The Tim Ferriss Show - #188: Dom D'Agostino on Disease Prevention, Cancer, and Living Longer

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Starting point is 00:03:28 He is an associate professor in the Department of Molecular Pharmacology and Physiology at the University of South Florida Morsani College of Medicine and a senior research scientist at the Institute for Human and Machine Cognition, IHMC, which also has a great treatment in the current issue of Outside Magazine, on which there's a clown who looks a lot like me. He has also deadlifted 500 pounds for 10 reps after a seven-day fast. He's a beast. Also a good friend of Dr. Peter Attia, who's also been on this podcast. The primary focus of Dom's laboratory is developing and testing metabolic therapies, including ketogenic diets, ketone esters, and ketone supplements to induce nutritional or therapeutic ketosis and low toxicity metabolic based drugs. That's a mouthful, hey?

Starting point is 00:04:14 Much of his work is related to metabolic therapies and nutritional strategies for peak performance and resilience in extreme environments. This is where I get very interested. I recently went up to altitude and used exogenous, not androgynous, exogenous ketones to help me acclimate and function at high altitude. But it also works in the opposite direction, underwater, for instance, both related to hypoxia. His research is therefore supported by, among others, the Office of Naval Research, the Department of Defense, and other private organizations and foundations. In this part three, Dom has been on twice before, Dom focuses on disease prevention, cancer, and more mastery of the ketogenic diet.

Starting point is 00:04:56 So as I always say, without further ado, please enjoy this tutorial and masterclass with Dominic D'Agostino. Okay, I covered the ketogenic diet and I covered questions about exogenous ketones, and that took about two hours. So now I'm going into cancer research questions, or just questions in general about cancer. So the first one I'd like to address, I've gotten many emails about this. I've seen a few questions on Facebook. Does the ketogenic diet be chemo for all cancers? And I would say absolutely not. But that does not mean that it should not be used as an adjuvant or a support for various cancer therapies that are out there. A number of situations where the ketogenic

Starting point is 00:05:46 diet may not be the preferred therapy for most cancers, I would say leukemia, lymphomas, Hodgkin's lymphoma, thyroid cancer, testicular cancer, if caught early, prostate cancer, melanoma, breast cancer, all these cancers can be effectively treated with chemotherapy or radiation in some cases. And also brain tumors. If it's class 1 or 2 tumor that's not our grade 1 and 2, it's not very metastatic and it's more localized, then surgery, radiation, chemo can be very effective. We focus on cancers that are not really treated effectively with the standard of care. Brain tumors, grade four would be a glioblastoma cancer. It's highly invasive, highly aggressive, sort of has a metabolic phenotype, we say, that expresses the Warburg effect. So it's very glycolytic.

Starting point is 00:06:53 So the name glioblastoma multiforme, it's comprised of a very diverse heterogeneous array of cells that are resistant to therapy. And it's genetically very heterogeneous. Metabolically, probably much more homogenous in regards to being able to target it from a metabolic standpoint. So we focus on this aggressive metastatic cancer and brain tumors in our lab. And we think the standard of care, we know that it does very little. We do feel that the ketogenic diet, when properly administered, can dramatically enhance the efficacy of standard of care. So even though the standard of care may not buy much time for a patient with glioblastoma, we think that we could dramatically enhance the efficacy and maybe reduce the side effects of standard of care with the ketogenic diet or

Starting point is 00:07:58 maybe combined with intermittent fasting. I would recommend looking at the work of Dr. Adrienne Scheck, and she's at Barrow Neurological Institute. And she's done some studies with a preclinical mouse model of glioblastoma. And that work has inspired a clinical trial that's now recruiting patients to use the ketogenic diet combined with standard care, which would be temozolomide and radiation. And her work is really remarkable in that it shows the ketogenic diet dramatically enhances the efficacy of radiation therapy. And it does that through a number of different mechanisms that

Starting point is 00:08:46 she's looking at. I think most importantly to highlight, if we kind of look at the sum of all her work, which is an incredible body of work that she's done. She was working on this long before I came into the field. I was directed to her by Dr. Jung Ro, who's probably the leading ketogenic diet researcher, chair of pediatrics in Calgary now. He was at Barrow Neurological Institute, and I contacted him, and he directed me to Adrienne Sheck's work, and it really blew me away. She shows the effect of the diet can be dramatically enhanced with radiation. So I was kind of pretty critical of radiation therapy for cancer, especially for glioblastoma, for various reasons. But when looking at Adrian's work and just hearing from feedback from patients,

Starting point is 00:09:44 my thoughts on radiation therapy have softened a bit. And in the context of radiation therapy given with ketogenic diet, it appears that nutritional ketosis enhances the tumor killing effect of radiation. And it does that through a number of different mechanisms, probably crippling or reducing glycolytic flux through the tumors, which would impact their antioxidant and dodges antioxidant status by reducing things like the pentose phosphate pathway, which helps the cell regenerate glutathione. And we know that the efficacy of the radiation therapy really results from generating oxygen-free radicals in the tumor tissue. And tumor cells are already at an elevated state of oxidative stress. So further stimulating

Starting point is 00:10:45 reactive oxygen species production with the damaging effects of radiation can put them over the edge and be very destructive. So the ketogenic diet seems to enhance that process. And simultaneously, the ketones tend to lower inflammation in the normal healthy tissue and protect your normal healthy brain tissue. We think that there's a lot of potential for the ketogenic diet as an adjuvant. For all our studies, we've always used the ketogenic diet as one piece of a combined metabolic therapy approach. So the ketogenic diet is an adjuvant to hyperbaric oxygen that we've used. And now we're looking at ketone supplementation and combining that with hyperbaric oxygen. So the ketone supplements tend to further augment the therapeutic efficacy of the ketogenic diet by lowering blood glucose and elevating blood

