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. Dr. Matt Kaeberlein, PhD. Dr. Anton Titov, MD. 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. 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. Dr. Matt Kaeberlein, PhD. Dr. Anton Titov, MD. 

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. Dr. Matt Kaeberlein, PhD. Dr. Anton Titov, MD. 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. Dr. Matt Kaeberlein, PhD. Dr. Anton Titov, MD. But I don't think there's a lot of data to support that at this point.