more likely to be high risk of cancer, which is a disease of cell division, are sometimes at lower risk of dementia, which actually if you think about maintaining a healthy brain, neurogenesis, cell division, maintaining cells is important. So you start to have these trade-offs. You think about autoimmunity versus infection, that people are more susceptible to infection, actually may have less risk and and the data and the genetic data and the biological data shows this because of the nature of their immune system, they're less likely to have autoimmune disorders. So biology starts to become about these trade-offs. Now, if you think about what we're here, we talk about nutrition and what to do. When you start to see these diets or these foods or these and you you've kind of seen it in the anti-aging where you talk about rapamycin, when you talk metformin, and they're actually they're actually impacting the mTOR, the protein synthesis pathway and the IGF growth pathways. They're very interesting compounds, but there's going to be trade-offs with all these components.
Dr Rupy: Talking of opaqueness, I just want to double click on the epigenetic aging field, these epigenetic clocks because you mentioned methylation and those markers that are suggestive of someone who is of a younger chronological age. Um, am I right in thinking that those can be heavily gamified? So I can be eating normally as I would do in an excess calorie consumption and then if I fast for a week or so or I do some activity, it can change my methylation such that if I was to do that test that looks at my longevity or my chronological age, sorry, my biological age, just to say, I appear to be younger than my chronological age.
Dr Stuart: So I I think there are the people that have formulated them and then and and trying to put them in the the commercial space have shown that you can modify your methylation profile. So the one thing we do at fitness genes, we're a genetic testing company, but actually we're not, we're a biological modelling company. So we we have blood testing data in our model, we have a lot of questionnaire data. I've actually been looking at these methylation arrays over the last year because I think because in as a commercial end, it's quite a cool thing to have. Like go to fitness genes, we tell you what to do, we do a methylation test on you and then you follow all our advice in six months time, isn't this great? You know, so so yes, in theory that's great. The one thing we realised very quickly that increasing exercise or actually someone going from sedentary to exercising from from the reports that were put out there had no change on the methylation at all. Now because we're kind of an exercise first with nutrition supporting it company, that wasn't very good for us. Now this doesn't mean the methylation analysis is is not something that will be very useful in the future. But we are, but but it's sort of the gut microbiome went through that phase a few years ago where and it's still very underrepresented. The the arrays they use are looking at a very small amount of sites within the genome. So you're kind of having a basic, it's kind of like it's kind of navigating the UK where you just know where all the cities are but none of the roads and none of the villages and everything else. It's it's a very low resolution map at the minute. So I think there is going to be scope for using it more specifically because ideally what you want to do is look for location specific changes. So if I exercise, this happens, if I eat a high fat diet, this happens, and then start to then link that very much into, well, I know that these genes are associated with these specific pathways. I can see the methylation changes that are regulating or changing the regulation of these genes and link these all together. Then you can overlay then microbiome data, blood data to have a holistic view and nature, a holistic view of of your biology. So I guess my executive summary on the methylation arrays, they they they're cool and interesting. If I just don't think we're quite ready to to to put them in the system yet.
Dr Rupy: Gotcha. Um, if I'm looking to improve my brain health and prevent dementia and I want to slow the aging of my brain, essentially, what should I know about my genes and and health in general if that if that's my goal?
Dr Stuart: Cool. I think this is a good time to talk about ApoE.
Dr Rupy: Yeah.
Dr Stuart: Uh, so ApoE is, I think over 20 years now, it's been associated with dementia risk. Uh, so it's a protein like all the apos, uh, is associated with lipid metabolism. They think again, the mechanism of how it may cause dementia, particularly ApoE, which is uh, which is the the the variant that causes uh, dementia. They're not sure how exactly it causes it, but they think it's involved with lipid metabolism in the brain, neuroinflammation and impacts the way the glial cells. So the brain has neurons which have the connections and the glial cells are, well, they're in the old days supportive cells, but they have many functions in regulating the function of neurons, the establishment of synapses, memory, everything else within the brain. Uh, so what we've seen with people with two versions of the epsilon 4 variant, which is based on a couple of single nucleotide polymorphisms, uh, have a very high increase in the risk of dementia. Now, there's been a recent paper in Nature Medicine that has shown that people with both copies of the epsilon E will have, uh, all have some hallmark of dementia. And when I say hallmark, a biological hallmark, you get the build up of proteins in the neurons that then leads to these neurons dying, which leads to the dementia and the cognitive, the loss of cognitive function.
Dr Rupy: To everyone with these?
Dr Stuart: So everyone with these, uh, these, uh, these two variants will have the the the biological hallmarks. And I'm being very specific here, the biological hallmarks of dementia. So what do you mean by biological hallmarks? Well, actually you've got some of the pathology in your brain. But then when you do tests, the classical tests and look at brain scans, not all of these were presenting in the clinic yet, which is I think is a very interesting point. And what you see with dementia is if you have cognitive reserve, you can actually mitigate, uh, mitigate the presentation of of the disease.
Dr Rupy: So what does cognitive reserve mean?
Dr Stuart: Well, actually it's the ability to have cells dying in your brain, but still have enough neuronal capacity. So this could be numbers of neurons, uh, but also the the synaptic connections within the neurons to actually still be able to function as a human, uh, whilst some of those cells may be suboptimal because they've got the protein build up within the neurons, which is indicative of of dementia.
Dr Rupy: Now, how do you build cognitive reserve?
