Ozempic and Wegovy slow down biological ageing; creation of synthetic bacterium; geology of the Russian earthquake

0:25This episode is brought to you by Google Chrome. when science finds a way. Welcome to the World, the Universe and Us, a weekly news podcast from New Scientist. I'm Rowan Hooper. But you're not Penny Sarchet? No, I'm Sam Wong. On today's show, we talk with a professor of tectonics about the recent Russian earthquake, which is the sixth biggest quake ever recorded. And we have the startling news that a bacterium has been created with more than 100 ,000 changes to its genome. So we can almost say we've created a life form. Almost, but not quite, but it's definitely the most unnatural thing we've ever created.

0:59That's coming up. But we're going to start with the equally exciting news that the weight loss drugs, Ozempic and Wegovi, they slow down biological aging. Now we've all heard of Ozempic and Wegovi. They use a hormone mimic called semaglutide to dramatically help people lose weight. And it's been extraordinary how the use of these drugs has taken off over the last few years. It's transformative. And I think I've said on the podcast before, I can't think of another drug that's had quite as big an impact as those. And now we have evidence that semaglutide based drugs appear to slow the ageing process itself.

1:36And here to discuss this news is Alexandra Thompson. Alex, do you bear the elixir of life with you? What's the story here? Yeah, I mean, this is really quite something. So we already had animal research and some observational human data that hinted that drugs like a Zempic might slow biological ageing. But now we have the first clinical trial data that proves direct evidence of that. And it's not just slowing aging, it could even reverse it. This does remind me of Benjamin Button, you know. His life goes backwards, your life starts reversing and you revert to childhood. I mean, how far are we taking this?

2:13It's not quite that dramatic, not quite there yet. All right, but look, semaglutides, they're famous not just for the treatment for obesity that is being so dramatic. But for the other effects they're having on cardiovascular disease, on addiction because of the way it changes behaviour and on dementia as well. Yeah. And so to add to that list, we now have early data that hints they slow biological ageing, which is the rate at which our cells age over time. So one way to assess that is through epigenetic clocks, which identify patterns of DNA methylation. So that's sort of the chemical tags that are added or removed from DNA that affect gene activity.

2:53And these patterns shift with age and can be sped up or down by lifestyle choices like our diet, whether or not we smoke. So that means our biological age on the inside can be younger or older than our chronological age. So to tell you about the study, researchers at a diagnostic company called True Diagnostic in Kentucky, studied the epigenetic clocks of 108 people with HIV-associated lipohypertrophy, which is a condition that causes excess fat and it's associated with cellular ageing. So in a gold standard clinical trial, half were given semaglutide, actually as the exempic dose, once a week for 32 weeks and the other half got a placebo.

3:34So these are all people with HIV? Yes, they had HIV and they had a complication of HIV. But the pathways that semaglutide works on aren't specific to HIV pathology. So the researchers are quite confident that this will have the same or similar effects in people without HIV. Good to know. So using blood taken before and after the trial, the team identified the biological age of 84 individuals. And what they found was those on semaglutide became on average 3.1 years biologically younger by the end of the study compared to at the beginning. But those in the placebo group showed no significant change.

4:11And the researchers also found biological age was slowed in several organs and systems, including the heart and kidneys, and the most pronounced effects were seen in the inflammatory system and the brain, where the drug appeared to slow biological ageing by almost five years. I mean, this is stunning, isn't it? Because we normally have dramatic effects in nematode worms or something. But this five years in people, has anything else had such an impact? You know, not that I can think of. I mean, we hear a lot about metformin, which is another diabetes drug that slows aging. Then there's rapamycin, which was originally developed as an immune suppressing drug for people undergoing organ transplants.

4:51But like you say, it's been in nematode worms, mice, if you're lucky, non-human primates sort of extending their lives. But to have a robust trial like this in people just doesn't come along very often. And it's extra reassuring because we know about these drugs. because they've been used in diabetes for a while, and we know they're by and large pretty safe. And how old were the people in the trial? The average age was 49. Do we have any clues as to how semaglutide does this? So the researchers believe the effects stem from its influence on fat distribution and metabolic health. So excess fat around organs can trigger the release of pro-aging molecules, which alter DNA methylation in key aging-related genes.

