Thursday, October 17, 2019

Flavonoids and Brain Health. Podcast with Dr. Pamela Maher

More than 2000 years ago, the Roman poet Virgil wrote, “Time robs us of all, even of memory.”

Humans have long recognized the insidious toll that aging takes on the body – including the brain. But it is only very recently in our history as a species that we have been able to conceive of plausible ways to halt or even reverse it. As we gradually unveil the fundamental mechanisms of biological aging, we are starting to develop interventions that directly combat the diseases emanating from this process.

And there is surely no target of this kind of research that is more important than the brain. Your brain, after all, is what truly makes you who you are. For most of us, the threat of losing our memories, our personality, and our connections to one another is perhaps more frightening than anything else. 

It is also a daunting challenge. Modern medicine has enabled us to repair or even wholly replace many other parts of the body, including vital organs. And in the future, exciting advances in regenerative medicine may allow us to develop new tissues from our own cells, to restore those that are lost to injury or disease. But how do you regrow or replace an aging mind?

Indeed, research into medical interventions to address problems associated with aging in the brain has been particularly disappointing. Just as one example, pharmaceutical drugs designed to treat Alzheimer’s disease have the highest failure rate of any disease area (99.6%). This dismal situation isn’t much better for other conditions (like stroke, Parkinson’s, Huntington’s, ALS, etc).

Why is this? One reason, perhaps, is that the brain is terribly complicated, and a constellation of different factors have been implicated in age-related decline in the function of the brain. Consequently, using a drug to target a single aspect of the disease process (for example, eliminating soluble amyloid-beta in the context of Alzheimer’s disease) is unlikely to be completely successful. To have any chance for solving this monumental problem, it is thought that we will need to identify molecules that have multiple biological activities and ameliorate multiple aspects of aging. And that brings me to our guest for today.



In this episode of humanOS Radio, Dan speaks with Pamela Maher. Dr. Maher has a Ph.D. in biochemistry from the University of British Columbia. She was formerly an associate professor at The Scripps Research Institute in La Jolla. In 2004, she moved to her current position as a research scientist at the Salk Institute for Biological Studies.

Her research has centered on understanding responses of nerve cells to oxidative stress, and how chemical compounds can modulate these responses to enhance nerve cell function and survival. Her current work is focused on using natural products such as flavonoids to maintain nerve cell function in the presence of toxic insults. Flavonoids are a diverse class of secondary metabolites found in almost all fruits and vegetables. One of the great advantages of these phytochemicals, in this particular context, is that they are tiny molecules – small enough to cross the blood-brain barrier. This has been convincingly demonstrated in studies of rodents. For instance, when rats are fed blueberries for ten weeks, and then dissected, anthocyanins from the fruit can actually be found distributed inside the brain!

Maher and her colleagues have been focusing their attention particularly on a few of these flavonoids as potential neuroprotective agents. One of these is fisetin, a flavonoid that is most highly concentrated in strawberries. We have discussed it previously on the show as a possible senolytic agent. Maher and her group have been developing more potent and more bioavailable versions of the flavonoid that might protect nerve cells and even promote learning and memory. Good stuff! 

Another phytochemical we’ll be discussing on the show is sterubin. Sterubin is a flavonoid found in Yerba santa, a plant that native tribes in California have long prized for its medicinal properties. When Dr. Maher screened for plant extracts that could act on toxicity pathways relevant to age-associated degenerative disease, sterubin emerged as one with broad protective effects in cell assays.

To learn more about the power of flavonoids, and the future of anti-aging research, please check out the interview below!



