Ginny Robards
Professor Julie Andersen, PhD
81
We have long recognized, on an intuitive level, that the gut and the mind are linked.
You can look no further than some of our idiomatic expressions to find evidence of this. Just as one example, have you ever had butterflies in your stomach before getting up in front of a group of people to speak?
However, it is only relatively recently that we have been endowed with the technology and expertise to really understand the relationship between the gut and the brain. Much of the interaction between these organs appears to be mediated by the gut microbiota – the collection of bacteria and other microbes living inside the gastrointestinal tract. For instance, we now know that gut bacteria generate neurotransmitters, including dopamine and serotonin, which play a role in mood and cognition. Additionally, gut microbes produce metabolites like butyrate, which may influence brain function.
The composition of your gut microbiome gets established relatively early in life, and seems to be relatively stable. However, it does appear to be modifiable in response to probiotics or dietary interventions, making it an interesting potential target for psychiatric treatment. In one intriguing study, women were randomly assigned to consume either a yogurt with probiotics or a milk product that was bereft of beneficial bacteria (control). When participants underwent brain imaging, those who had been eating the fermented yogurt showed differences in the activity of brain regions controlling emotions, and appeared to be responding more calmly to a series of images being presented to them.
So, the gut can affect the brain, and we can influence the gut in ways that may impact the brain. But what about in the context of brain pathology, such as in neurodegenerative diseases? Research into medical interventions to address diseases associated with aging in the brain has been particularly disappointing.
Just as one example, clinical trials testing pharmaceutical drugs designed to treat Alzheimer’s disease have the highest failure rate of any disease area (recently estimated at a dismal 99.6%).
You might not think that modulation of gut microbes would be a very productive area of investigation for something as serious and daunting as this, but preliminary evidence has been somewhat encouraging. One past study found that daily doses of probiotics moderately improved cognitive performance in patients with Alzheimer’s. Some very clever researchers are pursuing this further.
And that brings me to our guest.
Guest
In this episode of humanOS Radio, Dan speaks with Julie Andersen. Julie has a Ph.D in neurobiological chemistry from UCLA, and subsequently did her post-doctoral fellowship in the department of neurology at Harvard.
Presently, she is a professor and researcher at the Buck Institute, an independent biomedical research institute that is dedicated to investigating aging and age-related disease. Her lab is working on identifying novel therapeutics to delay or prevent the age-related molecular processes that drive neurodegenerative diseases. For example, she and other researchers at the Buck have been investigating compounds that could clear out senescent cells, which have been linked to age-related functional decline, as we have discussed previously on several shows.
Recently, Julie and her colleagues received a grant from the NIH to examine a natural bioactive known as urolithin A. Urolithin A does not come directly from the diet – it is actually a metabolite that results from the biotransformation of ellagitannins and ellagic acid via the gut microbiota. These phenolic compounds are found abundantly in edible plants, most notably in pomegranate, walnuts, berries, tea, and fruit juices (as well as certain types of wine).
However, consuming these foods and beverages may not be enough, at least for some of the population. We have discovered that there is considerable individual variability in the extent to which we can convert ellagitannins into urolithin A. In fact, some unlucky folks don’t appear to be able to generate it at all. In other words, if you don’t have the right gut bugs, you may not produce the metabolite no matter how much pomegranate you eat.
In animal models of aging, urolithin A has shown great promise. Older mice that were given the compound exhibited a 42% improvement in endurance while running, compared to control rodents of the same age. And nematodes that were exposed to urolithin A experienced a 45% boost in lifespan. And the first clinical trials in elderly human subjects suggest that the compound is safe and effective for reversing age-related muscle decline.
So what makes urolithin A so powerful? It appears to enhance autophagy, the natural mechanism through which cells effectively cleanse themselves by removing dysfunctional proteins and cellular components. This property makes it an enticing therapeutic compound for addressing neurodegenerative disease. One of the hallmarks of Alzheimer’s disease is the accumulation of irreparably misfolded proteins in the brain. It is thought that deregulation of the autophagy pathway with age leads to reduced clearance of these broken proteins, which in turn leads to the formation of toxic aggregates that are typically found in deceased patients.