5:32Semaglutide also prevents low-grade inflammation, which is another driver of epigenetic ageing. Yeah, so we often talk about inflammation and ageing, but we know that inflammation is involved in all sorts of diseases, right? Yep. So chronic inflammation can compromise the immune system and it can cause arteries to harden. So we often associate it with heart and the circulatory system. But like you say, it's been linked to a number of conditions, so to name a few, depression, pain, arthritis. and GLP-1 drugs are thought to sort of strike a Goldilocks balance between reducing inflammation enough to ward off or treat those conditions but without putting you at serious risk of infections or conditions like cancer.

6:08Can these make me taller and better looking, Alex? What can't they do, these drugs? You're already perfect, Rowan. It does seem like they can do just about everything. We're actually waiting on two large, randomized controlled trials that are testing these drugs for Alzheimer's. And I think really the proof will be in that pudding because Alzheimer's is littered with drug disappointments. You know, they seem promising and then you get to that late stage trial and it doesn't work out. So there's also an ongoing trial for Parkinson's, which isn't actually such a slam dunk because there was another GLP-1 drug called Exanatide, which recently failed to slow Parkinson's progression in a late stage trial, although exanatide is considered slightly more, I suppose, primitive as a GLP-1.

6:57But one of the scientists we spoke to said it's not that surprising that ageing slowed by these drugs. He was called Randy Seeley at the University of Michigan Medical School because they reduce the metabolic burden on a range of cells and they reduce inflammation, which are both major drivers of ageing in many different types of cells. So he thinks much of This stems not from semaglutide's direct effect on cells, but more broader improvements to overall health. And if I was asking for, say, on behalf of a middle-aged friend, should we take semaglutide not to lose weight, but because we want to rejuvenate?

7:30Well, you can tell your friend. I think it's too soon for that. We need more trials, larger trials, trials on people with a range of conditions, trials on healthy volunteers. We're still learning about the effects these drugs may have on lean muscle mass. That's particularly important for older people who are already more at risk of falls. But it is exciting, the idea that we could repurpose drugs for age-related conditions, partly because repurposing speeds up the approval process. We already have an idea about safety as well. And there are lots of these kinds of drugs around. And so just to make it clear, semaglutide is a mimic of a gut hormone called GLP-1.

8:06That stands for glucogen-like peptide 1. And that's what Ozempic and Wegovi are. They're brands of semaglutide. But the other big names that people will have heard of are Monjaro and Zetbound. And that's the brand name of a drug called Terzepatide. And that also mimics GLP-1. And it also contains another hormone mimic that works on appetite satiation. So that's another class. And then there's Liraglutide. And they're sold under brand names Saxenda and Victoza. So let's just be clear that this research we're talking on are on semaglutides. So that's the Zempin and Wegovi ones. And I suppose we just don't know about those other GLP mimics at this stage.

8:53We don't know. I think we can be quietly confident based on just the mounting evidence of observational data. But until we have these trials, we just don't know. It's really fascinating stuff. And to talk more about it, I spoke to Andrew Steele. He's an ageing scientist. he's an aging scientist he works on aging and he's the author of the brilliant book ageless the new science of getting older without getting old uh it's a book about the biology of aging and here's what he said and while you watch this do if you're watching this do admire the cycling infrastructure in the clip because he's recorded it in outdoors in berlin these weight loss drugs the so-called glp1 receptor agonists seem to cure well almost everything so could it be that they slow down the aging process as well?

9:38Well, there's a big debate currently going on in longevity science about firstly, whether they do slow down aging, and secondly, how they do so. So it might be, the first idea, is that they slow down aging by causing that weight loss. We know that fat cells, and in particular the visceral fat cells that bunch up between your organs, they're the things that give you a beer belly as you get older, they emit a bunch of inflammatory molecules, essentially accelerate aging throughout the body. So it could be that by losing weight, by losing some of that visceral fat and then losing some of that inflammation, that's how these drugs are slowing down aging.

10:08It could also be that they have a more direct effect on the aging process. Maybe they hit inflammation in a more direct way, maybe they have some other biological effect they're yet to uncover, and slow down aging that way. And that might sound like an absolutely wild idea, but we do know of a number of different drugs that slow down aging, in the lab at least. We can see them slowing down aging in animals like mice. The problem is that doing a trial on one of these drugs would take a very, very long time. it might even take decades if you were to start it early enough and we'd have to watch and see if people got ill less died less frequently when they were taking those drugs to prove that it slowed down the ageing process and that's why these measures of biological age like epigenetic age tests are so exciting Now time for a word from our sponsor The Best Science isn't just a laboratory endeavour it changes lives but that link between researchers and the impact they have on people is often forgotten That's the gap filled by Wellcome's podcast When Science Finds a Way Host Alicia Wainwright is a botanist turned Hollywood actor who invites researchers at the cutting edge to tell their inspiring stories alongside the people in communities around the world who are working with science to improve lives and shape their own futures.

