Utilizing Targeted Ketosis to Benefit Patients Webinar Replay

Many people know about ketogenic diets. Certainly been in the news a lot for many years now, since about 2014. It’s become a very hot topic in Google search. Today I’m going to talk about the role of what I call adjustable targeted adjuvant ketosis in neurodegenerative and neurocognitive impairment. I think that in talking about neurocognitive disease, we’re all very concerned about it and rise of Alzheimer’s, the rise of Parkinson’s disease and other diseases such as atrophic lateral sclerosis, also known as Lou Gehrig’s disease increases with age. If you look at charitable donations to Alzheimer’s organizations and charities, the largest amount of money comes from the baby boomers who are actually more concerned about cognitive disorders than they are about cancer in recent surveys. So the objective of today’s talk is to basically talk a little bit about brain energetics and kinetics, the role of ketones in brain metabolism, the role of endogenous ketones versus exogenous ketones versus substrates for the development of ketones, endogenous ketones such as medium change IDE acids as basis for ketone formation by the liver. 

Then we’re going to discuss the role of glucose hypometabolism and neurodegenerative diseases. We’re going to talk a little bit about covid brain fog. We’re going to talk some about these cerebral spinal fluid and c n s penetration of antivirals from a historical perspective and what that implies as we go forward in developing treatments. And then we’re going to review how ketone supplementation may alleviate glucose hypometabolism and incorrect energy deficits in the brain and nervous system. So the brain does require a lot of power. The human brain will take 20% of total energy at rest and up to 35% in periods of high brain use, and the usual supply is glucose. But how glucose gets into the brain requires insulin. And for those of you practitioners who have done lumbar punctures, you notice that there’s always a differential between the concentration of glucose in the spinal fluid versus the glucose in the bloodstream, and there is only a limited supply of brain glycogen, which gets depleted fairly quickly. The energy that is produced a t p is used for ion gradients in the neuron phospholipids, cytoskeleton, axonal transport, and not enough glucose as in certain diseases such as glute one deficiencies portend to seizures and movement to other disorders, as well as other cognitive issues. Therefore, alternative energy sources such as ketones are often utilized when glucose supplies restricted inadequate, such as during fasting or in low carbohydrate diets. 

Mitochondria, of course, is the powerhouse. This is just a reminder that our mitochondria are very similar to a typical battery in which it produces flow of electrons. The body’s battery is about minus 70 millivolts or minus 70 millivolts depending upon what function you’re talking about. And the car battery is 12 volts in your house is 120 volts. And basically when you turn on the switch, you get enough voltage to drive the machinery, the light goes on, the refrigerator goes on, your computer goes on, your car starts, et cetera. And similarly, the body, you’re able to talk, your hands pump your heart, et cetera. So the differential between the two different energy systems that we exist on, and it’s only ketone bodies and only glucose. Therefore, sugars such as sucrose, moose, fructose, have to be converted in the liver to glucose to supply energy. And ketones actually on a per gram basis produce about 40% more energy, which preferentially is taken up by skeletal muscle, brain tissue, and cardiac tissue, because ketone is basically the fuel of fasting when there’s not enough energy. I don’t know why that went over, and therefore when we have the, lemme see if I can go backwards here. 

When we have the 40% more energy, it’s used for hunting since generally fasting is associated with hunting, and it gives you enough cardiac output, enough muscle strength and enough savviness and mental agility to capture and kill your prey so you can survive. It’s a very teleologic concept here for ketosis. Ketones are used in ion pumping, neurotransmission, synaptic plasticity, neuron glial interactions, metabolic coupling, and in pathological conditions, a T p reduced production or reduced availability has been implicated in the diseases that I mentioned earlier. And we’re going to talk a little more about that. I really sort of liken the brain as a similar to the brain computer brain in a car that’s a hybrid such as the Toyota Prius, you’ve got two fuels gas and electric. You’ve got sort of dirty fuel versus clean fuel, and you have a differential in the power that is achieved by gasoline versus electricity. 