Unfortunately, the capacity to generate urolithin A also appears to decline with age. To that end, Julie and her team plan to try to rejuvenate the gut microbiota of older mice using targeted probiotics, which should enhance production of urolithin A. They will then track neuropathology, memory loss, and mortality in a rodent model of Alzheimer’s disease, and compare outcomes in mice treated with urolithin A and controls.
To learn more about this fascinating research, check out the interview!
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Transcript
Julie Anderson (00:00): ... having good mitochondrial function is important and in preclinical studies your life and has been shown to improve mitochondrial function.
Dan Pardi (00:10): Research into medical interventions designed to delay or prevent diseases associated with neuro degeneration, like Alzheimer's Disease and Parkinson's had been disappointing to say the least. Some believe that in order to address this growing challenge we need a new approach. One potential answer lies oddly enough in compounds found in pomegranates and that is why I am pleased to be here live with Julie Anderson at The Buck Institute of Aging. Julie has a PhD in neuro biological chemistry from UCLA and then did her postdoctoral fellowship in the department of neurology at Harvard University. And currently she is a professor and researcher here at The Buck.
The Anderson Lab identifies novel therapeutics to slow or prevent the age related processes that drive neurodegenerative diseases. For example, she and other researchers at The Buck had been investigating compounds that clear out senescence cells, which have been linked to age related functional decline. As well as molecules that can ramp up autophagy, the natural mechanism through which cells effectively rejuvenate themselves by clearing out dysfunctional proteins and other components. Recently she has received a grant from the NIH, the National Institute of Health to examine the effects of Urolithin A, a gut metabolite produced from dietary allergic acid on Alzheimer's pathology in a rodent model of neuro degeneration. Julie, how did you first become interested in aging?
Julie Anderson (01:39): I have to admit it was a bit of a fluke. My training really is in neuroscience and I was always associated with neurology departments, but when I was looking for faculty positions in the early 90s, one of the places I interviewed was the School of Gerontology at the University of Southern California, and ultimately I ended up accepting an offer from them and although I was recruited there because of my expertise in neuroscience, I ended up teaching an undergraduate course at USC on the biology of aging for non science majors. So it was what they take as one of their GREs to graduate. And it was a lot of fun because it allowed me to expand my knowledge of aging beyond just the nervous system, but sort of the body as a whole. I got a lot more interested in aging and also being at that school I was interacting with different aging researchers that were working on different types of projects. And funnily, as an aside, my husband and I met each other at an aging meeting, because we're science nerds.
Dan Pardi (02:45): When I think aging, I think romance. That's right.
Julie Anderson (02:47): Me too.
Dan Pardi (02:48): I always like to ask that question because it's often almost serendipitous interaction with aging. You first become aware of the idea and it captures the imagination.
Julie Anderson (02:58): Yeah. Historically, scientists, we tend to study the body in silos, so it's like people studying the brain or the heart or whatever. So I think one of the really wonderful things about being here at The Buck Institute is it's all about aging and age-related disease and it's a cross discipline. So it makes you think out of the box a little bit. And we've been here about 20 years and it's still so fun to be here.
Dan Pardi (03:26): I can believe that being at an epicenter where the daily collisions of who you might run into at the cafeteria stimulate new ideas.
Julie Anderson (03:31): Yeah, absolutely.
Dan Pardi (03:34): Wonderful. Okay, so you're examining a metabolite known as Urolithin A.
Julie Anderson (03:36): Right.
Dan Pardi (03:37): What is Urolithin A and where does it come from and why are we interested in it?
Julie Anderson (03:43): It turns out that Urolithin is a metabolite, so a breakdown product of a ellagic acid. Ellagic acid is a polyphenol that's found in a lot of edible plants and it's actually converted and by bacteria in the gut to Urolithin A. And Urolithin A has been shown to have a lot of protective effects in terms of different diseases, but it really does require breakdown of that natural food product by the gut microbiome.