11:14Episodes cover topics ranging from cholera prevention in Kenya to wildfire management approaches rooted in indigenous practices. When Science Finds a Way is available now wherever you're listening. Now, this week, researchers have announced the creation of a synthetic bacterium with an incredible 101 ,000 changes to its genome. The entire genome has been recoded to free up seven of the 64 codons in the genetic code. Michael LePage reported on this for us. Michael, can you tell us why this is such an incredible achievement? Hello, yes. I think it's probably fair to say this is the furthest we've ever gone in terms of creating life that is different to anything that's evolved naturally.

11:53Now, as things stand, this bacterium simply has seven codons that it isn't using. But in future, the team can assign these codons to amino acids that don't occur naturally. OK, so before we go any further, we should probably just have a quick reminder of the genetic code. And what are codons? What do you mean by recoding? OK, yeah, quick recap. So proteins are these strings of amino acids and they're put together in a particular sequence, a particular order, and that sequence is encoded in genes in the DNA. So DNA is made of four different letters along the helix, and each set of those three DNA letters, called a codon, is assigned to a particular amino acid.

12:34The thing is, we've got these four DNA letters, which means there are 64 different codons, 64 different triplet codes, but living organisms only use 20 different kinds of amino acids. That means there's a lot of redundancy in a genetic code. So in living organisms, just about every amino acid actually has two or more different codons assigned to it. So if you get rid of some of that redundancy, does that mean you can you free up the codons to do different things? Yeah, so to give an analogy, at the moment, in English, we have two different spellings of colour with the sort of OU and just with the O, and both mean exactly the same thing.

13:12Now, let's be, I'll be a little controversial here. And let's So we do this sensible thing and decided to get rid of the U and just everyone spells color with no U. In that case, we've then freed up that spelling of color with a U and we could give that a different meaning. But then we'd have to go through every newspaper and book and change all of those spellings if we wanted to sort of revamp our language. So that essentially is what a team at the MRC Laboratory of Molecular Biology in Cambridge had been doing with the genome of E. coli. They changed some of these alternative spellings of amino acids to free up seven codons.

13:48Now, this recoded E. coli is called SYN57 because it now uses just 57 of the 64 codons. Okay, can you take us through again why we want to free up the codons? I know we can get rid of the redundancy, but why do we want to free them up? Yes, Wes Robertson at the Cambridge Laboratory, whose team did this work, told me that was done as proof of principle. but there are potential commercial applications one of them is that by making further tweaks to this bacterium they can make it completely resistant to viruses now that's because viruses rely on their hosts to make viral proteins so if you change the genetic code in a cell then when a virus infects that cell its viral proteins are going to come out all wrong and it's not going to be able to replicate now obviously viral infections can be a huge problem if you're trying to brew chemicals using bacteria and suddenly you get a viral infection that comes off and kills all of those bacteria you can you can lose a whole batch when you say brew chemicals what kind of thing are you talking about oh so bacteria have been used for decades to make medicines such as insulin and some cosmetics and even food agreements but i wrote the story the other day about a team that have produced a milk protein called casein and bacteria now casein is a protein that you need to make cheese.

15:04So people are thinking about, you know, can we actually make cheese from bacteria rather than getting it from cows, which of course would be much greener. Yeah. And just to clarify, the bacterial milk wouldn't come out green, but it has a much smaller carbon footprint than cow's milk, which has a horrendous carbon footprint. That is what I meant. Yeah. But getting back to SYN57, the other reason for freeing up these codons is so these bacteria can make new kinds of proteins unlike anything that exists naturally. Remember I said there were 20 natural amino acids. So once you've freed up codons, you can then reassign those to different amino acids that aren't part of those 20 natural ones.

15:45So in theory, syn57 could produce proteins that contain 27 different kinds of amino acids, which opens up all kinds of possibilities. And is Robertson's team working on these applications? Well, they're exploring some of them, but his team is doing the pure research. However, the Cambridge Laboratory has recently spun out a company that's called Constructive Bio, and it's exploring commercial applications for this kind of thing. So in fact, this is the second bacterium of this kind. Back in 2019, Robertson's team created an E. coli with three free codons. That was called SYN61, and that's already been commercialized by this company.

