Associate Professor in the Department of Neurosciences at UC San Diego School of Medicine, Paula Desplats, PhD talks about slowing the progression of Alzheimer’s with intermittent fasting and better sleep.
Interview conducted by Ivanhoe Broadcast News in 2023.
Can you tell me how the circadian rhythm plays into Alzheimer’s?
Desplats: Okay. So 80% of the patients that suffer Alzheimer’s disease will manifest some K in the regulation. And from the clinical point of view, this is specifically a very severe sleep wake reversal. These patients will be very sleepy during the day fragmentation of asleep, but then during the night there will be awake, they will be experience what we consider sound downing. And that is the other side. We call it sound downing specifically because it happens in the evening. And this is a severe cognitive impairment. Being more aggressive, agitated, disoriented during the night, and then really having a higher rate of hallucinations and being very active. So these two things are basically incompatible with the rest of the family. So suddenly these caregivers that are taking care of the Alzheimer’s patients will really have a hard time tending to the patient. Because we see patients are in this phase, they can be harm to themselves. This is usually the moments when they go out of the house and get disoriented or lost, or they try to do something in the house that may be harmful for them. So someone needs to be accompanying and caring for them. But then there is again the moment of sleep. So we have as big a sleep interruption in the caregivers and usually these two behaviors lead or really lead the placement of these patients in the nursing home. So yeah.
Also though, like if you come to that part, and everybody knows like when you get a bad night’s sleep, your cognitive function is already bad. So if your cognitive bunch already bad and then you get a bad night sleep.
Desplats: It’s forward feed cycle, right? And you make a very important comment. It’s not only the fragmentation and what happened with the being active and not a sleeping, but the sleep quality really decreases in the Alzheimer’s patients. There are issues in initiating a sleep and staying asleep. And that exactly has to do with an ether generation because one of the important adaptations of a sleep is giving our brains a rest. And the rest of neuron activity also served for the glymphatic system, a system of vessels that are in the brain that will circulate the CSF liquid will take care of, let’s say removing the trash that our cells produce during the day. So when you have the interruption of a sleep, you have that system malfunctioning and also changing the balance towards adding more aggregates in the brain. So you are even contributing to neuro degeneration by having more plaques, for example. So secreting clock controls both, right, our rhythms of activity but also a portion of a sleep so that’s the other factor that is very important in Alzheimer’s.
And in your paper, you also discussed how that actually might be this lack of sleep, this lack of, this destruction of rhythm that drives Alzheimer’s instead of you get Alzheimer’s and then you can’t sleep.
Desplats: Yes, that’s a very important direction and we have been really focusing in that aspect in our research because the impairments in and rhythm has been observed for many years in the field. But usually we’re associated with the latest stages of disease, so it was accepted as neuro degeneration progresses through different areas in the brain and finally, neuronal loss is happening also in the hypothalamus, which is the region where the main scythian clock, or pacemaker resides in the rain. Then we lost neurons there, then you start having these issues with the regulation of the rhythms. But many studies from even clinical studies have shown that, for example, mid age women that have no other health issue, if you measure the actigraphy, so the rhythms of activities throughout the day and these rhythms are broken. That is even a biomarker or a potential predictor of developing dementia down that road. So that’s an indicator that things starts to break early. And our own studies have shown that, and other labs too from the molecular point of view, we detected issues with the rhythm and the expression of the genes, even at stages in our animal models that have very low plaques and pathology, meaning that a regulation is happening earlier and most likely contributing to pathology and not being just a mere consequence.
So how does intermittent fasting come into play with this?
Desplats: So that’s another great question. And in fact, for us, we are not particularly looking for intermittent fasting per say. We were looking for the tool to modulate the kiting clock. And there are enough studies showing that the feed fat cycle is really strong queue for our clock to assimilate and to adjust to the time of day. For example, with sword animals, if you start feeding them at a certain point, they will anticipate. And that behavior is so strong they are really waiting for the food at certain point. And we can see it in the brain, if the time when each gene expresses. So we found rhythms in gene expression that were broken in Alzheimer’s. So we wanted to see, can we fix this clock by any other intervention with the organism and try to see what happened with this gene expression. And that’s why we selected time restricted feeding because other colleagues have shown very beautiful results in Huntington’s as well. We knew for human studies that doing this intermitting fasting is quite important and have a lot of other benefits metabolically in, for example, people with diabetes, insulin resistant hypertension. So those things were normalized, so it’s okay. Per se, it will modulate some factors of our health and our metabolism that also influence our risk to have Alzheimer’s. Let’s see if by doing this we can modulate the clock and see what happened with the expression of the genes in the brain. So this is why they sided with this time restricted feeding, that’s how we call it in the animals, or intermitting fasting.
So what was the intermittent fasting from all the hypro people did. Is it like 16 and 8, is it 12 and 12?
Desplats: So it’s quite different what we do with the animals. In this case for the animals who is more restrictive, they have access to food for six hours. But that’s not the core relink with the human, because these animals will spend the other part of the day sleeping and there are more uniform than us. What we think is a good parallel. It’s, potentially, a 14-hour fasting for humans. There are, of course, many considerations and that requires a studies in humans, because also it’s very different at what age of your life you are doing this, what other comorbidities you have? If you are an elderly person, you have a different need of nutrition, you have a different rethamassleep, so all those things take care. And put probably we assume that 14 hours it will be enough fasting to trigger part of the metabolic and physiological effects we saw in our animal models.