Dan Pardi (04:13): So we consume ellagic acid and ellagitannins, and then our gut microbiome will then metabolize those.
Julie Anderson (04:19): Right.
Dan Pardi (04:20): Those plant compounds into, I was pronouncing it wrong, Urolithin. I've be calling them Urolithins.
Julie Anderson (04:28): No, it's funny because part of being at The Buck, which is great, is there's a growing understanding of the relationship between the brain and the gut, what's called gut brain access, and in fact that the composition of the bacteria in your gut can have effects in terms of brain function. So I've been learning and it's the other thing I love about being a scientist is learning new things all the time, but I've been learning more about different kinds of gut bacteria and many of those names are Latin and really hard to pronounce.
Dan Pardi (04:58): Yes, there's a few I might stumble on in a bit here. Funny side story, but a lot of the work that I'd done previously was in narcolepsy and the people that discovered the peptide, hypocretin, named it after the gut peptide secretin, because they have similar chemical composition. That connection between the gut and the brain is profound.
Julie Anderson (05:17): Really interesting.
Dan Pardi (05:18): So if we could get a ellagic acid or ellagic acids from our foods, what are the food types that have a higher concentration of it?
Julie Anderson (05:26): You mentioned the one that seems to have the highest concentration, which is the pomegranate, but it's also pretty high in walnuts, different types of nuts, but particularly walnuts and different types of berries, including strawberries, raspberries, blueberries, different types of tropical fruits and I'm sure many people would be glad to hear that it's also high in oak aged red wine.
Dan Pardi (05:51): I did notice that. So then do people vary to the extent which they convert the ellagic acid into Urolithins? And if so, what is that based on?
Julie Anderson (06:01): Absolutely. So it really is based on, so everybody has a different composition of bacteria within their gut and there are people who have more or less of the bacterial species that are known to convert a ellagic acid, or EA to UA, is the easier way of saying this. So they're sort of known as low producers and high producers depending on the composition of their gut.
Dan Pardi (06:29): Right. And are there, it looks like metabotype zero. There's non-producers too.
Julie Anderson (06:34): Right. Yeah.
Dan Pardi (06:35): I thought that was interesting. Some phenotypic work that was done showed that people that were producing either a low amount or some amount, if they were given pomegranate, they would produce more. That's exciting.
Julie Anderson (06:46): Right.
Dan Pardi (06:46): But some people didn't, even if you gave him more pomegranate and more precursors, they still didn't make it.
Julie Anderson (06:55): It speaks to, and there's a lot of interest in prebiotics and probiotics, and it speaks to the utility of that, that that's something that's malleable. You can alter the composition of your gut, both depending on what foods you're eating, but also just taking pre and probiotics, right?
Dan Pardi (07:08): The first question when I stumbled upon that is, is there a way to know my own phenotype? Is there a test that I could take?
Julie Anderson (07:14): Yeah. There are actually tests for figuring out what the composition of your gut microbiome. Funnily, in some of the preclinical studies that we're doing, we're actually doing that with the mice that we're treating with Urolithin A, so we're collecting feces and we're sending them off to a company who's then analyzing the microbiome composition. And we're, beyond Urolithin A, we're interested in other types of natural products like vitamin D. Vitamin D has been shown to increase lifespan in some preclinical studies. There are some epidemiological studies that suggest that it helps stave off Alzheimer's Disease and really through our interest in Urolithin A, and then thinking more about how these different compounds get metabolized by the gut, we've become interested in looking at what happens with vitamin D in the gut and how that might alter the gut microbiome.
Dan Pardi (08:12): So at the moment, there are research ways to assess Urolithin A production, but there's not a consumer test that one could take?
Julie Anderson (08:19): Yes, you can't just go out and to the drugstore and pick up a kit where you're sending off samples. Yeah.
Dan Pardi (08:27): Too bad.