16:24So if they had SYN-61 in 2019 with three free codons, and now we've got SYN-57 with seven free codons, how far can they go with this? Can we free up even more codons? Okay, so in theory, this is possible. You need one codon for each of the 20 different natural amino acids, and you also need one codon to say when a protein is complete, known as a stop codon. so that means you've got 21 codons that are absolutely essential and in theory you could free up those other 43 the trouble with doing that is every time you make a change every time recode one of these codons there's a chance that that change has a detrimental effect that maybe you haven't foreseen you know it can even kill a bacterium so basically the more changes you make the harder it is to ensure that the bacterium are healthy so in fact with those 100 to 1000 changes needed to make the sin-57 bacterium this was a major problem the team didn't just synthesize the whole genome stick it in a living bacterium and hey with jobs done instead they had to make it in these little pieces they had to put each little piece in the living bacterium they had to find out what was wrong with it they had to correct those problems and then they joined up the fragments and they repeated the process with bigger and bigger fragments and so on until it was all complete.

17:46And that was obviously, it was a really laborious process that took years of work by lots of people. Robertson described it to me as a gargantuan effort. And even with all this work, the final bacterium is still growing much more slowly than a normal E. coli would. So it's still going to need some tweaks and improvements to speed it up. Yeah, we blithely talk about, oh, let's synthesise E. coli, they're only really simple. but life is insanely complex isn't it even bacterial life? Yeah so you know E. coli's got four million DNA letters it's got thousands of genes we still don't completely understand everything about it and we certainly don't understand the consequences of all of their changes so that there can be some sort of overlapping in genomes so you sort of change something that you think is not going to have any other effect but it turns out to have some completely unanticipated effect somewhere else.

18:41So anyway, to go back to the question of whether we can free up even more codons, that's just because of these problems with unintended, harmful consequences, that's going to be a huge project. I'm sure someone will do it eventually, but for the moment, Robertson said to me that his team isn't planning to go any further. And for many purposes, it's probably not necessary, for instance, to create resistance, viral resistance, you know, freeing up seven codons should be enough. When you say viral resistance, I mean, that would be a really useful application if we could make farm animals, say, chickens and cows that are resistant to bird flu.

19:16Is that the kind of thing that they're planning to do? Oh, biologists are definitely talking about it. But this is going to be an even bigger challenge than creating these bacteria. So birds and mammals, for starters, they've got a lot more protein codon genes of bacteria. So that means for each codon, you've got to make a lot more changes. and then of course it's going to be much harder to test whether those changes are having harmful effects instead of just looking at a bacterium growing in a petri dish you're going to have to actually create an animal and see if it's normal and healthy so i don't think that's going to happen anytime in the near future but i'm i would bet that it is done eventually so michael you mean we reported 15 years ago now on the creation of um a so-called synthetic microbe by craig venters group.

20:06And I was wondering about the differences between that breakthrough, as we reported then, and what's happened now. And I had a chat with Wes Robertson about this, and I started asking him about his gargantuan effort and the differences between that and Craig Venter's work. And here he is. We use different techniques compared to Venter's because we had a different goal, actually um our goal is to engineer the genetic code and to do that we did it in a more stepwise fashion compared uh to the venter's group well venter was also trying to do something different as you say right he was trying to get a minimal genome wasn't he and and that's not really that that's not where you're going yeah exactly they were interested in sort of the the the minimum amount of genetic requirements to sustain life which is a really cool um conceptual question they had.

20:59And they also, in addition to the original demonstration, they whittled down the one megabase to about half a megabase in 2016 from the original design to really understand this minimal requirement. And that was quite an interesting question, but they weren't engineering the genetic code itself. They're really just compressing the genome. Yeah. I mean, that's something we've heard about over the years is this dream of getting a a synthetic E. coli that can clean up oil spills or even, as you say, sequester carbon on a huge scale. So is that getting us significantly nearer to that dream? The idea with synthetic genomes is if we can add in all of these different features wholesale throughout the entire organism, we should be able to better engineer and tune these microorganisms to focus and be more efficient at these specific type of tasks, as well as you're not really limited to just single species in that case.

