New Research Shifts Thinking on Metabolism and Aging

Transcript:

Intro: I’m Dr. Nathaniel Chin, and you’re listening to Dementia Matters, a podcast about Alzheimer's disease. Dementia Matters is a production of the Wisconsin Alzheimer's Disease Research Center. Our goal is to educate listeners on the latest news in Alzheimer's disease research and caregiver strategies. Thanks for joining us.

Dr. Nathaniel Chin: Welcome back to Dementia Matters. I'm here with Dr. Tim Rhoads, an assistant scientist with the Rozalyn Anderson lab at the University of Wisconsin's School of Medicine and Public Health where he studies the effect of caloric restriction on metabolism and aging. Recently, Dr. Rhoads and Dr. Rozalyn Anderson wrote a commentary for the journal Science called “Taking the long view on metabolism”. In this article, they break down new research that shows what we thought we knew about metabolism might be wrong and explain what this means in the context of aging and diseases of aging such as dementia. Dr. Rhoads, welcome to Dementia Matters. 

Rhoads: Thank you so much. I'm excited to be here.

Chin: Well, we’re excited to have you. I always like to hear from our scientists and researchers what got them into the field, so to start, how did you get involved in aging research and choose caloric restriction as your area of focus?

Rhoads: I didn’t choose it as much as it chose me. So it was actually originally via collaboration. I was a postdoc here in Joshua Coon’s lab working on proteomics and kind of systems biology type work. We had a collaborative project to look at liver samples from the non-human primates aging and caloric restriction study here at the University of Wisconsin. That eventually connected me with Roz Anderson. And my time in Josh's lab was ending and I wanted to go back to something that was a little bit more biologically focused in terms of research, and so her lab was a natural fit. As we worked on those samples, she and I were communicating frequently and so it just sort of made sense.

Chin: This is a very complicated topic so I'm going to ask that you do your best to translate it for the rest of us who are not in metabolism and and aging research but metabolism is so important, and I think all of our audience members recognize that, so could you share with us, at the most basic level right now, how is metabolism related to diseases of aging – things like Alzheimer's disease or dementia – and how might changes in metabolism actually impact our brain?

Rhoads: Sure. Most people think of metabolism as basically energy, how our body takes in energy, how it uses energy. Pretty much every activity that we do requires energy, and that includes the brain. But metabolism is actually more than just energy usage because it also encompasses things like synthesis and modification of the basic building blocks that we use in our cells. That means that metabolism is basically a regulator of fundamental cellular activity. Everything the cell has to be able to do is going to require metabolism at some level. So the example I would use for something like dementia – AD is characterized by these protein aggregates and there's a lot of debate about what exactly they're doing in the context of AD, but our cells have a system for dealing with protein homeostasis and maintaining proteins. So when you have something like aggregates, that indicates at some level there's a failure in that machinery. That machinery requires energy to function so you're getting to a failure of metabolism eventually. It's not always obvious and apparent but a lot of – almost all of this stuff traces back to metabolism eventually. 

Chin: That's kind of deep there, Tim. So metabolism is not only about energy, but it's also about the creation and then even the modification of the building blocks of our cells and how we use the proteins or the machinery of our cells. 

Rhoads: Yes, absolutely.

Chin: Then fundamentally most diseases eventually relate to metabolism one way or the other.

Rhoads: I would definitely agree with that, yeah.

Chin: (laughs) Okay. Well then with that in mind, now you co-wrote this perspective in a very important journal Science and in that article you describe four distinct phases of metabolism in the lifespan of a human being. So if you could share with us, what are those phases and why does this matter?