And similarly, the body switches back and forth just like the car switches back and forth to the energy substrates based on what it means. And the car brain of the Toyota will take in consideration the ambient temperature, what the payload is, the driving style, is it going uphill, downhill around a curve, what speed it is? And by switching the power back and forth, it optimizes the longevity of the car and when it maximizes the utility of the parts, et cetera. Well, the body’s very similar in that it switches back and forth. Certainly if you look at the ancestral man who didn’t really sort of roll his window down and have a burger and a coke and a fries thrown in, he had to actually hunt. And similarly, like animal wild animals such as wolves, Alaskan wolf today, this part of switching in and out of ketone versus glucose energy, meaning that the 

Ketone engine is running, the glucose energy is resting and it’s not off unlike an automobile. And while the glucose engine is resting, it’ll be cleaning out the toxins, replacing parts, and this swapping back and forth is important for the longevity of the animal as well as keeping the energy systems balanced. And important fact, if you look at an Alaskan wolves and you follow them out, they live about 40 to 80%, sorry, 40 to 60% in ketosis. And man, Americans live about 92% in glucose and 8% in ketosis. And this is important for us to sort of understand why some of the diseases that we have today are related to this differential. So in glucose hypometabolism, which is sort of the root of all evil, and it’s a common feature in neurodegeneration and brain metabolism and disruption, you see this in functional MRIs in a variety of biochemical experiments and in all throughout the literature that Alzheimer’s disease, Parkinson’s, A L s, Huntington’s, et cetera, will generally be associated with the area of involvement with hypometabolism is the area that is sort of associated with the disease, whether it’s movement disorders or seizures. 

And even in covid, long covid cognitive problems, neurodegenerative issues are also associated, and I’m going to show you that in a few pictures that the affected regions are correlated to disease severity. Where are the ketones that are utilized by the brain come from? Well, it basically comes from the metabolism of fat during starvation as well as endogenous manufacturing from the liver. And when we give things like medium chain triglycerides such as coconut oil, we can improve the endogenous production of ketones. However, even if you overnight fast, you get a low level of ketosis and it contributes less than 5% of brain metabolism. However, if you continue to fast, it will produce as much of 60% or provide as much of 60% of the brain’s energy needs. And ke anemia can be achieved in a non-fasting state by the encouragement of ketogenic diets or by the ingestion of supplements in the form of meat. 

MCTs, medium chain fatty acids or exogenous ketone salts, esters, mono esters and DERs. Ketone bodies are also raised by prolonged fasting. You can even give them iv. What’s important to remember about ketones is that the concentration in the blood is actually equivalent to the concentration in spinal fluid, unlike the glucose which is there is a differential. So if you are in need of ketones in the brain, you can administer them and raise them in the blood. And because the molecule is so tiny, it traverses into the spinal fluid and provides immediate energy boost in the spinal fluid, therefore energizing the brain and the rest of the nervous system. The idea of therapeutic ketosis is not new. Ketogenic diets were developed by Dr. Wilde in 1924, and IV infusions were used at that time for the treatment of epilepsy. This was well before the development of seizure medications. 

Medicinal fasting in the Greeks and Chinese were noted in history as far back as 200 to 500 bc and however, since about 2010 ketogenic diets and then subsequently around 2013 or 14 exogenous ketones became available and were used by the public for weight loss and sports and now expanding to other sorts of indications we’ll talk about. We can observe that ketone and glucose levels can be adjusted, and it’s sort of my proposition that as primary care physicians become more knowledgeable and experienced in using ketones, there will be a day in the very, very near future that healthcare professionals will be called upon to manage ketone levels just like we manage glucose levels. And companies such as Abbott and Keto Mojo are now coming out with blood meters and for continuous ketone monitoring, just like we have continuous glucose monitoring for diabetics as well as for performance and other therapeutic and wellness strategies. The future, we are involved in cancer trials at Cedar-Sinai for glioblastoma, and we’re working on cardiovascular diseases as well as neurodegeneration with other universities. So these are things that are being explored extensively in the literature world literature by major universities and institutions around the world. 

However, the issue is that endogenous ketone production is really a slow process. And because high levels of insulin, insulin resistant is so prevalent in obese, patients with cardiometabolic syndrome and high carbohydrate consumptions have limited the production of ketones. So we’re making sort of the case for exogenous ketone use. Medium chain triglycerides are produced in a non-insulin dependent way of the liver, but there’s a limit to that and it becomes peaked out fairly soon, and you can only put so much M C T into the system. Exogenous ketones in the form of ketone salts and esters are easily orally absorbed, convenient and reach elevated blood levels in a matter of minutes to look at how ketones get in the brain. This is a sort of a complicated picture, but you’ll recognize some of the familiar cycles here. But ketone ketogenic diets require the breakdown of fat or lipolysis and free fatty acids go to the liver and then therefore you’re making the ketone body’s principally beta hydroxybutyrate, medium chain fatty acids included as supplementation as part of the diet, ketone salts enter directly and the concentration that’s seen in the blood is also immediately available to the brain. 

