It's widely accepted that more exercise generally leads to slower aging and a healthier, longer life. However, emerging research suggests a more complex reality. A new 2025 twin study has produced some interesting findings that challenge this idea. The study indicates that high levels of physical activity might actually be linked to certain molecular signs of accelerated aging. So what does it really mean? Well, let's take a look together. And welcome back to the Building Life On Ethics podcast. Thanks so much for stopping by. I really appreciate it. For those of you who haven't had a chance to meet me yet, my name is Jordan Renneke. I'm a dual board certified physician in sports and family medicine. And the goal of this podcast is to keep you active and healthy for life through actionable evidence-informed education. And today we're looking at a study that is looking at a recent paper that questions our presumption that the more you exercise, the longer we live. So let's get started. So this episode looks at a paper titled The Association of Long-Term Physical Activity in Adulthood with Later Biological Aging and All-Cause Mortality, a prospective twin study. And this was released in 2025, so it's recent. And the main goal here, the primary objectives were to explore if biological aging measured by these things called epigenetic clocks mediates the link between long-term and leisure time physical activity and all-cause mortality. So stepping back, what does that mean? They're trying to say that, hey, looking at this, is the improvement in your fitness and is that leading to slowing down of your aging or is something else going on? 'Cause a lot of times what their kind of thesis is, is that, hey, when people exercise, it does lead to longer lives potentially, but they don't think it's necessarily exercise. They're saying, hey, is it due to the slowing of these clocks and this epigenetic clocks, epigenetics just means above the genome, right? So epi is above genetics genome. So what is happening is you can make changes to your DNA without actually changing the DNA. So you add certain things called like methyl groups, you attach them, but epigenetics are very, very, you know, talked about a lot, they are well-known and we don't quite understand them, but we know that they have certain things and can play a role in how you express and read your DNA. And we also tend to use things called these clocks, right? So these, there's certain signatures that say, hey, this is a hallmark of aging, these different methyl groups at different spots and on different molecules, leads to saying, hey, you are looking like you're advancing age. This is what all the biohackers are talking about. It's like, hey, I reversed aging by this much by doing it. So it's very much a proxy marker. So the idea is between chronological age and biologic age. So they're saying there might be difference, but they wanted to take a look at it and kind of see. And they also in this, they aim to determine how these methods for accounting, like can we rule out reverse causality or other genetic factors in terms of, are they improving long-term health? And so the goal here of this podcast is to unlock the study's findings, its implications, and what that might mean for your personal health routines or exercising and anything like that. So why this matters? Well, it's kind of interesting, right? The common understanding, largely from most of the observational studies we've seen in the past, they link physical activity to reduced mortality and improved health, right? I don't think it's any surprise if you were to hear me say, the more you exercise, you tend to be healthier and live longer. That's like the general consensus and what the idea is. But this paper, they're trying to say, is the causal nature, meaning that exercise increases it, is that actually true? That's like what they're kind of looking at, which is interesting. They're trying to say, is this connection, it's being questioned due to inherent and methodological limitations, meaning, hey, previous studies have not accounted for other things, other co-founders. So we're gonna try to isolate those out to see if exercise really does link into it. They also say that there's not really any randomized controlled trials that have definitely confirmed that leisure time, physical activity, or exercise prevents premature mortality. So they talk about leisure time, physical activity. I'm just gonna say exercise 'cause that's easier, but essentially what leisure time physical activity means is that you are not just working in physical exercise, right? So you are making a conscious choice to be more active, whether that's walking or exercising, what have you, that you are doing something above and beyond what you do for your daily times, what's during your leisure time. And yeah, that's kind of what they're saying here. They thought that maybe, you know, there's been an absence of actually exercise trials designed specifically to look at mortality as the primary outcome or, you know, a true causal link between these two things. So that's what they're looking for. And yeah, it's interesting because past researchers have had challenges separating lifestyle choices from genetic predispositions or pre-existing health conditions, and that might actually influence activity levels, meaning reverse causality. So when I talk about reverse causality, what we're saying is that it may be that people don't exercise because they have medical conditions, not vice versa, meaning like, oh, you could get these medical conditions so you don't exercise. So we're saying, is there any