Valter: Good, good, how are you?

Gordon: I’m good, I’m good. So you’re in Europe right now?

Valter: I’m in southern Europe, yeah. In the land of centenarians.

Gordon: You know, we were recently talking with Satchin Panda and, there’s-there’s all sorts of things we talked about. Caloric restriction, intermittent fasting, fasting mimicking diets. Valter could you take a brief amount of time and just define some of the terms that-that, that are floating around? Caloric restriction, um, I think most of our listeners have reasonable, knowledge of that, but what’s that compared to fasting? What’s that compared to starving and-and what’s that compared to intermittent feeding?

Valter: Yeah, so fasting is just not eating at all. In most cases, for anywhere from, you know, 12 hours to 20 days, right? And, time restricted  eating, refers instead, about the, um, the time you restrict your eating too, right? So meaning that if you start eating early on, and you end at 8:00 p.m. that’s 12 hours, right? Twelve hours of eating, and then at night to 12 hours of fasting. And, um, and so, that’s time restricted eating. And usually, the 12-hour fasting is the minimum, and then it goes all the way to say, 20 hours of fasting. So some people or even 22. Some people say to fast for 22 hours and eat for two hours, right? Then, the fasting mimicking diet is that — is something that, you know, we developed many years ago because we started the first, um, cancer trial at USC Norris Cancer Center, and we were — we thought, “Everybody’s going to do water-only fasting.” It was water-only fasting for three days: two days before chemo, one day after. And we realized, and the oncologists realized, and-and most people did not want to, do water-only fasting. It’s really tough to do. And then, we, you know, then we understood why people should do it in a specialized clinic. And then, you know, the [Unintelligible] Cancer Institute and the Institute on Aging, they had funded research, um, together with others to develop a fasting mimicking diet, right? So can you — can you let the cancer patient eat and yet — and-and achieve lots of the changes that you would normally see with water-only fasting? So we had lots of markers that we looked for like IGF-1 insulin, ketone bodies, glucose, GFPT1, et cetera so yeah.  So then that’s what a fasting mimicking diet is. Uh, now, just to-to, um, to summarize, four days for cancer patient of a fasting mimicking diet or five days for normal subjects and diabetic subjects. Then it goes to seven days for multiple sclerosis, autoimmunities. In the trials at least that’s what we were — that’s what we were, testing, right? So four, or five, or seven days based on the different compositions.

Gordon: Let’s go back a little bit into the science and just how the different diet regimes that we’ve talked about interact with what’s known from worms and, you know, other aging systems. You know, what’s the connections between, um, exposure to nutrients? The time that nutrients are taken in and the rest of the aging biology that we think we understand.

Valter: Yeah, I think it’s very, very much conserved and maybe even more conserved  than we realized, that, you know, whether you’re a bacteria or you’re a person, um, there is an alternate state, that is, um, always being triggered by starving. And-and-and not necessarily calorie restriction, right? So maybe calorie restriction was like an in between, like a coincidental thing. That some, you know, somebody 100 years ago, McCay and company ended up, you know, you couldn’t starve a mouse or a rat for-for-for years, right? So, they calorie restricted them, and I don’t know if it was voluntary or not, but, but maybe the origin of all this will always be starvation.

Gordon: Mm-hmm.

Valter:   And, and, you know, and so, what do you do if you have nothing? Well, what do you do if you have bacteria? What do you do if you’re a mouse, and what do you do if you’re a primate? And, um, yeah, so I think that clearly some of the same pathways, you know, toruses, kinase and some of the growth factors and-  lots of other genes that have to do with growth. They seem to, they seem to come up over and over in, in all these different systems. And, um, yeah, so I think that’s, um, probably a fundamental property of all organisms.

Gordon: And, you know, you’ve shown in your reviews the interconnectedness between different aging systems, but also, do you have a particular interest in fat? You seem to be publishing in that area quite a bit.

Valter: Um, not really, um, but, but I think I’m very interested in starvation responses and the fat is of course, part of the survival program under starvation response, right? So —

Gordon: Mm-hmm.