Dr Stuart: I guess it's the great question. Well, well, at the moment, exercise is the great one, cardiovascular and I think weight training is a really important one. The the dash, which is the one associated with blood pressure and the Mediterranean diet are really important. Omega-3, there's there's there's supplements that are been bandied around with for such as ginkgo as well. Now again, I think they're the things you go for if you've got money burning a hole in your pocket and and and you want to buy those things. I I wouldn't say it's the first port of call, but actually social interaction, friendship networks, uh, uh, just education, lifelong education. This these really seem important. Uh, there's interesting and we we have a bit of internal debate at fitness genes here. There's interesting conversations around alcohol.
Dr Rupy: And enjoying alcohol as well.
Dr Stuart: So the you see in a couple of the the biobank studies and you see this with other conditions, but particularly with uh, uh, with dementia, sorry, where you moderate alcohol intake is more protective than not taking alcohol. So so on a cellular level, that makes no sense. Uh, and there's two ways of of uh, of describing this. Now, the teetotallers of fitness genes team go, oh, it's because people who are teetotallers very often have had bad lifestyles and therefore it's it's a presentation of that bad lifestyle. They're just coming up in the data as teetotallers. Now, where we are, and of course you can factor that into your analysis. I think where the drinkers of the team are going from, and I think there's a lot of the data is starting to go this way as well, that a few drinks, and we're not talking going to my bay and killing yourself here. Uh, a few drinks can help you relax, it would destress you, but actually it's often an instigator of social interaction. So if you're going for a few drinks on a Friday and having a group of friends that you see, you have similar hobbies to, you meet them, you you keep those friendships throughout life. That is incredibly important. There's also studies as well, there's the one which uh, I only skimmed through but it was but being religious can increase your life expectancy by four years. Now, I'm not here claiming God exists. Uh, my friends will tell you that that's definitely not where I'm coming from. But actually in terms of if you think about religion offers community, offers community into later in life. It offers you hobbies and you know, think think about go down the old C of E route where you've got your women's institute, you've got all these uh, going into church, flower arranging, those you've got all these social interactions that sit around the church that actually if you don't have that sort of religious sort of central point and location to go to, you may just be sitting in your house by yourself. So in terms of, I appreciate this is a nutrition podcast, uh, I I would put exercise and and social interaction first. And then but the nutrition of course underpins that. And again with with people who are carriers of ApoE, blood pressure and diabetes are huge drivers. So for example, if you're an ApoE carrier and also have diabetes, that's again really going to drive the the the the impact of of that allele and probably going to lead to you more likely to present in the clinic as opposed to just being a biological hallmark. So again, you can start to think about, you know, the the dash diets and the Mediterranean diets actually underpinning mitigating those risks. So instead of going, and I think you it's always nice to think that there's going to be, okay, well I've got this risk, I need to take this pot of things or eat this vegetable. And it's not the case. You've got to build those lifestyle diets that are going to mitigate those long-term risks. Those long-term risks are going to be your broad high blood pressure, high cholesterol, diabetes, and then the lack of exercise and the lack of social interaction that kind of fills around that space.
Dr Rupy: Yeah. I mean, I obviously have my bias towards nutrition, but it's very hard to deny obviously the impact of other lifestyle factors and you know, just an anecdote, my my wife's uh, grandmother, who's soon to be a great grandmother if she can survive until our our son is born later on this year.
Dr Rupy: Cheers. Um, she's 105.
Dr Stuart: Wow.
Dr Rupy: And uh, she uh, grew up in Italy. So she's a nonna. Um, we uh, she she was a midwife, uh, she, you know, lived through the Spanish flu or whatever we we call it now. Uh, moved to Australia, you know, it's had like a really fulfilling life. Lives in a nursing home at the moment, but has strong faith. She sees both her son and daughter multiple times a week. We speak to her every single week. She's sharp as anything. Like she remembers everything. Like stuff that I've told her the week before, she'll pick up on. She's always cracking jokes. And her diet is terrible. Her diet is so it's mainly cheese at this point. And she's been a big cheese and pasta like uh, lover and and stuff. So I mean, I'm not denying that she would have had some vegetables in her lifetime, but it's definitely not the thing that I can point to that has led to her to to lead such a brain healthy life and the fact that she's so sharp right now. So there's definitely something going on there.
Dr Stuart: Do you touch on another point which was the location of children? Now we live in a world, a meritocratic world where we're told social mobility is key, go to your university, go work in London. And what you're doing is family, so I've got two kids. Uh, we're lucky enough that my family's from the Midlands and we live in Oxfordshire. So it's only an hour and 20 minutes drive. But there's a lot of families that are separated. There's other studies that show that the proximity of children and grandchildren to the individual has a big health effect as well. So it's really, there there is there is a lot of evidence around this social structure, social interaction space that's really important for for the dementia, for the dementia sort of mitigation.
Dr Rupy: Yeah. I want to talk a bit more about the ApoE alleles. Um, so I understand that uh, these have an impact on lipids, inflammation and glial cells. Do we know anything about the other alleles, i.e. the ones other than ApoE4 that we test for?
Dr Stuart: So they, yeah, they they they function in the same in the same way. I I think the the epsilon E, they believe just raises the neuroinflammatory processes within the cell. So I don't think there's a gain of function in any way that this is going around doing something terribly bad in the cell. I think they're just it it it is impacting one of those processes. Now we in essence, we just don't know. We just don't know the uh, the mechanism for it. We just know what the protein does in the cell. We know the variants that's associated with the disease. Uh, it's researchers will be working on at the moment to understand exactly how it's impacting and how it's raising uh, uh, the the risk factor, but it'll be associated probably with the build up of uh, of protein aggregates in the cell, potentially. It but but that's only based on the latest hypothesis within uh, dementia.