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Pamela Maher: 00:00 The first compounds we did was a fairly small group of different Flavanoids and Fisetin stood out among all of those because it had all of these activities and it was also particularly good maintaining the intracellular levels of glutathione.
Dan Pardi: Hello, everyone. Welcome back. Today I would like to welcome Dr. Pamela Maher to humanOS Radio. Dr. Maher has her PhD in biochemistry from the university of British Columbia. She formerly was an associate professor at the Scripps Research Institute in La Jolla in 2004, where she’d worked for about a decade. Then she moved to her current position as a research scientist at the Salk Institute for biological studies also in La Jolla. Her research is centered on understanding responses to nerve cells to oxidative stress and how chemical compounds can modulate these responses to enhance nerve cell function and survival. Her current research is focused on using natural products or just Flavanoids, which are polyphenolic compounds that are widely distributed in fruits and vegetables and herbs to maintain cell function in the presence of toxic insults. This is particularly relevant in the context of dementia and other neurodegenerative diseases associated with aging.
00:16 Simply getting older is a leading risk factor for many chronic diseases in our modern world, and as we’ve come to better understand the fundamental mechanisms of biological aging, we’ve begun to try to develop interventions that delay or even entirely prevent diseases from emanating during the process of aging. All tissues in the body are subject to the ravages of aging, including the brain and unfortunately research into medical interventions to address problems associated with aging and the brain had been particularly disappointing. Drugs to treat Alzheimer’s disease have the highest failure rate of any disease area. 99.6% of the trials have failed and the situation isn’t much better for conditions like stroke, Parkinson’s disease, Huntington disease, ALS, et cetera.
Many different factors have been implicated in the age related decline and function of the brain. Consequently, using a drug to target a single aspect of the disease process, just as an example, eliminating soluble amyloid beta in the context of Alzheimer’s disease, is unlikely to be successful. We need to identify molecules that have multiple biological activities that ameliorate multiple aspects of the aging process and that is very much what Dr. Maher has been focusing on of late. So Pamela, welcome to humanOS Radio.
Pamela Maher: Thank you. That was a great introduction.
Dan Pardi: To begin, I’d love to hear more about your research background and how you became interested in therapeutic uses for Flavanoids.
Pamela Maher: 02:15 My background historically was more on small proteins called growth factors or in the brain, similar proteins are called neurotrophic factors. They are produced by the cells in the brain and they play a role in maintaining nerve cell function and they’ll help. Quite a while ago now I was working on these and we got interested in seeing if they could help prevent nerve cell death. That led us to develop some models of nerve cell death and it turned out that these factors, actually the one I was working on, did not work well in the context of nerve cell death. But then we got interested in trying to identify compounds that might be effective and particularly these neurotrophic factors are proteins, so they’re big and they’re very difficult to get into the brain and they’re also very difficult to use for therapeutics because if you take them orally or something, they’d broken down in the stomach.
So we started looking for small molecules that might actually protect nerve cells and also have a better chance of getting into the brain. When we thought about where do we start with this, we realized that many of the major drugs that are out there actually came out of plants, so we decided to go back to the original pharmacy, which is plants and start looking at some of those compounds. We decided to focus on Flavanoids, which as you mentioned are a polyphenolic compound because what had already been reported on them suggested that they had at least some of the activities that we thought could be beneficial for promoting the health and survival of nerve cells. That led us to beginning our studies looking at different Flavanoids and also looking at extracts from plants that have a historical use for pharmacological purposes with traditional societies.
Dan Pardi: 02:17 These small molecules, Flavanoids that can cross the blood brain barrier because of their size, are there other structural components to these compounds that make them particularly interesting for brain health?
Pamela Maher: There’s sort of a misconception out there that Flavanoids are all pretty similar. There’s something like 4,000 different Flavanoids that have been identified in different plants and they’re actually quite specific in their activities. For instance, one of the compounds we’ve been working on recently, Sterubin, another flavonoid that is almost the same. It just has one group that is shifted in position and it is completely inactive in our assays. We’ve also found recently that just another little change in the Sterubin structure completely eliminates its anti-inflammatory activity.