Starting point is 00:11:46 ketone levels. That therapeutic zone that Tom Seyfried calls the metabolic zone. The glucose ketone index is simply the ketones, the glucose by the ketones. An index of, let me see, one or two, really an index of one is what you want to shoot for. And when you achieve an index of one, you essentially get a blood glucose level and blood ketone level that are essentially the same. So like 3.5 millimolar. A level of glucose and ketones that a person could sustain and would be sort of physiologically optimized. He has a paper on that, Nutrition and Metabolism, describing the glucose-ketone index, and that has been thought to be sort of the optimal therapeutic zone for a patient using

Starting point is 00:12:41 the ketogenic diet to manage their cancer or combining it with a standard of care. So it makes sense to use a metabolic-based approach on tumors that have a Warburg phenotype, so tumors that are highly glycolytic, which include about 80 to 90 percent of cancers. And the cancers that tend not to be the ones that are more glycolytic are also the ones that you don't have to worry so much about. These are ones, cancer cells, that generally are not very invasive or aggressive in regards to growth. The ones that are not glycolytic, so cancer cells, for example, that wouldn't show up on a PET scan. And that would be like prostate cancer, for example. Yeah, the ketogenic diet does not beat chemo.

Starting point is 00:13:30 We know that chemo can be effective for a number of different cancers, and if caught early, sort of a growing list of different types of cancers. Ramsey Metcalf asked the question, after listening to his chat on Dr. Rhonda Patrick's show, I want to know more about the detoxifying effects of ketosis on pre-cancer cells and on healthy individuals. And how does one jumpstart daily ketogenic cycle without supplements? And how can you maintain lean muscle mass when fasting? So a number of questions there. As I mentioned, I'll kind of talk about, refer back to the metabolic zone, achieving the metabolic zone, a glucose ketone index of one or two. So Google the glucose ketone index and download that paper in Nutrition Metabolism.

Starting point is 00:14:26 It's open access and kind of gives you a description of where you have to be when you do fasting or the ketogenic diet. That could be very therapeutic in regards to cancer prevention, really effective at targeting sort of precancerous cells and maybe even jumpstarting your immune system, making your immune system use exogenous ketones. Oh, okay, without supplements, you ask. Jump-starting can be done with exercise. I wouldn't recommend vigorous exercise. I would recommend a walk, a two, three-hour walk, for example. You might want to preface that with a short high intensity, 10-15 minutes as something to just kind of activate your sympathetic nervous system, but not too much. Do some push-ups, chin-ups, a little bit of a few sprints. I believe that when you activate your sympathetic nervous system, mobilize a lot of free fatty acids for fuel and set your body up for a more effective fat burning and more effective transition into ketosis when you do kind of a a low a low impact walk done a lot of testing on myself of glucose and ketone levels

Starting point is 00:16:00 in different scenarios and that seems to work really well. I did that yesterday, actually. So fasting can stimulate autophagy and perhaps, you know, make the immune system sort of more hypervigilant against cancer and precancer cells I mentioned. But you need to acknowledge that if you fast too long or you calorie restrict too long, that can suppress your immune system. Let me see, lean body mass. So there's a couple ways to get around the loss of lean body mass that's going to happen. You have to realize that you're losing a lot of water when you do a fast. So your weight may go down, but a lot of it's going to be water weight. You could probably

Starting point is 00:16:45 mitigate some of the muscle loss with branched chain amino acids. And I would buy just a pure branched chain amino acid product that's just branched chain amino acids and nothing else. Consume that sort of, if you're going to continue doing any form of exercise, I wouldn't recommend doing high-intensity exercise if you're fasting. But if you do do any exercise, take your branched-chain amino acids before and maybe during. It's important. I always emphasize this when people talk about wasting away when you fast. And George Cahill's work at Harvard shows that the physiological shift that occurs when you fast. And George Cahill's work at Harvard shows that the physiological shift that occurs when you're fasting, when you enter a state of fasting ketosis, functions to have a really profound protein sparing effect. So your brain is a highly

Starting point is 00:17:40 metabolic organ and it's a big glucose sink and when you elevate ketones that prevents a lot of the gluconeogenic amino acids from being broken down the skeletal muscle so it's very protein sparing in that regard so otherwise right if we fasted we would rapidly waste away probably within you know less two weeks. But there's reports of people fasting. There's a guy that's 500 pounds that fasted for over a year. And there was no major ill effects reported from that. And you fasted down to 190 pounds. Some of the helpful supplements that I think utilized during a fast would be, like I mentioned, branched-chain amino acids. My good friend Lane Norton did his PhD on leucine.

Starting point is 00:18:33 And he did it in the lab with Donald Lehman. So if you're interested in kind of understanding anabolic or anti-catabolic effects of branched-chain amino acids. Go on the PubMed and look up Lee Norton's studies on leucine. I've experimented with a few things. I think serotonin precursor 5-HTP can be beneficial. If we're taking in branched-chain amino acids, we're actually limiting the transport of tryptophan across the blood-brain barrier because it competes. I tend to get the munchies at night. So my appetite gets really high at nighttime when I was fasting. And I fasted too with branched-chain amino acids, but I think a supplement like 5-HTP at night may be able to reduce some of the hunger

Starting point is 00:19:29 cravings and also help put you to sleep. So if I'm hungry, I found it kind of hard to sleep after a while, but my body adapted to it. So that product, ketones, MCT oil and MCT oil powder may be helpful, but not absolutely necessary. There's a book out there called The Fasting Cure by Upton Sinclair. And you just Google The Fasting Cure and Sinclair, you'll find it. And it's a free PDF to download. And it's a fascinating little book that just talks about the benefits of fasting so next question is Lowell Kubik and he asked in addition to an update on ketosis effects on cancer is there any updates with ketosis affecting chemotherapy recovery what types of cancers does ketosis have the largest impact on? So I kind of answered that already. Managing brain tumors and metastatic cancer, I would say, would be at the

Starting point is 00:20:32 top of the list. And as I mentioned, as an adjuvant to chemo and radiation, see Adrienne Sheck's work at Baroneurological Institute, her preclinical work, and also an ongoing clinical trial. And I would also encourage anyone, you know, who's really passionate about seeing this transition into the patient population, if, you know, if they're interested, they could support Adrian Scheck's work at Barrow. It's difficult to get funding for these types of studies. And I know sort of the project was stopped and started because of funding. And I don't think it's a lot of money either. So if you look up Adrienne Scheck's work, and maybe she may have some kind of donation link there.

