By Rob O’Brien and Karen Ring
Dr. Alicia Kowaltowski is a professor at the University of Sao Paulo’s Institute of Chemistry in Brazil. The focus of her research is the relationship between nutrition and metabolism in mice and rats in order to better understand how specific genes, hormones and metabolites respond to different patterns of food intake. This is an important area for multiple diseases associated with aging, including diabetes and obesity, and as we have reported in the past, alteration of food intake has important effects on the lifespan of worms, flies, mice and (in some studies) primates. We have also reported on a group of people who hope that these effects will extend to human beings as well, and subject themselves to calorie restriction in the hopes of living a longer, healthier life.
A major problem in the field of calorie restriction is variability in results that may be due to differences between feeding methods that call themselves “calorie restriction”. Dr. Kowaltowski has identified multiple feeding methods that all fall under this heading (for example calorie restriction, CR: reduction of total food intake; intermittent fasting, IF: feeding normally with periods of fasting to reduce total food intake; calorie restriction with vitamin/nutrient supplementation: reducing the amount of calories taken in without altering vitamin and mineral intake) and has worked to understand how these different diet regimens affect total animal calorie intake, weight, muscle mass and responses to sugar. Dr. Kowaltowski sat down with SAGE to discuss her research.
Q: Your talk succinctly covered different feeding paradigms that lead to difference in metabolism in animals. Are any of these findings directly translatable to humans?
AK: I always like to say that the reason we study these things is to understand the mechanisms more than anything else. So I don’t translate these diets very easily into the human paradigm. I think they are very different. But on the other hand, if you do understand the molecules that are responsible, then you have targets. I mentioned that we found that adiponectin was the hormone responsible for the activation of eNOS and mitochondrial biogenesis. So now that we know there is one hormone responsible for this, we can mimic different processes by adding or removing adiponectin. That’s the really important part. The diet stuff and metabolic rates are too different. You can’t compare 24 hours in mice to 24 hours in humans. What we really have to work on is understanding mechanisms of when things go wrong.
Q: What advice do you have for people who read about fad diets based on animal studies?
AK: Don’t do fad diets. What I always tell people is that the American Heart Association has dietary recommendations on their website. They have published guidelines that are very reasonable and are scientifically based. And it’s really moderation at all levels. Don’t overeat, do a little bit of exercise, don’t eat too much protein, don’t eat too little protein, know what are good fats, and what are bad fats.
Q: You found that the intermittent fasting (IF) diet has drastic changes on metabolism in animals. These animals experience higher body temperature after feeding, and eat far more food than a normally fed animal when given the opportunity, yet they lose weight. Are there humans that have similar metabolic changes?
AK: There is one group of people who have very inefficient energy conversion. They are young girls who have had anorexia nervosa. They are not being studied from a metabolic view, which I think would be really interesting. The interesting thing is that when you try to feed them, you can give them 5000 calories per day, and they gain very little weight. They have an inability to gain weight and enhanced thermogenesis, and we really don’t know the mechanisms for this. One of the interesting things about the IF diet in mice that I didn’t mention is they have a break between normal energy expenditure and hunger. So they are very hungry animals, but they have high energy expenditure. And normally hypothalamic control mechanisms make it so that when you are very hungry, you have very low energy expenditure. So that’s another aspect of this study that we are considering, what’s breaking in terms of this control: why do they have activation in the anorexigenic pathways but they don’t have activation of the mitochondrial uncoupling pathways which would allow them to reuse this energy better.
Q: You mention that regular diets [SAGE note: we’re referring to freely fed or ad libetum] induce symptoms of metabolic syndrome in mice. Should we take this into consideration when doing any mouse studies?
AK: That is Mark Madison’s paper that I introduced my talk with. Diet affects everything. We are studying models [that are] couch potatoes. So that is something we should be thinking about. Maybe we should be studying slightly calorie-restricted animals as well. Depending on the age of the animal you are looking at, you’re going to have more or less effects of this. So for example, the leptin results [that fasted mice are more responsive to leptin than freely fed animals] were surprising to me because these [freely fed mice] were not insulin resistant animals. I always thought they would be leptin sensitive but they are not. They have already lost their leptin sensitivity. And this phenomenon seems to happen pretty early.