Dr Rupy: Yeah.
Dr Stuart: Gone through a few phases where people didn't believe the uh, protein aggregation uh, uh, theory of of dementia at all. So uh, we're we're always open to new ideas. And of course, it's not the only uh, it's not the only driver of dementia as well. Uh, it it will be, I'm guessing, uh, modifying other pathways that are naturally progressing in neurons as they age as well. So it's not just that is the only driver of that dementia in ApoE carriers. There'll be other things going on. There'll be the energetics of the neuron, neurons are long-lived as in they're not replaced very often. They're highly demanding in terms of energetics. So there's lots of different things that are going on in the cell and understanding the interplay with this change in lipid metabolism, how does that accentuate the pathology of aggregate build up and then how does then that lead to the degeneration of the neuron? We're not quite sure yet.
Dr Rupy: Okay. I want to talk about cancer. Um, again, similar question in terms of genes, what should I know about my genes if I'm in the business of trying to prevent cancer as as best possible?
Dr Stuart: I cancer that so there's a lot of heritability in cancer. Uh, there are certain people that have again, single mutations that lead to cancers, but that'll be very much early on childhood cancers. Uh, the the again, there'll be in terms of the polygenic sort of uh, area, there are lots of variants that increase your risk of cancer. Uh, but cancer in itself is is a very complex disease and the nature of cancer is you will get what you call somatic mutations. So within the cells, you'll get mutations occur. So the the where disease genomics is going with cancer is actually to sequence the tumours because the tumours will have their own genetic makeup, which is actually will be potentially different from say my genetic makeup today. Uh, so you may have the uh, repression or the deletion of tumour suppressor genes, you'll have maybe have lots of different proteins associated with cell division that are regulated. You can actually have it where you duplicate proteins associated with uh, with cell division. There's certain changes in the cell which change the metabolism. It's called the Warburg effect where they it's aerobic glycolysis where they they use energy in a different way. So where genetics is going in terms of cancer is you would sequence the tumour, you'd understand uh, the genetic nature of that tumour and then you can start to target specific drugs or chemotherapy or particular drug immunotherapy which are, you know, uh, a lot of is being made of at the moment. So it's it's I in in the space of fitness genes, we don't do the cancer biology or those components at the moment. We could say you're more, you have increased or decreased risk of certain cancers, which has some merit, but I don't think the one thing we want to do at fitness genes is be able to give you direct advice to mitigate the risks we're describing. And with with the cancers because okay, you have a slightly increased risk of cancer, but generally everything we do at fitness genes is is towards mitigating the risk to a certain extent. Uh, but we cannot be very, we cannot give specific advice on different cancers because of the nature of cancer itself.
Dr Rupy: In in the grand I I totally get that point and I guess the question was probably, you know, a bit tongue in cheek because cancer is very much an umbrella term and there are so many differences as you've eloquently described. In terms of the number of uh, potential mutations, again, sort of ballpark figure of all the different uh, snips that we're aware of that would push someone's risk profile to higher risk uh, of all different types of cancers. Let's just talk about the the big ones, breast, uh, uh, prostate cancer, uh, lung cancer. Do we, do you have an idea of the number of of snips that could be for those as well?
Dr Stuart: There's there's there's sort of moving towards the monogenic forms, which is called where you've got single genes. There's kind of the classically described ones associated with breast and stuff called which is BRCA1 and BRCA2. Uh, but again, the increased, I think the the risk associated with that is around 15%. Uh, but again, it's it's it's polygenic. So so so in terms of how many variants are associated or linked with changes in risk of cancers, we're talking thousands, 10,000. And then you'll have your different uh, specific cancers will have their different groups of those variants that are associated with them. Some will be more broad. So so there's the tumour suppressors and the cell the proteins associated with cell division. You'll find mutations that increase the risks in many proteins. Then there are other genes that will be associated like the BRCA1, BRCA2, uh, which are associated with particular types of cancer. Uh, so you again, you have very rare mutations which can create tumours very early on and you'll see that in childhood cancers very specifically because the rare mutation totally changes the way cell division occurs and you get very aggressive tumours. And then there's kind of the the cancers more derived around lifestyle where you're smoking and drinking and eating poor food and not working out that then will increase your risk of uh, of the cell cell cycle which drives the division process going awry and then creating creating different types of tumours.
Dr Rupy: I'm just wondering if there is a world, and I'm not too sure whether I'm in agreement with this, but uh, you know, if I chose to take up smoking, for example, I could broadly speaking, figure out whether I'm going to be in that category, everyone's had that anecdote of, I know someone in my family who smoked for like 60 years and they never got cancer and they were fit and healthy until they died of something completely unrelated, or the camp where, you know, uh, I would die after a decade of smoking related to a cancer associated with um, smoking. I I wonder if there is a world in which we can actually risk profile someone who comes into the clinic and is an active smoker and I can pull up their their genes and say, your genes are not great for a smoker. You're not going to be one of those people that survives into their 80s and 90s smoking the way you're doing right now. So do you know what I mean? It gives it gives even more impetus to someone to actually make that change and give them the motivation.
