Uncover Lifestyle Secrets For Cognitive Longevity

David Perlmutter, MD, FACN, ABIHM

Let me back up just a little bit, and I promise we’ll get there. Why nitric oxide? It’s quite clear that brain degeneration is not fully related to the accumulation of a particular protein. What we do understand is that brain degeneration of the Alzheimer’s type, for example, is metabolic. It’s related to how the brain uses energy. Call it a bioenergy issue. Interestingly, in the Journal of the American Medical Association back in 2020, there was an editorial that said that in the field of Alzheimer’s research, bioenergy moves to the center spotlight, meaning moving away from the idea that accumulation of beta-amyloid is the cause of Alzheimer’s disease. We need to focus on metabolism and how the brain utilizes energy, and there are multiple pathways we could explore that topic through. But I would just mention two. One is that it has to have a good blood supply to the brain and that it has to be able to utilize fuel predominantly glucose. It turns out that, getting back to your question, nitric oxide is playing a pivotal role in those two areas.

 Nitric oxide allows insulin to do its job, which does other things in the brain. Aside from allowing glucose in various areas of the brain to become used as fuel, insulin is also a trophic hormone, which means it nurtures brain cells. It nurtures the very synapses that are generated in the Alzheimer’s brain. Alzheimer’s being, according to my good friend Dale Bredesen, synaptopathy: a great word that you coined, but nitric oxide is what I’m talking about, and we’re not talking about nitrous oxide that you get at the dentist. Nitric oxide is a gas, so the transmitter knew, along with hydrogen sulfide, that there are gases within our bodies that are signaling for things to happen, that are allowing insulin to do its job, that are allowing blood vessels to dilate, and that are allowing various organs to get a lot of blood or the blood that they need. Now, I’ll take a step back. There was a recent study that looked at the medical records of close to seven million individuals and did an in silico analysis comparing the drugs they may have taken with their risk of developing Alzheimer’s and tried to determine if there were any drugs that may be associated with a lower risk of Alzheimer’s, and it turns out that one drug, Sildenafil, was associated with a 69% risk reduction for the development of Alzheimer’s disease.

What is this drug? It is, of all things, Viagra. Viagra is a drug that was originally designed to increase blood supply for erectile dysfunction, and it does so by increasing nitric oxide functionality. So this again gets us to understand the role of this nitric oxide in terms of blood supply and in terms of allowing the brain to use fuel, predominantly glucose, to power its cells. You said something a moment ago that was quite interesting. It is, and we’ve talked about this for quite some time, that the seeds are sown for brain degeneration, specifically Alzheimer’s, in our 20s and 30s. That’s when the metabolic consequences of our lifestyle choices begin to take root in the brain and begin to be manifested such that we can even imagine them. By using advanced PET technology, Positron Emission Tomography, and looking at glucose utilization, we can predict who’s already setting himself or herself up for brain degeneration when they’re 60 or 70. It is so important that we recognize this important role, this fundamental role of metabolism ism, or dysmetabolism, what I call metabolic mayhem earlier in life. Of course, then what are those lifestyle choices that we have adopted that are either going to allow our brains to utilize fuel that metabolizes well or not?  Interestingly, this nitric oxide story is just sort of coming on the scene right now.

We know that we make nitric oxide. 50% of the nitric oxide that is so important in our bodies is made in the body as a consequence of what’s going on in the mouth. Who knew that when we eat foods that are high in nitrate or NO3, the specific bacteria that live on the top of the tongue convert that to nitrite, which is then in the body and ultimately converted to what we want, nitric oxide. What’s going on in the mouth is the oral microbiome. We’ve been talking about the gut microbiome for a couple of decades now. The oral microbiome similarly plays an incredible role in our metabolism, not just as it relates to nitric oxide in the brain but throughout the body. Another fact that is quite interesting is that there is a chemical produced in the body that will dramatically lower nitric oxide, and it is called uric acid. We certainly all in medicine have been vetting uric acid levels over the year in the context of a disease called gout, where crystals are going to accumulate in your toe joints and you’re going to have a lot of pain. You’re going to have to take medication. It’s very painful. But we now recognize that there’s a much bigger story related to uric acid, which is brought on by a diet that’s high in certain types of chemicals called purines. But predominantly these days, it’s fructose sugar, and higher levels of dietary fructose, which are what characterize the modern-day diet, will raise uric acid, compromise nitric oxide, and therefore compromise metabolism and pose a pretty significant threat to the brain.

Dale Bredesen, MD

Very good point. So you mentioned the bacteria, the oral microbiome. The dental world has come to the same sorts of conclusions and realized that there are a lot of things about oral health. But now they’re all about oral systemic health. This has to do with mercury levels, the oral microbiome, nitric oxide, the airway, and all of these things. We are always interested in actionable items. Do you like to see people taking oral probiotics? Do you recommend things like Dentalcidin, and what sorts of things do you like to see in terms of improving the oral microbiome and improving nitric oxide levels?