Rhoads: Right so the original article that the perspective piece was based on, which is also in Science, was using a technique called doubly-labeled water to examine just overall energy expenditure in humans as they go about their lives. They found that energy expenditure basically had, as you said, these four distinct phases and they correspond roughly with infancy, so up until about two years of age, childhood and adolescence up until about 20 years of age, adulthood from 20 all the way up until 60-65, and then advanced age. These phases are important because energy expenditure was substantially different across these different phases. Infants had dramatically higher energy expenditures than full adults. During childhood and adolescence, it slowly comes down until it settles at about the level it is throughout adulthood. Then after age 60 or 65 it starts to decline a little bit. And so one of the examples of how important this might be is for things like drug dosing and pharmaceuticals. Most of our pharmaceuticals are tested in full adults, but with metabolism playing such a role in how drugs are trafficked in the body, what we learn from drugs in a full adult might not apply to children and adolescence. Especially now that we can kind of see that metabolism is starting to decline in advanced age and most of these drugs are going to be against chronic diseases of advanced age, that has some important ramifications for how we think about drugs and how they should be dosed and things like that That's really one of the important consequences of looking at metabolism in this way.

Chin: And you know, to me as a geriatrician, of course that makes a lot of sense because I view the body differently for my patients who are 65 and older. I will tell you, Tim, I don't know if I would use the word advanced age, maybe older adults. I'm not sure if that could be modified in these papers. I think it's a really key thing here. And an important finding – one of the things in the paper that I thought was really beautiful is that your baby or a baby's metabolism mirrors that of its mother initially, like for the first month or so of its life. 

Rhoads: I think that was one of the surprising findings. And actually that during pregnancy, the amount that a woman's metabolism changes during pregnancy can basically be accounted for by accounting for the additional mass that goes along with pregnancy. That there wasn't any sort of distinct difference in metabolism as a result of being pregnant was one of the surprising things that we learned from this.

Chin: This just seems like this is such a key study. Are there other important findings that have really shifted our view on metabolism or our understanding of the impact of metabolism on our bodies?

Rhoads: Well I certainly looked at this and thought, well I can no longer sort of excuse an expanding waistline on a declining metabolism. I think one of the general assumptions that people have held is that metabolism – like the paper showed – peaks around young adults but then that it immediately starts to decline and shows this gradual decline all the way until the end and what this paper shows is that's probably not a great assumption. Actually your metabolism throughout adulthood is fairly stable and it really doesn't start to noticeably decline until you're older – 60 to 65 years of age. That, again, goes very much against what, I think, was the expected result. That's one of the things that was so important about studies like this. This was a very, very large study – over 6,000 participants– and it involved an unprecedented level of sort of data-sharing across lots of different sites and researchers. So that's one of the reasons why I think this is such an important study

Chin: And you're right. We cannot use metabolism or slowed metabolism as a reason for weight gain. Certainly we have seen that in this country, in particular, but throughout the world – this increased obesity epidemic or pandemic. You know, your paper also comments on the heterogeneity or the variability of metabolism. For my audience this is really that there's no one set value of metabolism for everyone. These are general trends. So is metabolism different between men and women? Large individuals and small individuals? Active people versus couch potatoes?

Rhoads: Yes I think heterogeneity is a very underappreciated facet. You know, our genetic code is 99+% identical across all of the humans, but there's so much individual variability and it's something as researchers we have to grapple with quite a lot. Speaking of metabolic variability, the biggest thing that this paper revealed was that size is really one of the dominating factors. The difference between men and women, as far as overall energy expenditure, mostly disappeared once they controlled for differences in fat and lean mass. In other words, women on average tend to be a little bit smaller than men and when you account for that difference, the metabolic difference between men and women largely goes away. That's not to say that there wouldn't be some differences between men and women metabolically. It's just that in the case of sort of overall energy expenditure that doesn't appear to be the case. As far as activity levels, I think it's another one where the difference is probably difficult to see at this scale. There’s almost certainly differences between active and more sedentary individuals. Active people are going to be using more energy but one of the things that I think people forget is how much energy it takes just to do the basic functions every day. Activity level can add to your expenditure a little bit but in the context of the amount of energy it takes to get your body through a day of just basic function, it's relatively small. So at the scale of this study I think it's hard to see.

Chin: I appreciate that comment though because that is a good perspective. It is good to exercise and get that activity but from a caloric standpoint, it really isn't a huge number, unless of course you're an athlete or professional athlete. But for the rest of us, yeah. 

Rhoads: And I don't want to minimize the effects of exercise and how good it is for you because it definitely is extremely good for you, but in that context of the amount of energy it takes to keep our body going is you know, that’s a large amount of energy.

