Entries in Parkinson (2)

Thursday
Jul072016

How young blood might reverse aging. Yes, really

Based on Tony Wyss-Coray’s TED lecture of Aug. 2015

 

 

The famous Fountain of Youth. If you drink its water or you bathe in it, you will get health and youth. Every culture, every civilization has dreamed of finding eternal youth. There are people like Alexander the Great or Ponce De León, the explorer, who spent much of their life chasing the Fountain of Youth. They didn't find it. But what if there was something to it? What if there was something to this Fountain of Youth?

I will share an absolutely amazing development in aging research that could revolutionize the way we think about aging and how we may treat age-related diseases in the future. It started with experiments that showed, in a recent number of studies about growing, that animals -- old mice -- that share a blood supply with young mice can get rejuvenated. What Tom Rando, a stem-cell researcher, reported in 2007, was that old muscle from a mouse can be rejuvenated if it's exposed to young blood through common circulation. This was reproduced by Amy Wagers at Harvard a few years later, and others then showed that similar rejuvenating effects could be observed in the pancreas, the liver and the heart. But what I'm most excited about, and several other labs as well, is that this may even apply to the brain.

So, what we found is that an old mouse exposed to a young environment in this model called parabiosis, shows a younger brain -- and a brain that functions better. And I repeat: an old mouse that gets young blood through shared circulation looks younger and functions younger in its brain. So when we get older -- we can look at different aspects of human cognition, and you can see on this slide here, we can look at reasoning, verbal ability and so forth. And up to around age 50 or 60, these functions are all intact, and as I look at the young audience here in the room, we're all still fine.

But it's scary to see how all these curves go south. And as we get older, diseases such as Alzheimer's and others may develop. We know that with age, the connections between neurons -- the way neurons talk to each other, the synapses -- they start to deteriorate; neurons die, the brain starts to shrink, and there's an increased susceptibility for these neurodegenerative diseases.

One big problem we have -- to try to understand how this really works at a very molecular mechanistic level -- is that we can't study the brains in detail, in living people. We can do cognitive tests, we can do imaging --all kinds of sophisticated testing. But we usually have to wait until the person dies to get the brain and look at how it really changed through age or in a disease. This is what neuropathologists do, for example. So, how about we think of the brain as being part of the larger organism. Could we potentially understand more about what happens in the brain at the molecular level if we see the brain as part of the entire body? So if the body ages or gets sick, does that affect the brain? And vice versa: as the brain gets older, does that influence the rest of the body? And what connects all the different tissues in the body is blood. Blood is the tissue that not only carries cells that transport oxygen, for example, the red blood cells, or fights infectious diseases, but it also carries messenger molecules, hormone-like factors that transport information from one cell to another, from one tissue to another, including the brain. So if we look at how the blood changes in disease or age, can we learn something about the brain? We know that as we get older, the blood changes as well, so these hormone-like factors change as we get older. And by and large, factors that we know are required for the development of tissues, for the maintenance of tissues -- they start to decrease as we get older, while factors involved in repair, in injury and in inflammation -- they increase as we get older.

So there's this unbalance of good and bad factors, if you will. And to illustrate what we can do potentially with that, I want to talk you through an experiment that we did. We had almost 300 blood samples from healthy human beings 20 to 89 years of age, and we measured over 100 of these communication factors, these hormone-like proteins that transport information between tissues. And what we noticed first is that between the youngest and the oldest group, about half the factors changed significantly. So our body lives in a very different environment as we get older, when it comes to these factors. And using statistical or bioinformatics programs, we could try to discover those factors that best predict age -- in a way, back-calculate the relative age of a person. And the way this looks is shown in this graph. So, on the one axis you see the actual age a person lived, the chronological age. So, how many years they lived.

And then we take these top factors that I showed you, and we calculate their relative age, their biological age. And what you see is that there is a pretty good correlation, so we can pretty well predict the relative age of a person. But what's really exciting are the outliers, as they so often are in life. You can see here, the person I highlighted with the green dot is about 70 years of age but seems to have a biological age, if what we're doing here is really true, of only about 45. So is this a person that actually looks much younger than their age? But more importantly: Is this a person who is maybe at a reduced risk to develop an age-related disease and will have a long life -- will live to 100 or more? On the other hand, the person here, highlighted with the red dot, is not even 40, but has a biological age of 65. Is this a person at an increased risk of developing an age-related disease? So in our lab, we're trying to understand these factors better, and many other groups are trying to understand, what are the true aging factors, and can we learn something about them to possibly predict age-related diseases?

So what I've shown you so far is simply correlational, right? You can just say, "Well, these factors change with age," but you don't really know if they do something about aging. So what I'm going to show you now is very remarkable and it suggests that these factors can actually modulate the age of a tissue. And that's where we come back to this model called parabiosis.

 

So, parabiosis is done in mice by surgically connecting the two mice together, and that leads then to a shared blood system, where we can now ask, "How does the old brain get influenced by exposure to the young blood?" And for this purpose, we use young mice that are an equivalency of 20-year-old people, and old mice that are roughly 65 years old in human years.