Julie Anderson (08:27): Yeah, it is too bad. I mean, the technology's there and it's pretty straightforward to do.
Dan Pardi (08:32): Okay. Innovators, if you're listening. There is a good idea for you.
Julie Anderson (08:37): Yeah.
Dan Pardi (08:38): If you are a producer of Urolithin A, does that change across the lifespan?
Julie Anderson (08:44): It's not completely clear based on the human studies that have been done exactly what all the bacteria are that could be playing a role in conversion. So people are high and low producers, but we do have alterations in our gut microbiome with age and it seems in general that there is a decrease in bacteria that allow conversion of EA to UA. And so you think with an older individual drinking pomegranate juice that may not be as effective as it would have been when they were younger.
Dan Pardi (09:20): Yeah. Okay. So we have different Metabotypes or different producers of Urolithin A, and that seems to be dependent on the presence of certain gut microbes. And if you are a producer of Urolithin A, the composition can still change. So what do we know about the types of gut microbes that are important in the conversion of ellagic acid?
Julie Anderson (09:44): This is one of these that I won't be able to pronounce, but actually it's interesting because recently, and I wrote it down for myself recently, there was suggested that they had discovered a bacterial type that they weren't really aware of before called [inaudible 00:10:03]. I'm probably slaughtering that, but people are interested in that particular bacteria type because it seems to be important in terms of the conversion. And you could imagine that rather than most pre and probiotics where you're in essence taking something that's introducing new bacteria into your gut.
It's a mix of different bacteria and it's often like lactobacillus and things like that. You could imagine that if we really pinpoint this particular microbiome is being involved in the conversion, you could take that in pill form just like you do for a mixed pre or probiotic to help in the conversion, so you're drinking your pomegranate juice and you're taking this particular bacteria in the form of a pill.
Dan Pardi (10:43): If we were to arrive there, that seems incredibly easy to take action.
Julie Anderson (10:48): Yeah. You wouldn't have to necessarily get a prescription from my doctor to do that.
Dan Pardi (10:52): I'm going to just have a little fun with this because I'm going to try to pronounce two of the bacteria types that seem to play a role.
Julie Anderson (10:56): Okay.
Dan Pardi (10:57): The Gordonibacter Urolithin faciens, was one.
Julie Anderson (11:01): Yeah.
Dan Pardi (11:06): And the other one was Gordonibacter Pamelaeae.
Julie Anderson (11:07): Yeah, which clearly was named after pomegranate.
Dan Pardi (11:12): Yeah, exactly.
Julie Anderson (11:12): There are different studies, which have pointed to different bacteria as being involved, and that's part of our interest is trying to assess that out more particularly in terms of in these preclinical Alzheimer's and Parkinson's models.
Dan Pardi (11:28): The one strategy that is, look at the future of bit, there'd be a test to know what type Metabotype you are and if you're a producer of Urolithin A, and if not, maybe there would be the ingestion of a pre and probiotic that could make you one and maybe you'd want to do that anyway over the lifespan just to keep levels of this metabolite high.
Julie Anderson (11:48): Right.
Dan Pardi (11:49): The other idea is to synthesize Urolithin A directly and I know that that's occurring now.
Julie Anderson (11:56): There are actually, and I'm sure you noted this, there are the first clinical trial with Urolithin A was published this year. It was in 60 healthy older individuals and they were given Urolithin A orally, it was for two weeks or something. And what the researchers looked at in particular was muscle function. Cells, just like our body have organs that we call organelles. So the nucleus is the brain of the cell. There's something called mitochondria that are really the power plants of the cell.
And if you think about tissues or cells that require a lot of energy, of course, our muscles are using a lot of energy. Having good mitochondrial function is important. And in preclinical studies Urolithin has been shown to improve mitochondrial function. So they looked particularly in these individuals at what kinds of genes were getting turned on by adjusting Urolithin, particularly genes that were improving mitochondrial function. And they found that they were up-regulated. So it's cool that it was in such a short period of time, they were able to see that benefit and it doesn't seem to have side effects. We were really happy to see that study.