Valter: The storing of fat, and then — and then burning it, right? Then — and so, yeast of course, we  saw back in the days the ????? and the glycogen being accumulated, and then it’s moved to worms and higher eukaryotes. Then you see more of the fat storage process occurring in these — some of these mutants. So yeah, it seems to be one of the conserved behaviors right there  or, mechanisms that all these organisms entered, when they were starved or where, when they were, you know, mutated in this, um, starvation response pathways. So — and then, of course, now, you know, because 50 percent of Europeans and 72 percent of Americans are overweight and-and-and obese  it’s a very important area, um, you know,  to accompany the anti-aging effects, right? So certainly, this understanding of the fat pathways, so I mean, the idea of course, is can you deplete fat or reduce fat in — without affecting lean body mass, right? So and without affecting frailty, right? This is really something that we’ve focused on, you know? Can you get a mouse to live long with low fat and-and strong, right? And, it’s not — it’s not so easy, right?  You know, based on-on just simple dietary restrictions you’re not going to get that so — and even simple fasting cycles you’re not going to get that. So-so – yeah, so then that’s-that’s something that we’re very interested in.

Gordon: This is — this-this is fascinating to me. I mean, the-the idea of the-the cycling, um, it seems really important in all of this, um, because it-it seems like, I guess, single periods of starvation, um, in a mouse for example, how long do the beneficial effects last? And therefore, presumably that’s why you get into cycling fasting in various ways.

Valter: They last pretty long, right? So, we published a couple years ago one paper where we gave mice a high fat, high-calorie diet. Very bad. It had become big very quickly, and then just once a month for four or five days, I forgot  all the five days we give them a fasting mimicking diet, right? And, and then when we look at the fat, I think 14 days later, but also, when we look at the ketone bodies four days later after we return to the high fat diet they still keep on burning fat. Or still the-the-the fat is still in a — in a different, um, you know, more bio — mitochondrial biogenesis. More-more oxidated [unintelligible], phase, right? So it seems like, um, their entering, if anything, a  fat-catabolic, high-metabolic, mode, right? So — and they keep ge — and-and the — yeah, and then of course, we reversed the, using this, we reversed the effect of the high-fat, high-calorie diet. Um, longevity, heart, function, cholesterol, glycaemia so it’s really, remarkable. Now, we are actually testing exactly that now in a big trial in-in — here in southern Italy. That’s why I came. Five hundred people. Three groups. We already recruited 200 so one group, does nothing, and this is southern Italy. This is like one of the worst areas for obesity and diseases in all of Europe. And, um, so, yeah, 167 who are-are regular diet. A hundred and sixty seven do a fasting mimicking diet once every three months. And a hundred and sixty-seven, they do — go to a fasting mimicking diet and a longevity diet which is this diet that I, um, that I came up with to-to, um, sort of put together everything we’ve ever learned from-from lot of different labs.

Gordon: Can-can you give me a summary of the outcomes for either different diseases or, you know, functional aging? Um, just, um, yeah, really, just a summary of what you’ve seen so far.

