Metabolism and aging -
Researchers calculated TEE in all subjects using doubly labeled water measurements the gold standard for measuring energy expenditure. They used additional datasets, mathematical models, and adjustments to account for differences in body size, age, and reproductive status.
Their findings revealed four distinct phases of adjusted total and basal energy expenditure over the lifespan. Neonatal 1 month to 1 year : Neonates in the first month of life had size-adjusted energy expenditure similar to that of adults.
Energy expenditure increased rapidly over the first year, reaching a peak at 0. Childhood and adolescence 1 to 20 years : Although total and basal expenditure as well as fat-free mass continued to increase with age throughout childhood and adolescence, size-adjusted expenditures steadily declined throughout this period.
Sex had no effect on the rate of decline. At Of note, there was no increase in adjusted total or basal energy expenditure during the pubertal ages of 10 to 15 years old. Adulthood 20 to 60 years : Total and basal expenditure and fat-free mass were all stable from ages 20 to 60, regardless of sex.
Adjusted TEE and RMR remained stable even during pregnancy, and any increase in unadjusted energy expenditure during pregnancy was accounted for by the increase in body mass.
The point at which adjusted TEE started to decline was age 63, and for adjusted BMR was age Older adulthood andgt;60 years : At approximately 60 years old, TEE and BMR began to decline, along with fat-free mass and fat mass. However, declines in energy expenditure exceeded that expected from reduced body mass alone.
Adjusted TEE and BMR declined by 0. The study authors were interested in effects of physical activity and tissue-specific metabolism the idea that some organs, such as the brain and liver, use more energy than other organs, and constitute a higher percentage of body weight in younger individuals across the lifespan.
Through various modeling scenarios, they determined that age-related changes in physical activity level and tissue-specific metabolism contribute to TEE across different ages; in particular, elevated tissue-specific metabolism in early life may be related to growth or development, while reduced energy expenditure in later life may reflect organ-level metabolic decline.
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 , 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, 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. 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.
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. 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 s 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 s 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.
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. There are definitely similarities.
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