David Perlmutter, MD, FACN, ABIHM

On the downside, as it relates to the oral microbiome, it would be similar to the things that relate to the gut microbiome, like antibiotics. A lot of people are using an oral antibiotic every day in the form of mouthwash. You look at the advertisers on television or in print, and what they want to leverage is the fact that this kills 99 percent of germs.  Let’s not characterize them as germs. By and large, bacteria in the mouth are doing some good stuff and, as mentioned, are helping us have the availability of the substrate from which we can form nitric oxide. The subject of two studies of interest that were done about three years ago and demonstrated in following individuals over two years that those who used mouthwash two times a day or greater had about a 50% increased risk of developing type-2 diabetes and a close to 100% increased risk of developing hypertension.

Those are, in my opinion, strongly related to the compromise of nitric oxide. I mentioned the two things it does. It’s involved in regulating how insulin does its job, hence the diabetes, and it’s involved in the relaxation of blood vessels, hence the high blood pressure. Who would think that by using oral mouthwash, we want to kill those terrible germs so we don’t get bad breath? My gosh, of course. and I’m certainly not saying we shouldn’t be brushing our teeth, etc., that toothbrushing is an appropriate thing to do using Waterpik. That’s a brand name, and I apologize for that. But flossing is very important. We are certainly probably a little off-topic on this relationship between a particular bacteria Porphyromonas gingivalis, which though tends to overgrow in the mouth, the relationship of Porphyromonas to Alzheimer’s, even detecting components of it in the brain. However, we do see a relationship between poor dental health and higher levels of Porphyromonas gingivalis. 

So it is something to consider. We’re at the primordial stages of understanding these relationships, but some ideas are valuable, and the notion of sterilizing the mouth is probably not what we should be doing. That said, on the upside, what can we do to increase the availability of nitric oxide in the body and hence improve metabolism, which is good for the brain? That is, to consume foods that are rich in nitrate, which bacteria in the mouth can then convert to nitrate, then we can have higher levels of nitric oxide and foods that are rich or generally colorful foods, in particular foods like pomegranate and foods like beets. You see advertised on Amazon and television, etc., beet-based products for sports performance, etc. It’s based upon this very good science that ultimately you will increase nitric oxide, which will increase blood supply in this case to your muscles and throughout your body. That science won the Nobel Prize in 1988. The discovery of the role of nitric oxide in terms of allowing it was what was called first this vascular endothelial factor. What was it that allowed blood vessels to relax? It turns out it’s nitric oxide. Now we know it does. much more. It’s involved in regulating our blood sugar via its role in insulin functionality. Eating nitrate-rich foods is a very good thing.

Dale Bredesen, MD

I remember many years ago at UCLA a meeting with Professor Luigi Lauro and his talking about Endothelial-Derived Reaction Factor, EDRF, which turned out to be, as you said, nitric oxide, very exciting stuff. Of course, he went on to win the Nobel Prize for that very exciting work. Let’s go down to the sinus. It was the relationship between the sinuses. Their concern is about the sinus microbiome. Does it tend to be reflective of the oral microbiome? How much should people be thinking about this and utilizing it? There have also been, of course, things like trying to change the sinus microbiome or your rhino sinal microbiome. What is your sense about that?

David Perlmutter, MD, FACN, ABIHM

It just hearkens back to our naivete and myopia in terms of understanding the relationships that we have with organisms that live within us or upon us. The sinuses, in the mouth, are external or internal. Is the entire digestive system an epithelium that’s exposed to the outside environment? It’s profoundly an interface of our bodies with the external world. Some of the discussions that we have concerning sterilizing the mouth are relevant as they relate to the sinuses. People get sinus congestion and immediately reach for various medicines to deal with that problem. Vasoconstrictors are at the top of the list to reduce the secretion of fluids into their sinuses, as are steroids. We know that throughout the body, in the skin, in the gut, in the mouth, and the sinuses, steroids change the mental state; they change the balance of organisms, and they and steroids change what these bacteria and other organisms are producing. We favor the overgrowth of organisms. When we use steroids, certainly in the gut, we favor the growth of the fungi.

It leads to increased gut permeability. We see very direct communication for the microbiome in the sinuses, in the oropharynx, and throughout the oropharynx, as well as relevance as it relates to total body health. We’ve morphed people away from the notion of using medications, particularly as relates to the sinuses, steroids that have kind of devastating effects, not just for the sinus-related organisms but throughout the body. These become systemic. These steroids that are injected in the nose—inhaled steroids—are, in my opinion, prescribed for various pulmonary issues, though there may be a time and place, that’s for sure. However, we need to have a good discussion with patients in terms of the systemic consequences of using steroids in any delivery system.