02:25 Historically, there’s been arguments that these compounds can be potent antioxidants and that’s true in test tube assays or cell culture essays, but it’s pretty much thought that in animals and in people, the direct antioxidant activity isn’t all that relevant because the levels of the Flavanoids are going to be quite low relative to compounds like vitamin C, ascorbic acid, which is also an antioxidant and is found at much higher levels in the blood. So it’s now thought that one of the activities that a lot of these Flavanoids have is the ability to induce certain antioxidant pathways that lead to the production of a variety of endogenous antioxidant proteins. So they’re not directly antioxidants, but they increase the synthesis of a number of proteins that the cell makes that can have antioxidant activities. So that may be one of their more common properties that a lot of these compounds have this activity.
Dan Pardi: This reminds me of a former guest that I’ve had on, Dr. Michael Ristau out Switzerland. We discussed primary and secondary antioxidants. Primary being ones like vitamin C and D that directly quench free radicals. Secondary antioxidants, instead of actually quenching those free radicals, stimulating the production of endogenous antioxidants. In doing so, there’s other gene pathways that are activated like suppression of cancer pathways that have benefits that you don’t want to suppress if you quench those free radicals too powerfully with high doses of vitamin C and E. It seems like we’re having an increased appreciation, but it’s the induction of our body’s ability to produce these antioxidants that generate a lot of the health benefit, so there’s a huge amount of Flavanoids that exists. There are two compounds that you honed in. Fisetin and Sterubin. How did you identify that these were the ones that had interesting properties that you wanted to explore further?
Pamela Maher: As I mentioned, we were interested in understanding how nerve cells die and also understanding how we could develop assays to test for compounds that would protect from this. A number of years ago now, we’ve created a battery of different assays that we think mimic a variety of the changes that occur in the aging brain. These include an assay for protection against oxidative stress induced death. Another assay for protection against energy loss. There’s a decrease in glucose energy production in the brain and aging. One of our main focuses of the lab is on Alzheimer’s disease, so we have a specific essay for protection against the amyloid peptide toxicity. We also think that having anti-inflammatory activity is very important. There’s an increase in inflammation in the brain with aging and that’s exacerbated in all of the neurodegenerative diseases you mentioned earlier. We also think it’s important to have molecules that could potentially mimic these growth factors or neurotrophic factors that I’ve mentioned earlier.
04:09 So we put together this set of assays and we run of collections of compounds, particularly Flavanoids and also plant extracts, through these different assets. The first compounds we did was a fairly small group of different Flavanoids and Fisetin stood out among all of those because it had all of these activities and it was also particularly good maintaining the intracellular levels of glutathione, which is a major endogenous antioxidant that cells make. That was what led us to pursue Fisetin, then other studies suggested that it did work in mice in a various models that we tested it in, so we have kept working on that and then the Sterubin story is more recent. That actually came out of screening plant extracts that had a history of medicinal use and we identified the extract from a plant that’s native to California called Yerba Santa. The species we use was eriodictyol californicum. We then characterize the different active compounds in that it turned out that the most active, or the only one that was really active in all of our essays was the flavonoid Sterubin.
Dan Pardi: I’ve got some more questions on Sterubin in a moment. Let’s go back to Fisetin. This is a compound that’s come up on the show before. I interviewed Paul Robbins, who’s the head of aging research at the University of Minnesota. He and James Kirkland have been involved in a study together looking at the usage of Fisetin in high doses to clear senescent cells. As a reminder for our listeners, where do we find Fisetin in nature?
Pamela Maher: 04:22 It’s actually a fairly rare flavonoid. It’s most abundant in strawberries but you would have to eat quite a few strawberries to get the kind of doses that we have found effective in our animal studies, maybe even more so that they found effective in their studies on aging in mice. There’s other sources but they’re all pretty low so actually getting it from the diet can be a challenge.