22:00If you think about it in terms of potentially synthetic chimeric genomes, you can try to integrate different features from different species. So ideally, engineer microbes for these newfound sort of new to nature properties, I would say. This episode is brought to you by Google Chrome. You think you know a browser, but Gemini and Chrome, that's new. It can help you with practically anything on the web, like restoring a vintage motorcycle from a 50-page restoration block, or finally break down that long article you've had open for weeks. Gemini and Chrome is here for it. Ready to make anything online make sense?

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22:44Now, on Wednesday morning, there was a huge earthquake off the east coast of Russia, magnitude 8.8, which makes it the sixth biggest of all recorded earthquakes since 1900. Yeah, so to put that into context, the great Tohoku earthquake of 2011 in Japan, that was magnitude 9.1. And then the Indonesian Sumatra earthquake of 2004 on Boxing Day, that was 9.2. And both those quakes caused devastating tsunamis. On this occasion, the tsunami caused by the Russian quake has basically been manageable. So to learn more about the geology of this fault, I spoke earlier with Lisa McNeill, and she's a professor of tectonics at the University of Southampton, and here she is.

23:29Yeah, so the earthquake ruptured part of the Kuril-Kamchaka subduction zone, and this subduction zone, or any subduction zone, is where one tectonic plate collides with and slides under another, and this generates the largest earthquakes on Earth, such as the ones you just mentioned. The earthquakes happen on large faults that form between the two plates, and as the plates move relative to each other, the energy builds up and is stored over hundreds of years, although sometimes shorter or longer timescales, depending on how fast the plates move relative to each other. And then this is released really quickly in seconds or minutes in an earthquake.

24:02And because many of these earthquakes are mostly under the sea, this type of earthquake, they can also generate tsunami, as we saw. The Kural Kamchatka subduction zone has had large earthquakes in the past. These include a very large magnitude 9.1 earthquake in 1952, not far from the 2025 earthquake. Before yesterday's earthquake, there was a series of other earthquakes on the subduction zone nearby. These included a magnitude 7.4 on July 20th, so only a few days ago. But the problem we have is that some large earthquakes have a smaller earthquake before, but many do not. And this is why we can't simply use smaller earthquakes as a sign of something bigger to follow.

24:41Overall, there are many factors that control exactly when an earthquake happens, and this is why we can't predict them, unfortunately. But what we can do, as geologists and geophysicists, is use the record of past earthquakes, the geological structure of the fault zone, and the rate of buildup of strain on the fault to estimate the probability of an earthquake in the future. And that's how we do the hazard assessment. The recent large earthquake has release much of the strain that had built up on this part of the fault. But it's normal that an earthquake won't release all of the strain. And that's partly why there are lots of smaller earthquakes happening now after shocks.

25:15Most subduction zone faults are quite long and composed of multiple sections. So although significant slip has been released on this section, there will be other parts that are in other stages of the seismic cycle. But the tsunami warning systems in the The Pacific appear to have worked very well this time and should do in the future, so long as they continue to be maintained. So the tsunami warning system worked very well, as you say, and the warnings themselves were lifted quite rapidly because the waves generated, well, they were manageable, weren't they, all over the place. So do we know why we didn't get a big tsunami like we've had before?

25:53So if we compare with the two examples you gave, the Japan-Tohoku-Oki example in 2011 and the 2004 Indian Ocean earthquake offshore Sumatra, those were considerably bigger. The earthquake magnitude scale is logarithmic. So although this was an 8.8 and those earthquakes were 9.1, 9.2, that is a considerably larger earthquake. In fact, the Sumatra-Andaman earthquake was much longer as a rupture zone. So probably up to about 1600 kilometres. So that because they were much larger overall, the larger area, larger slip, probably, that tends to lead to a larger tsunami. So that's one explanation. I mean, there's lots of factors that control the size of the tsunami, including the source earthquake, secondary factors such as landslides, but also the sort of local coastal morphology.

26:47So the size of the tsunami probably wasn't unexpectedly small. It was still up to, I think I saw examples of a few metres in Kamchatka, but probably what you might expect with this sort of relatively smaller earthquake. That's all for this week. You've been listening to The World, The Universe and Us. Do go ahead and subscribe and spread the word. Thanks to all our guests and thank you for listening. We'll see you next week for a special episode marking the 80th anniversary of the atomic bombing of Hiroshima. So look out for that. Bye for now. This episode was sponsored by Wellcome's podcast, When Science Finds a Way, available on all podcast platforms.

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