So ways to increase our goals to increase the circulatory pool of ketone bodies. Fasting eight 16 fasting, which has become quite popular in an attempt to mimic ancestral behaviors and animal behaviors to encourage ketosis have been well recognized over the last few years, tend to be somewhat slow better if the diet is keto centric. That is 70 to 80% fats. However, there’s some tolerance issues. Many patients have sort of fear of eating that amount of fat for not necessarily legitimate reasons. There’s certainly evidence to show that high fat consumption may not necessarily contribute to cardiovascular disease and stroke. Nutritional ketone supplements again are the most rapid way to get high concentrations, and there is a differential that the ketone salts are generally lower, cost about $4 for a daily dose ketone esters can cost upwards of up to $35 per dose and have been used extensively in performance and athletics as well as some disease states. 

The shortfalls in terms of ketogenic diets, they’re oftentimes associated with weight loss, which if you’re trying to treat neurocognitive neurodegenerative diseases in the elderly who are already perhaps thin may not be the best option. Vitamins and mineral deficiencies due to a strict diet have been demonstrated even salts and mineral imbalances. Again, patients with high insulin levels have a harder time making ketones. High level of keto have been associated with neurodegenerative disease improvement in the four to five mini molar concentrations and are associated with diets that are difficult to adhere and comply with, and so can provide a certain amount of nutritional forgiveness. If you’re taking the salts, you can have a modest amount of ketones and still be in good level of ketosis and ketone supplements may be more applicable in neurocognitive disease groups where you’re trying to affect neurosignaling, which may be less area under the curve dependent and may be more dependent on spike peak levels. For neuros signaling, the most ketogenic MCs are caprylic acid or C eight, and you can buy this at the grocery store and usually as ketone supplements in nutritional stores, vitamin stores, et cetera. And they will definitely raise the level of ketones. But if you’re really good with it, maybe you can get 0.6 millimolar. 

So typically beta hydroxybutyrate salts and ketones can raise your ketone level up to 2.4 millimolar within about 40 minutes after ingestion. So I’m just going to switch a little bit to understanding that there is a gradient of effects as ketone levels rise. And in medical school we were always taught to fear high levels of ketones for the fear of diabetic ketoacidosis and cerebral edema and vasculopaths, et cetera. But these are really associated with ketone levels of 15 millimolar or above. And in a modern society like America, D K A really is sort of relegated to type one diabetics who are recently discovered like in children. But in a typical internal medicine practice, people who go into D K A are few and far between. And so I think that more recently the idea of getting continuous ketone meters are for people who are actually trying to achieve the benefit of targeted ketosis. And this is what’s in the frontier for us. If you look at this chart here, you see that as you raise the ketone levels, you can improve insulin sensitivity, you can reduce endothelial and vascular inflammation. H DACs are a new approach to chemotherapy. Also, H DACs are associated with seizures. Beta hydroxyl, hydro hydroxy mutilation occurs, which provides antioxidant effects, anti-inflammatory effects, and potential longevity effects in the higher levels of let’s say 2.5 to five range. 

If we look at how ketone supplements have been used or ketone support metabolism besides just being an energy substrate, we see that it actually improves mitochondrial dysfunction, it reduces oxidative stress, it improves neural conduction. These are many of the things that we see in both literature and laboratory and clinically in patients who are in adequate levels of ketosis. What we can do is look at some sort of a meta analysis of studies of media chain fatty acids. Actually, no, this was not a meta-analysis. This was the largest of which were 168 patients, which showed no difference in the keto diet versus regular diet, however, but the ketone levels are very small. So however, in other studies with Alzheimer’s using salts, and Esthers definitely showed a positive cognitive function. The so-called benefit trial, which was six months placebo control of patients, showed that nine out of 17 improved with typical cognitive testing in the arm that was receiving the fatty acids versus the arm. 

The placebo arm here is the sort of meta-analysis, which looked at a bunch of cognitive testing associated with ketosis and exogenous ketones, and we were able to show global cognition, improved memory, improved language, and these are our tests ranging from 90 minutes after ingestion to six months duration and studies between 12 and over 400 patients. If you look at Parkinson’s disease as sort of a disease that people have explored using ketogenic diets, the number of patients that were able to sustain ketogenic diets was actually fairly small. And recently in San Diego at the keto meeting, they were looking at even Alzheimer’s disease, and less than 30% of elders with Alzheimer’s were able to comply with the diet for six months. However of that, those groups, 60 to 70% of people improved their cognition. And in patients who were able to tolerate and adhere to a Parkinson’s diet for four weeks, were able to improve on the Parkinson’s scale of measuring efficacy or improvement, I should say. 

