Dr. Dudley Lamming discusses how restricting protein building blocks called branch chain amino acids extends male but not female mouse lifespan and the potential application to human diets.(University of Wisconsin)
Welcome to the NMN.com podcast. I’m your host, Brett Weiss, and today we have Professor Dudley Lamming from the University of Wisconsin. Dr. Lamming has studied the effects of mouse dietary restrictions for specific protein building blocks called branch chain amino acids that stimulate a central regulator protein complex of metabolism and aging called the mechanistic target of rapamycin complex or mTORC. He found doing so throughout life improves overall mouse health and extends lifespan sex-specifically – in healthy males.
NMN.com: What got you interested in studying dietary protein composition in the first place?
Dr. Lamming: There’s a really interesting study published in 2014 by Steve Simpson, in which they looked at how different dietary macronutrients affected the lifespan. What they found, looking at a large number of diets, I think 25 diets in total, was the mice that lived the longest tended to be those eating low protein. In fact, if you look at human epidemiological data, despite the fact that high protein diets have a positive reputation in the diet fields, long-term looking at people who’ve eaten different quantities of dietary protein, typically people who eat more protein, have a variety of age-related diseases. These include increased rates of cancer and cardiovascular disease, and across the board, there is an increased rate of diabetes. And that, in particular, is seen in a lot of different studies.
NMN.com: There’ve been previous studies showing that mice have had extended lifespan with dietary restriction of protein specifically a branch chain amino acid composition.
Dr. Lamming: No. Dietary protein has been known to be linked to lifespan for a long time. I think some of the first studies were actually done in fish, going on a hundred years ago or maybe even a little more. But this was shown in rats and mice as well. It sort of fell out of favor for a while because the results of the studies were inconsistent. I think one of the reasons they were inconsistent is due to the fact that the degree of that restriction may have been too much just like calorie restriction. If you restrict calories too much, you sort of enter into starvation mode. I think that that’s true for protein as well. And also people use a variety of different types of dietary sources. In fact, that was something we struggled with initially as well.
Just if you order different diets, even though they may contain the same amount of protein, the protein source seems to matter. And probably why protein source matters is that there are different amino acid compositions based on what type of protein is in there. That suggested to us, among other things, that maybe dietary protein quality, the sort of makeup of the dietary protein, really played an important role prior to our work while no one had really studied branch amino acid restriction in great detail. And in fact, methionine restriction has been sort of known for about 20 or 30 years to be able to promote health. This is true in both rats and mice, that if you restrict dietary methionine, which is believed to be low in vegetable-based diets like vegan diets, then that can improve both metabolic health as well as extend the lifespan of rodents. This wasn’t the idea that restricting any dietary component was certainly not new. What’s really new here is that we investigated these branch chain amino acids restriction in some detail and found that particularly what started young, we got a lifespan extension effect in male animals.
NMN.com: What exactly differentiates branch chain amino acids from other protein building blocks?
Dr. Lamming: One of the things that branch chain amino acids are best known for is their role at skeletal muscle building. Lots of people are taking branch chain amino acid supplements while working out. We think, although we have not really studied the effects of this on exercising animals, that the sedentary context is relevant to a lot of people today. Our animals are sort of better models of sedentary behavior. I want to stress that we don’t necessarily have any insight into the advisability or not of taking branch chain amino acid supplements for when you’re exercising, but in the sedentary context, in the context overall of sort of biology, branch chain amino acids are well known to agonize a protein kinase called mTOR. mTOR is a protein that senses amino acids as well as a variety of other nutrient types.
One of the interesting things about mTOR, from a longevity standpoint, is that rapamycin and other things that seem to inhibit mTOR activity generally speaking extend lifespan in rodents. So, that was one of the reasons that we started looking at the branch chain amino acids. The second major reason we were looking at the branch chain amino acids is we originally came at this from the aspect of diabetes and obesity. And there has been a correlation between branch chain amino acids and diabetes for a long time. So, it was shown back in the sixties that they’re actually elevated in the blood of people who are obese. And more recently, we showed that if you protein restrict, the amino acids that go down in the blood are the branch chain amino acids. Twelve other things like my finding are not affected. This really suggested to us branch amino acids would be pretty important in regulating metabolism. Some work by people at Duke has also shown that if you supplement branch chain amino acids in excess particularly in the context of a Western high-fat high-sugar diet you can worsen diabetes and other phenotypes in rats. That was another reason that we thought branch amino acids would be a good thing to look at.