Dan Pardi (13:11): I've been following that work from the company. It's a Swiss company named Assentis.
Julie Anderson (13:15): Yeah. That's right.
Dan Pardi (13:17): And they did a variety of preclinical work in first in nematodes and then in mice, and they showed that the nematodes lived almost 50% and then the mice had greater times to exhaustion, so they were more fit.
Julie Anderson (13:29): Yeah, so their muscle function was better.
Dan Pardi (13:32): Yeah, and it looks like Assentis is specifically going after age-related decline in muscle functions with sarcopenia, which I was alarmed by some of the statistics. About 30% of people that are 60 have some form of sarcopenia and 50% over 75.
Julie Anderson (13:48): Right. Yeah.
Dan Pardi (13:50): And of course, you can see how that leads to frailty.
Julie Anderson (13:52): And falls, because here at The Beck, we are involved in something sort of very much like what Assentis did that we're starting with invertebrate models, like [inaudible 00:14:02] people. For the lay person that's seems nutty that you're looking at this little worm, but it turns out that a lot of genes that are involved in aging or longevity are evolutionary preserved from worms, all the way to human beings and there are certain conserve pathways that seem to be involved and it seems like Urolithin is impacting on some of those pathways. It's also very cool in the sense that because it's impacting on some of these basic pathways, UA is a compound that may be good for not only improving muscle strength, but brain functions, these basic aging mechanistic pathways that could have global effects in terms of many different age related diseases.
Dan Pardi (14:53): Out of the nine hallmarks of aging, no one of those hallmarks that diminished mitochondrial function does not influence.
Julie Anderson (14:59): Right.
Dan Pardi (15:00): We think of them as the powerhouse of the cells, they're doing a lot more than that, but maintaining adequacy of energy for all of the functions necessary to life is critical.
Julie Anderson (15:09): Yeah.
Dan Pardi (15:10): Let's talk about mitochondrial dynamics. Is there only one mitochondria in a cell?
Julie Anderson (15:15): There's like hundreds, and it's funny, they're always represented as this jelly bean shaped, but they're were like all inter connected and communicating with each other and there's hundreds in a cell. So not only the efficiency of the mitochondria, but the number of mitochondria in the cell. All of those things are important. The pathway by which we got Urolithin really started with our laboratories interest in Parkinson's Disease and it turns out with Parkinson's Disease, one of the age related functions that impact on PD is mitochondrial function.
And so we have a longterm interest in how to keep mitochondria healthy in patients with Parkinson's Disease. And we were actually then screening from a natural compound library, from looking at natural compounds that were enhancing mitochondrial function in the context of preclinical models of Parkinson's Disease. One of the compounds that we looked at was rapamycin, which is the first compound that in a mouse in terms of aging in mice demonstrated an increase in lifespan. One of the properties of rapamycin is to improve mitochondrial function by getting rid of defective mitochondria. Based on some studies that we published in preclinical Parkinson's mouse models with rapamycin and trying to understand the mechanisms that were involved. Then screening for drugs that were impacting on that mechanism. That's how Urolithin A came into the picture for us.
Dan Pardi (16:47): So as I understand that these networks of mitochondria, they live a very active social life.
Julie Anderson (16:53): Yeah.
Dan Pardi (16:54): They are fusing together. They are then separating in a process of vision. And as we get older, due to unknown reasons, the ability for the normal quality control mechanisms of mitochondria get impaired and so the mitochondria get larger and then can evade the normal mitophagy breakup processes.
Julie Anderson (17:15): Yeah. So this is this idea that the cells have come up with a means of both making mitochondria and once they get older and decrepit, breaking them down again. And that continuous process and when you break down decrepit mitochondria, the components of the mitochondria can be used to make new mitochondria. So it's both what we call biogenesis and mitophagy, which is this breakdown of mitochondria and one of the important proteins that's involved in that is there's a master regulator called Transcription Factor EB, which basically when it's up-regulated, it turns on expression of a lot of mitochondrial genes that are important, actually for both biogenesis and mitophagy.