We had put an attorney who was a 75 year old gentleman who had Parkinson’s disease declining, declining after two years of standard of care, he had decreased cognitive function, abnormal gait, he was unable to walk more than a block. He had lost his handwriting, unable to practice law sign his name or drive. He was begun on oral D beta hydroxybutyrate and twice daily and six months later, his handwriting returned. He was able to resume law practice, his neuro symptoms improved. He was actually able to resume driving. I actually interviewed this gentleman while he was driving his professional race car at a hundred miles an hour and he had smooth cognition and was able to drive pretty well, which is another part of this anecdotal case report is that he inadvertently left his ketones at home and went off for a two week trip driving around California with his child. And at day seven he was up in Northern California and was unable to get out of bed. And so he had to be driven back to his home in Los Angeles here. And after taking resuming his exogenous ketones, after about three days, he got up out of bed again. After three years, he was actually able to resume riding on his stationary bicycle. So pretty impressive.

So if you look at a variety of these ketogenic therapies in the clinical management of various types of diseases, we see that exogenous ketone agents are potentially much more feasible than 

Dietary interventions in neurodegenerative diseases, basically because of compliance and adherence to the diet is so hard. This is a trial instituted by the national, the NI National Institutes of Aging, which is a division of the National Institutes of Health, and they are looking at ketone esters and the effect on biomarkers, cognitive performance in cognitively intact 55 year old people. It’s double blinded, randomized, placebo controlled, and it’s utilizing not only executive function testing, but high levels of MRI, functional MRI, CT scans, vascular studies, etc. It’s a very complete study, one that could only be supported really by the government. 

And the results of these trials are going to be published soon. But it’s very encouraging and shows that ketone supplementation may be very useful for this. If we’re looking at ketosis and costs, ketogenic diets are very cheap, hard to comply with. Low carb diets are also inexpensive. Keto foods are a little more expensive. In fact, recently I was looking at a loaf of bread at the grocery store and it was like $7 for a ketogenic loaf of bread that only gave four net carbs per slice as opposed to the typical one, which is like 20 or 30. Intermittent fasting–there’s really no cost, but it’s very slow. Exogenous ketone supplements such as the D salts, DBHB salts are relatively cheap. The mono esters are extremely expensive. The DL salts are less expensive, but then the DL salts are less efficacious in terms of raising ketone levels. Medium chain fatty acids such as oral caprylic acid is not very expensive, a little slower. We are now able to remotely monitor people. We have breathalyzers, we have urine test strips, we have blood meters, and we also have the ability to have Bluetooth weight scales, which can help us calculate the percentage of fat. 

There are some genetic caveats, that is patients who are ApoE4, generally don’t respond very well to ketosis with Alzheimer’s disease. And this is sort of unknown, but it may be speculated the differences of acceptance of ketones in people who are ApoE positive versus negative. Here’s just some pictures of some blood meter on the left, breath meter, urine strips, even the ability to computer read the strips and plot them for urine. The difference is that urine can be diluted. If you drink a lot of water, you may get a false low reading in the breath meter. If you’re drinking alcohol in the previous 12 hours, it may give you a false high reading. 

I want to switch a little bit to brain fog, which a lot of people are concerned about. In particular with the advent of covid, there were a number of people had permanent loss of smell and taste, chronic thinking disorders and including episodes of anxiety and depression and some memory loss. This is COVID is a neurotropic virus, and I’ll show you later on, very similar to there are sub strains of HIV that are also neurotropic in that preference to cause problems with the neurologic system. We’re looking at early papers here, looking at the blood glucose transport as a problem in Alzheimer’s disease and ability to have glucose metabolized is reduced. And so when should we consider this? Well, obviously in patients who have problems with cognition, coordination, et cetera, sometimes diets can be difficult and intermittent fasting might be difficult with these types of individuals. 