Dan Pardi: When you consume them in natural fashion is that effect hard to see because it wouldn’t show up in a six week study but it does make a meaningful impact across a lifespan if you have, let’s say, high strawberry intake in your diet?
Pamela Maher: It’s really hard to know. For instance, in the context of Parkinson’s disease there is some evidence that people who consume more berries, which would not just be Fisetin but other Flavanoids as well. There is epidemiological evidence for a lower incidence of Parkinson’s disease, but it’s not specific to Fisetin. Most of the epidemiological studies either look at a group of fruits or vegetables or sometimes specific ones, but they don’t narrow it down to the specific compounds that are present in those fruits or vegetables.
Dan Pardi: 05:53 It’s like the drug discovery approach versus the natural health approach, which is the high consumption of a variety of plant compounds over time versus the identification of the most potent compound and its clear effects on physiological parameters in a timescale and that’s not necessarily the whole life span. It’s an interesting question. What were some of the results of giving Fisetin to animals?
Pamela Maher: We saw a variety of things. Our initial studies, we found that it could improve memory in normal mice on a very simple memory test that’s called the object recognition test. We identified at the basic level in the brain working with a colleague in Japan that it increased what’s called longterm potentiation in the hippocampus, which is the main part of the brain involved in memory. Loss of memory is the major hallmark of Alzheimer’s disease. We then have gone on to test Fisetin in multiple mouse models of Alzheimer’s disease. The transgenic model, which mimics the very rare genetic form of the disease that a very small percentage of human patients have this genetic form and also a model that we think mimics more closely the sporadic form of the disease, which is about 98% of all of the Alzheimer’s disease patients. We also saw beneficial effects in a model of diabetes, particularly on kidney function in the context of diabetes, and we’ve had some positive results also in a mouse model of Huntington’s disease, which is another neurodegenerative disease where there’s really no good treatments.
Dan Pardi: 06:42 So this flavonol has neurotrophic activity. It enhances learning in a healthy population of animals. It preserves cognition in various models of either accelerated aging or Alzheimer’s disease and Huntington’s disease. From what these models and research tell you is, it’s not necessarily something that would just be a pharmacological therapy when you have an existing condition, but it’d also be something that might preserve brain function and health over time.
Pamela Maher: Yes, and that’s what James Crooklyn and Bo Robbins, more of their focus of their research with this. Well, preservation of function with aging.
Dan Pardi: Always better to try to avoid getting conditioned and trying to treat it once it’s there, but both are important. Let’s switch gears to the Yerba Santa. I liked your approach here. No plant is more highly valued as medicine by all tribes of Mendocino County and this is the treatise published in 1902 on plants used by native peoples in Mendocino County. That’s interesting that this has been used as medicinal therapy for a long time. You mentioned it before, but how did you go about finding Sterubin as a promising compound to investigate further?
Pamela Maher: 08:53 We first identified in this collection of different plant extracts that the Yerba Santa extract was one of the very best in all of the assays that I mentioned. We use a technique called high performance liquid chromatography, HPLC, to fractionate the different compounds to separate them out in the Yerba Santa extract and we then tested each of those in our primary assay and there was just one of these fractions that was active. Then we use a technique called mass spectrometry to identify the mass and then you can use it in a different way to break up the molecule and look at the fragments of the molecule and each molecule fragments in a unique way.
Based on that, we were able to determine that it was not two of the more common Flavanoids in Yerba Santa eriodictyol and homo eriodictyol, but rather it matched the fragmentation pattern of Sterubin, which was a surprise because this has not been studied much. I’m not even sure what other plants it’s found in. With this data we then found a German company that produced small amounts of Sterubin as sort of a byproduct of some other things they were doing and they were willing to send us some to confirm our results. So then we were able to do some more studies with the Sterubin from the company.
Dan Pardi: 09:13 After directly studying Sterubin, what were some things that you identified that the compound can do in your models?