That's really the protein that we screened on. We were looking for things that were affecting TFEB activity and we were doing it in this natural compound library. And Urolithin was one of the things, and it had already been known from the preclinical studies that you alluded to, that it seemed to be aiding in mitophagy, in those [inaudible 00:18:25] and mouse studies that had been published.
Dan Pardi (18:27): So exciting. Mitochondria are our energy sources that are absolutely fundamental to life and the preservation of youthful function as we age and as they degrade the ability to execute quality control, which includes both biogenesis or new mitochondria formation, autophagy, clearing out the old ones is impacted. That leads to reduced function. It really could be affecting every part of the body.
Julie Anderson (18:50): Yeah, because it's in every cell.
Dan Pardi (18:51): Yeah. How does the gut microbiome influence the nervous system and potentially neurodegenerative diseases, such as Alzheimer's?
Julie Anderson (18:59): Those of us in the neuroscience field studying diseases like Alzheimer's and Parkinson's, historically we were very fixated on what was going on in the brain and how loss of different types of neurons within the brain could drive disease. So in Parkinson's Disease you have these dopamine containing neurons in the midbrain and this area of the brain called the Substantia Nigra that are lost with age and they're part of a circuitry of neurons that are involved in voluntary motor movements. So when people lose those neurons at a higher rate than everybody else does, as a consequence of normal aging, they start freezing. And with Alzheimer's it's hippocampal and cortical neurons within the cortex and they have a campus that are involved in memory and learning. And even at that level, we still don't completely understand why do certain individuals are more at risk for Parkinson's, more at risk for Alzheimer's, besides rare genetic defects, which don't account for most of the cases of PD and AD. We used to completely concentrate on the brain.
With Parkinson's Disease though, people started to realize that there were certain functions that went awry outside of the brain that occurred 10-20 years before someone developed PD. They would develop IBD or a gastrointestinal problem. There would be loss of smell, reductions in REM sleep, et cetera, et cetera. In fact, there's a push to look at those changes as biomarkers for potentially developing Parkinson's Disease. We started to realize, well, maybe this isn't just those neurons in the brain. There are things that are going on below the neck that could be driving the disease. And there's been a growing interest in the gut microbiome. Studies have been done where it's been shown that patients with PD do have an altered microbiome compared to age matched older individuals, and realization that certain bacteria that may be producing toxins that are released into the blood that can cause neuro inflammation in the brain, and conversely there are things like Urolithin that may be protective.
So they're produced in the gut and released into circulation and cross the blood brain barrier and increase mitophagy within neurons and increased function of mitochondria. It's becoming a burgeoning field now and I really love it because it is a race on Tetra at The Buck, we're looking across the whole body, so looking past whatever the primary organ is of whatever disease you're looking at, people that are starting to realize how important that is.
Dan Pardi (21:48): It's all connected. Okay, so let's talk about how autophagy then might be affecting this process of neurogeneration. Are those two related?
Julie Anderson (21:57): Yeah. Also, with age, again in almost every cell in the body you have this loss in autophagy. So continuing with this analogy about the neuron being the brain and the mitochondria being the powerhouse, we have another organelle called the lysosome, which is really kind of the recycling center of the cell. So both damaged mitochondria, different damaged organelles and also damaged proteins get recognized by the cell and tagged and they get directed to the lysosomes.
The lysosome is really a sack of enzymes, so the protein and mitochondria get taken up within the lysosome, and they get broken down into their components for reuse. And unfortunately with age, the function of the lysosome like mitochondrial function also diminishes. When that occurs within neurons, you end up with defective proteins. You can end up with proteins that are more prone to aggregations. So with Alzheimer's Disease, you have these plaques and tangles, which are really protein aggregates that have built up over time. In Parkinson's, you have what are called Lewy Bodies, which are made up of aggregated alpha-synuclein protein, so that process, if autophagy is working properly, you're making sure that you have functional proteins and organelles.