Chin: Well I do want to touch on this because that finding that at 60 to 65, metabolism starts to decline but it really isn't a dramatic decline. It's just a slow decline. How is that important when we think about chronic diseases in older people – and these are of course things like Alzheimer's disease? And then in that context, are the things that we could do that might prolong a higher metabolism?

Rhoads: Yeah, I think the interesting thing to both Roz and I was that age 60 or thereabouts is right when the risk for these chronic diseases starts to really increase. So the fact that that's also when metabolism starts to decline, we think that can't be a coincidence. We think there's almost certainly going to be links there. Like I said towards the beginning, everything kind of comes back to metabolism ultimately. And so there can't be a coincidence. So I think maintaining a higher metabolism – I don't know if higher is necessarily the word I would use. Maybe more resilient metabolism might be better. But I certainly think that a healthier lifestyle would have benefits for both metabolism and disease risk. One of the things that I think is difficult is knowing exactly what will work for each individual person – going back to that heterogeneity concept. There's just so much variability that it's hard to often pinpoint for one individual what the best lifestyle is for them. II don't think it's a coincidence. We call them healthy lifestyles for a reason.

Chin: And then – I'm going to pivot here because you also do work within Roz Anderson's lab on caloric restriction and understanding the early molecular responses of caloric restriction. Can you tell us a bit more about that work within the lab?

Rhoads: Yeah. What we're trying to do is really to understand aging at a molecular level so that we can start to identify these biological mechanisms that result in this increased disease risk. Caloric restriction is a really useful model for this. It's been known since about the 1930s that caloric restriction actually extends lifespan; those initial experiments were done in rats. What that tells us is that caloric restriction alters the aging process. At the time it was kind of uncertain how well it was going to translate into humans. Back in the late 1980s here at the University of Wisconsin, a study of caloric restriction in the non-human primate Rhesus monkey was started. They're genetically very similar to humans and they have a similar risk profile for chronic diseases. That study was ongoing for 40 years and involved collecting tissues and assessing the health of the monkeys throughout. So my work in Roz's lab uses molecular profiling tools where we're trying to assess all of the biological molecules in a bunch of these different tissues and we compare monkeys that were on control diets, where they could eat as much as they wanted, and monkeys that were calorically restricted to try and see if we can see molecular differences in proteins, metabolites, and mRNA – the real popular molecule lately – and to try and understand why they might be different.

Chin: That's quite a task, Tim. And so if you could summarize for us, what is the impact of caloric restriction on the body and how does caloric restriction actually impact metabolism?

Rhoads: So the way the term that we use is it reprograms metabolism. It shifts what our body uses for fuel, how it stores energy, and you end up with the metabolism that is, generally I would say, more efficient because it has to be. Your body is adapting to lower nutrient intake. Especially if it's sustained for a long period of time, your body has to be able to accommodate that and still be able to function. And so it reprograms the metabolic set points. Really the question that we're trying to figure out is how does that lead to extended longevity. 

Chin: In your work does caloric restriction impact people differently or Rhesus monkeys differently based on their age? For instance, if you were to caloric restrict in your twenties compared to doing it in your seventies?

Rhoads: Yeah I think there's definitely going to be differences there. It's not always exactly clear what aspects of CR (caloric restriction) are you going to get if you start in your twenties versus in your seventies and eighties. One of the things about this is that a lot of the work has been done in rodents, and in rodents you can start CR very early, basically as soon as they're weaned. They’re very young, you know, 21 days of age. The earlier you start them on CR, the longer lifespan extension you get. However that may not be the case in primates. So I mentioned the UW non-human primate study. Around the same time, a study was started at the National Institutes of Health also in Rhesus monkeys, but they had a slightly different implementation. They had some different age groups. They started it in younger monkeys, for example, that weren't fully developed. They weren't full adults yet and there actually was a slightly higher mortality level in those individuals. So once you get to primates – I suspect this probably has something to do with brain and brain size and development – there might be a developmental cost to the lowered caloric intake really early on.