Pamela Maher: It was very protective against multiple inducers of nerve cell death. It also has very strong anti-inflammatory activity and that was one of the major uses of the native tribes of California was for anti-inflammatory effects, particularly in their case was used a lot for lung infections actually. It also has this neurotrophic activity similar to Fisetin. We also found similar to Fisetin that both can bind iron. This is another way that these compounds can have antioxidant effects because too much iron can increase the production of reactive oxygen species, so compounds that can modulate or lower the levels of what are called free iron can have indirect antioxidant effects because they prevent this oxidizing effect of iron. So it’s like rust. I mean, if you have something with iron in it, it gets exposed to the air, you get rust, so it degrades more quickly and that’s kind of what happens.
Dan Pardi: 09:35 That seems like that would be a pathway of protection independent of its effects acting through the NRF2 pathway. How does it chelate iron? Does it directly bind to it? Does it induce a process that helps to excrete it?
Pamela Maher: These compounds can actually directly bind iron. There are several sites that can bind the iron. Many Flavanoids have what are called hydroxyl groups, so oxygen in combination with hydrogen and they’re fairly close together and the iron is generally bound between two of these hydroxyl groups. There’s a couple of sites on Fisetin that have been shown by other people to be able to do this. Sterubin has at least one of those pairs of hydroxyl groups, which is probably what binds the iron.
Dan Pardi: 09:47 That’s so interesting. If we have higher levels of iron that’s going to generate higher levels of reactive oxygen species. Those super high levels of reactive oxygen species can induce iron, induce apoptosis to cause cell death. So not only does Sterubin independently affect your ability to detoxify, but it also is binding the causative agent in this case, and so helping in a multifactorial manner.
Pamela Maher: There’s a reaction that’s called the Fenton reaction. It’s a chemical reaction and it converts a moderately toxic reactive oxygen species hydrogen peroxide to a much more toxic form, which is the hydroxyl radical, and this is mediated by iron, so that’s one reason it becomes much more damaging when you have excess iron that can cause this conversion.
Dan Pardi: 10:20 Do you know if any other metals are chelated by Sterubin?
Pamela Maher: I know that by Fisetin can bind copper and I would guess, but I haven’t tested that Sterubin also might be able to bind copper. But I don’t know that for sure.
Dan Pardi: 10:44 I’ve been hearing it pronounced differently. But you say Fisetin?
Pamela Maher: I don’t know. It was named before I started working on it. That was how I looked at it and said it, but I know a lot of other people pronounce it Fisetin, so I don’t know what’s correct. I don’t know if anything is correct. Whatever you want to say.
Dan Pardi: 11:52 So we see that it has a positive effect on preserving glutathione levels in the face of toxic challenges. It lowers reactive oxygen species, it chelates iron, which also can help lower reactive oxygen species. It induces certain antioxidants, proteins, and also has an anti inflammatory activity. Inflammation in the brain is one of the hallmark characteristics that seem to be consistent across a variety of neurodegenerative disorders. When you have something that’s powerful like this, do you foresee a therapeutic usage that would be regular ingestion of these types of compounds as something that could keep you healthy?
Pamela Maher: I need to be careful because I’ve been called out [inaudible 00:18:01] before. I personally think that at least Fisetin because we haven’t tested Sterubin in animals, but we’ve done a lot of work, as I mentioned with Fisetin in animals and it has appeared safe and I know it’s sold as a supplement and I haven’t really heard of any negative reports. So I think potentially Fisetin could be of benefit as the preventative, but it hasn’t gone through clinical trials. So this is speculative. James Kirkland, the man you mentioned earlier, is doing a clinical trial on what’s called frailty, which is in older people to see if it could reduce that.
12:18 I believe there’s another clinical trial listed, but it hasn’t started recruiting yet. I think it’s Fisetin in combination with something else that’s also for age related changes. But I don’t know the details of either of them, but those potentially could provide some hard data, at least the frailty aspects of aging that this might be beneficial or no, it’s useless. There’s also a trial for kidney function listed, at least on the website. So with Fisetin there are some studies that are at least starting that have the potential to provide some solid human data that this could be beneficial.
Dan Pardi: Whenever we’re isolating and taking a natural compound, but in a pharmacological dose, the dose that you would not get the nature through food consumption, it’s seductive to say this is something that’s going to be healthy because it’s natural, but there are some risks of that thinking. It’s that balance of excitement for ways to prevent conditions of maturity, but also sobriety that says this is the amount of data that we have now. We need to be cautious.
