DNA Methylation

Adrian: What I'm questioning is the implications of that for your longevity. But I think if you genuinely believe that your birth certificate is secondary to your biological age in terms of determining your age, I think that would be putting more faith in it than I would. Yeah, I get it. Never make any hardship support any brand.

Brent: Pick yourself up and keep moving through the pain. Keep moving forward. That's what you need to do when it comes down to today.

Intro: Welcome to Death Clock. I'm your host, Brent Franson. Today we speak with Sir Adrian Bird about DNA methylation. At least for me, the topic of DNA methylation is a little bit technical, but I think Sir Adrian really helps us understand what its role is in the context of health and longevity and what it isn't. You know, there's a lot of hype in longevity, and DNA methylation, as you'll hear, is certainly no exception.

Intro: But if you're interested in understanding things like Yamanaka factors, if you've heard about DNA methylation to understand your biological age, this episode is a great primer on all of those things. We talk about CRISPR. It's a really good conversation, and I think pretty accessible for somebody like me who's not deep on topics like DNA methylation.

Intro: Hope you enjoy.

Intro: Sir Adrian Bird, welcome to the show.

Adrian: Thank you very much.

Intro: So you had said before we started recording that you don't love being called Sir. I had joined the conversation there, but I have to ask you: What's the experience like of being knighted by Queen Elizabeth? That sounds like an amazing experience to me. What was it to you?

Intro: Did it feel like a wonderful sense of accomplishment? Were your parents alive? Were they able to witness that, or is it no big deal?

Adrian: No, it would have made my mother's decade, if not more, if she had been there. She has died, and so has my father. Left to myself, I'd probably be a republican, but I happen to live in a country where this goes on. I have to say, I treat it as an honor.

Adrian: I don't see it as a particularly big statement about royalism, but it's very nice to have. Recognition is something humans tend to crave, and I'm no different from anybody else.

Intro: And by republican, you mean you're not talking about in the American political context. Maybe you are a Republican or identify as Republican or Democrat, but what you're saying is you are a fan of republics as opposed to monarchies.

Adrian: Absolutely. I'm glad you pointed that out, because that is a mistake I wouldn't want to make.

Intro: Okay, wonderful. I'll call you Adrian from now on as requested, but I can't help asking about the knighthood. So the topic today is DNA methylation, and you've really set the gold standard in work around understanding DNA methylation and how it can be helpful. Let's start with the basics.

Intro: What is DNA methylation when we hear that term? What does it mean?

Adrian: The phrase DNA is obviously familiar to everybody as a double helix, and this is what genes are made of. Genes are very important for deciding who we are in detail. DNA is just a memory store for information to make all the proteins that we consist of. DNA methylation is a little chemical addition.

Adrian: So it's a little lump consisting of a carbon and three hydrogen atoms that gets added to the DNA. It's not built into the DNA when the DNA is made. When a cell divides, it makes a copy of its DNA that goes into each daughter cell and so on. DNA methylation is added on after that, and it's added in a pattern because there's a pattern there that has the potential to convey information.

Adrian: And that information is not in the DNA, so to speak. It's added to the DNA afterwards, so it can vary in different types of cells, etc. It is the fact that it is on the genetic material DNA, but it is not encoded by it—it is encoded afterwards—that makes it so interesting.

Adrian: That makes it so interesting.

Intro: If I were to repeat this back to you: everybody's got a unique DNA, and that DNA, in terms of the genes that are turned on and off, actually changes over the course of our lives. It's not static. It's not just, "Here's your DNA and that's it."

Intro: It changes based on lifestyle, environment, and different external factors. Methylation is the process by which the genes turn on and off based on those factors. Is that the right way to think about it?

Adrian: Yes. There is a difference between your emphasis and the way I would emphasize it, and that is that, to me, the logic of where this extra information is added is internal to the cell. It's actually not necessarily determined by our environment. Now, I realize that is not generally considered to be the case.