Dr Stuart: So yes, I I think it's kind of like we're you're going to run across a motorway which has five lanes or 100 lanes. You know, it's kind of a thing. So so yeah, you absolutely can see and and this is where polygenic risk scores very much come into uh, their own is you can very much identify people that are very high at risk. And and there's quite a few studies that have shown that these are the people that are most amenable to lifestyle change. Now, if of course, if you think about any disease where you're in the highest risk category, it doesn't mean that's where all the disease sits in those individuals. Of course, through lifestyle, something like, you know, cancer, even if you're not a BRCA carrier or not in that highest uh, risk uh, category group, other people within the population are still going to get that breast cancer. But for those individuals in that high risk group, these people seem to be the these are the people we should be sort of suggesting particular lifestyle interventions for. Just to go back again on the prediction, I think the predicting thing is very interesting. And the one thing we're seeing now in terms of predicting things very far in advance is the constant re-evaluation. So something called health trajectories. So the one thing we do at fitness genes, we continually collect data. We actually update our polygenic risk scores when new information comes in. So it's the predictive capabilities, okay, well, we know you're at increased risk, but there's no way in a million years where you touched on at the beginning we'll go, well actually, you're 100% fine because you just do not know the complexity of that system. There are many genetic variants we've not discovered yet that will be causing disease. We've talked about that, you know, there there will be many people have what you call rare variants. So so we can just be in you or a few family members which cause a common disease, be it diabetes, be it uh, dementia, that actually uh, we don't know about. So when we look at our genetic array, we're not picking these things up. So it's it's it's the health process, the evaluation and the the wellness uh, preventive health care space needs to involve constant re-evaluation. It's the same with predicting anything, predicting the weather, predicting an economy, you know, it's it's you've got to have that continued evaluation because there's all these additional inputs that are altering the system and infection, for example, like COVID, look at what COVID's done to the health system. And that in itself in terms of not just getting COVID and having the immune response of COVID, but the social isolation, we've talked about social interaction, dementia. Those components that are just you cannot predict within the system, uh, is is is is going to keep us on our toes for a long time in terms of of scientists.
Dr Rupy: Um, I want to talk about obesity and fat and where we store fat and something that comes up time and time again, which is belly fat. And is there something or are there genes or tests that we should be aware of when it comes to how we can best prevent uh, fat, particularly visceral fat as well, that's something that I'm very interested in. Um, and is there a sort of explanation as to why certain people keep and store excess energy in the form of fat in certain parts of their body as well that that is determined by by genes and so on?
Dr Stuart: I I think the the storage is that there's definitely genetic variants, I can't remember which ones they are, linked to increased risk of visceral fat. So fat around the organs. In terms of the storage of fat, I think you're probably looking at more broader body composition uh, uh, sort of traits. So so obviously the major ones are are sex and the hormones associated with sex and they drive where you put fat down. Of course, height, everything else, these things will impact where the the fat goes down. But the majority of the variants associated with obesity are are mutations in the brain. They're associated with our response to hunger, so to to satiety. So the leptin melanocortin system is one that's uh, regularly talked about. Uh, so we're starting to find mutations uh, in leptin. So leptin's a protein uh, that's secreted from fat cells uh, to say we're here, we are fat cells. So it's a way of telling your body uh, that you have adequate supplies. So if we go back to the evolutionary route here, we think about ourselves in terms of the obesogenic environment, but actually the biggest risk would be not having enough fat, not being obese. So they found that these individuals incredibly fat, uh, had an insatiable appetite and they kept eating. I think the anecdote was they would go to a freezer and eat raw fish fingers. Uh, and what this is doing is it you can either have mutations in the the secretory protein, the leptin itself, or the receptor on cells. So leptin binds to go, yes, there's fat here. So the more fat you have, the higher levels of leptin. Because the mutations either in the protein or the receptor, uh, the body thought it had no body fat, even though you you were obese, your body thought you had no body fat. So it was driving you down the survival, gravage yourself to death sort of pathway. Uh, there's other ones in the melanocortin system, which is associated with, you know, the the signalling pathways associated with feeling full. There are certain mutations that are linked to what is called fat taste. But actually when you eat certain food, you're you you don't taste it in the same way of salt or sugar or anything else, but you it binds to a receptor that tells your body you've ingested fat. So it's a way of going, great, we've got some fat coming into the system. So therefore it decreases the hunger. So obesity is very much linked to these proteins that are that are detecting nutrition, detecting fat in the body, and detecting the passage of particular nutrients through the gut. Uh, so that's very much where a lot of the obesity genetic knowledge has has pointed us in that that actually obesity is because in the old days it was it's a metabolic issue, it's I don't burn enough fat. And there are components around uncoupling where some people can be thriftier or less thrifty. Some people need more and I think that is true. Uh, some people will when the mitochondria, so the powerhouse of the cell that metabolise all our energy, uh, they can be less efficient in converting the food energy into what is the currency in the cell, which is ATP. So that's the one that all the molecules and systems and muscles in our body use and the brain is ATP, which is a molecule which has energy in the bonds. So when you break these little bonds, it releases the energy. We don't literally feed glucose into a muscle cell. We have to convert it to uh, to ATP first. So we very much in the old days we thought it was efficiencies or inefficiencies around the energy. Actually what it seems to be, it seems to be nutrient signalling, nutrient sensing, our ability to feel full. Now, the more and more you eat and if you're obese and this is not linked to any genetic defects, you can get something called leptin insensitivity. So actually your body stops recognising the leptin signalling and that then can lead obese people to find it a lot harder to lose weight.