Dale Bredesen, MD

Good point. You mentioned earlier energetics and the critical notion that this is important for what will ultimately become Alzheimer’s disease and loss of synapses. It changes your synaptic elastic and the synaptic blasting ratio. If you want to lower energy, you can reduce blood flow, you can reduce oxygenation, or you can get someone to have sleep apnea. For example, you can reduce mitochondrial function or you can add a drag on it, which is inflammation or toxicity. As you mentioned earlier, in P-gingivalis, you can see plaques in your brain. These things do communicate. I Want to get to areas that are changing kind of rapidly here. One of them you have written a whole book about is the gut microbiome. As you pointed out years ago, and as Dr. Knight and others pointed out years ago, this is an area where there’s a lot we don’t know. Do you want a specific species? Do you want diversity? So if you’re going to be taking oral probiotics, do you want to look at the one that survives the most? You want to look at the one that has the most different species. Do you want to focus on specific species like Akkermansia, fecal bacteria, or prausnitzii? One of these kinds of anti-inflammatory ones. What is your current feeling about how to optimize the gut microbiome for the brain?

David Perlmutter, MD, FACN, ABIHM

It relates to the notion that what makes a good brain go bad is metabolic dysfunction.   We have certainly seen a robust amount of literature being generated in the past five years relating to things going on in the gut, specifically for the organisms that live there and the role of the products made by these organisms in terms of influencing our metabolism and metabolic function, even going so far as changing our gene expression as it relates to metabolism. Studies have demonstrated that fecal transplantation, for example, is an aggressive and bizarre sounding approach, but transplantation of fecal material from a non-diabetic individual into a diabetic individual is showing improvements in their blood glucose and their insulin functionality—that’s pretty way out there. But it just demonstrates this intimate relationship between what’s going on in the gut in terms of the organisms, the viruses, the bacteria, and the fungi that live there in terms of their influence. Those organisms living there need to keep us healthy because when we’re gone, they’re gone. everything that we do, every choice that we make in life from a lifestyle perspective, day in and day out, whether it’s stress or, as you mentioned earlier, not getting enough restorative sleep, having breathing issues, certainly taking various medications like NSAIDs and various acid-blocking drugs. Antibiotics, of course, the types of water we consume, the types of food that we consume, whether we’re consuming a diet that’s high in ultra-processed foods or not, all of these directly impact the variety, diversity, and functionality of the organisms that live within us.

One area that gets a lot of recognition is the importance of the function of these organisms in terms of maintaining the barrier of the gut, the gatekeeper. It is the gatekeepers that determine what can transcend from being a gut-related chemical to getting into the body and influencing things like metabolism and certainly inflammation, a cardinal feature of neurodegenerative conditions in general. We take that science a little bit further and recognize that, strangely, these levels of metabolites coming from the gut have a role to play in the maintenance or destruction of the blood-brain barrier, which regulates what can get into the brain and influences whether the brain is healthy or not. To conceptualize the idea that our gut organisms are influencing the patency and functionality of the blood-brain barrier is pretty profound.

It’s scary from the perspective of what’s going on concerning these gut organisms these days, but on the other hand, it’s empowering because it allows us to conceptualize approaches to stabilize both the gut barrier and the blood-brain barrier. Something as simple, for example, as extra virgin olive oil has been demonstrated in comparison to standard olive oil, I might add. I wouldn’t say it was a placebo, but it was an interesting study. Demonstrate that consumption in humans of extra virgin olive oil tends to enhance the way the blood-brain barrier can do its job. This is an evolving science, that’s for sure. What I just portrayed to you, I did not know at the time I wrote that the book about the gut-brain connection was called Brain Maker. This is a rapidly evolving area of science, and it’s so empowering. It’s so interesting, especially one area that I find interesting, and that is when we talk about the incredible number of bacteria that live within the gut, but guess what? Viruses living in the gut outnumber the bacteria by 10 to one. Viruses in the gut are, by and large, doing good things.