Pamela Maher: 12:27 If you’re interested in trying something, as I said, there’s a lot of animal data. People have been taking this for awhile. As far as I have seen on the internet there isn’t any evidence of toxicity, but you don’t want to overdo the dose either, so going crazy because the doses are going to be a lot higher than you would get from just consuming it in the diet. You do need to take some care but I don’t know. I think it’s hard to say. I think you mentioned everybody needs to make their own choice and definitely don’t start out with a whopping dose because really high doses for sure there’s no testing at all. Other thing I would add is that there are other groups of people that work on Fisetin in the context of cancer and it also has shown, at least in animal models, benefits in a variety of different cancer models. Cancer, which is also associated with aging, at least the increased risks of cancer. Not something it’s going to cause because it does seem to have pretty good anticancer activity as well.
Dan Pardi: I was having a conversation the other day with a friend who’s in the cannabis industry. They have an investment fund. There’s something that’s been talked about for awhile in that industry, which is this entourage effect. The idea that the compounds that accompany the THD versus the isolated cannabinoids are a part of the beneficial effects, so whether it’s the terpenes, [nercenes 00:20:55], lemonals, the other phytochemicals that come along act together relative to your work on these flavanols. Sounds like much of the effects can be isolated to a few active compounds. Let’s say a plant has 50 different phytochemicals contained within it, only a few of them seem to be causing the majority of the benefit. Is that what you’re finding?
Pamela Maher: 12:58 That’s a difficult question. That is what we have been finding, but for the most part it’s kind of what we’ve been looking for. But on the other hand, when we have had several studies where we fractionated plant extracts, the one with a Yerba Santa, but we had another one a few years ago where we identified a completely different compound. In both cases, there was really one active compound in the plant extract. It may have something to do with the nature of our assays, although they’re pretty diverse because as I mentioned, we’re looking not only at protection against cell death by different insults, but we also are looking for anti-inflammatory activity and the neurotrophic activity so we’re not just focusing on one potential activity.
There is still the possibility, which we haven’t explored very much, that combinations of these compounds might be more beneficial or you might be able to go to lower concentrations and that may be an aspect of the entourage effect that when we use these individually, they’re perhaps relatively high concentration and if you’re consuming them from the plant itself, perhaps in mixtures they’ll be more effective at lower doses. So that actually might be portion of the entourage effect that in combination with other compounds that are in the plant, even if one is maybe more active, it’s much more active at lower concentration when it’s in the presence of these other compounds.
Dan Pardi: Let’s look at one healthy meal, a salad, and it’s got herbs on it and it’s got a variety of citrus and in there you’ve got hesperidin and [inaudible 00:22:50], all these different compounds that come with it individually might lead to a modest effect, but overall you might be activating NRF2 transcription pathway through 15, 20, 30 different compounds that together lead to a more powerful effect. That’s really hard to study, but you can clearly see why that could be a true reason why aspects of a healthy diet come together to lead to the outcome we want.
Pamela Maher: 14:18 I think that’s quite possible. It’s not very hard to study pairs of compounds, but once you start getting more than that, it gets really complex and a lot of work as well. That may be underlying both at diet as you mentioned and the entourage effect with marijuana where you have lower levels of a lot of these compounds, but when they’re together it’d look like there’s a lot more of maybe a single compound.
Dan Pardi: Since the 90s that typical drug discovery method of using structural biology, combinatorial chemistry and high throughput screens were able to find drug discovery targets that had good selectivity and good affinity for receptors, but they’ve been disappointing the phenotypic approach to drug discovery. What happens when you take this compound and what are the end results to the organism? That’s pretty interesting to me. It’s almost like we’ve gone back in time to move faster.