Adrian: It is generally considered that DNA methylation is susceptible to being altered by the environment. When you do some exercise, get a disease, or something dreadful happens, then somehow your DNA picks up this information through DNA methylation. That is a common belief, but I am not one of those who considers that to be clearly demonstrated.

Adrian: So I'm a bit of an outlier in that respect, although there are other scientists who also think the same as me.

Intro: Are you making a technical point? Meaning, broadly, you would agree with the statement that an external factor like exercising can have an impact on my DNA, having a positive impact where we can turn on genes that might make me more youthful.

Intro: Technically, what's happening is inside the cell, so you don't think about it as external. Or are you saying that although it's a common belief that exercise might influence your DNA and the rate of aging, you disagree with that concept more generally from an umbrella level?

Adrian: It's a bit of a mixture between the two because when you exercise, there are signals used to build muscle mass, for example, and that involves gene expression. Gene expression is affected by DNA methylation—the activity of genes when they are making their proteins.

Adrian: DNA methylation is also affected by gene activity. When a gene switches on, it leaves a mark on DNA methylation. The question is: which is the primary activity of DNA methylation? Is it to lock genes off when they're off so that it's leakproof, like a deadbolt on a door, or is DNA methylation actually being talked to by the environment?

Adrian: The idea that DNA methylation comes in, takes a happily active gene, and says "shut down"—I don't think that is true. I think the first explanation is more accurate: DNA methylation does what it's told according to the rules of gene activity in the cell. That makes it, in a way, less interesting from the point of view of a podcast.

Intro: I don't think so. I think we're getting to the ground truth. These things are always more complicated than we like. We like to categorize things in binary, simple ways, but having spent your whole life studying this, it's just pretty complicated.

Intro: And it doesn't work exactly how people think it does. That sounds truthful to me and consistent with many truths.

Adrian: Yes, and biology is particularly messy. There are exceptions to everything. It's extremely complicated with loads of components. As humans, we like to fixate on simple generalizations, but you're absolutely right that it's difficult to find them at the molecular level in biology. Still, DNA is where the genes are.

Intro: In the context of longevity and extending life, DNA methylation is a process happening naturally. There's work going on to artificially use that process to turn harmful genes off and beneficial genes on to help people be healthier and live longer. Are you a buyer of that technology and DNA methylation being used to help people live longer, or are you more skeptical?

Adrian: I'd be considerably more skeptical, I'm afraid. Scientists always say, "We need more information; we need to study it more." I can't say yes or no definitively, which is a bit tedious, but I think the evidence that DNA methylation drives aging in any way is really quite weak.

Adrian: There are correlations. As people get older, there are changes in DNA methylation. It's impressive that you can measure 30,000 different DNA methylation sites and find subtle changes. Added together, they allow you to say, "This blood came from a person who is 60, plus or minus three years."

Adrian: That is impressive, but to go from a correlation like that to saying that the change in DNA methylation is causing the aging process—and to ascribe to it the phrase "biological age"—is going too far.

Intro: I've got one of these biological age tests here on my desk. It's a finger prick. I dab blood onto a piece of paper, send it in, and they tell me my biological age. You're saying you could use blood to determine roughly how old someone is, but you're a skeptic on understanding how healthy you are based on that small bit of blood?

Intro: But this concept of measuring your biological age, so understanding how healthy you are based on that small bit of blood, you'd be a skeptic on that.

Adrian: I would be a skeptic if that was all you did. If you don't do very much exercise, there are all sorts of signals associated with health or the lack of it.

Adrian: DNA methylation does correlate, so it's not irrelevant. It's whether or not it's causing aging that I demur from the idea behind the biological age movement. The errors are also quite large; people doing different tests often get rather different results.

Adrian: In the population, you can draw a beautiful trend line, but you might be one of the points off the line, meaning there's an element of uncertainty. I'm not pooh-poohing the idea that DNA methylation is relevant to health.