Everybody thinks of viruses, the pandemic, or whatever virus you want to eat. Whatever virus comes to mind immediately, we feel threatened. But we have a microbiome that lives within us that is involved in regulating the activity of the gut bacteria from moment to moment, such that we’re now seeing interventional trials giving these various types of viruses to regulate bacterial activity and hence have a manifestation in terms of improved metabolic health. We’re certainly seeing improved memory in rodent studies whose gut bacteria are modulated with what are called bacteriophages. These are viruses that are administered to laboratory animals and show improvements in memory. There was a time when we thought it was probably going to be a misfolded protein, end of the story when we could develop these monoclonal antibodies. Problem solved. That didn’t happen even as recently as two months ago. A third-generation monoclonal antibody directed against beta-amyloid was described in the New England Journal of Medicine. While it did pretty much dramatically lower brain amyloid levels in comparison to the placebo group, the change in cognitive function was negligible. What’s the point? Yet, when we look at the downsides, like the development of these areas or amyloid-related imaging abnormalities, these areas of micro hemorrhage, these areas of swelling, etc., it is pretty dramatic in the group receiving across the board these amyloid-related drugs in comparison to placebo. That is certainly not a free ride, especially in the context of not harming.

Dale Bredesen, MD

Great point.  You may have seen the piece that just came out, a study from UCSF looking at a thousand people with PCA, Posterior Cortical Atrophy, also called Benson’s Syndrome. Professor Benson was a professor at UCLA who described this syndrome, which largely affects the parietal and occipital lobes. It turns out to be a presentation of Alzheimer’s disease. Now, the point of the article was that it’s not 70% that turn out to be Alzheimer’s. If you look at biomarkers, it’s 90%. I use this as a way to bring up biomarkers as such a rapidly moving field and also to bring up the fact that in the paper, what they said was that virtually all these people have Alzheimer’s disease, but there’s nothing we can do about it except to give an anti-amyloid antibody that might slow it up a little bit. On the other hand, we have firsthand seen people who have PCA revert their PCA. We have a woman recently who got back her ability to read, who got back her ability to work on the computer. Someone was working with Kerry Mills Rutland, a wonderful brain health coach from New York. Again, this is part of the new era, but this ushers in the issue of when do you look at your biomarkers. Could you give us a little synopsis of your feelings about the blood biomarkers—the p-tau, the 42/40 ratio, GFAP—all these things that have not been available before suddenly become available?

David Perlmutter, MD, FACN, ABIHM

I sense that we’re right at the very beginning of understanding the utility of looking at these biomarkers. that as it relates to tau and amyloid-related biomarkers, while interesting, we need to be more upstream of that when these have started to both enter and exit shallowly. We’re already in a situation where the brain is compromised, allowing this to accumulate. It’s valuable to go upstream, and there is a suite of newer related biomarkers, such as neural filament and light chain. One that I like is ACL carnitine, which is involved in the maintenance of membranes and fatty acid metabolism, gene expression, and protein functionality, but most importantly, mitochondrial function. It leads me to a part of our discussion where I want to lay my nickel down. At this stage of the game, though, maybe I reserve the right to pick my nickel up in five years when we talk again, but that is ultimately we are going to see that regardless of the subtype of Alzheimer’s and indeed other neurodegenerative conditions, they are a manifestation of mitochondrial dysfunction, i.e., an acquired mitochondrial apathy.

As we look at mitochondrial function, we are moving forward in terms of biomarkers that reflect the same measurements of free radical media, like serum lipid peroxide, DNA, oxidative stress, etc., protein, and carbon yields. As it were, we are going to find markers that are modifiable in terms of intervention that we can follow over time once we begin to target mitochondrial function. The reason I’m getting back to this notion of being as upstream as possible that I want to go there is because we are seeing studies in Alzheimer’s using metformin, which targets mitochondrial function by downregulating complex one and hence leading to increased levels of autophagy, i.e., the clearing of dysfunctional mitochondria, which then paves the way for the growth of better mitochondria and mitochondrial biogenesis. But the influence of mitochondrial function on immune function. We know that mitochondrial function is compromised, as you mentioned earlier, by inflammation, which gets back to the gut, and that’s further downstream as far as I’m concerned. But mitochondrial function does relate to the functionality of a variety of cells in the brain that are involved in immune functionality in the brain, like the microglia that ultimately and in peripheral macrophages as that mitochondrial function is a powerful determinant in terms of is that macrophage going to be friend or foe that these macrophages and in the brain the microglia exist in at least eight different isoforms but let’s just say two, for now, a good M2 characterize phenotype or functional microglial cell that wants to digest damaged proteins, that wants to assist in the development of synapses, that wants to aid in the process of growing new neurons, and then its evil twin, the M1 phenotype which fosters the growth of these abnormal proteins that tends to not support the health of neurons.

It tends to want to digest away the synapses, and the difference between these two is strongly influenced by mitochondrial function. In high school biology, we learn about the power plant of the cell. I get that. But when we now recognize,  that mitochondrial function is upstream of immune regulation, it’s upstream of inflammation and influenced by inflammation as well by directionally, it is highly influenced the function of mitochondria, by the things going on in,  in another country in the gut, things going on in the mouth and things going on related to nitric oxide, the food we eat, the care we take of our mouths, whether we’re using steroids in our sinuses or not, whether we’re eating a food that’s high in ultra-processed foods, whether we got a good night’s sleep last night or not, whether we’ve had repeated head trauma via the sports in which we engage so many factors over which we have control right now that lead to Rome, that ultimately to are they going to be helpful or hurtful as it relates to mitochondrial function,  are so valuable when we can break them down and provide bullet points for individuals to understand why it is they need to exercise each day.