Starting point is 00:21:21 I'm not sure she does, but it would be great for people listening to support her work in that clinical trial because there's sort of a lot riding on that trial. The research is being conducted in a way that really fits the criteria we think is important. So we're being assured that the patients are actually in ketosis and they're monitored and recorded in ways that will help really get questions answered. The clinical trial is in progress right now, so they're continuing to recruit more patients. for targeting cancer, this Warburg phenotype, and that would be like 80 to 90% of cancers, will have an increase in, will demonstrate high intensity on fluorodeoxyglucose PET scan. And these are the cancer cells that are more glycolytic are also the ones that are going to be more invasive and more deadly. And they're the ones that are growing more rapidly.

Starting point is 00:22:33 So as they're consuming more glucose, that glucose is shuttled to not only energy, but also the biomass of the tumor. So when you're imaging the cancer cells lighting up, that's really, they're shuttling all that glucose to increase the biomass of the tumor. So when you're imaging the cancer cells lighting up, that's really, they're shuttling all that glucose to increase the biomass of the tumor. And when you look at like a cancer or prostate cancer where it's not lighting up, it's growing so slow that it's not really, its glucose demands are not that high. So in many cases, it's probably just better left alone. You know, when people are diagnosed with having a tumor, they kind of think about it as like this alien that needs to be chopped out of the body and with slash and burn techniques. But there's many autopsies. I was reading a number of books and papers on this. There's many autopsies have been done on people that die from completely unrelated causes that are full of tumors that had, you know, that have tumors and absolutely no problems at all.

Starting point is 00:23:35 So they may have lived, you know, many years, if not decades with with tumors and had no problems at all so if you're diagnosed and you know that's why um it's just watching and waiting is an important thing so thus we can live you know with cancer many types of of tumors with with no problem dr fine and dr feinman i believe did And Dr. Feynman, I believe, did some work in vitro on multiple different cancer types with ketones and showed that the gist of their work was that a large majority of cancer cells cannot effectively use ketones for energy. So that goes across multiple different cancer cell lines. And I know Dr. Brent Reynolds, he's doing work at University of Florida. He gains, Bill, he's done work, preclinical work on colon cancer, breast cancer, and glioblastoma. And some of the glioblastoma cells were taken from patients. He uses a patient-derived xenograft model. I think most importantly, it's like the evidence points to this being the ketogenic diet is doing no harm, right?

Starting point is 00:24:56 Do no harm therapy. So we know through at least two or three, two pilot trials that the ketogenic diet is well tolerated. We know from the epilepsy community that the ketogenic diet, you know, very well tolerated. I think it was Melanie Schmidt that did work on, the title of the paper was the effects of the ketogenic diet on the quality of life of 16 patients with advanced cancer, a pilot trial. So of those that completed the diet for three months of treatment, there were patients with ovarian, breast, sarcoma, osteosarcoma, esophageal cancer, pancreatic cancer, thyroid, colon, endometrial, lung, and stomach cancers. So a variety of different cancers.

Starting point is 00:25:50 There was an improved quality of life, and there was no sort of major adverse effects on various blood parameters. And the side effects reported were really minimal. So they were kind of like temporary constipation and fatigue. There's a lot of good evidence already that the ketogenic diet can work on a variety of different cancers. We need more studies. Some of those studies are in progress. So I'm going to transition now to random questions here. So Scott Shearer asks, I know Scott. Hey, Scott. Talk about ketosis and hyperbaric oxygen therapy.

Starting point is 00:26:34 How, why, and when? So it's a good question. And I think it's going to vary depending upon the individual. And I think generally younger patients can tolerate more hyperbaric oxygen and get benefits from it. hyper oxygenating the area that you're trying to treat, right? Whether that be an ischemic wound, you're trying to reverse tumor hypoxia and saturate a tumor with oxygen to stimulate oxidative stress, right? And apoptosis in the, in the wound, in the, in the cancer, which is much like a wound actually. So you have that effect. If someone has a brain tumor, they're going to be more susceptible to CNS oxygen toxicity. So you want to start them really lower, like 1.5 atmospheres of oxygen and do that for 45 to 60 minutes and then work up from there.

Starting point is 00:27:50 So the protocol that we used in our preclinical model was 2.5 atmospheres of oxygen three times a week. And that varies from what's used for wound healing, which is kind of Monday, Wednesday, Friday, or no, Monday through Friday, five times a week, like two atmospheres of oxygen. So it really depends on kind of who you're treating, what you're treating. And the approved therapies for hyperbaric oxygen, there's like 14 different FDA approved, and you have air and gas embolism, bone infections, osteomyelitis, burns, carbon monoxide poisoning. So you want to use the maximum concentration of oxygen to push that carbon monoxide off of the hemoglobin molecule. And it's also occupying cytochrome 4, the electron transport changes, causing tissue hypoxia. So you want the maximum amount of oxygen for that or tolerable. Certain types of brain or sinus infections, decompression sickness.

Starting point is 00:29:11 So this is sort of gas gangrene is another that's an anaerobic bacteria. So hyperoxygenating it can help to kill it. Necrotizing soft tissue infections, radiation injury. For example, damage from radiation therapy for cancer can be effectively treated with hyperbaric oxygen therapy, skin grafts, and wounds that have not healed with other treatments. For example, treating a foot ulcer or someone with diabetes or very bad circulation. healing process is enhanced by increasing tissue perfusion and or increasing the oxygen content you know within the actual tissue lowering reactive oxygen species so which is kind of a secondary effect and lowering inflammation so when it comes to cancer so that would be an off-label use a non-fda approved use of hyperbaric oxygen if you're not getting radiation therapy and i would ask you just look at some of the research that my colleague research associate dr angela Poff was first author on a number of manuscripts. If