Adrian: I am casting doubt on the idea that it's driving aging. In the literature, those two things get mixed up. Correlation is useful—for example, in characterizing tumor types, because gene expression peculiar to a specific tumor leaves a mark on DNA methylation.

Adrian: That mark gives you a lot of information. Where I am nitpicking is whether or not it's the cause of aging and tumor types, or simply a useful consequence for diagnosis.

Intro: So we have this gene expression layer: we all have DNA, and that sequence of genes over the course of our life turns on and off and changes over time.

Intro: When we're younger, more youthful genes are turned on, and as we get older, those turn off and aging genes turn on. Then DNA methylation is a process involved in that gene expression.

Intro: Are you saying you don't believe underlying gene expression impacts aging, or that the process of turning those genes on and off via DNA methylation is not impacting aging? Or am I thinking about it the wrong way?

Intro: Or my thinking about it in the wrong way?

Adrian: High-level questions like those are nearly always the most difficult to answer. First, the idea that genes active when you're young switch off and a new set of "old" genes switch on is too much of a simplification.

Adrian: People still argue about the causes of aging. One theory is that it's due to accumulated damage, such as telomere shortening. The chromosome ends shorten as cells divide, and once they reach a critical length, the cells become quiescent.

Adrian: As you accumulate quiescent cells, your organs don't work as well, which isn't so much about gene expression. That is a major theory of aging. The DNA methylation theory suggests that you change the level of DNA methylation over genes that didn't have much methylation when you were young.

Adrian: As you get older, methylation increases and interferes. It's not "young" versus "old" genes; it's the same genes working less well because DNA methylation makes them less responsive. We spend a lot of time repairing damage to our DNA when we're young.

Adrian: The efficiency of this repair goes down as you get older. You can imagine it taking the edge off processes that were sharp and precise when you were young, making them sloppier. DNA methylation could in principle be doing that.

Adrian: If you ask me for a specific example where that is happening, neither I nor anybody else could point to one.

Intro: You're skeptical of using DNA methylation to control gene expression in longevity. However, you're not skeptical of its role broadly in health, given your pioneering work understanding its role in Rett syndrome.

Intro: Rett syndrome is a cognitive disorder affecting toddlers, primarily females, impacting motor skills and development. Can you tell us about that, and why understanding DNA methylation is helpful in debilitating diseases but perhaps less so in longevity?

Adrian: I don't doubt that DNA methylation is there for a reason. It can switch off and suppress selfish genes in your genome that would otherwise cause damage. Its presence is usually associated with turning off active genes.

Adrian: Instead of making that protein, those genes are silent. There is no doubt about that. Regarding Rett syndrome, we got into studying it by trying to understand the role of DNA methylation in gene expression. Rett syndrome is a tragic disorder.

Adrian: It nearly always affects girls. They develop normally for a year and a half, learning to walk and talk, and then enter a crisis where they lose those abilities and never regain them. Their lifespan can be 50 to 60 years.

Adrian: During that time, they need constant nursing, so it is a terrible disorder. We began studying it because we found a protein that recognizes methylated DNA and binds to it. When there is no methylation, it doesn't bind.

Adrian: We found that this protein binds to methylated sites and brings in a protein machine that dampens down the expression of genes, particularly in neurons.

Adrian: The pattern of methylation across the genome determines where this machine goes. It attracts the machine to places with high methylation density, keeping neurons fully functioning. It is very demanding to be a neuron.

Adrian: Neurons spend a lot of time setting up connections that must last for decades in humans. This protein, MeCP2, is involved in that process. Without it, neurons function at sub-optimal levels.

Adrian: They're not very good at being neurons, leading to dreadful consequences. That is the connection between gene expression and Rett syndrome.

Intro: In Rett syndrome, from birth to 18 months, the brain functions properly. Over time, a missing or altered protein disrupts DNA methylation, impacting neurons and reversing development.

Intro: In understanding that, could we use DNA methylation or CRISPR to prevent that protein deficiency or restore normal function? Is that the hope?

