Dr. Dudley Lamming discusses his recent work on how fasting, not merely reducing calorie intake, drives metabolic benefits and promotes longevity in mice.
Welcome to the NMN.com podcast! I’m your host Brett Weiss. And today we have professor Dudley Lamming from the University of Wisconsin School of Medicine who will talk about his most recent study published in Nature Metabolism. His paper about this study is titled, “Fasting Drives the Metabolic, Molecular, and Geroprotective Effects of a Calorie Restricted Diet in Mice.” Dr. Lamming, thank you for joining us.
Dudley Lamming (00:33):
Thanks for having me.
Brett Weiss (00:35):
You showed in your study that fasting, not merely calorie reduction, drives the metabolic and aging-related benefits from calorie restriction in mice. So I’m wondering, why did you do this study in the first place, and what was the question that the field is struggling to understand?
Dudley Lamming (00:55):
Well, my graduate student Heidi Pak was trying to investigate the role of calorie restriction on metabolic health. And when she was doing these studies, she noticed that the mice tended to eat their food very rapidly. So after about two or three hours, the calorie restricted mice, which were fed a reduced portion of food once per day were very hungry. And so they ate up the food and were fasted for the rest of the day. And a number of studies over the past decade or so have pointed to the idea that fasting for a portion of a day or time restricted feeding fit eating only during a portion of a day has beneficial effects on health than even life span in a variety of different model organisms. And so she was interested in trying to understand whether this imposed sort of self-imposed fast was contributing to the beneficial effects of CR in these mice.
Brett Weiss (01:53):
Okay. So could you briefly rehash some of the findings from your study?
Dudley Lamming (02:00):
Sure. Just to sort of set the stage, what we did was use a series of different diet regimens. So we have mice that have normal access to chow all the time. We also had our sort of traditional calorie restricted mice that were fed once per day and ate their food really rapidly and then for the rest of the day were fasted. And then we had a couple of groups of mice where we either use a timer or diluted diet so that those mice didn’t have the same fasting period. And so, in the diluted diet mice, where we did a lot of our work, they had free access to a low energy diet and they ate during the entire day more or less. But as a result, they were calorie restricted to the same number of calories as the mice that were in our traditional calorie restricted group.
Dudley Lamming (02:51):
We also had a final group where we tested the effect of feeding mice for just a portion of day and then took the food away. And so, in these mice fed, if you will, our time restricted group they ate a normal number of calories, but very quickly learned that the food was going to disappear. So they ate that number of calories about three hours. So, they’re sort of the opposite of a CR group, because they ate it in the same amount of time as the CR group, but they ate a normal number of calories instead of a reduced number of calories. So what we found was that in the fasting group, a lot of the phenotypes that we associate with calorie restriction could be reproduced just by fasting and that if we eliminated the fasting period through the use of automated feeders or the diluted diet, we lost some of those effects, and calorie restriction has lots of beneficial effects.
Dudley Lamming (03:48):
It reduces weight and adiposity. We see that happen regardless of what group we’re looking at. And so that particular type doesn’t seem to require fasting, but all animals, including humans that are put on calorie restricted diets have improved insulin sensitivity. And in our study, our mice required fasting. And so mice that didn’t have this prolonged fast during the day didn’t gain insulin sensitivity. And if you were just fasted, but ate a normal number of calories, you had improved insulin sensitivity anyway. And so fasting seems to be very important in that phenotype. We also looked at essentially fuel utilization. This is sort of how you use the different types of calories in your diets. So your sugars and your fats and your protein. And normally we spend a lot of our day digesting or using carbohydrates is protein. Calorie restricted mice and fasting mice actually use it for carbohydrates for a very short period of day and subsist off of fat the rest of the day.
Dudley Lamming (04:51):
And so they actually burn carbohydrates very quickly, store them as fat. Then they use them during the rest of the day. We think that that might have some metabolic benefits to mice as well. Finally, my lab is really interested in aging and so we’ve followed what happened to mice when they’re placed on either a normal diet, a calorie restricted diet or diluted, low energy diet. And so as we anticipated calorie, restricted mice were healthier. They live longer, they had reduced frailty as they age. And they even had improvements in memory. And conversely, when we looked at a diluted diet group, they didn’t have any of these benefits, even though they’re eating less calories, they were just as frail as a normal mouse. They didn’t have improved memory. They didn’t have improved insulin sensitivity and they actually had reduced lifespan. So they actually lived about 9% less than mice, just on eating a normal diet. And so this really suggests to us that fasting is a really critical and important part of their response to calorie restriction.