What we found is quite remarkable. We find there are more neural stem cells that make new neurons in these old brains. There's an increased activity of the synapses, the connections between neurons. There are more genes expressed that are known to be involved in the formation of new memories. And there's less of this bad inflammation. But we observed that there are no cells entering the brains of these animals. So when we connect them, there are actually no cells going into the old brain, in this model. Instead, we've reasoned, then, that it must be the soluble factors, so we could collect simply the soluble fraction of blood which is called plasma, and inject either young plasma or old plasma into these mice, and we could reproduce these rejuvenating effects, but what we could also do now is we could do memory tests with mice.

As mice get older, like us humans, they have memory problems. It's just harder to detect them, but I'll show you in a minute how we do that. But we wanted to take this one step further, one step closer to potentially being relevant to humans. What I'm showing you now are unpublished studies, where we used human plasma, young human plasma, and as a control, saline, and injected it into old mice, and asked, can we again rejuvenate these old mice? Can we make them smarter?

And to do this, we used a test. It's called a Barnes maze. This is a big table that has lots of holes in it, and there are guide marks around it, and there's a bright light, as on this stage here. The mice hate this and they try to escape, and find the single hole that you see pointed at with an arrow, where a tube is mounted underneath where they can escape and feel comfortable in a dark hole. So we teach them, over several days, to find this space on these cues in the space, and you can compare this for humans, to finding your car in a parking lot after a busy day of shopping.

So, let's look at an old mouse here. This is an old mouse that has memory problems, as you'll notice in a moment. It just looks into every hole, but it didn't form this spacial map that would remind it where it was in the previous trial or the last day. In stark contrast, this mouse here is a sibling of the same age, but it was treated with young human plasma for three weeks, with small injections every three days. And as you noticed, it almost looks around, "Where am I?" -- and then walks straight to that hole and escapes. So, it could remember where that hole was.

So by all means, this old mouse seems to be rejuvenated -- it functions more like a younger mouse. And it also suggests that there is something not only in young mouse plasma, but in young human plasma that has the capacity to help this old brain. So to summarize, we find the old mouse, and its brain in particular, are malleable. They're not set in stone; we can actually change them. It can be rejuvenated. Young blood factors can reverse aging, and what I didn't show you -- in this model, the young mouse actually suffers from exposure to the old. So there are old-blood factors that can accelerate aging. And most importantly, humans may have similar factors, because we can take young human blood and have a similar effect. Old human blood, I didn't show you, does not have this effect; it does not make the mice younger.

So, is this magic transferable to humans? We're running a small clinical study at Stanford, where we treat Alzheimer's patients with mild disease with a pint of plasma from young volunteers, 20-year-olds, and do this once a week for four weeks, and then we look at their brains with imaging. We test them cognitively, and we ask their caregivers for daily activities of living. What we hope is that there are some signs of improvement from this treatment. And if that's the case, that could give us hope that what I showed you works in mice might also work in humans.

Now, I don't think we will live forever. But maybe we discovered that the Fountain of Youth is actually within us, and it has just dried out. And if we can turn it back on a little bit, maybe we can find the factors that are mediating these effects, we can produce these factors synthetically and we can treat diseases of aging, such as Alzheimer's disease or other dementias.



PD Dr. med. Rainer Arendt
FMH Cardiology, Internal Medicine
Regenerative Medicine 

SWISS  PREVENTION  CLINIC
Klausstrasse 10
CH-8008 ZURICH
T +41 43 336 7260
M +41 78 825 0803
F +41 43 336 7261

rainer.arendt@swisspreventionclinic.ch

www.swisspreventionclinic.ch
www.patientcircle.org

Saturday
Apr112015

Gut Bacteria And Parkinson's Disease

Based on: Gut Bacteria May Influence Parkinson's Risk, Phenotype. Medscape. Apr 06, 2015.

 

Researchers in Finland have discovered what could be an important clue to what drives Parkinson's disease (PD). Their new study has shown a reduced abundance of the Prevotellaceae bacteria family in the gut microbiome of PD patients compared with healthy control persons.

 

The boxer Muhammad Ali and the actor Michael J. Fox suffer from Parkinson's disease

Although the new findings only "scrape the surface," they "give us good reason to dig deeper," said lead author Filip Scheperjans, MD, PhD, Department of Neurology, Helsinki University Central Hospital, and Department of Neurological Sciences, University of Helsinki, Finland.

If further research verifies that PD is caused by dysbiosis and a diminished number of Prevotellaceae in the gut, boosting levels of these bacteria by probiotics or gut microbiome transplantation might slow the progression of the disease, or even prevent it.

 

"Intriguing" Theory

 "It's an intriguing theory," said Dr Scheperjans. "I think it's something we will be looking at, because the ultimate goal of why we're doing the study is that we want to find something that we can correct."

However, perhaps a more pressing goal is to confirm that these changes in gut microbiome occur before patients develop PD. It has already been shown that PD patients tend to have gastrointestinal dysfunction, particularly constipation, and that these symptoms may precede motor symptoms by several years. "So from a clinical point of view, we know that the gut is basically affected very early in PD," said Dr Scheperjans.