NMN.com: I remember reading that the branch chain amino acids can act as an agonist to the mTOR.
Dr. Lamming: What we anticipated based on our work and previous work looking at dietary protein and the branch chain amino acids was that this might be one way to inhibit mTOR signaling. In fact, we do see that there’s reduced mTOR activity in the skeletal muscle of our mice as well as we saw some decreases in the liver. Interestingly, the decreased mTOR activity and the increased lifespan only took place in the context of males, not females. We don’t know why that is, and we have proven that that’s the reason for the sexually dimorphic effect on lifespan. They definitely seem to correlate together.
NMN.com: That leads to my next question. You talked about the mechanism relating to mTOR in male lifespan extension. Do you have any specific ideas of what mechanism extends male mouse lifespan?
Dr. Lamming: Overall mTOR inhibition has been shown to have numerous different beneficial effects in different organ contexts. One thing that it does is repetitive inhibition of mTOR signaling has been shown to preserve skeletal muscle undergoing sarcopenia. While we did not look at this specifically, we saw frailty in the animals, which is probably heavily driven by skeletal muscle phenotypes, was decreased on a low branch chain amino acid diet. So, that could be one thing that contributes to this effect, but mTOR inhibition has been shown to have beneficial effects, essentially all tissues sort of preserving the ability of the liver to regulate autophagy, ketogenesis, good cardiac function, and to rejuvenate stem cells in multiple tissues, including the intestinal stem cells. So, probably mTOR inhibition, at least to a certain degree, is good in all of those tissues and probably there are contributions overall to that effect. Overall, we saw about a 30% increase in lifespan extension in the males by either amino acid or protein restriction, which is pretty significant sort of relatively speaking on par with the type of thing that is seen when we calorie restrict animals.
NMN.com: Do you have any idea why you didn’t see the same results in females?
Dr. Lamming: Well, it didn’t change mTOR signaling. So, our general idea is that those two things correlate. Now as to why, one of the things that we do not really know about is a lot about sex-specific differences and branch chain amino acid catabolism, or even how dietary protein amino acids might be used for skeletal muscle levels. We didn’t instead simply investigate whether other degrees of restriction would have extended female lifespan. Maybe they needed to be restricted more in order to inhibit mTOR and get that benefit. That’s certainly something that could be looked at in the future. Not a ton is known about exactly what type of dietary levels of protein are best for health in either humans or mice. And I think we’re still learning a lot about how the individual amino acids are catabolized and utilized.
NMN.com: Do you think there could be any connection to the microbiome, the bacterial composition of the gut?
Dr. Lamming: The microbiome definitely changes. We didn’t publish those results. But we have previously looked at dietary proteins’ effects on the microbiome, and we see very big effects overall. However, we originally thought that the microbiome might play a role in the response to dietary protein restriction, so we tested this, which we published a couple of years ago. We ablated the microbiome using antibiotics, and we saw that in all of the effects that we see, all of the metabolic effects of dietary protein restriction were significant. It didn’t matter whether or not it had an intact microbiome. We actually think that the microbiome is not really involved in this effect and a different group hasn’t published yet but has been researching this user germ-free mice and generally come to the same conclusion that at least from the metabolic standpoint, dietary proteins effects on metabolism are not really mediated via the microbiome.
NMN.com: How consistent are these results in different repeats of the experiment?
Dr. Lamming: We haven’t redone this particular lifespan experiment, but we showed that the longevity effect was in two different strains, as well as wild-type mice. So, that’s fairly robust. We’ve also looked at its effects on the branch chain amino acid metabolism in a number of different strains of animals. Generally speaking, we see improvements in glucose tolerance and/or insulin sensitivity across the board. And there’s even a little bit of data now from two groups that conducted very short-term branch chain amino acid restriction in humans with various types of metabolic diseases. And even in a very short-term construct context, they’ve seen some positive effects on insulin sensitivity. We think that from a metabolic standpoint, this is very robust and would be true. Samantha’s group also showed a branch amino acid restriction improving glucose metabolism in their animals on the other side of the earth in Australia. Pretty much Madison and Perth are at antipodes. So, it really is on the other side of the earth. We think pretty strongly that we’re going to be continuing these experiments and overall in our continued experiments, we see beneficial effects of restricting branching amino acids.