Adrian: In Rett syndrome, a mutation inactivates the MeCP2 protein. Normally after birth, the amount of MeCP2 protein and methylated DNA it binds to both increase. In Rett syndrome, they don't increase enough.

Adrian: You end up with a deficiency of this protein. It's the absence of the protein rather than an active disruption. All the methylation sites are in the right place, but there is no protein to bind to them, which disrupts the nervous system.

Adrian: It's just there's no protein to bind to them. And this then screws up the nervous system.

Intro: Are you optimistic about CRISPR or gene editing to go in and fix the genome so it starts producing enough of that protein?

Adrian: Yes, because there are clinical trials ongoing based on an experiment we did in a mouse model of Rett syndrome. Contrary to what everyone thought, putting the protein back—even in an animal that has been sick for a long time—makes them better.

Adrian: Everyone assumed that once developmental problems occur in the brain, it's too late to reverse them. We showed that if you put back this protein, the DNA methylation is already in the right place, like a machine getting a missing part back.

Adrian: This led to work in biotech companies and clinical trials to put the gene back so the missing protein is produced. Phase 1/2 clinical trials are currently testing safety, toxicity, and efficacy.

Adrian: While mice aren't identical to humans, Rett syndrome in mice and humans looks very similar, and in mice, it's reversible. We are optimistic, though final human data isn't in yet.

Adrian: But the the trials are not over. So we're in the middle of waiting to see whether we have a therapy of that kind. But the answer is, if you believe that mice are an approximate imitation of the human condition, there's quite a lot of arguments for that isn't always the case with mice. They are obviously very different.

Adrian: But in this particular case, rat syndrome in a mouse and Rett syndrome, a human look pretty similar. And in mice it's curable. So we're optimistic. But you know the the the final data are not in yet.

Intro: Curable in mice is a major statement. So in mice, it cures the condition?

Adrian: Mice with Rett syndrome have severe mobility issues, obesity, and breathing apnea—features shared with human patients.

Adrian: Every measured symptom goes away, and the mice look like normal mice. When we first did this, someone asked me what cognitive state they would be in after being restored from such a debilitated state.

Adrian: You can only answer that question in human trials, not in mice. It's an exciting moment, but we have to wait for full results.

Intro: If someone has been cognitively in infancy their whole life and is now 25, it's a fascinating question of what cognition looks like when restored. Have we learned things from DNA methylation here that could apply to diseases like Alzheimer's or Parkinson's?

Intro: It sounds like is what you're saying, but it's it's good to hear that. It's that it's promising. And have we learned something about DNA methylation here that could be applicable to other diseases like Alzheimer's or Parkinson's? Is is there some learning here?

Adrian: It was assumed by neuroscientists that brain diseases were permanent. This was the first example showing that wasn't the case, raising the question of what else we've missed. Several neurodevelopmental disorders have now been shown to be partially reversible.

Adrian: Fragile X syndrome, the most common inherited form of intellectual disability in males, involves the shutting down of the FMR1 gene due to an improper deposition of DNA methylation. Using CRISPR, you can bring in an enzyme that removes that DNA methylation.

Adrian: And it's due to the shutting down of the, fragile X. So the FMR one gene, as it's called. And this is caused actually by DNA methylation. So there's a there's a massive, deposition of DNA methylation right where it shouldn't be. And it shuts this gene down when it's not supposed to be shut down. There are now ways of targeting, using Crispr that you mentioned earlier to bring in an enzyme that removes DNA methylation.

Adrian: In neurons in a dish, peeling off that DNA methylation reactivates the gene. That shows another way targeting DNA methylation can address brain disorders.

Intro: So CRISPR can be used to dial down excessive DNA methylation directly, rather than just snipping genes?

Intro: That's creating some negative effect. And you're saying that same technology can also be used to, in this case, dial down the DNA methylation. There's basically too much DNA methylation going on.