Starting point is 00:30:26 you just Google ketogenic diet and hyperbaric oxygen. So we have a number of manuscripts that are open access and that are downloadable that describes the use of this approach, the combination of nutritional ketosis with a diet or supplemented ketogenic diet with hyperbaric oxygen. We think that this combination is not only effective, but nutritional ketosis will enhance the safety and the efficacy of hyperbaric oxygen by preventing the potential of CNS oxygen toxicity seizures. So the limitation of a Navy SEAL diver is CNS oxygen toxicity. The limitation of the therapeutic potential of hyperbaric oxygen therapy is the limitation of the dose to avoid CNS oxygen toxicity. So we can more safely use a higher dose of hyperbaric oxygen therapy and sort of blast the tumor with high levels of oxygen and oxidative stress. We could

Starting point is 00:31:36 do that more safely in the context of getting the patient into nutritional ketosis. And we think that nutritional ketosis will cripple the antioxidant defenses of the highly glycolytic tumor cells that rely pretty heavily on the pentose phosphate pathway or shunt to generate the reduced intermediates and to actually generate the glutathione, reduced glutathione in the cell. So that sort of process is limited or crippled when a patient is achieving that metabolic zone. And so the hyperbaric oxygen therapy would work much more effectively. Next question, Justin Bowman. How long would an amateur endurance athlete need

Starting point is 00:32:28 to be in ketosis to get the full benefit of being fat adapted for a marathon? And what would you recommend as a supplement stack to fuel a marathon, for example, MCT powder combined with MAP, essential amino acids, sodium, and some form of electrolyte every hour? So question mark. Good question. And it's one that I get often. So I included it in here. Ben Greenfield has spoken pretty extensively on intra-race supplementation. Any ketone supplement that you use during a race, you want to make sure that you've tested that pretty thoroughly before you actually use it. You know, you've tested it through your training extensively and titrated it up you can tolerate before you start using it for intra-race supplementation.

Starting point is 00:33:30 We've done some experiments in the lab, and I've done experiments myself. And the pure caprylic triglyceride, or the C8, may be the best alternative to medium chain triglycerides, which is a combination of the C8 and C10. So the longer, so that would be helpful supplementation. Branched-chain amino acids, I think, are really helpful. Other than that, I think, you know, as your preparation is really what's going to be most important is that you're adapted to burning those fuels. And the longer you're on a ketogenic diet or keto adapted, the more benefits you're going to derive from it and the easier it gets too. So this may take

Starting point is 00:34:17 months or even years to get fully optimized to the ketogenic diet. So when you switch fuel sources, your body's physiology doesn't automatically switch over. So there's a lot of complicated things happening from an upregulation of the transporters, various enzyme systems, liver metabolism, gene expression, for these to be fully manifested, it's going to take some time. It's going to take a significant amount of time to be fully optimal. And from the really advanced athletes that have communicated with me, they said it took about a half a year for them to sort of get their stride on a ketogenic diet. So I would say just keep that in mind.

Starting point is 00:35:09 Johnny Valimer asks, this is a question I get often, should an APOE4 carrier be careful with a ketogenic diet? It's a great question. So interestingly, the study that was done by Sam Henderson, which looked at the effects of an MCT oil-based product, at the time it was called AC-1202, with mild cognitive impairment and found that the patient population that was ApoE4 positive did not respond as favorably at least to medium-chain triglyceride supplementation in regards to enhancement of cognitive performance. And they had a mild, very modest boost in beta hydroxybutyrate i would direct your listeners tim to the ihmc stem talk and it was episode 12 with uh dr dale

Starting point is 00:36:16 bredison and discusses this topic fairly at length um and you know covers a lot of things that I was interested in as far as what signaling effects ApoE4 is manifested in the brain and how we can target that actionable things that we can do as individuals to mitigate some of the effects of being ApoE4 positive. And we know that ApoE4 seems to play, seems to influence NF-kappa B signaling. So the issue is that ApoE4 enhances the pro-inflammatory effects of NF-kappa B and tends to reduce the activation of SIRT1. So if we think about what the ketogenic diet does, and you can apply this to calorie restriction and intermittent fasting, to the metabolic and signaling effects of nutritional ketosis would be favorable to those with APOE4. I think I would emphasize

Starting point is 00:37:27 that not just an MCT-based supplement, which was done, the Henderson study using AC1202, which was published years back, but actual carbohydrate restriction associated with nutritional ketosis. You know, inflammation is really the driver here from how I understand it. You know, nutritional ketosis, intermittent fasting, all these things activate pathways that are down-regulated by having this beneficial pathways that are down-regulated by having this genotype. And it also doesn't silence, but it attenuates a lot of the pro-inflammatory pathways that are associated with being ApoE4 positive. So, you know, having this ApoE4 gene, these carriers would have a survival advantage in several different situations. So the negative effects of being an ApoE4 carrier really happen later in life. So as we age, it'll be more important to follow

Starting point is 00:38:47 nutritional ketosis and perhaps an intermittent fasting protocol. You know, exercise. We know exercise increases BDNF. Intermittent fasting, intermittent dietary restriction. So even if you're not fasting, you know, do calorie restriction. Strength training. So strength training is going to build the lean body mass that functions in glucose disposal. So other supplements that may help individuals that are ApoE4 would be berberine and maybe metformin too. I think we need to study that. I don't know if there's any, it seemed like an obvious thing to do kind of a study on those that are ApoE4 positive

Starting point is 00:39:31 and the effects of metformin. So I know there's quite a few individuals out there. I'll look on clinicaltrials.gov to see if that's. Matthew Maverich has a question regarding cheat meals any downside to kicking out of ketosis for an occasional cheat meal or does one need long-term sustained ketosis to get the benefits i found that i can get back relatively fast especially especially if I run the next day. That's what he said. So, so there's no downside unless you are using it to manage a disease process, right? So Andrew Scarborough talked about having a brain tumor. I listened to his podcast yesterday. So I would definitely recommend your readers look up the podcast. I think it's on Quantified Body by Andrew Scarborough, who has like a grade three brain tumor, and he's using the ketogenic diet and an interesting