Q: Did you look at leptin levels in the circulation of these mice?
AK: Yes we found that intermittently fasted animals had lower leptin levels. That’s because they are more sensitive to it. So it’s like having high insulin levels in a diabetic animal. The ad libitum animals actually have higher leptin levels than normal because they are less responsive to it.
Q: Can we identify factors that could improve human metabolism so that not everyone needs to do something like the CR diet?
AK: Well that’s the whole thing. If you find the molecules, then you can really interfere with these mechanisms in a much more effective way. Because not many people are going to practice a diet like that easily.
Q: IF diet weight loss was due to loss of muscle but you said there was higher turnover of fatty acids, don’t those observations contradict each other?
AK: So they have lower fat deposits when they’re intermittently fasted, but not when they’re fed. They still weigh less when they are fed, so they are turning over their fats, but they are resynthesizing them [after feeding]. What they always end up with is less muscle. So they are smaller and weigh less when they are fed because they have less skeletal muscle. When they’re fasted, they have less of both. So I guess the question is, is that really healthy? Considering the loss of weight and muscle, and changes in hypothalamic effects, you have to wonder.
Q: How is mitochondrial function affected in obese animals?
AK: That’s a really complicated question to answer. It depends on the type of tissue, the kind of obesity. And the results in the literature are very very inconsistent. Comparing CR to ad libitum diets, some people are seeing a lot more mitochondria in CR, others don’t at all.
Q: What is the future of your research?
AK: We are doing lots of different things! I work at a place that is a completely different from the US. Doing science in Brazil is very different. We don’t have to (A) prove to anybody that we can cure cancer to get a grant, and (B) if I don’t do what I have in my grant but I do get good results on other things, then I’m fine. So it’s very different. And that means if I get a postdoc who says, “Oh! I want to study this.” Then I say, “Sure!” So things are more flexible and student/postdoc oriented in my lab. Right now we are studying a lot of different things. In the calorie restricted line, there are two things that I’m excited about that we’re looking at. One is the neurological effects of CR in terms of excitotoxicity because that has not been studied very much. And we see a lot of protection against cytotoxicity. It seems that mitochondrial calcium metabolism is very much changed. With the serum from calorie restricted animals and also animals off calorie restriction, so we are dealing with multiple models. Another thing that we are studying in the lab is how calorie restriction changes stem cells. Both stem cell differentiation and also the quantity and types of these cells in the different niches.
Q: What advice do you have for postdocs who want to pursue academic careers?
AK: Staying in academia means that you really really like to do research. It’s not a job if you want to make a lot of money. It’s not a job if you want to work 9-5. Everyone I know who enjoyed it, did really well. There are few places to be an academic, but they are there. There is a program online that calculates your probability of being a PI. It’s called PIpredictor.com. And they look at what the things are that make people PIs and they are pretty predictable. A good number of papers and good impact factor journals, mostly first author. You can upload your papers to the website and then have it predict your chances.
One difference between being an academic here in Brazil versus in the US is the whole the freedom aspect. The other is the difficulties: we don’t have the same facilities. I also can’t pay people from my grant. Every student or postdoc has to come in with his or her own fellowship. That’s fine because there are plenty of those, but they don’t have fellowships for staff. That has to come from the universities and the universities just don’t have the money for that. So we don’t have lab techs, so you administrate for yourself. I do a lot of teaching, up to 20 hours a week. Another issue is with imports, it takes a long time to import stuff to Brazil and there is a lot of red tape. So you have to think ahead. But there are pros and cons and ultimately it’s fun.
Q: Did you always know you wanted to be a PI?
AK: Yes. I didn’t know where. I could have stayed here easily if I had an opportunity. I was very young when I became a professor and I was offered a lab here and the opportunity to do whatever I wanted.
Q: What are your hobbies?
AK: I play the violin! I play in an orchestra. I also read and garden. Having hobbies maintains normalcy. You have to interact with people outside academia once in awhile to ground yourself. And also, you should do something completely different. Sometimes your best ideas come from when you are doing something totally different.