So, in your recent science feature article about diets and aging, there is several very interesting finer points that you make with your co-authors. And one of them is, is it possible that all caloric restriction does is help us perhaps avoid obesity? So there is perhaps no magic in it? Or what can help? What can you comment on that?

Yeah, so I think that's a reasonable question. Dr. Matt Kaeberlein, PhD. Dr. Anton Titov, MD. My personal feeling is that that's very unlikely to be the case. So I think that obesity, certainly whether this is in laboratory rodents or in people, is associated with and almost certainly causal for a variety of negative health outcomes during aging. Maintaining normal body weight, it certainly in mice. You get further benefits for lifespan, from caloric restriction, as opposed to, you know what I think we would consider a normal body weight or healthy body weight, sort of moderate adiposity. So my personal feeling is it's very unlikely that that caloric restriction is simply proof that the effects of caloric restriction are simply due to preventing obesity. I think in humans, it's a harder question to answer. And in part, that's because humans age so slowly, we live a long time. And really, nobody can do long-term controlled studies of caloric restriction. So in that context, it's harder to know whether or not a sort of moderate or even severe caloric restriction long-term and people would positively impact the biology of aging. So it's a guess. Dr. Matt Kaeberlein, PhD. Dr. Anton Titov, MD. And I think, you know, as long as we recognize that it's a guest, then then I'm comfortable saying my guess is that, indeed, caloric restriction, beyond just preventing obesity, probably has positive effects in people on biological aging. My concerns are that because people live in a very complicated environment and are genetically heterogeneous, there is a risk associated with severe caloric restriction or even moderate long-term caloric restriction in people that is not appreciated based on the mouse and rat studies in the laboratory. And, you know, I think when you're thinking about strategies to maximize healthy longevity, you always need to think about the risk-reward ratio, right. And we know that there are some pretty potentially big rewards from positively modifying the biological aging process, enhanced lifespan. Dr. Matt Kaeberlein, PhD. Dr. Anton Titov, MD. But there are also risks associated with any strategy that we take. And, you know, I think in the context of caloric restriction, you know, one obvious example would be that, you know, if you're chronically calorically restricted, there's a, there's a pretty reasonable chance that you're going to be at higher risk of infection, or at least failure to fight off an infection once infected. That's speculation, but I think it's a reasonable speculation. And if that's the case, it doesn't do you any good if you're aging more slowly if you get infected with influenza, or COVID-19, and die because you're in a nutritionally restricted state that isn't able to fight off the infection as effectively. So I just say that to make the point that it's hard to answer the question that you asked definitively. And even if the caloric restriction has significant benefits in the context of aging, I'm not convinced that the benefits will offset the risk that goes along with long-term caloric restriction and people. And that was another point that we tried to make that, you know, some of these diet gurus that get on the internet and, you know, try to sell their favorite diet don't really evaluate the potential negative consequences and side effects associated with some of these diets. And, you know, culturally, we're not, we're not trained to think of diets or nutritional strategies as having side effects, but they do. And I think it's important to appreciate that.

I think you also mentioned in the review that the famous caloric restriction researcher, Roy Walford, tried to popularize and did write a very famous book on caloric restriction. He died in 79. So quite short of the 120 years that he proposed. Do you know what is the cause of death?

Yeah, so it's my understanding that, that Dr. Walford suffered from a form of ALS. And, you know, I think it's it's total speculation whether or not that was at all impacted by, you know, his quite public adoption of caloric restriction, nobody knows. And, again, I think it's, you know, this is a challenge with interpreting anecdotal data from people who have been practicing caloric restriction because it's always very small numbers of individuals. But again, I think I think the point is valid that, you know, the Android wrote a book called the 120-year diet, you know, sort of making the case that caloric restriction will be likely to allow most people to reach that sort of threshold of 120 years, which is still sort of viewed as the longest, the longest natural lifespan in people. And, you know, certainly, in his case, he didn't make it. And as far as I know, you know, there aren't any examples of people who practice long-term caloric restriction which reached even 110 years. So doesn't disprove the idea that caloric restriction could allow some people to achieve, you know, extreme healthy old age. But I don't think there's a lot of data to support that at this point.

So, you know, that probably, you know, why there is an interest in intermittent fasting with fasting-mimicking diets. But then again, the question is something that you addressed in your numerous publications is the fact that there is no control for the total amount of calories. Dr. Matt Kaeberlein, PhD. Dr. Anton Titov, MD. So, in fact, it could be, you know, intermittent fasting, a fasting-mimicking diet, could be just a rebranding of the caloric restriction. So what is known about those types of dietary modification?