Starting point is 00:40:36 sort of list of supplements and foods to manage his brain tumor above and beyond what he said was even possible. And he happens to have seizures too. So this seizure would be an indication that he's not following, you know, is kind of getting out of that metabolic zone that is sort of optimal for the management of the cancer. So he called it like a blessing that the epilepsy was sort of helped him with cancer management because when he got a seizure he it sort of was an indication or an aura before having a seizure sort of like a pre-seizure event and that he had a protocol that he could quickly administer things like magnesium chloride and or you know exogenous ketones to quickly get them back into a state of ketosis to i don't know if you're an athlete or kind of managing some kind of

Starting point is 00:41:35 pathology but occasional cheat meal for performance i think is totally fine the the problem that i run into if i do a cheat meal, uh, I don't like that. I just call it like a refeed and I like eating a ketogenic diet. So I tend not to cheat that much. Uh, what I'll do is sometimes just eat more of the same foods. Uh, but occasionally I'll go out for sushi and have rice and, and some other things. And what I noticed when I do that is that I get hungry at night. So I will wake up, instead of waking up my normal time, I'll wake up an hour or two or three earlier

Starting point is 00:42:12 and just be really hungry. Because the carbs that I ate the night before, if I cheat, it's usually in the evening, get what is likely an insulin dump that makes me hypoglycemic in the middle of the night. And, you know, if I don't have the ketones there, if the insulin shuts off my own ketone production, that my body senses that hypoglycemia and I feel I wake up with the shakes and I feel get that hypoglycemic effect at night. And that happens. You know, that that's what I notice. So my suggestion would be if you're going to do a cheat meal and you want to, if you're doing nutritional ketosis, do a slow carb approach and add sufficient amounts of fats.

Starting point is 00:43:02 And I think you'll get a better response. I don't know why, you know, if you do a cheat meal, I guess you're just trying to restore your glycogen levels or kind of reset your system. I think you'll get a better restoration of liver and muscle glycogen and you'll get probably a better hormonal response in terms of restoring some of the hormones that you think may be suppressed. So T4 to T3 conversions or that sort of thing. If you sort of balance the meal out and just don't go crazy eating, you know, keep in mind that a cheat meal can do an incredible amount of

Starting point is 00:43:37 quote unquote damage in regards to fat gain. So it should be a calculated sort of meal and you should cap it off and do some, you know, you might not need to bring a scale with you, but just figure out, you know, how many calories you're going to eat. I'm not going to go over like 400 grams of carbs or something like that because I've seen people eat a thousand grams of carbs in one sitting and that's no lie so uh so if you tend to go out of control uh and eat a big bowl of and just you know eat a huge bowl of fries or just go out of control with chocolate cake or something like that one strategy that i've done is um if i'm going to go out and have sushi for example or have some kind of meal that's carbohydrates, I'll have a big bowl of soup before. And that will sort of send a signal to my brain. Your brain's pretty good

Starting point is 00:44:34 at sensing the amount of volume and weight of food that's in your stomach. So if you send that signal to your brain before you actually start eating the food. That'll kind of cap off the amount of calories that you'll comfortably be able to eat. So the next question comes from Blue Light Diet. So I assume it's the author of this book or website or whatever. And in caps, he says, explain this donna i guess you know ketogenic diets have no metabolic advantage uh as shown from the nusi study so i i've gotten a lot of emails about this and you know i don't know i know nusi is doing a lot of really great funding a lot of great

Starting point is 00:45:21 research and i know one of the studies may have surfaced, at least in an abstract form at a conference in the form of a poster. So from my understanding, there's really nothing to explain. If calories are completely isocaloric between the diets, sure, that makes sense to me, at least, that there's not going to be sort of a metabolic advantage. You know, when I think of the ketogenic diet and when one sustains nutritional ketosis for some time, it's actually enhancing metabolic efficiency. There's some theories out there that if you follow a ketogenic diet, it will increase brown fat accumulation, which could allow one to burn off more calories. If you want to lose weight on a ketogenic diet, you simply have to calorie restrict. That's sort of thermodynamics, right?

Starting point is 00:46:19 Just like a standard diet. So the advantage of, and I hope this comes out of the research, I'm sure it will. The advantage from my perspective of a ketogenic diet is that your appetite is suppressed. So you naturally eat less. So if you're, you don't have these big postprandial blood glucose excursions and trigger a hypoglycemic response, it's not going to trigger cravings. So I've seen it in myself, and I think that's the main advantage of the diet. You know, if you want to hear like a counter argument to what was sort of presented as no metabolic advantage from the ketogenic diet. If you want to hear a counter argument to this, there's a 10 minute YouTube video that you can read

Starting point is 00:47:14 from Dr. David Ludwig or Dr. Feynman's response to that. So there's more data to emerge but we need to we'll leave it you know at that for now and until more of the studies start to surface so Hamilton our Blair writes Dom in a podcast with Rhonda Patrick you alluded to the fact that dairy doesn't do well for you and that you have a mild allergy to nuts. What is your primary sources of fat for a modified ketogenic diet? MCTs, coconut cream, milk, oil, butter. So my primary fat sources are eggs. And I'm kind of picky about the eggs that I get. I try to source out you know local eggs kind of

Starting point is 00:48:06 from free-range chickens avocados olive oil yes MCT oil probably about a third of my calories come from fat calories come from MCT oil or coconut oil with combinations too. Fatty meats and fatty fish for sure. And I don't do well with a lot of nuts, but I do okay with like maybe a half cup of macadamia nuts per day. And that's a pretty big amount of fat. So yeah, I can't think of any other kind of fat sources, but you could pretty much fill the gap in calories with egg yolks and avocados and MCT. And especially if you're sourcing out fatty meats or poultry with the skin on it. So Damian Matthews writes, I listened, but don't remember if he discussed metformin or methylene blue or other non-food substances he's exploring for longevity. So, methylene blue, yeah, I know a little bit about that, but I know a little bit more about metformin. So, there's a couple of interesting studies sort of ongoing