They need to understand what their blood sugar is doing by wearing a continuous glucose monitor. They need to take a certain suite of supplements in our time when supplementing the foods that we eat makes sense. Wearing a helmet when we’re involved in riding a bicycle, a scooter, or snow skiing—all of these things are incredibly valuable because, as I mentioned earlier, we are the architects of our brains and destiny. It’s where you come into play when things have begun to manifest when we see changes in these blood markers that are related to talent related to amyloid, and then we follow them to determine the efficacy of the intervention. Exceedingly valuable, but I’m more inclined to think that something as simple as knowing your insulin level fasting, knowing how your blood sugar responds to your food by wearing a continuous glucose monitor and making darn sure that you’re getting good sleep and measuring it wearing an Oura ring or an Apple Watch, whatever it may be, These are the actionable points that we can be taking today. John Kennedy said that the time to fix the roof is when the sun is shining. I hope that while individuals are watching our time together right now, many of them are thinking about what I can do for my spouse, my mother, my father, or another loved one. Those who are intact cognitively can understand that in this day and age, prevention is the key and anyone can do it.

Dale Bredesen, MD

Great point. I’d love to get your opinion on some very practical matters. Number one, someone says, David, you’re right, my mitochondria aren’t functioning. How would you like to support mitochondrial function?

David Perlmutter, MD, FACN, ABIHM

I’d say that exercise is probably the biggest thing that you can do. that we don’t want to damage our mitochondria, and we damage them when we have higher levels of inflammation in the body. A very sophisticated tool that we can use is called a tape measure. You put it around your waist, and you look at the number. I’m not a real keen fan of so-called BMI, but being overweight and certainly obese threatens mitochondrial function. But by all means, exercise each day, get a good night’s sleep, and keep your blood sugar under control. I’m not sure that’s half the battle. It could be 48% of the battle. It could be. Who knows what percent? But those are the big three that relate to brain health, heart health, and maintaining a healthy body in every way. The reason it’s so influential as it relates to brain health is because the brain is the most metabolically active part of the body. It’s the most demanding for blood supply and insulin functionality. using variously quoted 25% of our resting energy while representing only two to 4% of our total body weight.

But that said, it’s metabolically active. It’s going to be where a metabolic issue manifests itself. 85–90 million Americans are either pre-diabetic or diabetic now. That is a situation in which their metabolism wants this. That’s the medical term. But with all due respect to those individuals, pretty much becoming pre-diabetic or diabetic is a choice. It’s not something we inherited because mom or dad had it. This is based upon how much time we spend sitting down, how much time we spend actively involved in exercise, how much sleep we get, and certainly what we eat. I emphasize sleep because it’s valuable to understand that sleep is hugely influential in terms of insulin functionality the very next morning. How do I? I went to sleep at ten, and I woke up at seven. I got a good night’s sleep. did you? What is the quality of sleep? How many times did you wake up? How much deep sleep did you get? Which we all know is important for the brain in terms of activity in the emphatic system. How much REM sleep did you get, which is important for the consolidation and contextualization of our daily experiences? We don’t know that unless we metastasize our sleep, i.e., go out and buy whatever wearable device we want to buy now and find out the very next morning. I slept for seven and a half hours, and here’s how much time I sleep. I spent in REM sleep here; how much time did I spend doing this or that? For me, I’ve learned some interesting things by wearing an Oura ring. I’ve learned that my deep sleep is compromised. If I have a single glass of wine,  we’ve changed our positioning on recommendation 4, which had been in place for many years.

I’m going to say that while we enjoy the glass of wine, in an interview I did with our Dr. Austin Perlmutter, he said, You’ve got to think about the upsides of the social interactions that are fostered by having a glass of wine with somebody. I get that. But for, I recognize that polyphenols are good for me, but they immediately compromise deep sleep, and I’m not in a position to be particularly fond of that response. Is it then worth it? Not so much. I might still have a glass of wine from time to time, but alcohol is a neurotoxin. We recognize that. At this stage of the game, nobody’s getting any younger. As we age, we have to tighten up even more on the lifestyle choices that we make.

Dale Bredesen, MD

In related questions, what do you think about CoQ,  PQQ,. L-car within a wall, all these mitochondrial supports? What’s your take on these?