Dan Pardi (23:20): I've used this visual motif years ago to help myself understand that process of autophagy better, I imagined autophagy being this process of a vacuum cleaning up broken products and then brings it to the incinerator, which is the lysosome, to break them all down.
Julie Anderson (23:31): Yeah, that's a good analogy too.
Dan Pardi (23:36): Sometimes those are helpful. Is there any work then looking at this directly, pomegranate and Alzheimer's Disease?
Julie Anderson (23:43): For the last decade or two, there have been studies where people have looked at giving pomegranate juice, not only just to mice that have been engineered to have Alzheimer's Disease, but to patients, and the reports suggest that a pomegranate juice does seem to help. The thing about giving something like pomegranate juice, there's so many components. Because we have scientists who are trying to figure out what is in the pomegranate that's actually eliciting this effect.
Dan Pardi (24:14): I had a really wonderful conversation with senior scientists, Pamela Maher, from the Salk Institute. A lot of her early work was looking at eutrophic factors, trying to create drugs that would act propitiously.
Julie Anderson (24:26): Right.
Dan Pardi (24:28): And they all failed. But, when she started to move to nature's original pharmacy, plant compounds, she had a lot more success. And one of the main reasons why is it filled a really important criteria of being able to get into the brain.
Julie Anderson (24:42): Right, yes. Thank you for that. Because I think it's something people don't think about a lot, the brain has what's called immune privilege. You don't want any random toxin getting into the brain. So there is this blood brain barrier. Things within the circulation aren't allowed to just drift into the brain. They have to be taken up. So there is this blood brain barrier, which is great for us as human beings, but in terms of developing drugs, it's another hurdle that you have to overcome. Is it going to be capable of entering the brain?
Fortunately, Urolithin A is something that crosses the blood brain barrier.
Dan Pardi (25:22): So it can get into the brain and induce autophagy, which then will help to break down these aggregates that are toxic, if they accumulate.
Julie Anderson (25:31): They can. Now, originally when people were looking at postpartum tissue from Alzheimer's or Parkinson's, you saw these protein aggregates will, this must be the cause of the nuerodegeneration, but as we've started to study, the more we realize maybe they're not, maybe the aggregates form to prevent the buildup of soluble toxic forms of those proteins, which initially may be good, but eventually if you have too much of a buildup, it's not a good thing.
Dan Pardi (26:02): Initially it's a protective response that then ultimately leads to more problems.
Julie Anderson (26:08): Right, exactly. The consensus is both in terms of alpha-synuclein and with Parkinson's are A Beta or Tao, are the components that make up the plaques and tangles in Alzheimer's. That it may very well be those soluble toxic forms that are bad and causing problems.
Dan Pardi (26:25): Right. I understand that some drugs that were targeted at trying to prevent the aggregations actually led to worse clinical outcomes.
Julie Anderson (26:34): Yeah. It is true that there's been a lot of immunotherapy that's been targeted at getting rid of A Beta or Tao and those have not been clinically successful. We think it may be that this process that you alluded to, cellular senescence, we think that it may be that A Beta can elicit the cellular senescence within neurons. Cellular senescence is another one of these pathways of aging, which involves cells in response to stress. They stop dividing, so it prevents them from becoming cancer cells, but they also unfortunately secrete inflammatory factors that can affect neighboring tissues. We are testing a hypothesis, testing whether A Beta illicit cellular senescence within neurons or other cells, but then the spread is independent of the presence of A Beta. And therefore, even if you get rid of A Beta that's not going to stop progression of the disease. The laboratory really works on those two basic aging mechanisms, autophagy and cellular senescence as they relate to Alzheimer's and Parkinson's Disease.
Dan Pardi (27:44): So hearkening back to the comment a moment ago, my conversation with Pamela Maher, we were speaking specifically about some flavonoids. One, [inaudible 00:27:52], which we know is a senolytic in a high dose.