Adrian: Exactly. CRISPR exquisitely targets a single place in the genome. Instead of making a cut, you take the targeting mechanism and hook it up to an enzyme that removes methylation to peel it off where targeted. It's an amazing, versatile technology.

Adrian: You make this kind of hybrid thing and it goes in. And people have shown that this works. You can peel off the DNA at the place you've targeted the Crispr too. So Crispr is very versatile. It's I mean, it's an amazing technology. And it can be used for cutting or for other things.

Intro: Do you have concerns about off-target effects with CRISPR, like unintended mutations or cancer risks, similar to how growth hormone can stimulate both good and bad cells?

Intro: And there can be concerns of increases and cancer. I always think about this similar to, human growth hormone. You know, human growth hormone helps the cells grow. And it's it's going to help good cells grow and bad cells grow. And so maybe you're going to get stronger, but you might also have some cancer cells that replicate at a higher rate than you would like.

Intro: There's some version of that happening. Seems to be happening. If we're turning off cells and just seeing what happens. Do you have that same set of concerns I have?

Adrian: Targeting is very good, but not perfect. Across trillions of cells, rare off-target events can become significant if they initiate cancer. You have to weigh the benefits against the risks for severe or fatal disorders.

Adrian: Research across academia and industry is focused heavily on reducing off-target effects as low as possible.

Adrian: But you, you, you you have to look at each particular disorder and see whether, whether or not you are saving a life or whether or not you are transforming a life and whether or not the low, the low, hopefully low risk of cancer is, offsets that or not. But I think also what's happening now is, is a kind of ferment in, in academia and in research institutes and in industry trying to get the, off target effects down as low as possible.

Adrian: Gene therapy with viruses is relatively crude. What you really want to do is rewrite the genome to correct mistakes, and CRISPR will be key to that.

Adrian: But really, what you really want to do with many of these disorders is rewrite the genome. You want to correct that mistake and put in the right basis. And Crispr is going to be a key part of that. And initially, yes, it was a bit sloppy cutting. You got all sorts of, junk, when it was repaired.

Adrian: Sophisticated methods now allow correcting multiple mutations while drastically reducing off-target effects. We are in a revolution that will lead to changing DNA sequences for the better.

Intro: Okay. And so in the context of so I'm, I'm a 43 year old, male who's, you know, I've got kids. I want to be healthy, I want to I want to live a long time. And it sounds like, just to summarize, the work you've done in understanding DNA methylation led you to a break. What might be a breakthrough in treating RET syndrome?

Intro: It's still early, but the signs are positive. We figured it out in mice were in phase one, clinical trials to, to understand this treatment in humans. There's some up. We think what we've learned here can be applicable to other cognitive issues. And so there's there's a nice trajectory on that work in terms of helping for rats and for, for for other, for other issues.

Intro: Is your skepticism about DNA methylation driving longevity rooted in it being too early to tell, or do you doubt it will yield benefits for healthy individuals in the next 15 to 20 years?

Intro: Or would you say, probably your kids and not you, or you're skeptical that it's going to be me or my kids?

Adrian: In basic biological science, you get used to being wrong. While you shouldn't listen to my skepticism too much, I am not persuaded that DNA methylation itself is a driver of aging.

Adrian: Simply altering DNA methylation may not impact aging directly. It can be a useful marker for health status, but whether it is causal is where I remain doubtful.

Adrian: Data might emerge showing that preventing specific methylation changes slows aging, but right now I don't see that likelihood.

Adrian: If your biological age test looks older than you'd like, the standard advice remains: get exercise, eat well, and sleep well. DNA methylation may just be an indicator marker for those habits.

Intro: What about Yamanaka factors—reversing cellular aging by turning back the clock on cells to make them stem cells? Do you have an opinion on those, and is there a relationship to DNA methylation?

Intro: I think probably the, the optimist there would say, hey, maybe we're going to live to 120 or 150. Seems a little wild to me. But do you have an opinion on Yamanaka factors, and is there a relationship between those and DNA methylation?