reverse causality going on there? Once again, I know that's a little heady, so step back. The big thing is looking at is, hey, is there a direct association between physical activity and decreased biological aging and mortality? That's really what they're looking at there. I just want to break that down. So going into it here, this study utilized an older Finnish twin cohort. So these twins out of Finland, it's a prospective twin study, and it was designed to compare either monozygotic, which identical twins, or dizygotic or fraternal twins. They looked at it, and the design is particularly powerful for disentangling these associations from other markers. So if you share genetics, we can think, hey, hopefully we can pull that and remove that, saying it's not necessarily your genes, and also common familial environmental influences. So if you have twins who were born with the same genes and raised in the same environment, well, you're removing some of the potential confounders. That's kind of the idea behind the twin studies. And it did have a pretty large sample size of over 22,000 people, aged 18 to 50 at baseline. And that was the main cohort. And then the study followed extensive follow-up for 30 years up to 1990 and 2020, and from 1990 to 2020. And then a major strength is a focus on long-term physical activity patterns assessed at three distinct time points. So they asked them, essentially at 1975, 1981, 1990, how much physical activity were they doing? So it wasn't just a one-time, hey, what's your physical activity? And then 20 years later, it's very different because they're 20 years older. So they kind of tried to control for that. And what did they find? And then kind of looking at, well, they looked at these biologic versus chronological aging, a central interest in neuroscience. So you talk about the longevity world, you talk about these biological clocks and whatnot, and that's up for debate whether they're actually impactful or they matter. So that's a whole nother podcast discussion, but it did look at multiple epigenetic clocks looking at a smaller subset. So of the big 20-some thousand, they went down to about 1100 people as they looked at and looked at these biologic clocks. And they looked at some specific ones, DNAM, grim age, and dunnage and pace, not that we need to know what they are, but they are two markers that kind of predict the pace of aging, or they look at general markers of aging. And that's what we were gonna go with there. And so the idea was that these molecular markers offer a potential to quantify aging at a molecular level, possibly yielding more precise indicators of healthspan and lifespan than chronological age. So they're saying, hey, a person is this age, chronologically means they've lived this many years, but does their epigenetic or biologic age differ? That's what they're using these markers for. Once again, these are suspect in general, how much do they actually matter? Do they actually show that you're slowing down? That's a whole thing up for discussion, but we'll keep moving on. So what did they find? They did use a different statistical analysis. That's the big thing here. This was still an observational study from a big cohort. So they didn't randomize, I mean, they didn't necessarily have a randomized controlled trial. So they had used a lot of statistical analysis here. And what they kind of do is they divide it up into four distinct exercise groups, essentially sedentary, moderately active, active and highly active. And then they got this once again, based off those questionnaires for three years. And how they do this, well, they base it off of metabolic equipments or METs hours per day. So kind of METs we've talked about before, they're kind of this weird arbitrary thing where like one MET is you just like existing, like sitting there existing. And then based off of how much you exert, you kind of get MET hours. And it's arbitrary and nobody really gets it, but that's how it's really like really, really well known in the literature that that's how you can assess physical activity. So that's how they did that there. So just worth mentioning. And what did they find? There was a particularly interesting finding, right? They kind of had an unexpected U-shaped association was there between long leisure time physical activity and biological aging. So what they're saying is they found a U curve, meaning that's kind of weird. It means if you didn't exercise or exercise too much, they both led to accelerated aging, which is kind of interesting. However, they did do lots of adjustments. And after extensive adjustments, both the sedentary class, and once again, the high activity class, exhibited accelerated biological aging compared to the moderately active and active classes. And this is looking at those epigenetic clocks, right? And they did make bunch of different adjustments, right? So after adjusting for other lifestyle related factors like sex, age, timing of the blood draw, education levels, smoking, alcohol use, BMI, all these things. And these associations seem to kind of hang around somewhat. They were more attenuant, so they weren't as big. But we, yeah, we did see that there was kind of this pattern that if you didn't exercise at all or exercise too much, we kind of saw that. And even at the end for the people who had high activity, they found that on one of the biological markers on average, they were older biologically, according to that, by like 1.2 up to 1.6 years, which is kind of interesting. So they're saying that, hey, you actually look 1.6 years older than where we'd expect to be based on just like a regular