Right. So again, I think it's important to kind of separate what we know in laboratory animal studies from what we think we know in humans. So in the laboratory, animal studies are pretty interesting. There have been a few studies now that have attempted to address this question, you know, and the question is, with something like intermittent fasting, where the mice maybe are fasted every other day, for example, every other day feeding is what that's called. There are studies reporting significant increases in lifespan and healthspan metrics in mice from intermittent fasting every other day feeding. If you actually look at those studies, in nearly every case where there was a significant effect on lifespan, those mice were also calorically restricted, meaning that on the day that they were fed, they did not make up for the deficit that came from the day that they fasted. So it becomes very difficult to separate. Dr. Matt Kaeberlein, PhD. Dr. Anton Titov, MD. Whether or not the beneficial effects were due to caloric restriction or due to the time-restricted nature of feeding. So it's, it's an area that is a little bit murky. Right now, there are people doing work in this area with different time-restricted feeding regimens. My take on that body of literature as a whole is that so far, the data are very suggestive that you can get a small lifespan benefit from intermittent fasting in an ISO caloric situation. But it's nowhere near the magnitude of the effect achieved by true caloric restriction. So this is my interpretation of the data. Most of the benefits that have been seen in laboratory animals are due to caloric restriction. There may be some small benefit achieved from isocaloric time-restricted feeding in laboratory animals. In people who know, right, because nobody again has ever done a carefully controlled, you know, even medium-term study of time-restricted feeding, fasting, mimicking diets, intermittent fasting, so we just don't know. Dr. Matt Kaeberlein, PhD. Dr. Anton Titov, MD. And again, my personal view on this is if time-restricted feeding or intermittent fasting helps some people to maintain normal body weight and not become obese, that's probably quite valuable. I don't think there's much reason to believe that these strategies will have a significant impact beyond the benefit that you get simply from not being obese. But I could be wrong, but that's kind of my take on, you know, what I've seen of the human data so far and the animal studies that are available.

Well, this is very interesting data, because clearly, you know, individuals in public there is almost an equation between the dieting or caloric restriction and longevity and as an as a panacea. You rightly highlight that there are risks involved in real-world connection to the, you know, immune system, various other, you know, non-controlled conditions, which for mice are very well controlled. Dr. Matt Kaeberlein, PhD. Dr. Anton Titov, MD. 

Right. Yeah. And I think, you know, this is an area that I've tried to be vocal about, I think, people, so researchers and the general public don't appreciate that. When you make a significant change in your dietary intake, you know, there are lots of biological effects that go along with that, to some extent. That's, I mean, it's obvious to say that, and I think anybody who even has a basic understanding of biology will recognize that that's true. If you restrict your calories, or if you go to eating every other day, there are biological effects associated with that intervention. What people typically don't appreciate is that there are side effects associated with that kind of intervention very similar to the way that there are side effects associated with a drug, right, something, you know, a pharmacological intervention, we're all attuned to the idea that when you take prescription medicine, there is a risk of side effects, in addition to hopefully, the effect that you're going for the targeted effect. But people don't appreciate that with diets. Dr. Matt Kaeberlein, PhD. Dr. Anton Titov, MD. And so, I think it's important to make that point. And if you think about, you know, some of the side effects associated with caloric restriction, you know, they can go to the potentially more severe adverse effects like susceptibility to an infection, which could lead to death. I think we all agree with that. Malnutrition is a potential side effect. But there are sort of, you know, more common ones that I think everybody can appreciate. Hunger is a side effect. That is not the effect you're going for when you calorically restrict. But it is an effect that is real, and most people will experience it. And it's unpleasant for most people. So that would be considered a side effect. If you took a drug that made you hungry and made your stomach hurt, that would be considered a side effect. People don't think that it that way was something like a dietary intervention. And so I'm not saying that that's a good or a bad thing, I think it's just important to recognize. I think the other piece that is equally important to recognize is that unlike a small molecule, which can have a very specific biochemical effect right, there are many molecules where we know exactly what the target is and what the biochemical effect is. And it's very specific. Those are sort of colloquially referred to as clean drugs. Dr. Matt Kaeberlein, PhD. Dr. Anton Titov, MD. 

Then there are small molecules that people call Dirty drugs because they have lots of targets in the cell. They might bind to 10 different proteins and do ten different things. So that's a dirty drug in a small molecule world. Well, any dietary intervention is far dirtier than the dirtiest drug. And again, what I mean by that is that the downstream biological changes that happen when you dramatically change your nutritional intake are immense. There are probably hundreds of proteins that are altered at gene expression or the biochemical level. So caloric restriction, intermittent fasting, time-restricted feeding are among the dirtiest drugs out there in terms of off-target effects. Dr. Matt Kaeberlein, PhD. Dr. Anton Titov, MD. And again, I'm not saying that's good or bad; I think it's just a biological reality that most people don't ever even think about.

Well, that's, I think, very important to know, because you know, as you were when I did my Ph.D. at the Rockefeller University. I worked with yeast, and when we overnight, put a less nutrition medium in the east, and we were doing one of the first gene chip experiments to look at the expression pattern changes. Dr. Matt Kaeberlein, PhD. Dr. Anton Titov, MD. Now, well, obviously, I saw some very, very significant effects across 1000s of genes, the patterns of gene expression looked completely different in just mild overnight caloric restriction of the East medium, and it was very profound. So that's exactly as you said, the dirtiest effect, compared to the clean, you know, small molecules.