And what were some of those surprising findings?
Desplats: So the first thing that we saw is that we were effectively affecting the way the genes expressed in the brain, and I think that was a first, because all these works were center metabolism. You can see how the liver changes in the cycles when you do fasting. But that coming to the brain and affecting a large majority of rhythmic genes was really a surprising finding for us. But the consequences or implicacis for Alzheimer’s, is that we previously determined that many genes that are affected during Alzheimer’s pathology, in fact, are also rhythmic, and many of those genes were the ones recovering the rhythmicity. Some of those start expressing almost as the wild type control animal, so that was a very important confirmation that by tapping into the organism, we could manipulate the clock in the brain. But more importantly for us was that we saw these fantastic rescue. More important for us was the effects that we saw directly in Alzheimer’s pathology, and we saw rescue of the phenotype. These animals that were fasting had really fewer senal plugs in the brain, and we did this in several groups of animals, because we didn’t expect it to be so consistent and such a large effect. So we investigated many aspects of how these senal plus form, so we saw that there is a decrease in the rate in the Amul depositing in the brain. But there is also an increase in the clearance of those plaques, so microglia were able to clear that and the whole inflammation start reducing. So all these pleotropic effects sum up to rescue the pathology and even rescue memory function in the animals. So in all in all, we have a decrease in the progression of pathology that is highly significant.
You have all these scientists, everybody like you working on drugs to get rid of plaques and Taus and procedures and all of this stuff, and could it come down to diet change could be something that impacts Alzheimer’s?
Desplats: Well, I won’t go that far and I don’t think that’s the way we won’t cure the disease with disease. But definitely our life- the whole metabolism and the whole exposure of the organism has a lot to the risk of disease. For us, what is fantastic is that thinking and that we have an option now that you can interact with the circadian clock from a natural way. Just changing your behaviors when it comes to eating. Basically coming back to a more natural way, if you think about it. A more biological, meaningful. But we hope that this could be a tool for helping other type of therapies. This could make it additive to the drugs that we need to develop. And the importance also that we need now, to really pass this to humans and understand how we apply this. We have to keep in mind that we are working with a population of patients that have severe cognitive deterioration. Are they able to really stand the 14 hours of fasting? Will they cope with that? If they are in the middle of a sun downing episode? Will they- how much they can interrupt the fasting and still reap the benefits. That’s really what we want to do in the next step. The next stage is hopefully, if we get funding, a collaboration with the Alzheimer’s Disease Research Center and passing this into a pilot study for patients and really understanding feasibility. What’s the best way? Is these 14-hours doable? What type of support? And then very importantly, what are the outcomes? What are the tools we need to use to measure and understand the benefits of this. If we can have this in a rigorous way, we can provide sound scientific evidence for the effects of fasting. Because by now, we have this hype in the community. I keep making the joke that by the time I can do a clinical trial, everybody will be fasting, so I won’t have a population control. But all those things are things that are here. This person told me to do 14 hours, 16 hours in different type of also health challenges. So we need rigorous and sound data to move this into the clinic. Hopefully, and that’s what we really want. If we can improve, if we can change even a little bit this progression curve, if we can keep these patients with their families, that’s what we want to try to do.
Is it correct for me to say, and I just want to want to know that this intermittent fasting you’re setting to be a preventative and a treatment, something that could slow it down and possibly help to prevent?
Desplats: Maybe yes, and that’s also what we need to study. We started early, because with this idea that king the regulation happens early. We wanted to intervene early. So in our animal model, we started at the moment that plaques were almost minimal in the brain, and we were able to change that. Then we try in another animal model that was a little more advanced and we saw benefits. There will be a line, potentially, in how much we can interact when the system has already so past certain threshold we might not be able to get the benefits. So that’s also important to understand when to start. And for that, we need more biomarket trying to anticipate when the disease starts. Regardless of that and regardless of what we can do with Alzheimer’s, in general, or specifically the metabolic benefits are there. If you move those metabolic effects, you improve a sleep and you improve your insulin glucose balance, you have already eliminated two important risk factors for developing Alzheimer’s. So in the end, you are improving your lifestyle, eventually, and helping changing the balance.
Why can’t you study something like eating In-N-Out burgers every day?
Desplats: That would be fantastic. I will say chocolate, but yes.
So is there anything we’re missing?
Desplats: So, the other thing that we are doing of course, and you mentioned this idea of manipulating the Circadian clock, and that may be a broad application. But we also want to identify targets. And again, this will be complementary to other treatments. So what we are doing now is just going to unveil the mechanisms. What happened during the fasting that moved the clock and then clear the plaques. So we have several ways of doing that. We detected pathways that are affected. That’s where we’re going next. We really to find molecular targets that might be new therapeutic approaches to modulate and get all the benefits for this fasting. Maybe even to translate to patients that for different reasons cannot complete the fasting.
END OF INTERVIEW
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Miles Martin Olivia Ott
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