The human body contains some 10 times more microbial cells than human cells, and these microbes carry about 100 to 200 times more protein- coding genes than the human genome. Almost all of these genes are of bacterial origin.

Intestinal microbiota influence epigenetics (unlike genetics based on changes to the DNA sequence, i.e. the genotype, the changes in gene expression or cellular phenotype of epigenetics have other, not inheritable causes in our immediate environment), the immune system, and the absorption of nutrients, vitamins, medications, and toxic compounds.

There is mounting evidence of an intense bidirectional interaction between gut microbiota and the nervous system, influencing brain activity, behavior, and levels of neurotransmitter receptors and neurotrophic factors.

 

The new study included 72 PD patients (mean age, 65.3 years; 48.6% women), and 72 age- and sex-matched control individuals who were without signs of parkinsonism or potential premotor symptoms (mean age, 64.5 years; 50.0% women). The median time from motor symptom onset in PD patients was 5 years. All but two patients were receiving an antiparkinsonian medication. The study excluded individuals living in the same household and so presumably having a similar diet.

From fecal samples collected from each study participant, researchers pyro-sequenced the V1-V3 regions of the bacterial 16S ribosomal RNA gene. They used random subsamples of 4500 sequences for analysis.

They found that the mean abundance of Prevotellaceae in the feces of PD patients was reduced by 77.6% compared with control individuals. This bacteria "is a normal inhabitant of the human gut," with people having varying amounts of it, said Dr Scheperjans.

It's important to note that PD patients had less of Prevotellaceae, which may indicate dysbiosis, and additional changes in their gut microbiome. The decreased abundance of Prevotellaceae was not explained by more severe constipation in PD patients, although the abundance of other bacteria, but not Prevotellaceae, was associated with degree of constipation, or by differences in comorbidities.

Less abundance of the bacteria also was not affected by medications. Dr Scheperjans noted that the COMT (catechol-O-methyl transferase) inhibitor was the only PD drug that was associated with changes in the gut microbiome. "That was interesting, because that drug causes GI side effects like diarrhea," he said. "But we accounted for that in our analysis, so the basic finding of the difference between PD patients and controls is not explained by the medications that patients are using."

The study showed that another type of intestinal bacteria ― Enterobacteriaceae ― was linked to the severity of postural instability and gait difficulty (PIGD). These bacteria were significantly more abundant in patients with a PIGD phenotype than in patients with tremor dominant (TD) phenotype.

There is a wide variation in clinical manifestations in PD patients ― with some having mostly tremor, and others, rigidity ― and the question is whether these phenotypes represent the same disease. It is possible, said Dr Scheperjans, that different PD subtypes are linked to different bacteria in the gut.

Role of Diet?

The role of diet is also not clear. Evidence in the literature does not suggest major differences between  the diet of PD patients and that of other people, and studies of the impact on PD of particular nutrients or foods have shown small effect sizes and contradictory results, said Dr Scheperjans.

The idea that gut bacteria is involved in PD is intriguing, according to the authors. Alpha-synuclein, which is the hallmark protein for PD, has been found not only in the brain as the main component of Lewy bodies but also in the gut.

There is evidence, said Dr Scheperjans. that the alpha-synuclein "protein pathology" progresses "in a prionlike fashion," migrating from the enteric nervous system to the central nervous system. "There is a hypothesis that these pathological proteins can jump from one neuron to the next," and that the vagal nerve is involved in the spread of the pathology, he said.

In the last 2 to 3 years, scientists have learned a lot about the presence and amount of these intestinal bacteria, "but we don't know a lot about what they're actually doing; that's the next step," said Dr Scheperjans.

Remarkable Finding

In an accompanying editorial, a group of authors, including Alberto Espay, MD, University of Cincinnati, in Ohio, point out that the demonstration that selected bacterial populations could influence disease and phenotype "is a remarkable finding" and could have important implications.

"For starters, Scheperjans and colleagues have given us the opportunity to envision a future in which specific motor features of PD could be modified by controlling the relative populations of certain species of microbiota."

In addition to helping to shape novel treatment paradigms, gut microbiota also have the potential to inform the understanding of the etiopathogenesis of PD, they write.

It is "tempting" to speculate that gut microbiota might be in the pathogenic pathway that determines disease phenotypes and is "poised to become a target" for disease-modifying pharmacology, they note. "Gut microbiota may even have a role explaining the differences in PD prevalence between rural and urban environments, between countries and perhaps even between sexes."

The new information adds to the evidence suggesting "that this may be the beginning of a leap forward in our understanding of and treatment options for PD," the editorialists conclude.

Microscopic identification of the microbiota in healthy (left) and inflamed intestine (right) using specific gene probes.

 

We offer gut microbiome exchange (transplantation) as new treatment for neurologic and psychiatric disorders

We have successfully treated neurologic and psychiatric disorders by gut microbiome transplantation from young healthy human donors. Such transplants appear to prevent disease progression, benefit overall physical health, gut health and the health of the brain.

 

New hope for patients with Parkinson's disease