Dr Rupy: Yeah, yeah. So this is really interesting because it seems that there is a spectrum all the way from um, leptin severe leptin resistance where you just cannot tell whether you are satiated or not and ergo you start eating raw fish fingers because you can't wait to cook them. Um, and then there's the the sort of grey spectrum where you can almost instill leptin resistance through the eating behaviours that are quite unquote westernised. Do we have a sense of just how many of us have that leptin resistance as a genetic abnormality?
Dr Stuart: So so we've so we look at mutations in the leptin system, the rare mutations now as well, and in the melanocortin system and I think it was about 0.1%. So it's so so we have we have people on our who are members who are have rare mutations and we can look at the data and they are obese or clinically obese. Uh, then yeah, in terms of then we go back into the polygenic uh, uh, perspective on yeah, then you have, so there's genes you may have heard of FTO, which was coined as the uh, the obesity gene. Again, linked to nutrient sensing and many other, it seems to be a regulatory region in the genome that may have many, many impacts. The leptin melanocortin system, so we look at many of the associations with mutations in that system, which is about the do you feel full? You know, when you've eaten, do you have those feelings of of fullness? Then there's sort of the ad hoc kind of pathways associated with fat sensing, sugar sensing. So some people just don't sense when they eat it, they don't get the the sort of the signals to go, you've had your sugar now. Uh, and then you have a build up and again, it becomes then a polygenic score. You get all these different, you can create a great burden of all these different variants associated with slightly different components of the you eat, you recognise it in the mouth, you digest, the gut recognises it, you signal to your body to let your body know you've had food. And again, it's how much do you eat during a single sitting, but also when's you when do you initiate your next meal? And these variants can impact all those different timing points of of eating. Uh, but but the obesity, the one thing we find the obesity, at least in the polygenic sense, it is hugely manifested by the obesogenic environment. Again, you think about 100 years ago, these uh, these variants uh, were still prevalent. There was no obesity. It's it is, you know, there there were beneficial, I guess, in terms of it is important to when there is food around to eat and eat well. Uh, but in in terms of whether they've been selected for in that way, I'm not quite sure because you you would expect everyone to have the obesity genes in that case, wouldn't you? Or at least the common obesity variants. So I'm not necessarily thinking uh, these are genes that have been massively selected for. I think there's just been a diverse human population and some people have variants that in an obesogenic environment are problematic because they feel full slower. They're more likely to eat quicker and they don't sense the intake of certain certain macronutrients, which means they will then go on to eat for longer.
Dr Rupy: Yeah. I guess this is sort of part of a wider question which is, you know, how much we should be caring about our genes given the impact of our environment and the impact of, you know, other things like our microbiota. And I think there is a sense that whilst it's nice to know what your genes are and what your probabilistic risk is, does it change too much in the context of what we need to do in terms of our environment and how much of this is having a driver versus the environment?
Dr Stuart: It it depends on the trait and the person. So someone with a high genetic burden, uh, it can give them an understanding. So in terms of, you know, why because if you say to someone, okay, well, it's just your obesogenic environment and then you'll have some advice like, well, just eat to when you're full. And that that's advice that's given a lot, isn't it? Well, actually if you know when you don't feel full, you could be metabolically full, that that piece of information is very important. And so the genetics can actually and we found actually because I was at the festival of genomics, someone came up to me and says, do you feel people get annoyed when they find out this information? Do they feel stigmatised? And actually no, it it basically the penny drops for them is because when you're feeling hungry, you feel you need to eat. It's it's it's a fundamental driver of human being. But if you know you have these variants that increase your ability to overeat, ability, I think ability is the wrong term, but you know, can drive you to overeat because you are not uh, you you are not feeling as hungry, sorry, not feeling full or satiated quick enough, then that's a really important piece of information to give someone. Uh, so yeah, I think but but again, of course, it only manifests. So you'll feel you'll have people and we've done studies within and looked at our cohorts where they have the burden of these genes and then you you you talk to them and we've done this, we're over 11 years old now as a company, we've always talked a lot to our customers and you you have a conversation with them and they have incredibly rigorous behaviours around food, what they eat, how they cook meals, how they eat food slowly. So actually they have they have without thinking put in the the the methods of stopping weight gain by themselves. And that's very interesting for us as well because we can use that data then to communicate. So when we do the genetic analysis, we give advice. So for some of the people who very much respond, you know, people say, well, what foods to eat? And of course, get rid of processed food and everything else. But sometimes it's replacing that impulse with something that's enjoyable but not food. So go listen to your favourite track and go for a walk. Go to see your pet dog and stroke it. Have you got a favourite book at the moment or a favourite song or TV program? Go to those things for that enjoyment because some people as well have that and there's another component of overeating which is the impulsive uh, dopamine sort of uh, circuitry where you're just going for that that hit of enjoyable food. And there's that that's something else that if someone sat down and really thought about their their behaviours, they could probably work it out by themselves. But when you have the tangible data behind you saying this is what it is, it the kind of it becomes less opaque. They they they can they can actually it gives them it gives them something to push off to to make the lifestyle change. Uh, because it gives it gives them direction. It gives them an understanding.
Dr Rupy: Yeah. In terms of that energy expenditure model, you know, you've got your the thermic effect of eating, you've got your non-exercise thermogenesis and you've got your your basal metabolic rate. And notwithstanding the fact that you can change that slightly by reducing calories, changing your muscle mass, is there a genetic determinant of someone's basal metabolic rate that would distinguish a thinner person from a bigger person?