Starting point is 00:49:19 being set up now. Actually, the MILE study, which stands for metformin in longevity study is a pilot study to examine the effect of metformin treatment on sort of the biology of aging in humans it's really looking at the how metformin can restore the gene expression profile of older adults with impaired, so older adults that tend to be impaired in glucose tolerance to that of young healthy subjects. So how does metformin alter that gene expression profile? Really interesting questions. We don't have answers yet. I know there's a University of Alabama is doing a multi-year trial on metformin and longevity. I think there's maybe a couple other studies that are being developed now that you might be able to find on clinicaltrials.gov. So it does appear that metformin has a calorie restriction mimetic effect in regards to signaling. So it lowers blood glucose. It suppresses, it lowers insulin a little bit. It lowers glucose in those that have

Starting point is 00:50:37 high blood glucose. And in those that don't have elevated blood glucose, it lowers it, but not that much, very little. It does, I found myself and in others, and I think in animal models is showing this too, there's an elevation of ketones. And I think that elevation in ketones is further enhanced if you're on a ketogenic diet, suggesting that it may be enhancing fatty acid oxidation in the liver. Metformin is a pretty powerful activator of AMP kinase, and it may lower mTOR signaling, et cetera, et cetera. So all these things are things that calorie restriction do, and we think that the benefits of calorie restriction are likely mediated by some of the things that I mentioned. And undoubtedly, there's many other things that are also happening.

Starting point is 00:51:35 There was a study done in rats, and it's important to acknowledge the type of strain because there's strain differences. We realize this when we work with different animals. These were Fisher 344 rats. And there's a study showing metformin supplementation on the lifespan of this rat model. And no significant lifespan extension was observed with metformin supplementation at least at the dose that they used in the study and i have to go back and look at the study when we give metformin a lot of some of the studies just kind of inject metformin as like a metformin hydrochloride solution we actually i think it's important to mix it in with the food and that's what we do with our study so when um you know the standardized standardized dose obviously

Starting point is 00:52:32 from a scientist standpoint it makes sense to just kind of go in there with a syringe and give x amount of metformin you know intraperitoneally or sub-Q to all the animals. So you know exactly how much you're doing, but the rodents pretty much eat the same amount of food, give or take a few grams every day. So we actually mix the metformin into the food. So when the animals eat the food, they will get the metformin, we think, when they need it, right? So the metformin we think when they need it right so the metformin helps to kind of normalize blood glucose in response to a meal and i think other investigators may do kind of injection of the metformin or they put it into the water but we think it's it's important to sort of give the metformin while you're giving calories that would increase blood glucose or insulin. So it helps to mitigate that effect.

Starting point is 00:53:28 So in this rodent study, they saw no extension of lifespan with metformin. My concern with metformin is that the side effects for long-term use. So I've used it sort of in myself and I kind of like the effects of it. I think it generally has like a little bit of a calming effect above two grams, starts to give some GI discomfort. One of the side effects that I've observed with metformin is that it caused, I guess we'd call it a photoreaction or photodermatitis on my wrist. And, you know, why is it doing that? That's something I don't know. I've kind of looked into. And so my wrists are kind of, the dermis of both my wrists are kind of messed up because I use lifting straps. And in the past, I've kind of handled a lot of weight with

Starting point is 00:54:27 doing shrugs, like kind of damaged the underlying dermis. And that area kind of would get eczema, which I did when I was following a high carb diet. It would occur in those areas. So those areas are just really sensitive areas of my body. And when I was on metformin, and I think it may have accumulated in my system, and I went outside, that those areas would be highly reactive to light, and it would start to sort of get hives in that area. So I stopped metformin, and then I transitioned to berberine, and that completely went away. And metformin also has the issue, a lot of GI discomfort with metformin, and there's also some data to indicate that it could reduce the transport and utilization of B12. So you might want to supplement B12 with that. But when it comes to using metformin for longevity, I think the jury's still out and

Starting point is 00:55:29 we need to look at that. And that's something we actually may do in the lab in our aged animal model. But for longevity, the things that I do are the big things, obviously, are just strength training, muscle. Biggest factor of aging, the biggest consequence, I guess you call it pathological consequence of aging, would be a loss of skeletal muscle. So the most important thing to do would be intense, you know, heavyweight training, a minimum of twice a week to help preserve as much muscle as possible and things that enhance our mitochondrial health and vitality. And that would be nutritional ketosis, intermittent fasting. I'm not a big fan of endurance exercise, but I do go for walks a couple of times a week. And I would need to force myself to do this, but I think high intensity interval training done two or three times a week would be optimal for getting longevity effects.

Starting point is 00:56:33 So I just have not been able to get myself motivated to do high intensity interval training. The next question comes from Josh Brackett. Does the ketogenic diet, can I use it for glycolytic training? Muay Thai. Question I get quite often. The combination of diet and training together produces an adaptation. So what you're really going for, yes yes you can use a ketogenic diet for glycolytic training but you have to train for that you have to sort of do the training and follow the diet and over time and time being like over three months, I'm convinced that your body, most people's

Starting point is 00:57:26 metabolic physiology will adapt to a ketogenic diet, you know, with glycolytic training. And, you know, if we talk about maybe losing some of that quick firing of the type 2 fast twitch, low oxidative fibers, you know, we want to keep that power, that strength. You can, if you're supplementing with things like creatine, and if you're eating red meat, I think it may be a little more important if you're on a ketogenic diet to supplement with a good creatine product,

Starting point is 00:58:00 creatine monohydrate would be fine. Not all people will be able to adapt to the diet so I think that's kind of important but I think most importantly it's to give it an honest try you've got to give it about three to six months and you may just shift to a low carb for a while with some ketone supplementation and before you actually try a ketogenic diet so so that may be why like short-term ketogenic diet studies on performance show a decrease right because there's a a lot of the low-carb studies out there that are quote-unquote ketogenic they just don't have the athletes follow the diet long enough to be sufficiently keto-adapted to really get the benefits of the diet.