Chin: That's a very interesting finding. I know that we can't speculate as to what that would mean for humans, but that is interesting to know. I do want to ask you a question about food and caloric restriction, and I know you will give a very politically correct and scientific answer but I'm still going to ask it. Is there a relationship among caloric restriction, what you are studying, and things like intermittent fasting or the ketogenic diet, two very popular things that are researched by the general public.

Rhoads: Yeah I certainly think there are similarities. The fasting response is undoubtedly an important part of how CR works. The general implementation of CR is roughly a 20-30% reduction, which means cutting out basically a meal per day. That’s tricky to do without some level of fasting involved. So there’s definitely going to be similarities with intermittent fasting in that regard. The ketogenic diets are basically designed to force that fuel switch where you’re using more lipids as fuel rather than carbohydrates, which is something that caloric restriction also does. There are definitely similarities. The jury, I think, is still out on what it means for longevity. The intermittent fasting and ketogenic diets, I just don’t think there’s quite enough study of what the impact will be for those on longevity. So that’s what I would say for that.

Chin: That's actually more than I was anticipating, so thank you, Tim. Are there things, though, that we could do now that could impact our metabolism, whether you're in your twenties, thirties, fifties, seventies. Just as we’re thinking about decreasing risk of diseases of aging like Alzheimer's disease, is caloric restriction or fasting – is this something that you think is appropriate or at least a plausible idea for people?

Rhoads: I would caution probably not, at least caloric restriction specifically. I think one of the things about CR is anyone that's ever tried it, it's really difficult to maintain. As I mentioned, you're talking about a meal or so per day and it's not like you get to replace it somewhere else. You have to just cut those calories out entirely, and so I think that's very challenging. There are people that do it and they stick to it. I admire them greatly for it, but I love food a lot. So I would have a hard time contemplating caloric restriction. So I think as far as what people can do to impact their risk of disease, it's going to be perhaps a very bland answer. You know, healthy diets, exercise, sleep, and water. We know those things are fairly important for our overall health and that they work fairly well. So with caloric restriction and other specific diets like that, those are really tools to look at how aging works but I don't know how appropriate they are for people to implement in their daily lives.

Chin: I think that's well said. It's a model. It's not necessarily a recommendation for a real life application. I'm going to ask you, now, my last question, one that I also enjoy asking our guests, is about your own brain health. And so specifically for you – I mean, you kind of answered part of this but – do you think about caloric caloric restriction or intermittent fasting or eating a certain type of food or a certain timing of food as you think of addressing brain health?

Rhoads: I think about calorie restriction and like the idea that I would have more energy and things like that, but it comes back again, it would be really really difficult to maintain. So I do not personally do calorie restriction or intermittent fasting. I think, especially for brain health, one of the things that I think is very interesting is how much impact there seems to be from just making sure your brain is active and actively engaged for a big part of the day. I guess I think that's where maybe scientists have some advantages because that is what I spend a lot of my day doing, kind of solving logic puzzles almost, looking at data trying to come up with explanations. That keeps my brain very very engaged all the time. I think that's a really important one. Like I said, I love food. So doing something like CR is just – especially living in Wisconsin where there’s so much good cheese and beer, I can’t restrict myself from that.

Chin: I appreciate your honesty but I also appreciate the fact that you're right – when we think of metabolism, we're thinking of energy use. Certainly when we keep our brain stimulated, we are keeping an active metabolism of our brain cells. That is a great way to end. Thank you, Dr. Tim Rhodes, for being on Dementia Matters and answering these questions and talking to us about metabolism and aging.

Rhoads: Thank you so much. I really enjoyed it.

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Dementia Matters is brought to you by the Wisconsin Alzheimer's Disease Research Center. The Wisconsin Alzheimer's Disease Research Center combines academic, clinical, and research expertise from the University of Wisconsin School of Medicine and Public Health and the Geriatric Research Education and Clinical Center of the William S. Middleton Memorial Veterans Hospital in Madison, Wisconsin. It receives funding from private university, state, and national sources, including a grant from the National Institutes of Health for Alzheimer's Disease Centers.

This episode of Dementia Matters was produced by Rebecca Wasieleski and edited by Caoilfhinn Rauwerdink. Our musical jingle is "Cases to Rest" by Blue Dot Sessions.

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