Dr Stuart: There is a component and we talked about the uncoupling where you can be less efficient or more efficient with food. So instead of using all the energy in your food to create ATP, you drive some of the hydrogen ions through the mitochondria and it gets lost as. So brown fat is an example that actually utilises that process quite nicely for keeping warm because it actually generates heat. The other one, so so the other uncoupling process drives different uh, signalling processes within the cell. Uh, but generally we're talking tens of calories maybe. So it's so so over over a lifetime it can be significant, but when we're talking two, three years when people really start to put weight on, it is the, yeah, there'll be we're trying to figure this out. I've not seen anything definitive but in terms of response to exercise. So there there's a lot of work at the moment that looks at like aerobic exercise where I think you you have an initial benefit and then you know basically then it trades off with so for example with running, you see that actually reduces inflammation, which is great for health, but actually it reduces the calorie need burden. So actually with aerobic exercise, it it it can over time you burn less. So you go on your Garmin says, you've burned 600 calories and it's just not true. Uh, when you start off running and you're inefficient and also if you're large, it is probably true because you are literally putting the work in. But you build in efficiencies and trade-offs within what where you reduce the calorie burdens from running. Like weight training, I think you've got to repair that muscle. Uh, so weight training is really good for uh, for maintaining or burning fat. Which it seems counterintuitive to people because you think you're getting bigger, don't you? And you've got to put a serious amount of work in to get bigger with weight training. But actually so so we are very much lean to sort of I'd say like 60, 70% weight training in kind of our again, it becomes personalised. But if you just to to come up with a standard high level sort of number, 60, 70%, even 75% weight training, sort of 25% aerobic sort of VO2 max. And the VO2 max, sorry, the cardiovascular stuff, yeah, it's like an 80/20 split around uh, like baseline to high intensity stuff.
Dr Rupy: Well, is that was going to be my my question actually around exercise. Do my genes determine the best form of exercise that I should be doing more of for longevity and healthy aging benefits, let's say, or metabolic benefits? So should I as a someone from a South Asian background with my set of genes, should I be doing more aerobic versus uh, weight training, for example? Is can we be that sort of distinctive?
Dr Stuart: Not not in so not in the primary sense in terms of we have a gene here which means if you do weight training, your diabetes reduces or if you do no, not in that. It you've got to think about it in terms of like weight training is really important for muscle mass. So I if you've got low muscle mass, do weight training. Now, in terms of how you respond to those training, so there are sets of genes that are associated with how, for example, you respond to VO2 max training protocols. Uh, now, that may mean if you're into running, you might if you're if your VO2 max training doesn't elicit the greatest results, you may want to do different things to improve your running time, be it economy running, maybe more baseline running. And it's the same with weight training. Genes will not say whether you respond better to weight training, but it may tell you whether you're not going to recover as quickly as someone else. And alpha-actinin-3 is a prime example where it decreases your uh, recovery time, basically. So I I I think generally weight training first with good cardiovascular health is is the general sort of overarching advice. However, how you then respond and recover and and and deal with those and what specifically do in terms of the aerobic training protocols, genetics can inform that in some way. But but in terms of general health, it's quite trivial. For for your muscle builders who we used to work with in the past or with with particular groups of athletes, it is highly interesting. For long-term health, it's it's a it's a it's an interesting sort of piece of information. It's not it's not mission critical for health at all.
Dr Rupy: Yeah. Are there any like sort of 80/20 in terms of the genes that you one would sequence uh, that would have the the most bang for longevity and um, uh, disease prevention benefits? I'm I'm very interested, for example, in my supplement stack and what supplements I should be taking. I take a B complex, uh, I take omega-3, something that we discussed earlier, even though the evidence is not obviously the the best, but um, I'm willing to take the the financial hit and the um, uh, the potential side effects. Um, and I take vitamin D3 because I know that my my vitamin D is is crashing low with with K2 as well. Um, yeah, are there are there things that like, are there genes that you know, everyone that you feel that everyone should know to to have sort of the the biggest impact?
Dr Stuart: So there we haven't really touched on this. So there are genetic variants, so it sits within what is called pharmacogenomics. So these are the genes in your body, many of them are expressed in the liver that metabolise the the the vitamins, the drugs that you put into the body. Uh, and some of them can mean you have lower levels of say serum vitamin D, lower levels of magnesium in certain instances, lower levels of different vitamins. So they they can highlight whether you have maybe an increased need for say vitamin D. And I think the variants associated with vitamin D metabolism have have the most evidence behind them. But in terms of uh, in terms of broadly, I I think the way I could before I came to this talk, I kind of factored them the genes in three ways. There was the causative, so we've talked about ApoE, we've talked about hypercholesterolemia. The predictive or the probabilistic, which are the the the large polygenic risk scores, and then the informative. So the informative I'll put in caffeine metabolism, for example. Everyone likes the caffeine metabolism gene. It does have impact on heart health in a small amount. It has an impact on sports performance when you take caffeine in a small amount. And a lot of these vitamin associated variants sit within this informative. It's it's when you're starting to really want to, you know, if you're healthy, if you're doing your 80/20 exercise, if you're on your Mediterranean diet, if you're feeling really good, this you can start to tease, start teasing these pathways apart. If you are doing everything to cover your your sort of long-term health issues, again, this is really the optimising biohacking crowd that will get value out of these. In terms of the general health crowd, there are other things you should be looking at.
Dr Rupy: Okay. I hope that makes sense.
Dr Stuart: Yeah, yeah, that makes sense. Yeah. I mean, you you probably sequenced your genes. Uh, what what are the some of the uh, the insights that you've you've gleaned from from your own data?