David Perlmutter, MD, FACN, ABIHM

It’s valuable to not take the CoQ10 and other forms of CoQ10 that are out there; you become known. You become all very people are arguing one side of the other. I don’t think it’s fair to take them off the table. We’ve seen some pretty darn good literature in the past that was supportive of mitochondrial upregulation with intervention. Perhaps the studies were not using a high enough dosage, etc.  We’re never going to find a single intervention to be studied, and to have a dramatic effect using cocaine along with something else you measured, alka-acetyl-l-carnitine is a good consideration. We’ve seen good literature related to alcohol. We’ve seen nice literature related to uplift in a way that relates to this whole notion of increasing mitochondrial function.

In a recent report that came out about a month ago, which reviewed the whole notion of mitophagy, or ridding our bodies of defective mitochondria and then allowing mitochondrial biogenesis to occur, olefin was listed along with a ketogenic diet, caloric restriction exercise, and your listening as an intervention. that looking at these in isolation may not show dramatic results. But as you have shown us, the notion of monotherapy is that it’s past its prime. The idea of monotherapy because it can be monetized—call it like it is—allows the development of specific drugs that are home-grown. But we’ve now got to look at brain metabolism, or the preservation of cognitive function, and brain metabolism as it relates to an individual with a degenerative problem. We’ve got to utilize multiple modalities—not just supplements and pharmaceuticals, but other lifestyle changes—and throw everything we can at this degeneration. As you have so elegantly demonstrated, we can turn it around.

Dale Bredesen, MD

Someone brings the car in and says my car’s not working. You say, What’s the one thing I can tweak to make your car’s ills go away? That doesn’t make a lot of sense. This, as you pointed out, is a systemic issue. It’s a metabolic issue. Yes, the brain is involved. But these are all things that work together in the thought that you’re just going to take one little thing and it’s going to fix everything, which is rapidly becoming outdated.

David Perlmutter, MD, FACN, ABIHM

But you have to have the data; you have to assess. There are some universalities that we could throw into the mix, some of which we’ve already talked about, including the lifestyle issue. But it reminds me of the time I pulled into the gas station because I thought my tire was low, and the guy in the gas station said it looked like a flat tire, but we’re going to run a bunch of tests just to be sure. I guess you can overdo it. But vis-à-vis your discussion earlier about what are the biometrics. Year by year we see new and exciting things being developed, especially related to mitochondrial function, but for some of the simpler issues that we talked about, like blood sugar and certainly insulin fasting, insulin level, etc., we want to make sure homocysteine isn’t elevated. We want to make sure B12 levels are where they need to be. There are a lot of things, but, right away as we have this discussion, we are running contrary to the mainstream approach that people are suffering from, a drug deficiency or whatever. Back in the day, it was Donepezil or Aricept. We think you need to have this or you’re in trouble. No. First, let’s define what the deficiencies are. We will complete those that are unique to that individual and do some genetic testing to determine what else may be going on. Where else do we need to look? Look at things like MTHFR to determine if that person is likely to require a methylated B vitamin intervention and may have elevated homocysteine. There’s a lot there, but to be positive, many pieces of this puzzle are now in place. The myopic view is that a single drug therapy is going to be the home run. I would embrace that as much as you would, too. We’re not anywhere near it yet. It’s going to be a multi-modality approach that’s already proving to be effective.

Dale Bredesen, MD

It has to be about outcomes more than incomes. We need to look at what’s working here. What other quick thing is here? Prebiotics, postbiotics, and probiotics. What’s your recommendation for people on those?

David Perlmutter, MD, FACN, ABIHM

This is also an excellent question. As time goes by, we’re seeing advances in all three areas, even a postbiotic. That’s what Urolithin A is. We mentioned Urolithin in the context of mitochondrial function. Urolithin is the manifestation unless you buy a product. But we’re making Urolithin when we eat certain foods like pomegranate. We’re making Urolithin from ellagic acid in the gut bacteria, which converts it into Urolithin A, which then does the wonderful things that it does. The good news is that you can buy that as a supplement. We are going to see continued wonderful advancements in probiotics, primarily in combinations of prebiotics to nurture the probiotics, and certainly in the arena of postbiotics, or the products made by the bacteria within us, as people are hard at it. The exciting new science of Akkermansia muciniphila. in terms of regulating metabolism, is very exciting. Seeing both live products as well as pasteurized products demonstrates significant activity. I am hopeful that we will recognize two things: that intervention concerning reestablishing health as it relates to our microbiomes is going to take hold more aggressively. But also, I hope that the science that is revelatory in terms of how we are damaging our microbiomes today will take hold as well. 