Adrian: Yamanaka factors were an exciting development. Previously, people didn't understand why differentiated cells couldn't turn back into stem cells since their genomes are identical.

Adrian: He found you could reverse differentiation at a low frequency. Yamanaka factors are mostly transcription factors—proteins that bind to specific DNA sequences to target precise locations in the genome.

Adrian: They are factors that can bind to specific DNA sequences. And they are therefore target. They can tell one bit of the genome from another if you like. They can find an address in the genome. They, intimately linked with DNA methylation. There was a kind of assumption that DNA methylation would be a great way of reversing differentiation and getting back to the stem cell state, where you can make anything, any type of cell.

Adrian: Yamanaka factors shifted focus away from DNA methylation, showing that transcription factors driving gene expression at specific sites are key to cell identity.

Intro: And if there. So if there was an answer in this universe of things we've been talking about to helping us increase life expectancy by 10 or 20 years, you've, you know, expressed multiple times your skepticism around DNA methylation specifically being causal there. Would you be more of an optimist around something like Yamanaka factors or, you know, Crispr for, gene editing specifically?

Intro: Would you have more optimism?

Adrian: It comes down to whether aging is hardwired into the entire system—where fixing one part causes another to fail—or if there are key pressure points we can modify. We don't yet know.

Adrian: The accumulated damage hypothesis suggests that as the system ages, like an old computer, it loses flexibility until replacement is the only option.

Adrian: The optimistic view is that we can identify key genetic pressure points and intervene effectively. As a scientist ridded with self-doubt, I have to say we don't really know yet.

Adrian: And, you know, I, I'm enough of a sort of, humble scientist, you know, riddled with self doubt that you have to be, if you're a scientist, that to be able to say we don't really know. Yeah.

Intro: The accumulated damage view has hard truths. If plaque builds up in arteries or amyloid plaque forms in the brain, changing gene expression doesn't automatically clear that physical damage. Systemic degradation is hard to reverse.

Intro: And so there is some truth to just systemic degradation being hard to reverse, it seems it seems likely. So maybe it's like everything else we've been talking about conversations. Yeah. The truth is, somewhere in the middle.

Adrian: Whether it is socially desirable for people to live to 120, given population demographics, is a separate question outside the scope of DNA methylation.

Intro: And so what's your view on in the context of general health and longevity, the utility of DNA methylation? I mean, so there's these, you know, I've got one on my desk. I can prick my finger and I can send that in. And ostensibly, I could look at what my biological age is over time, and I could make changes and I could I could track that.

Intro: Is there utility for the average person focused proactively on their health to test DNA methylation right now?

Adrian: I am curious about it. If you bought five different test kits, would they tell you the same thing? Testing tells you something, but I question the implications for longevity. I see no harm in it for curious individuals, but placing more faith in it than in your actual birth certificate goes too far.

Adrian: Then I can see no desperate harm in it. But I think if you genuinely believe that your birth certificate is, secondary to your biological age, you know, in terms of determining your, your age, I think that would be putting more faith in it than I would.

Intro: And it sounds like maybe you would question the utility. So let's even let's let's assume it's accurate. I know we're we're saying we we we don't think that it that it always is. Let's assume it is accurate in terms of directionally helping me understand. Am I a little healthier, am I healthier, less healthy, and dealing me somewhere along that spectrum?

Intro: If a 43-year-old gets a test result claiming a biological age of 50, the advice remains diet, sleep, and exercise. Knowing that number doesn't change the actionable advice.

Adrian: That sums up my view accurately.

Intro: Have you sequenced your own DNA or taken a DNA methylation test?

Intro: So have you sequenced your own DNA? Have you ever done one of these DNA methylation tests? And and you know why or why not?

Adrian: I haven't done the DNA test. Members of my family are interested in ancestry, but I haven't been intrinsically drawn to it.

Adrian: I try to stick to sleep, diet, and exercise. I view myself like any general member of the population regarding how to live healthily.