Valter: Yeah, so I think it’s pretty clear with the normal subjects or the relatively normal subjects that we get, um, if they’re not taking drugs they would get a reduction in blood pressure. We don’t seem to be getting a reduction in blood pressure in people that are mildly hypertensive or taking drugs. Uh, hypertension drugs. We instead clearly see a reduction of A1C, and this is over and over in a number of clinical trial-trials. Uh, A1C in the normal, um, but particularly in the, um, in the ones that are pre-diabetic. And now, clearly, the diabetic, right? So now, there’s a new trial from [Ladien] that is about to come out and-and-and several others  so that’s pretty clear. So I would say that now we have hundreds of people for diabetes and pre-diabetes, and I would be shocked if those were not. I don’t want to use conclusive, certainly, let’s say it’s pretty close to conclusive. Uh, cancer… it’s going to take a while because I think that there’s a lot of cancers, a lot of therapies, a lot of modalities, right? So-so yeah, unfortunately, it’s just very tough to say anything about cancer. Certainly, it worked well with the first you know, during the mice trials with clinical response and pathological response. Um, but then overall survival — I mean, a five-year survival we’re not really seeing, much of an effect. And I don’t know, I mean, of course, we — these were early-stage patients that, um, that, um, received surgery so — you know, we don’t necessarily expect a big effect of survival. You know, you just give them chemo with or without the FMD early on before surgeries, and then you’re waiting five years. Some of them didn’t — many of them did not, um, comply to the diet, right? So I would just that, we’re very, I mean, in mice it just works extremely well in-in our lab and many, in many labs. And no matter what the cancer, no matter what the treatment which is really hard to believe almost, but in people, I don’t know, we’ll just, just have to wait and see, right?  So the cancer is going to take a while to, it looks very promising, but it’s going to take a while we’re just going to have to wait and see. There’s, you know, inflammatory bowel disease and Alzheimer. We’re about to finish one and multiple sclerosis but yeah, those are early and-and, I mean, yeah, the first trial was fairly positive in a single-cycle fasting mimicking diet, but now, there is, one they just finished in Genoa and another one starting in Los Angeles so yeah, so I would say that-that, that we’re still early-on, um, with, with those. But I think in general, it’s just c-clearly going after the aging, risk factors, and markers, and – it’s over, and over, and over. It was IGF1, or a C-Reactive protein, or blood pressure. And it doesn’t, differently from calorie restriction. If you look at the calorie restriction data a lot of the times you may have a — somebody starting with say, glycaemia of 85, and they end up with 70, right? You don’t see this with the FMD. It’s already 85. It’s probably going to stay at 85. If they’re 103 they’re probably going to go down to 85, but not all the time, but I’d say, a pretty close system, right? We see this at least as an average. It’s an average we keep seeing this in. So it just seems to be more going after the fundamental aging, changes and just bringing them back to a more youthful state.

Gordon:  Super exciting.  

MUSIC BREAK

Gordon: Let me ask you about, um, your own sort of personal career progression. And it — and it’s really like you’re almost like the poster child, Valter, for someone who has applied the basic science to real human clinical research and interventions in-in-in humans both in cancer and in aging as well. So, was there any point where you said, “That’s it, I’m doing this”? You know, “I — we’re going into humans.” Um, or, you know, “Why not just go back to the lab, and do the most work, and do the yeast work, and be happy publishing, you know, great papers?” Was there something driving that transition?

Valter: I actually started, right, with Walford, taking his own blood and locking himself up in Biosphere 2 for two years. So I  started with the wrong guy, right, for that. but I also started very much with a medical-oriented, you know, attitude so I always felt that eventually maybe I’ll go to medical school, and I’ll do a PhD MD.  But I never did that because of course, I liked it too much when I was doing science, but yeah, I think that I started with mice and humans. And then, the humans, I mean, I like — I love science, but I, um, I really always liked this applied idea. I mean, I wanted to solve a big problem, right? I didn’t want to solve a yeast problem. I want to solve a  yeast problem to solve a human problem, right?

 Gordon: So o-our listeners are probably wondering how they can tap into all of this. Uh, di — you-you-you’ve written a book. I mean, what-what are the resources that are available to people to make a go of this?

Valter: Yeah, so the — “The Longevity Diet” book is really, um, lots of, you know, 30 years of-of my work, and lots of peoples’ work in the field. And, um, and all the way to the clinical application, and the epidemiological studies, and, yeah, so focus on aging and longevity. And applying this to lots of different diseases, prevention and treatment. It talks about both the everyday diet, and the fasting mimicking diet, and how they’re used in combination of one or the other to, um, attempt to-to help you, delay aging and-and-and protect against, age-related diseases. Um, then the — there’s a new book coming out that is focused on all of this. The longevity everyday diet as well  as the fasting mimicking diet and cancer. And, it talks about 10 clinical trials, and of course, these are best implemented if you contact the Create Cures Foundation clinic, um, and that’s, createcures.org.