Starting point is 00:58:51 So Jeff Bullock, in his FASTER study, did athletes that had been adapted to a ketogenic diet for like a year or more. If you look at their fat oxidation rates during training, these are endurance and not glycolytic training, but they're burning roughly two times more fat. And that's preserving glycogen. If your body is fat adapted and the athletes were burning considerably more fat just at rest, the practical advantage there is that you're preserving muscle glycogen for the event. Gerard E. Dawson III asked, what is it like to be an academic who also makes serious weight training a big part of your life? And how do you do two pursuits? How do these two pursuits complement or complicate each other? It's a good question. They complement each other because the lessons that I learned from training, you know, weight training over the years, the first book I read was Arnold, the education of

Starting point is 01:00:13 a bodybuilder. I think I was like 13 or 14 years old. And that book probably saved me in some way, because at the time I was like a horrible student. You know, I just kind of did what I needed to do to get past in academia. And when I was sitting in class, the only thing I wanted to do is leave class. You know, all I could just do is think about getting home and just doing, you know, just not being in school. So, um, training really, uh, serious weight training at the time, which I did in my teen years, it really, I guess, groomed my, my mind and my body too, for, for being resilient and kind of understanding that it really takes hard work to advance. Cause when I started training, I was like making no progress at all. I mean, it had to be hard training coupled with fortified with a game plan.

Starting point is 01:01:16 So I became like what I would call an obsessive planner. I would carry this little book with me and write down specifically what I was going to do. And I did that. I have training journals sitting in my office right now, training journals from when I was 14 years old and very detailed, like sets and reps. And I can look, I can go back and look at each of those workouts and actually remember it being downstairs in my parents' basement gym and remember it. And that, um, and I sort of parlayed that mindset being very structured and disciplined from weight training. And it took a couple of years, but eventually, but eventually by the time I was 17 or 18,

Starting point is 01:02:06 I applied that to my academic pursuits and I was more motivated to do so because my, the classes that I was taking were a little more challenging, like honors, biology classes and things where I was learning about diet. I was learning about a little bit about nutrition. And so in academia and for being a scientist, the sort of rigorous planning, note-taking, self-evaluation, being honest and critical of myself, I think really helps out a lot. So, you know, if I'm completely honest now though, I don't, I would not want to be sort of as big and stronger into lifting as I was when I was younger. So generally I think serious weight training when it comes to bodybuilding, powerlifting, powerlifting at a very elite level is kind of an unhealthy sport. So my focus primarily as I've been getting older is longevity. And your priorities change when you get older.

Starting point is 01:03:21 So it's not to be as big and strong as humanly possible, because that involves pretty much nonstop eating in my case, because I have kind of an ectomorphic body. So you're asking, so how do the two pursuits complement one another or complicate one another? Complicate. So yeah, so the pursuit of size and strength really contradicts what we want to go after for longevity, right? For longevity, we want to pretty much eat the minimal amount of calories that we need to sustain, whereas surplus calories can lead to, you know, the activation of certain pathways and genes and IGF-1 that could contribute to aging or an accelerated path to age-related chronic diseases and maybe even cancer. Right? So there's that balance. a lot of the strength that I've been able to accrue for my earlier years, but be able to

Starting point is 01:04:25 do it in a way and maintain that size and strength without compromising my health. And right now I'm just kind of in the maintenance phase. But I still make training a priority regardless, no matter how busy things get in the lab, at work, with teaching or travel or whatever, you know, I make it a priority. And I think it's important to be a lot more flexible in the way that you get your workouts in. So be creative. Uh, my time is much more limited. So, um, you know, be able to do a workout on the fly. I remember we were doing it actually on our way to, to Asia, my wife and I, things are before you travel, you're just kind of bogged down with trying to get everything done two or three days out. And I hadn't worked out for like three days, like at all,

Starting point is 01:05:23 I was completely sort of immobile behind my desk and, uh, we were on the plane and it was like a 14, no, I think a 17 hour flight. And, uh, and I had to get up and walk around and she got up too. And we basically, I started doing squats with her on my back in the middle of the aisle. These are things that I do now. I will do like pushups with her on my back. Like if I don't have access to a gym, I will go find a tree. You know, if you're really motivated and it's part of who you are and what you do, there's no excuse that you can't fit in a workout.

Starting point is 01:06:02 Daniel Barachena asks, okay, your thoughts on John Kiefer's carb night or carb backloading. So, yeah, this is, so carb backloading is actually really effective for gaining size and strength. And I did that probably a lot in the early 2000s. It was something that I was already doing, yeah, years ago. It's important now I understand and appreciate the importance of titrating the levels of carbohydrate to the individuals. And it's not, I don't, it shouldn't be in all you can eat sort of free for all after your workout. I don't care how intense your workout is. That's not going to be optimal. It's not going to be productive. So you want to prevent your postprandial glucose levels from getting too high, right? So you want to optimize your recovery, to optimize glycogen restoration, you want to prevent your glucose levels from getting

Starting point is 01:07:08 above, say, for me, it's about 130 to 120 to 130. And I find that I can, if I do carb backloading, which I took a little bit of time out and tried it a year or two ago, and I was getting a lot of questions on this. I could gradually sort of ramp up my carbs to about 350 after a hard workout. And that's my glucose would start to climb to about, you know, about 140. But I wanted to keep it below that. And also the types of carbohydrates I consume were pretty important too. But I think no more, even a large individual, that was way too much. I think I could get the same effects by 100 to 200 grams of carbs

Starting point is 01:07:57 for carb backloading. It's really important if you're going to do this on a on a daily basis uh or weekly or whatever it's important to acknowledge sort of all the negative things that can result from hitting your body with a massive glucose load and doing that immediately after you've done a lot of damage to the body where you've sort of stimulated the muscle in a way where you have a lot of breakdown, a lot of inflammation. If you throw a lot of glucose at it, the consequences are not going to be good. And we know that when your glucose level gets above 140 milligrams per deciliter, that can cause irreversible beta cell loss. So your beta cells are the cells that produce insulin. So if you routinely get your glucose levels above that, you essentially have

Starting point is 01:08:56 beta cell burnout over time. So that's been shown, that's published. There's a couple articles, you know, you can find on that. You can get potentially, you know, nerve damage with that sort of high glucose levels, especially in people that are a little more older and insulin resistance. The cancer rates increase if glucose spikes above, say, 160 milligrams per deciliter over time so if you're getting kind of 160 milliliter milligrams per deciliter spikes in your glucose by doing these big refeeds it's you could potentially increase your rates of cancer stroke risk is increased by about 25% for every 1 millimolar rise in post-meal blood sugars. So that has been documented.