Recognizing that drugs that are so commonly taken, like NSAIDs, for example, an NSAID non-steroidal anti-inflammatory drugs like ibuprofen, have a profound effect on the gut bacteria, and people who are chronically taking that type of drug for their arthritis, pain, or other issues have a very significant increased risk of dementia and vascular disease. Having a stroke. The same thing holds with acid-blocking drugs that people think they need to take because they had indigestion after they consumed some horrendous food. You look at the television commercial; people are eating awful foods, and then they pop a pill over the counter. These drugs are not a free ride, and these studies have been published, but yet they don’t enter the mainstream, you’re right, I forgot how you said profit versus what you said something earlier that I want to try to remember, and that is.

Dale Bredesen, MD

Income versus outcomes.

David Perlmutter, MD, FACN, ABIHM

Income versus outcome. Yes, it’s the income of people who are involved in the distribution of these drugs versus the outcome that I just described. about the care and feeding of these organisms that have your interest and your health in mind. We say that when a woman is pregnant, she has to be careful now as if she hadn’t before because now you’re eating for two. We’re each eating for billions; everything that we consume is affecting billions and billions. I sound like Carl Sagan of organisms that live within us and upon us and are directly involved in keeping us healthy, that are directly involved in the expression of our DNA, our life code. We can choose to ignore that information or embrace it as empowerment. Interestingly, we come back to the microbiome.

Dale Bredesen, MD

As you said earlier, this idea of anti-aging is everything now about reversing your age, and is that going to get rid of these problems? It’s going to be very interesting to see. So far, it’s looking at a couple of years. You’re not looking at decades. Cellular reprogramming may have done that for decades, but are you going to clean up all the thinking about that?

David Perlmutter, MD, FACN, ABIHM

We’re just thinking about that. We will see. Where Dr. Sinclair and the Yamanaka factors go. Having said that, depending on what metric you use, are you looking at telomere length or methylation clocks? Are you looking at functionality? To me, functionality is probably the most valuable thing to look at. How functional are people? How is their balance? How is their endurance? How fast are they walking? What is grip strength? What is the cognoscopy function? The term that you coined, how are they working cognitively? These metrics, functional metrics, are very valuable. Should there be stabilization or improvement in these? To me, it’s then that you’re accomplishing a job well done, and we will see where the methylation clocks go. But interestingly, since you looked at cellular reprogramming, we know that’s going to be about human health decades from now. But wow, that is some amazing science, and for sure, having said that, there is something a little closer on the horizon where we recognize that over time we accumulate.

Yes, our telomeres shorten. Yes, we accumulate these methylation changes on our DNA, but we also accumulate cells that are in a state of what we call senescence. As our cells change, they can either die, undergo apoptosis, or preprogrammed cell death. They can replicate themselves suddenly, quite aggressively we call that cancer that’s on the other side of the spectrum. Or they can enter a stage that should not be called dormancy, but a stage in which they’re doing neither. They’re not dying, and they’re not proliferating. We call them senescent cells, and they’re not dormant because, in this situation, these senescent cells are creating products that are influencing neighboring cells. There the cells enter a phenotype, senescence, associated secretory phenotype, and sass, meaning that they’re secreting chemicals that are doing bad things around them. We’re getting a lot of new understanding that the accumulation of these senescent cells over time is important as it relates to the aging of humans throughout the body. There are now techniques created to measure them, measure their accumulation, and then measure the effectiveness of so-called Senolytic Therapy. Therapies that are designed to rid the body of these senescent cells. One biomarker developed at the buck has some promise. A lipid-based biomarker, but certainly beta-galactose. This is being used now in other laboratories. As we look at the notion of treating these senescent cells, getting rid of them, or modulating them in terms of their activity by genetically manipulating them, certain chemicals can do that.

So that’s the difference between a senolytic therapy and a senomorphic therapy. But it may allow us to use existing supplements like quercetin, for example, or pharmaceuticals like Sinomed, which are being used in combination with D and Q, not DQ which would be Dairy Queen, which is being evaluated in clinical trials now to get rid of these senescent cells in the human body and determine what the outcome may be. There are a lot of interesting things that are developing, and we just have to do our best. You and I are you, and I have to stay as healthy and cognitively intact as we can so that we can ultimately leverage these new technologies and message to anyone listening that these things are on the horizon.

Dale Bredesen, MD

We should note, while you’re on that, that both the Senescence Associated Beta Gal and the SASS were discovered by the late Judith Campisi, a tremendous professor who I recruited to the book many years ago, who came over from Berkeley and contributed tremendously, including those two critical discoveries. Thank you, Judith, for that tremendous work. Let me finish with chronobiology because, again, it’s an interesting area. When you eat, it’s important, not just what you eat. Tell me a little bit about what you recommend. Two meals a day, three meals a day, and one meal a day. What times do you think are best, and do you think that metabolic flexibility is important? Do you think that ketosis is important at this time? These are all related to brain health, so I’ll finish up with that.