And we can show that if we try to target the ketosis between two and a half and five millimolar, that your ability to improve might be achievable. And we look at pet functional PET scans of people who had c ovid 19 patients were compared to healthy subjects who are not infected. And we can show that patients have problems of hypometabolism in the areas that were associated with problems that they got after covid. And I’ll show you these pictures here. So these areas are areas that are the ones that were affected by covid, and consequently they had the problems associated with that geographic area of the brain Here is looking at someone who’s healthy control. As you can see, there’s no hyper intense hyperintensity spots. If you’re younger, you have fewer, if you’re older, you have more pretending to the fact that as you get older, you may be more susceptible to how the virus crosses the blood brain barrier and affects damage to the brain. You see this a very similar pattern in people who have HIV-related dementia and other viral encephalopathies. 

What happened back in the days of HIV was initially we tried people just alive, but then as we developed protease inhibitors and triple drug therapy in these so-called cocktails, I remember that we began to see patients that had as survival improve, starting to have cognitive disorders. And these were identified fairly early on. And in fact, I had patient who was a physics major, or physics professor I should say, who could do complex mathematical computations without the use of a computer or calculate, which was phenomenal. And at that time, he was on double therapy, drug therapy, and he had an undetectable viral load in his blood. But he came in complaining of the inability to do these math problems. He wasn’t dropping pencils or falling on the floor or having double vision or any other neurologic symptoms, he just couldn’t do math correctly. And at that point, I had asked the UCLA lab if we could run viral load on his spinal fluid. 

And lo and behold, it ended up that he had a viral load of 3 million in his spinal fluid and undetectable in his blood. And if you look at his drug regimen at that time, he had drugs that were unable to penetrate the spinal fluid and kill the virus. So we switched his regimen around to a neuro penetrating group of drugs. And about six or eight weeks later, he came back and said that his ability to do computations in the brain returned. And at that time, I re lumbar punctured him and simultaneous blood viral loads and they were both below the level of detection. So that was pretty amazing. And subsequently, we worked on some trials with the Johns Hopkins and with the NIAID and we were able to show that interestingly enough, there was the development of differential strains, genetically different strains. 

And as you can see in this picture, there’s a departure in the genetics. We actually looked at autopsy specimens and sequence the viruses from both the spleen and from the brain and from the spinal fluid and the blood, and found that the spleen and the blood were the same and that the ones in the brain were different from the ones that were in the spleen. And the ones in the spinal flu were different than the ones in the blood and the spleen. So again, this is done at UCSD in the collaboration with the AIDS clinical trial group, which I was a member of. And so in this, we were, after looking at the drug regimens, we found that the drug regimen choices were pressured, the development of mutations within the central nervous system. So many, many years ago we began to look at the penetration of drugs. And as I said, we came to the development and understanding that certain drugs penetrated the central nervous system much better than others. And that in particular, the protease inhibitors, which were remarkable in 2012 when they came out and literally changed the face of AIDS and the survival. Ritonavir, which is a key component in Paxlovid, is actually a drug that does not penetrate very, very well.

So more recently, this is a very recent article published looking at COVID-19 and the new onset of Alzheimer’s disease, people with covid were significantly increased risk for a new diagnosis of Alzheimer’s within a year or so of diagnosis, especially people who were over the age of 85 and elder women as well. So this article in Journal of Neurology talks about c n s penetration of potential anti covid drugs. And as you can see here again, VIR Ritonavir has a 0.02% penetration in a human. And this is one of the issues with PAX livid in that it is a double protease and actually the ritonavir is used as a pharmacologic booster to boost the level of the other drug, which is probably higher in the blood than it is in the CSF. When we look at how viruses reproduce this article, which interestingly enough came out a few months before covid started, produced by three postdocs at UCLA in July of 2019, showed that glucose is a key component for successful viral replication. And basically you have something called the Warburg Effect, which was initially discovered that cancer cells reproduce poorly in a low glucose environment because they are not able to use ketones. And 35 years later, after Warburg’s initial discovery in the twenties by the thirties, it was understood that the Warburg effect applied to viruses. Well, these investigators demonstrated that for a whole host of viruses, which included SARS-1, dengue virus, Ebola, Hepatitis B, Hepatitis C, HIV, influenza, all have reduced replication capacity in the absence of glucose. 

So five actually filed a patent looking at rebound COVID for using exogenous ketone BHB salts as adjunct therapy in addition to conventional therapy with Paxlovid, and it may reduce the potential for rebound COVID. We believe that exogenous ketones will be a rising role in the wellness and therapeutic benefit for patients either due to reduced, improved utilization of ketones in the brain or even inflammatory small cell signaling.