Pamela Maher: 14:25 Well, the single target approach, they thought that would revolutionize the discovery of drug targets and the treatment of diseases. I think they forgot how complicated particularly the more intractable diseases are. Also the fact that they were always looking at something that completely inhibited it. A lot of these natural products, they don’t inhibit something completely. They reduce it, and that may be what’s good about them too, because most of the targets are required for normal cellular function. So if you really completely inhibit it, you can run into side effects or consequences that you don’t even anticipate. Whereas if you’d rather modulate it, that may be much more beneficial. I mean even inflammation, an anti-inflammatory, you want something that reduces the inflammation.
But inflammation is important in fighting infections and other types of problems, and so if you completely knock down inflammation, you end up having the ads for some of these treatments for rheumatoid arthritis that you can see on TV where they’re abusing TNFL antagonists. They say you have an increased risk of tuberculosis. Be careful if you travel to a foreign country where you might be exposed to odd diseases. There’s all these potential problems because with those, I think you’re really knocking down the inflammatory response, so modulating it, reducing it, but not completely knocking it out, I think has in the longterm much more possibilities for having benefits.
Dan Pardi: 15:19 If you look at some of the epidemiological evidence, it points to dietary components like fruit and vegetables being adversely associated with neurodegenerative diseases. Men with the highest quintile of flavonoid consumption have 40% lower risk of developing Parkinson’s Disease in a large epidemiological study and higher [inaudible 00:25:51] consumption associated with a 23% reduction in men and women. Those are really meaningful and that’s not a consumption of an isolated compound. It’s just the people that eat more of these than their counterparts.
Pamela Maher: Yes, and not sure with other diseases whether they’ve done that type of study, but that was a pretty dramatic effect.
Dan Pardi: 15:35 You’ve come up with some derivatives that you feel preserve their broad spectrum of fact but also might lend themselves to being better utilized for, let’s say, Alzheimer’s disease treatment. One is based off of setin, one’s on curcumin. I’d love to hear more about those.
Pamela Maher: The one that’s based on curcumin was developed by my colleague Dave Schubert and it’s called J147 and that’s actually in phase one clinical trial for Alzheimer’s disease. That was developed using the same approach but starting with curcumin. And then we have a derivative of Fisetin that we call CMS 121 that is currently undergoing the toxicology studies that are needed for what is called the IMD or investigational new drug approval. In order to move into clinical trials, the FDA requires you to do these toxicology studies and then you put them all together in this big report and submit it to the food and drug administration. Then if they approve it, you can then start clinical trials with the compound.
16:03 So we’re pursuing that avenue with the CMS 121 as well for Alzheimer’s. But we also have some really promising results with kidney disease, which is a lot easier to do clinical trials with. So currently thinking of Alzheimer’s, but if we can get some more animal data with regard to kidney disease, we may follow that route instead. It’s interesting because there’s a fair amount of epidemiological data suggesting that kidney disease can contribute to cognitive dysfunction in dementia. So there’s a possibility that by improving kidney function you could also reduce Alzheimer’s disease.
Dan Pardi: Because aging is becoming a much hotter topic, will your studies look at parameters of health across the lifespan of the model that you’re using? It would be really exciting data.
Pamela Maher: 16:27 Well, that’s actually the kidney results I mentioned. We’d been using for a number of our studies a strain of mice that have accelerated aging, but it’s not genetically driven so there’s not a specific mutation. It’s just that they were selected by breeding to have a shorter lifespan. So they look old when they’re only about 10 months old, but they look like an old standard mouse at 10 months. This was a study we haven’t published yet. We’re trying to get published with this CMS 121 compound and initially focused on the brain, which we did see that the compounds seem to preserve a variety of characteristics of the younger brain in the old mice. But we then started looking at other tissues specifically. This was where we found that in these old mice, there’s a lot of changes in the kidneys and we found that the compound was able to prevent those changes.
Dan Pardi: It’s great to be able to speak with you today and hear about your work on Flavanoids, being neurotrophic factors and augmenting cognitive performance in healthy controls, being neuroprotective and all the different mechanisms by which they’re acting through. So I appreciate your work and your time. Thanks for coming on humanOS Radio.
Pamela Maher: 16:49 Thank you. That was fun. I enjoyed being able to talk about my work.

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