NMN.com: Can you say any more about the preliminary data of a human health benefit from a low branch chain amino acid diet? I know you mentioned insulin.
Dr. Lamming: Two groups, one published fairly recently I think in Nutrients showing that in a one-week study, the people were restricted for branch chain amino acids. They had improvements in something called an insulin sensitivity index, which is, I can’t remember all the details of that study. There was another similar study I think we found when we were looking fairly recently for literature reviews from Germany. Again, sort of a very short, one-week study or so. And restricting amino acids is not very easy in humans. Because all foods essentially contain branch chain amino acids, they contain different levels. That’s not necessarily the end goal here either, right. You know, we might want to be able to identify the specific molecular pathways that are being engaged here and figure out ways of identifying new interventions in them rather than trying to switch everybody’s diet. Since everyone has their dietary preferences, it’s very difficult to change those.
NMN.com: I remember reading that beef, chicken, eggs, cashews, almonds, just various foods are high in branch chain amino acids. Has anybody tried dietary alterations in humans to find out if there are any specific benefits to that?
Dr. Lamming: We, with Fuji Fontana’s laboratory, which at the time was in Washington University in St. Louis, published on a human trial protein restriction in which humans were protein-restricted for six weeks. The study was done on people who are about 50 years of age and overweight or obese. What we found in that study was that the people lost about a pound and a half per week, primarily from mass, although there’s some lean mass loss as well, and they had a decrease in blood fasting glucose levels. Longer-term studies, as far as we know, haven’t really been carried out. But that definitely suggests again that some of these studies will likely apply to humans as well.
NMN.com: That being said, do you think people will start cutting branch chain amino acids from their diets to prolong their lives in the future?
Dr. Lamming: I don’t know specifically about branch chain amino acids, but as I’m sure you’re aware a number of people around the world are engaged in calorie restriction and many different people are following various different diets that they think will promote their health and longevity be they keto or other diets. Whether or not people do this, I think overall the idea that lower protein diets and possibly diets that happen to have lower branch chain amino acids might be something worth considering. One of the things that we did during COVID, and hopefully we’ll be able to get published fairly soon, is, one of our dietician students actually looked into trying to design some branch chain amino acid-reduced diets for people. Whether or not we use a clinical trial or not, I think it might be useful to get out there and start thinking about what type of foods are lower in branch chain amino acids and which are higher. I don’t know about the branch chain amino acids per se, it may only be amino acids that are going to turn out to be important from a longevity standpoint.
NMN.com: Do you have any ideas? Is there any preliminary data saying what other amino acids might be beneficial to cut out from your diet?
Dr. Lamming: Well, you can’t cut them out entirely from your diet. These are all essential amino acids you’ll die without them. But roughly speaking, we think that Americans typically eat somewhere between two to four times the RDA of branch chain amino acids, and probably a lot of other essential amino acids as well. There’s almost certainly room in the American diet at least to cut to the point where you can still be healthy and still have enough of these amino acids to grow and do your normal activities. But maybe with this excess level that we’re consuming, seeing some of the benefits from not going in great excess is feasible. Certainly methionine has been implicated for a long time in a lot of these pathways and definitely methionine restriction is being investigated in the context, not only of metabolic syndrome, but also cancer and maybe some other diseases as well as associating with aging.
There’s some literature about tryptophan. Although I think a lot of that’s quite old, maybe it needs to be revisited to sort of figure out whether those results are robust. Those are some of the ones that definitely people have investigated. But even more recently the NIH has intervention testing programs that found that high levels of glycine seemed protective for lifespan in mice. Potentially even high levels of certain amino acids and low levels of others might turn out to be sort of the best combination.
That does it for today’s podcast. Join us next time on the NMN.com podcast.