active person. So kind of interesting, definitely not what anyone would expect based on what we previously thought of. That's kind of the interesting part about this study. And the study also explored potential explanations for why this happened, right? When you see this result, you're not gonna be like, oh, that makes sense. You're gonna be like, no, I don't get that. It doesn't make sense at all. And so the authors did note that this USAPE association, it kind of is more pronounced for certain ones. So cystatin C and also this beta-2 microgliobulamine, which are essentially markers for kidney function and cardiovascular risks. So they're saying, is it something related to those specific things? They're not quite sure, but furthermore, the highly active class had higher smoking years as well, what they found. When they looked back on it, they said, hey, they seem to smoke more. So overall, like this, the data really doesn't make a whole lot of sense here. So it may indicate either under-reporting of smoking in this group or a shared pathway influencing this marker, meaning it looks like quote unquote, they're smoking more, but actually are they smoking more? Is there something else going on, size that, kind of triggers this? We're not entirely sure, but either way, the findings here require really cautious considerations and further investigation to rule out anything else what's going on. It's kind of, it's just interesting. It doesn't necessarily make sense. And it does raise questions though, based on their data, whether certain types or intensities of extreme activities could be leading to an issue in terms of helping you age faster than you're hoping for. So that's the general idea behind that, which is kind of interesting. But I thought that was, I wanted to talk about this 'cause I do think it's interesting, right? So everyone talks about the more exercise, the better. This is a contrarian viewpoint. Do I necessarily agree with this paper? We'll talk more, but that's why this is kind of interesting. And physical activity classes, like the moderately active, active, highly active, they did have the overall, a statistically significant decrease in their all-cause mortality by about 7%. So most people don't think that's pretty modest, 7%, right? So you're saying if you're active, moderately active, or highly active, you had a 7%. It didn't really show a lot more. And there's interesting, there's plateau effect, right? So what they're saying is that the maximum benefit or that 7% risk was achieved when you hit the kind of minimum amount of exercise recommended. So like the general physical activity guidelines, 150 minutes a week that we talk about, or 75 minutes of vigorous, when you hit that range, it seemed like you got all the benefit. You're like, all right, you're good. You got that 7% and going up higher didn't seem to necessarily have that, which was, I thought, interesting. And so there were no statistically significant additional benefits from higher levels of exercise in reducing all cause mortality. And yeah, that's just an interesting finding as well. 'Cause most people, the general thought is, hey, the more exercise, the better you'll get. And a key nuance, so there's lots of nuance, right? So the key nuance to this mortality finding is that there's time, right? So the association though of the 7% also was lower for shorter term followups. So when they followed it longer, they actually didn't even see that exist anymore. So they only saw that 7% improvement for a short-term followup and then the longer term followup didn't necessarily show quite as much. And so specifically higher levels of activity were associated with low risk of mortality only in the shorter timeframe. And authors were kind of scratching their head too. Reading this, they were definitely like, maybe this happened, maybe this happened. And it suggested from them that maybe this whole mortality association is susceptible to reverse causality bias. And we'll talk about in a second, but multiple times throughout the paper, they were like, oh, like we might have this finding because of this and that, and really didn't quite know, which is fair 'cause I don't know how they would know, but it was definitely interesting. And so we did wanna talk about confounders as well. A central conclusion of this paper is that the commonly observed association between higher exercise and lower all-cause mortality may largely be attributed to genetic factors and reverse causality. So for genetic confounding, meaning the study kind of suggested that genetic selection may partly account for some of these associations we see. Saying that generally healthy participants engage in physical activity, meaning, hey, if you have the genes that are gonna keep you healthy from anything big, like that will help you exercise more, thus improving mortality. Like because you are gonna do more, you're kind of almost predestined to do it, I thought was interesting. And within their twin pair analyses, right? So it controls for the genetic and environmental factors, the mortality differences between exercise classes were considerably attenuated after adjusting for other lifestyle factors and it's consistent with previous other studies. So what they're saying is when you take away all those different factors and you look at these classes, there's not a really big difference between the high exercisers and the moderate exercisers, which was interesting. And then regarding reverse causality, as we mentioned before, an underlying suboptimal physiology or genetics or disease state may actually negatively affect how much you