Dr Stuart: So, uh, yeah, it it kind of uh,
Dr Rupy: And is it sorry, just for for folks listening at home, is this something you do once in your lifetime?
Dr Stuart: Yes. Yes. So so the uh, so so we do one genetic uh, test. Now we can do we can do genetic tests in the future as we can be more comprehensive in terms of what regions of the genome we look at. But at the moment you do it once, there's one payment. Uh, this is something we're quite tight at fitness genes at the moment that we don't want to tie people's health data to subscription models. I think that's a really important. Now, of course, our shareholders love that. Or not, as the case may be. But actually I think in terms of when you're building health, a health tool, there is there is a value to be created across the health ecosystem. So we can talk about we've talked about it before, supplement companies that actually we're there are there are ways of finding the right consumers that have the right needs in terms of we've talked about with ApoE with certain types of diet, certain type of exercise, but also community groups. There's actually a way I think the health ecosystem can start to really have build advantageous products and services for preventive health care. So, uh, so yeah, we do it once, but we really see actually the the the benefit of this and as we talked about with longitudinal data and continuing to predicting the model, people will continue to give us information back. So we ask questions around eating behaviours, what they eat, how they exercise, how are you sleeping. That will keep coming back into the system and then the genetic models will change based on that ongoing information. Think about sarcopenia, which is muscle loss. The risk of telling someone about their sarcopenia risk and also knowing what they've done in their life in their 20s is irrelevant. But if you're 50, 60 and 70, we know what your diet's been like, we know what your genetic sarcopenia risk is, we know uh, we know what your training history is like, then that becomes a very different conversation. So you're buying the product but actually the information evolves as you we understand your your your journey through life.
Dr Rupy: Yeah. It feels like you you can layer in so many different um, inputs beyond just genetic uh, your your genetic profile to give a more holistic picture of someone's disease risk. And I guess everyone's sort of doing their own part, but that just seems like there's an opportunity there.
Dr Stuart: No, for sure. And and it's essential that the lifestyle data and the other diagnostic data, so the blood data is essential uh, in giving the right uh, the right advice because uh, we we if someone gives us a high LDL reading, we're not going to base it on the genetic prediction. We're going to base it on the high LDL reading. And that but then that then knowledge of that atherosclerotic risk will then have other impacts more broadly when you think about, well, if they're interested in, so for example, if they've got high diabetic risk within the system, that is important for dementia risk as well. So it's actually then the interplay with those components within the system that need to cross talk with each other. Uh, and and that's why it's an ongoing process. So we we've been around for 11 years, we've got customers that have been with us for eight years and still coming back. And we constantly update and release new information, which is not behind a paywall because that is that is what science is. It is the constant re-evaluation, the providing of new information. For example, one week a supplement may be banded as the greatest solution to a problem, next week it's killing you. So it's it's it's keeping on top of that information as well, which is really important. And you do have to offer that service, I believe, to customers in the long term.
Dr Rupy: So so going back to your insights.
Dr Stuart: Yes, yeah, I did a way I avoided that. Yeah, yeah. So so so for me, I was I I'm reasonably burdened on weight gain, uh, which makes a lot of sense to me. I am always hungry. Uh, luckily, uh, and which which makes sense in my family history, low on heart health risk. Uh, there's there's minimum heart health risk. There's I've I've got ApoE carrier status in part of my family. Uh, unfortunately, I'm I'm very fortunate that I'm not a carrier. Uh, uh, so yeah, it's uh, yeah, it's it's it's it's like everything. There's there's good and bad's not the wrong one. There's there's there's there's things to concentrate on and there's things to be thankful for, I guess, is the way I look at it. Uh, yeah, I I think that's the way I can evaluate it.
Dr Rupy: Has it influenced your your supplement stack or do you do you tend to take supplements or
Dr Stuart: I'm I'm not a big supplement taker. Like vitamin D is something I take. Creatine is the one thing I've gone to.
Dr Rupy: Okay.
Dr Stuart: Uh, I think I think creatine is something I take a lot more.
Dr Rupy: Is that from an exercise benefit or from the brain?