Brett Weiss (05:56):
So, you said that the diluted diet mice had reduced lifespan and they didn’t have the cognitive benefits that the restricted diet mice had. So I’m wondering has your lab done any survival analysis on mice that fasted without calorie restriction, like maybe that ate for three hours and then didn’t eat the rest of the day?
Dudley Lamming (06:29):
So we haven’t for, for technical reasons, but I think that’s a really important experiment. It should be done in the future. A study that came out of Rafa Kibo’s lab a couple of years ago, looking at mice that essentially were fasted for about 11 hours a day. So their food consumption was confined to half of the day. And then they fasted the rest of the day showed that there was some beneficial effect on life span in that context. And so we might expect that fasting alone might be able to give extended lifespan. And that’s something we’re very excited about testing in the future.
Brett Weiss (07:04):
That sounds like it would be an interesting experiment. So I’m wondering in your opinion, can we apply your study’s findings to humans to any degree?
Dudley Lamming (07:17):
Well, there’s a lot of controversy about that. Obviously mice are not just little humans. They have a shorter lifespan and a much more rapid metabolism. On the other hand, you know, there’s a variety of human data that suggests that time restricted feeding, eating for only four to six hours a day, might have metabolic benefits for the health of people. Some of those are associated with calorie restricted calories just because the shorter amount of time you have the harder it is to eat a normal portion of calories in that time. But you know, this is an area of very active research. And so I think over the next few years, we’re going to hear a lot more about what time restricted feeding and different fasting regimens might have in terms of benefits to human health.
Brett Weiss (08:04):
Okay. So I’m wondering besides potentially intermittent fasting are there any other new techniques or molecules that might mitigate the effects of aging?
Dudley Lamming (08:21):
Well, it’s an interesting question. And, you know, one of the comments that we got from this paper was, you know, there’s been a lot of attention to developing CR mimetics if you will that can reproduce small molecules that could mimic some of the benefits of CR, but if our studies do apply to people, maybe what we should be developing is fasting mimetics because reducing calories, at least, remind us didn’t really have much of a benefit while fasting had virtually all of the benefits of CR. And in fact when we looked at the molecular level, looking at gene profiles, induced by calorie restriction and fat and liver, what we found was that fasting, reproduced almost its gene signature, almost exactly. And so, you know, if we could find fasting mimetic molecules that maybe that would be a better path to translation than working on CR mimetics. Okay.
Brett Weiss (09:15):
Okay. So do you think that a fasting mimetic would stimulate the autophagy pathway?
Dudley Lamming (09:27):
So there is a paper recently that you’re probably familiar with looking at intermittent fasting or time restricted feedings in Drosophila showing that autophagy was very important in that response. And so we didn’t look at autophagy specifically and that, I believe, that pathway didn’t come up in our initial analysis. But trying to understand whether autophagy might be an important regulator here is something that’s a very interesting question. And so, you know, based on that fly data, it would certainly make sense that maybe the circadian regulation of autophagy or other processes might be important in the fasting response. So that’s something we’ll be looking at.
Brett Weiss (10:05):
Okay. Well, you know, that does it for my questions. Is there anything else that you’d like to add?
Dudley Lamming (10:11):
Well I think that this really represents a big change in perspective, the idea that, you know, it’s fasting rather than calories, because for a hundred years, people have done calorie restriction and called it calorie restriction because we thought it was less food that was driving this process. So if it wasn’t that, I think it means that we have to rethink a lot of our data and think a lot about strategies, both for people as well as what that means in terms of developing new drugs that might be able to give some of these benefits to everyone. So I think that it’s really a very exciting time in biology of aging. And I’m looking forward to seeing where this and other research goes.
Brett Weiss (10:57):
Excellent. Well I’ll be one of the first to read the newest publications in this area of research. And I thank you very much for joining us today. I think your study is very seminal and important. So I thank you for the research that you do and I hope you have a wonderful day, Dr. Lamming. Thank you for joining us.
Dudley Lamming (11:20):
And thank you for having me. Take care.