exercise and lead to premature death. So that's the one thing. When twin pairs with one or both of the twins had cardiovascular disease at baseline, they were excluded to try to eliminate that, right? So they said, hey, if you had underlying CBD to start, we'll take you out. And when they found that, when they did all those things and looked at the associations, and once again took away some of the improvement of exercise on long-term health is kind of what they came down to. And it's kind of interesting and it supports kind of the necessity of excluding different participants with baseline diseases to really see how much exercise is doing. So what they're saying is people who have genetic predisposition to certain diseases, like they will exercise less leading to worse outcomes, but it's not because they exercise less, it's because they essentially had this predestined disease was gonna happen. It was really heady, it was really interesting. I just thought it was a unique perspective that I haven't thought of or heard before. And taking kind of the studies conclusions, the main conclusion was that the observed association between exercise and lower all-cause mortality may largely be attributed to confounding factors like genetic and reverse causality. So they suggest though that participation exercise and the ability to increase it might themselves be indicator of good health and fitness, meaning that if you are able to exercise more, it's because you already had the baseline level of the physiology and the genes to do that. And they're saying people who don't have that luxury, who were destined to get whatever, that that's the reason why they're not, they're on high levels of physical activity 'cause they can never get there 'cause it's going on. And so what they're kind of implying though, is that exercise is more of an indicator of good underlying health and favorable genetics rather than being the primary independent cause of reduced mortality. So once again, that's their general idea is that underlying good health and favorable genetics is more important than necessarily the amount of exercise you do 'cause that kind of leads to it. It's interesting thought, that's for sure. I don't know, what does it really mean for you though? Crucially though, I think they don't recommend not exercising, right? They're not saying, hey, your genes are everything, who knows, they definitely acknowledge there's lots of benefits with exercise such as improvements in, you know, fat, your cardiovascular health, your bone strength, there's so many things. And so they're definitely saying exercise, they're not saying don't exercise, but it was kind of interesting. And yeah, there's lots of at least improvements to be having exercise despite, you know, their findings being a little different. And for me, we kind of look, I wanna look at like interpreting these modest mortality benefits, right? So how do we interpret this modest 7% mortality improvement? So this study suggests that exercise, independent causal impact on extending life might be more modest once genetics and pre-existing health are put in that equation. And the effect size here is definitely more conservative than other studies, right? So I've seen other studies looking at anywhere from like 19 to 37% reduction in mortality based on your exercise level. And there's been lots of large scale meta-analyses in observational studies that show this much bigger improvement in mortality. Why did this one not show that? Well, not necessarily sure. Who knows why that's going on. This study pushes towards a more nuanced understanding though saying that, hey, exercise is one component within a complex, you know, healthy aging phenotype or overall healthy lifestyle. I mean, the exercise is in everything, it's only a little part of it, which is kind of interesting, I think, to look at. And another interesting topic though is a sweet spot, right? So regarding this sweet spot in exercise and diminishing returns, they said meeting the general physical activity guidelines appears to capture most of the benefits that you'll get from exercising. And it's kind of interesting, right? So when you think about that, I think that's pretty standard though, is that we put those recommendations for a reason 'cause you get the most benefit. And we know that it does fall off a little bit after that where as you increase, usually you get a little bit better, but it's not exponential. You just kind of like this big, big, big improvement till you hit the guidelines. Then once you hit the guidelines, it's like, okay, you'll get some incrementally small improvements and kind of go for there. So I thought that was definitely interesting, but for all cause of mortality reduction, engaging in much higher volumes didn't seem to show in this study a statistically significant reduction in mortality, which was kind of interesting. And yeah, I think, yeah, taking the, we'll go through one really thing about there. So the bigger context of this though, it's really important to contextualize, right? So these U-shaped findings for biological aging has some resonance with other studies. There's been other ones that could say, hey, there might not be this direct association like we thought previously, but it's so it's not a completely out of left field. But yeah, it does contradict other evidence that we've seen. And it's kind of interesting from that perspective that, hey, like, where's this going? I think the big things we have to consider, there are also limitations, right? So there's always limitations. This is definitely looking at self-reported outcomes. So anytime you