David Perlmutter, MD, FACN, ABIHM

The answer to, I guess, all the questions is yes. When we look at the work of Dr. Satchin Panda and many others,  our DNA, and therefore our physiology and metabolism are included in that, has evolved as a consequence of the selection process that has formed the DNA that we have today. For 99% of the time that we’ve been on this planet, we have interacted with our environment and been informed by our environment in such a way as to assure our survival and our ability to reproduce in our environment. Includes big things like the time the sun comes up and the time the sun goes down and the availability of certain seasonal foods, for example. To be fair, we’ve lost that connection in a very big way. As such, we are influencing our physiology and our genetic expression in such a way that they are not able to function appropriately and certainly are not able to adapt. We pretty much have a Paleolithic genome. If not, it’s certainly a Neolithic genome. Influencing that genome, the expression of that genome, and our physiology based on modern-day influences like light in the evening, staying up late to watch TV, eating late in the day, and eating foods that have such a negative interface with our physiology and our genome threatens health.

Humans traditionally, as hunter-gatherers, mostly gathered, though they did hunt, we were beings that functioned in a life of feast and famine. As such, the notion of not being confronted with famine but being in a state where we’re not supplying ourselves with food for periods primes the body to be healthy so that it can survive and therefore be smart enough, adept enough, and strong enough to get that next meal. Aren’t those three things that we want to have going for them: to remain healthy, to be smart, to be adept, and to be strong? Those are the keys to health. therefore, to emulate or simulate the lifestyle of our ancestors. Getting back to the work of Dr. Lauren Cordani, who made us aware of this sort of paleo idea that we’re trying to present to our genome an environment for which it would be most conducive to health, has merit, and therefore goes to sleep when the sun goes down. that, of course, changes based upon your latitude in time of year, but getting enough sleep, getting back to what we’ve talked about earlier, and making sure that that sleep is restorative, is the most salubrious type of approach we can get. Timing our meals such that we challenge our bodies to fast as frequently as possible.

Now, when I say fast, people think, Oh,  40 days and 40 nights. No, I’m talking about 12, 14, or 16 hours, meaning extending that period between dinner and breakfast. When do you break, you fast? My practice is to generally not eat before noon. We have an early dinner. We’re now early birds and special people. If we go to a restaurant, we’re getting the early bird special. I feel like I’m on a Seinfeld episode. But most of us mostly eat at home, and we eat early, and then we don’t go to sleep with a full belly because that just doesn’t feel right, and it’s not right. You shouldn’t be doing your major digestion at bedtime. Your brain’s got a lot of work to do at night, and that food should be fully digested and available. The brain needs to be fueled. When we sleep, our brain is doing a lot of work. People think your whole body shuts down. A lot of other things are powering down, but not the brain. That gets back to our discussion of understanding the quality, not just the quantity, of your sleep.

The answer to the question is that getting into ketosis from time to time is a good thing—a very good thing to maintain what you described as metabolic flexibility. That’s a hallmark of a physiology that’s adaptable and that can deal with confrontations. Our lives are full of confrontations when we travel when good foods aren’t available, and therefore we don’t eat, which is what my default is, or we’re forced to eat at times, whatever is at the conference, right, or whatever is available. To have metabolic flexibility is very important. Dropping into ketosis is a good thing. I’ve mentioned a couple of reasons why enhancing this notion of senolysis or getting rid of these senescent cells is certainly a way of enhancing mitophagy or purging the body of these dysfunctional mitochondria. Getting into ketosis is worthwhile.

How would know? While you can measure, for me, I’ll know based on my blood sugar by wearing a CGM, or Continuous Glucose Monitor, which is very valuable. But, truthfully, in a 24-hour fast, that’s what’s going to happen. How much autophagy or getting rid of all sorts of damage? Other components beyond mitochondria that one activates with a 24-hour fast are unclear. It varies with the individual, but there’s not a great metric for that. Everybody talks about, how I fasted for X like the time because I wanted to turn on autophagy and rid my body and my cells of defective components. But how do you know? You don’t know. But we’ll have good markers in the future for that. But for now, it’s a good thing to do from time to time in an orderly manner, or maybe even extend that for a couple of days. But the notion of time-restricted eating—that’s certainly a way of fasting for some time. that there’s pretty good evidence that this is something worthwhile for us.

Dale Bredesen, MD

Dr. David Perlmutter, thank you so much for your tremendous work over the years, which has helped to lead to a reduction in the global burden of dementia, improved brain health, better prevention, and better understanding. Thank you very much. Fantastic stuff. I look forward to our next discussion.

David Perlmutter, MD, FACN, ABIHM

Thank you. Dr. Dale Bredesen. Good to see you, and I am looking forward to seeing you soon.