Starting point is 01:09:52 So that's important. So that's 18 milligrams per deciliter for every sort of rise. So you need to consider these things, the health consequences to these big boluses of sugar. So I've used this approach and I think it produces good results. Like I said, for me, I'm over 100 kilograms and I didn't find that I need any more than 100 to 200 grams of carbohydrates post-workout. And any more than that, what happens is carbohydrates post-workout and any more than that and what happens is that you just tend to spill over and you just kind of hold a lot of water after. You're not effectively storing the

Starting point is 01:10:34 glucose as glycogen, it just gets into your... it just spills over. So a slow carb approach to backloading is probably the best approach. So if you do this slowly, you know, add the carbohydrates in and do low, like lower glycemic carbohydrates to do that. The last question I'd like to address is that about the safety of the ketone salt products on the market specifically the dl beta hydroxybutyrate salts that are a part of the key genix product prove it keto os keto sports ketokina forever green cells ketopia these are all products that I've used and I like and there was a podcast Dave Asprey and Ben Greenfield had dr. beach on and he talked about the potential dangers of the DL beta hydroxybutyrate salts and even about acetoacetate. So our number one concern when we do research is safety.

Starting point is 01:11:49 So the FDA really decides kind of what's safe as it moves to market and not us. We screen all forms of exogenous ketones in our lab, including the D, beta-hydroxybutyrate, the racemic compounds and acetoacetate esters. It happened to be Dr. Bruningrabber's ester developed at Case Western that we used for our CNS oxygen toxicity seizure studies because beta-hydroxybutyrate esters, or the D, an antimer of beta-hydroxybutyrate, did not work. Whereas the bruning grabber ester elevated both beta-hydroxybutyrate and acetyl acetate.

Starting point is 01:12:33 So Dr. Veach's opinion is that the DL beta-hydroxybutyrate, because it's racemic, it has a lot of problems, potential problems regarding safety. Specifically that racemic it has a lot of problems potential problems regarding safety that specifically that racemic compounds are a lot of inherent dangers in using them it's important to note that many drugs are on the market are racemic and that would include things like adderall e Ephedrine, Ephedrine hydrochloride and Pseudoephedrine, Ibuprofen is racemic and these things are proven safe. And beta-hydroxybutyrate actually has a naturally occurring isomerase for the interconversion from the L to the D form. And there's a mountain of studies that clearly show that DL-beta-hydroxybutyrate suppresses seizures, inhibits cancer, suppresses reactive oxygen species, oxidative stress, protects the liver, promotes wound healing, reduces inflammation, protects against hypoglycemia and stroke,

Starting point is 01:13:46 is protective against leukodystrophy, and a number of rare disorders. So I'm just kind of looking through all the publications I have in my file here. And these effects would not be observed if DL-beta-hydroxybutyrate was dangerous or ineffective, which was proposed and discussed on the podcast. And you also need to consider that approximately 10 million doses of DL-beta-hydroxybutyrate salts have been consumed worldwide, from the Pruvit product to Forever Green to keto cana uh sells quite well and you know at least 10 million uh doses i believe have been sold and there's you know little if any i don't think any

Starting point is 01:14:35 adverse medical um side effects have been reported with this uh just besides diarrhea and kind of loose stools if the dosing gets too high. And I know some individuals that are dosing really high. If the DL-beta-hydroxybutyrate was toxic, it would have been reported, you know, by all these people using it, and also it would be reported in the medical literature for the use of, you know, to treat a variety of different medical conditions. And keep in mind that they're using the pure sodium beta-hydroxybutyrate, which, you know,

Starting point is 01:15:16 there's a lot of discussion about sodium being dangerous. And we don't think that's the case if it's kept at a particular level and not, you know, anything is toxic if it gets too high. But it's also pretty important to balance out beta-hydroxybutyrate and to spread it across various minerals. So to have a beta-hydroxybutyrate salt product that has potassium, calcium, magnesium, and sodium together would be ideal I've really gotten hundreds of emails from from people that have given me tremendous feedback on the ketone salts and feedback on performance and feedback or therapeutic use of ketone salts I don't advise using ketone salts for therapeutic purposes because clinical trials need to be done, but that does not stop people from using them. And

Starting point is 01:16:11 parents, you know, reporting back that their child is now able to achieve nutritional ketosis and getting many benefits from it. So I think we've taken up a lot of time here, and we've covered a lot of ground, probably more ground than we needed to. And if you have any, I've enjoyed kind of looking through all these questions. I haven't looked through all of them yet, but I looked through about 80% of them, I think. They're excellent questions. Thank you for listening, and I look forward to maybe being on again and handling more. Hey guys, this is Tim again, just a few more things before you take off. Number one, this is five bullet Friday. Do you want to get a short email from me? Would you

Starting point is 01:17:00 enjoy getting a short email from me every Friday that provides a little morsel of fun before the weekend. And Five Bullet Friday is a very short email where I share the coolest things I've found or that I've been pondering over the week. That could include favorite new albums that I've discovered. It could include gizmos and gadgets and all sorts of weird shit that I've somehow dug up in the world of the esoteric as I do. It could include favorite articles that I've read and that I've shared with my close friends, for instance. And it's very short. It's just a little tiny bite of goodness before you head off for the weekend. So if you want to receive that, check it out. Just go to 4hourworkweek.com. That's 4hourworkweek.com all spelled out. And just drop in your email and you will get the very next one.

Starting point is 01:17:48 And if you sign up, I hope you enjoy it.

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The Tim Ferriss Show - #188: Dom D'Agostino on Disease Prevention, Cancer, and Living Longer

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The Tim Ferriss Show - #188: Dom D'Agostino on Disease Prevention, Cancer, and Living Longer

There aren't comments yet for this episode. Click on any sentence in the transcript to leave a comment.