have self-reported activity, who knows what to make of that necessarily. Self-reports are usually susceptible to recall bias and social desirability bias, meaning, hey, I should be exercising more. So I'm gonna say that exercise more. So that's something to think about there. It also focused on a loose definition of what leisure time physical activity is. And yeah, they're also specific to these Finnish twins, right? So generalizability to other ethnicities and populations is also going to be challenging. And then we have to remember that biological aging was only performed on a smaller amount of people here and using these epigenetic clocks, which who knows the actual outcome of, does it actually matter from these aging molecules? And so it's just something to think about there, but yeah, it's something that there's lots of limitations. Nothing's ever gonna be perfect, right? And so to summarize though, the exercise paradox here, it seemed like exercise is undeniably good for oral health. That's great. But in this study, it's direct independent causal role and dramatically extending lifespan, especially when looking at very high volumes appears more complex and more confounded by genetics and preexisting health than often portrayed, right? So a lot of times the big thing you hear is exercise more, the longer you live, that's kind of the goal. Not necessarily if that's true. How do I interpret this? Like what's my take on this? Well, my take on this is that like, doesn't change anything, right? So if you have a base of knowledge, right? That we have exercise, the more you do generally, the better it is. And you have a piece of data that says, actually, hold on, you know, wait a second, that's not true. I kind of push pause on that, right? I say, okay, that's an interesting thing, right? We've kind of seen a couple of them indicate maybe that's the case, but I'm not ready to just say, oh, it doesn't matter, exercise doesn't matter. That being said though, when we look back on this body data, like the general body data and this new one, what are some commonalities? Well, the commonalities are getting to the physical activity guidelines, very, very important. And that's kind of another takeaway from this is like, if we can get the biggest bang for our buck is getting into that recommended physical activity per week. That's a big thing. You know, I think what the finding we see here that agrees with all the data is that when you get up to physical activity guidelines, like you are getting the most benefit. And then how much you get after that is probably up for debate, right? Some studies show more, you know, 17 to 30%, whatever. And here is only seven. So that's what I'm seeing is like that little tippy top, that's what we're kind of looking for here. I think generally based off what I've seen, probably the more exercise you do, the better. This doesn't change that, I don't think. But I do appreciate the fact that they say this makes things more complex. 'Cause I just love, I love nuance. That's where I live. I love that saying that, hey, sometimes it just be like that. Sometimes your genes are not meant for you to be the healthiest person. You know, you may not have the genes to live to 130. That just might be the real case. Unless you're doing crisper and completely changing your genes, maybe that's not for you. And I think that's a harsh reality for some people online. I think everyone online thinks that the harder you work, you're gonna have guaranteed results. If I've seen one thing as a physician, it's that sometimes things happen to people that don't deserve it or have no explanation for it. And that just happens. And you know, we do not understand genes yet. We don't understand the entire impact of them, what's going on, lifestyle factors, other influences. It's, I think I just laugh when I see people try to control their health to the utmost extent. Like, yeah, should you take accountability for your health and work hard and eat right and sleep? Absolutely, we know that's good for you. I will always say that. But trying to obsess over it, saying like, I can control every aspect. I think this is just a cool, another indicator that it might not be that easy. Like you may not be as in control of your life as you think. And for some people that's a terrifying thought. For me, it's kind of freeing. Like, hey, I'm gonna do my best and we're just gonna go from there. That's kind of how I generally see this and kind of think about it. And so, yeah, maybe that's, I don't know, maybe that's a little Debbie Downer, but I like that. I think it's freeing that. Do your best, work hard, don't obsess because we're not quite there. We can't quite control every single thing. And that's kind of how I think about it. And so, yeah, that's overall my take on this. Hopefully you found this interesting. And this was a little heady one, but I saw this. People were talking about this on LinkedIn. They're saying, oh my gosh, like this study doesn't make sense and whatever. And they're bashing it. And like most things, you know, there's kind of a kernel of truth to both things. And so I wanted to look at it. And so, yeah, that's really it. But that's going to be it for today. Thank you so much for stopping by. If you did find this helpful, it would mean the world to me if you share this with a friend or you liked it on YouTube or subscribe on YouTube. That'd be wonderful if you're on the podcast, just listening, leaving a five star review would be wonderful as well. But thanks again for stopping by, really appreciate it. Now get off your phone and get outside. Have a good rest of your day.