Dr Stuart: Exercise benefit with a with a look towards the brain health actually. Uh, for sure. I'm I'm evaluating taurine and and L-carnitine at the moment. Uh, and what that means more just from a scientific point of view, but I think it's quite interesting. I've looked at a lot of these uh, anti-aging compounds like spermidine and all these other things. And I I look at them with interest, but I think that's just because I want to live long, not because uh, or not not because there's actually the science is there yet sort of thing. So yeah, it's for me, I I eat a lot healthier now. Like I'm I'm all non-processed foods now. Lots of salads. My my biggest vice will be a nice couple of beers and a nice glass of wine. And again, it's back to trade-offs, isn't it? Not not just trade-offs in biology, but it's trade-offs in your lifestyle. Some things are uh, keepers, unfortunately. Uh, yeah, so I I'm I am I'm of a personality where I struggle to uh, stick to something for long periods of time, but it it gives me the framework to just just to give myself a bit of a kick up the butt to say, you know, you're not getting any younger, there are considerations. And of course, because of my ability to, I probably yo-yo diet, not yo-yo, sorry, I will put weight on particularly certain times of year in winter where I will go through phases of not exercising too much and feeling it's winter, therefore I can uh, eat a bit more, as it were. And it just gives me an understanding that when I'm feeling hungry, I'm not hungry. And that so so I I've taken quite a bit from the uh, the weight loss, weight gain component of our our modelling. Uh, less so much on the cardiovascular stuff just because the burden doesn't seem to be there in both looking at my family and also in the data. Uh, I'm looking through and and and unfortunately, I have skipped a lot of the variants associated with dementia. Uh, unfortunately for other members of my family, that's not the case. Uh, so yeah, I guess that's kind of how I've used it. And the one great thing is we keep adding more and more data to our system. So there'll be new traits, new evaluations. So you'll find things new things all the time. Uh, and that's one of the great things things about doing the research. Uh, but the the one thing actually and I I say we've been doing at the moment, we've been doing this for three years. So at the moment there's something like 180 traits that sits within the fitness gene suite. Uh, and if you're invested in your health, that's great because there's a lot of reading to do. But actually what you need to start doing now is actually understanding the relationship between all those different traits. So we've got a beta system coming out soon where instead of going, can you tell me your 23 uh, 23 cardiovascular traits? Uh, can you show me your, I'm probably about 30 weight loss traits. Actually, you can go in at the top and actually prioritise. So with all the different risk components and preference components in the system, you can go actually these are the things you really need to start concentrating on. These are the the genetic variants because as we talked about, you've got the rare variants which are more penetrant, you've got the polygenic risk scores that are probabilistic and then the information ones. As you can go into a lot of these sites go, well, they all seem much of a muchness. You need to build a system that actually ranks them and prioritises them to say, polygenic risk, you know what, this is something you should focus on. There's a chance that you have increased risk going forward or guys, you need to look at this right now. And the second component of what we do now is because the guys we need to look at this right now will require professional help. So we were classically a direct to consumer company, but actually now what we have is is is is a portal where clinicians, where doctors can actually take the information. So it doesn't go directly to the customer, but they can actually take it through their clinics and they can use it to give clinical advice. And you can triage it. So we've been talking about workout information, that can go to PTs, all the nutritional stuff. So the the things around how what nutritional advice to give to someone with higher cardiovascular disease risk or high dementia risk. Well, that information can go to a nutritionist or for example, the the nitty gritty stuff and we don't do the cancer biology or all those components at the moment. But in theory, that information could be put through then to go through to clinics where they can actually start looking at the information and if required, the genetic counsellors can be involved. So it's using what is eventually our our calculation engine to then assess someone's health holistically, but then to send them to the right places because we we there's a lot of conversation about AI. I think what was my favourite uh, quote, but obviously you probably hear this in investment as well. Everyone talks about AI and I think it was was it it was someone in the government that said something along the lines of AI in healthcare is like teenage sex. Everyone's talking about it, only a few people are doing it and the few people that are doing it are doing it very badly. And it's and it's not to say in terms of the diagnostics, AI is is not uh, important. Like with with identifying new lesions or or or cancer very early on. I think Moorfields, the eye hospital has a great AI sort of uh, uh, process where they can look out for all the different abnormalities in the eye. So so we've got all this sort of metadata going on and we're going to be replacing doctors soon and everything else, but no, we're going again, going back to the ApoE conversation, it's about communication. It's about people. It's about that interaction. So it's great to give someone a technical, a digital tool, but actually I think where this really will have its advantage is through the individuals in the health ecosystem.
Dr Rupy: Yeah. Yeah.
Dr Stuart: And I think that's a I think that's something we're quite strongly passionate about.
Dr Rupy: Yeah, definitely. I mean, if I just think about like my impression of this field, I certainly overindex on more information and I think data and being data-centric is something people need to uh, be more inclined to do. And I think we were chatting before about how people right now are perhaps problem unaware and things like DNA information, for example, makes them problem aware. And then it's a case of, okay, now you're problem aware, can we make you motivated to do something about it? And then once you're motivated to do something about it, you've started some changes, how can we introduce that consistency part? So bringing them along that journey from problem unaware to aware is something that uh, DNA sequencing can certainly do. That may even in and of itself provide some motivation to do something about the problem. The consistency piece, I think is something that everyone's trying to figure out.
Dr Stuart: I I think it's because you can build, hypothetically, you can build the the greatest biological model that predicts the future. But if, say for example, you can have someone, just for argument's sake, there's the same condition, you know, two people are identical biologically. So the advice is exactly the same. But if if you then compare, I don't know, an upper middle class woman in the city of London versus a young Bangladeshi lad in Birmingham, the way you communicate it, the way the the foods that they're exposed to, the educational level they're exposed to, uh, all these different parameters, getting those local solutions is essential because you have to make it relevant to them. And we we in science strive to have better predictability and everything else and we sometimes we have too much arrogance and we forget the the very personal components that, you know, someone might like mum's cooking or there's traditions in the family or people just don't like things or people are embarrassed to go to the gym and it's and it's those and it's those bits are actually potentially the biggest hurdles, not the fact that we can keep throwing data and building better models and predicting their health risk. It's how do we intersect the nerds with the people with communication skills. I think ultimately.
Dr Rupy: Yeah. Yeah. And I think that's that's that's where the success in healthcare, I think, will arise from. Yeah. Absolutely. Stuart, this has been super enlightening. I really hope people have found this useful. I've certainly found it useful and I've got a much clearer picture of the state of play and and just how impactful this technology can be and this data can be in combination with all the other things that you've you've spoken about. So appreciate, appreciate your time.
Dr Stuart: Thanks for the invite. It's been great. I've enjoyed it. Thank you.
Dr Rupy: Great. Good stuff.