Gordon: You know, as you look around now at the field, um, it’s really moved so far from where we started. What do you think is the most exciting thing right now in aging biology?

Valter:  Um, I mean, I-I really like the-the, epigenetic reprogramming. You know, Belmonte, and David Sinclair, and others, and  uh, yeah, so I think that’s-that’s really exciting. Un, and of course, we didn’t talk about it, but, you know, the fasting mimicking diet, one of the things that does in the — in the shrinking starvation process is it turns on Yamanaka factor, right? So — we’re very interested in, our cells  in, um, you know, tapping into that and-and is it, can-can this starvation refeeding cycle, um, activate some of this, um, reprogramming? Epigenetic reprogramming mechanisms. And, yeah, so I-I-I really like that, but of course, there’s lots of different ideas and, um, and so, I think that, that’s good, you know? And we’ll see what-what happens in the next 10 years. It’s  a very exciting moment to-to think different, yeah.

Gordon : Yeah, no, I have to agree with you, Valter. This is really exciting. We actually had David Sinclair on the — on the podcast, recently. And, you know, his amazing work as you point out on-on-on sort of reprogramming and-and, recovery of function. And just to hear the-the-the work that went into that. Uh, you know, post-doc slaving away trying different factors in different ways has been fascinating. Um, so it’s-it’s fantastic that you’re now connecting with that entire area, in this relationship between diet and reprogramming.

Valter: Yes, so we-we actually started a while ago, and, um, I think the first paper was, 10 years ago where we look at the blood system, and we were using chemotherapy, and fasting, and fasting mimicking diet. And we saw the [unintelligible] stem cell being turned on and-and-and having a clear advantage if the mice were fasting and, you know, generating — and self-renewing so stem cells making more stem cells. And then, eventually, w-we started to see what looked like reprogramming in the pancreas and, in another paper, this was 2016 – I believe, and-and we saw that we could damage the pancreas. The pancreas stopped making insulin, and then we would start fasting mimicking diet refeeding cycle, and we would see the-the, um, the pancreatic cells be reprogrammed into making insulin again even though they were, you know, terminally damaged, right? So then, um, then we started looking at the genes, and some of these genes were in fact, the Yamanaka factor, right? So — and it would be turned on, temporarily, and then for maybe one or two days, and then — and then come down. And then, we went on to show this in the gut. Um, now, we’re about to publish about the-the kidney. Uh, we’ve shown some of the same effects in the nervous system. Yeah, so we’ve published actually many papers on this, um, on this FMD fasting-dependent, turning on of-of these, what seems to be, you know, epigenetic reprogramming or certainly, cellular reprogramming leading to, a rejuvenated, more functional state, yeah.

Gordon: This nexus between aging interventions which slow down aging process is — but also, stimulate regeneration is absolutely amazing. It’s absolutely — I don’t think we would have predicted this a few years ago.

Valter: No, probably not. [Laughs]

Gordon: [Laughs] One final question is, um, what did you have for breakfast this morning?

Valter: Breakfast? I mean, I miss southern Italy. I normally have tea and this almond spread. And then, a Frisella. That’s my all-year-round. Now, here, I don’t have it because I’m not at home, so I have this, basically, milk and-and, and a Frisella, which is this whole grain, bread from southern Italy. And-and I-I, highly recommend it.

Gordon: Fantastic. Thank you again, Valter for your time. It’s been, really, delightful to talk to you.

Valter: Thanks, Gordon, great to talk to you.

SHOW OUTRO

Thank you so much for listening. Please subscribe, share and give us a five star review on Apple, Spotify or wherever you get your podcasts. We’re Not Getting Any Younger, Yet! is produced by Vital Mind Media: the Buck Institute’s very own Robin Snyder as the executive producer, Wellington Bowler is right next to me here directing the recordings, Stella B is behind the scenes ready to debrief when we wrap, and the esteemed Sharif Ezzat weaves the show together for you. 

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