Julie Anderson (27:55): Yeah, yeah.
Dan Pardi (27:56): Which, if you're not familiar with that term in the audience, it helps to break down senescent cells after the senescence has occurred. And that seems to be a favorable thing to eliminate some of age associated decline.
Julie Anderson (28:07): Yeah. In fact, we have some data and cultured cells that some of these senolytics, which are getting rid of senescent cells maybe having their impact through affecting levels of autophady. So as you were saying, most of these pillars of aging, they're not necessarily separate standalone. They do interact.
Dan Pardi (28:31): That leads into my next question. So you're Urolithin A is an antagonist of the Farnesoid X-Receptor, which elevates expression of the TFEB, which we mentioned previously. And in turn, enhances autophagy. Does antagonism of Farnesoid X-Receptor appear to have other effects on cholesterol homeostasis?
Julie Anderson (28:50): Right. There in lies an issue, because FXR, well, so I will say most of the studies in terms of FXR studies within the gut, because it's known to play a role in cholesterol synthesis and so forth. And through our studies we realized, and there are a couple of publications, a smaller publications in this as well, that FXR receptors also recite in neurons in the brain. Unfortunately, increase in FXR is a good thing in terms of gut function, but it could be a bad thing in terms of brain function. So to some degree this is in a broader sense when you talk about drug side effects, these are the things that we need to be aware of and it's probably why it's also important for scientists that are working in different disciplines to be talking to each other because we sometimes tend to work in a silo or in isolation and not thinking about the impacts of drugs on the rest of the body.
Dan Pardi (29:52): In 2004, I went to a workshop on obesity at the Society of Neuroscience, and Hans Rudy Berthoud made a comment that stuck with me. The systems involved in energy regulation, they are complex, distributed and redundant. You have one molecule that we know has certain effects, but it is doing something completely different in a different system.
Julie Anderson (30:13): Yeah. I know historically too, there is sort of this emphasis on drugs that people think are only affecting a single system, but I'm not sure it exists really. There is now an interest in dirty drugs that have multiple positive effects, like Metformin is in clinical trials as an anti aging agent, Metformin does a lot of different things that doesn't really impact on just one pathway.
Dan Pardi (30:41): Also, derived from the plant as well.
Julie Anderson (30:43): Yes.
Dan Pardi (30:43): Exactly.
Julie Anderson (30:46): Rapamycin from a fungus.
Dan Pardi (30:47): Yes. Well, going back to the work of your grant, you'll be studying a rodent model of neuro degeneration, so what makes mice a suitable representation for Alzheimer's pathology and what outcomes will you be tracking in these experiments?
Julie Anderson (31:02): Yeah, mice aren't humans. There's not a perfect mouse model of any disease, I would venture to say. But you can genetically engineer mice. You can put human genes that drive familial forms of Alzheimer's Disease and those mice then take on characteristics that you have in Alzheimer patients. So that's both the neuropathology, A Beta plaques, how neurofibrillary tangles. You have neuro inflammation, which is basically turning on of immune cells in the brain that are giving off pro-inflammatory factors that can be detrimental to neurons.
You can also run, which is cool, cognitive tests on mice, on learning and memory. So you can run tests to see how having this neuropathology tracks with their cognition. Those are the kind of things in these studies, we want to look at the impact of Urolithin and other compounds that up-regulate autophagy, how they impact on mitochondrial function within the neurons and how this then coincides with, we hope, improved our slowing of neuropathology. And how that in turn impacts on cognition, learning and memory in those mice.
Dan Pardi (32:23): Well, Julie, we all await eagerly to hear the results of this exciting line of work that you and your team are conducting. We're hopeful that Urolithin A will ultimately prove to be a very powerful therapeutic in ameliorating several age-related condition. So thank you very much for taking the time to discuss this with me today on humanOS Radio.
Julie Anderson (32:47): Thank you, Dan, for having me.
Other Episodes with the Buck Institute