Adrian: So I, I would say I'm a general member of the population as regards how to, how to live for as long as possible in a decent and a healthy way.

Intro: If you could jump forward 100 years, what scientific topic would you be most curious to look up?

Intro: Or would you look at something else? Oh, Yamanaka factors and what happened there? You know, if we had ten minutes in front of a computer 100 years from now and we could look at the almanac of what happened related to something, you know, related to something we've been talking about here. What what are you most excited about? What would that be?

Intro: What what would you be most curious about?

Adrian: It would be the brain—the forefront of human ignorance. Understanding how it works to prevent cognitive decline and dementia offers vast scope for discoveries and unexpected surprises.

Adrian: But to me, I'm most excited because this is an area where I feel there is still a lot of scope for there to be surprises and surprises of what we're after, discoveries where people find something that no one ever expected before. And that, to me, is what science can deliver. And, I, I would love to I would love to be here.

Adrian: I won't be, but I would love to be here in 50 years time to be able to see how that's come.

Intro: Compared to other organs we understand better, the brain is the most complex organ in the universe, and we still know so little.

Intro: And there's going to be a bunch of surprises. And your curiosity would be, well, what were those surprises? What did we what did we learn about the brain?

Adrian: I need to I need to know. So it's a good do I got a good reason for getting my DNA methylation test? Maybe.

Intro: Where can listeners learn more about your work and Rett syndrome?

Adrian: Maintain a high level of skepticism regarding claims around epigenetics and DNA methylation that lack strong evidence.

Adrian: So we haven't talked about the heritability of, of, the idea, but, but I am skeptical about that. So I would say keep skepticism high despite the, the influences of social media, which seem to work against, that kind of thing, unless it's a, mythology of, of a very, severe kind. So I would say that now, where do you go to find stuff out?

Adrian: For Rett syndrome, the Rett Syndrome Research Trust website provides clear information on current research efforts.

Adrian: I would, I would say, there are reviews in the literature you can find in PubMed. They're quite academic, though, and I think, you are, pointing out the fact that the sort of antidote to the general view about DNA methylation, finding where that is written down in a clear way is difficult. So maybe there's a need for that.

Intro: Epigenetics suggests lifestyle affects gene expression, which then gets passed down. Are you skeptical of transgenerational epigenetic inheritance?

Intro: So if grandma and grandpa ate a particular diet that was either good or bad, that I might have those genes, even if I don't eat that particular diet, that can have a variety of ways. And you're skeptical of that?

Adrian: Evidence in mammals that ancestral experiences or trauma are transmitted via the germ line is very weak, despite popular belief.

Adrian: And although the idea is very interesting, I think the evidence in mammals that the experiences, diseases, whatever, of your ancestors can be transmitted to you is, is very, very weak indeed. Yet it is widely believed in the general population. I think that this is, a valid form of inheritance. So you won't be surprised, since all I've done is expressed skepticism throughout the whole, program that that, that I'm skeptical of, that I'm particularly skeptical of that.

Adrian: And I think it's misleading.

Intro: So offspring are more of a blank slate, less affected by ancestral stress than popular science suggests?

Adrian: Studies like those on the Dutch Hunger Winter claiming multi-generational disease susceptibility are considered flawed by many scientists.

Adrian: They've gone into, they are seen as classic examples of how trauma can get its way into the germ line and influence future generations. So I, I of that I am particularly, skeptical and, I'm not alone.

Intro: Thank you, Sir Adrian Bird, for your work on DNA methylation and Rett syndrome.

Intro: So, you know, grateful for the work that you've done, over the course of your career and then really grateful for the hour you've spent with us here. Just understanding it and how how we how it might be applicable for us. So thank you so much.

Adrian: Thank you very much. Thanks for having me on the program.

Intro: Death Clock is recorded in Boulder, Colorado, and San Francisco, California. Produced by Patrick Gudino, music by Patrick Lee, and hosted by Brent Franson.