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To stay up to date on the cutting-edge of health and performance, H.V.M.N. Research Lead Dr. Brianna Stubbs tends to read a lot of scientific literature...a lot. Every month, she will dive into the latest and most exciting research papers by walking us through the experiment process, dissecting the results and implications, and candidly share her own thoughts on the study and subject as a whole.

This month, Dr. Stubbs dives into three studies relating to the topic of aging and longevity.

  1. BHB Prevents Vascular Senescence Through hnRNP A1-Mediated Upregulation of Oct4
  2. Quantitative Analysis of NHAD Synthesis-Breakdown Fluxes
  3. Young Blood Reverses Age-Related Impairments in Cognitive Function and Synaptic Plasticity in Mice

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For this very first episode, I've decided to talk to you a little bit about some research in the field of aging. Now, we're all interested in how we can live longer, and maybe more importantly, live healthier. I've been looking at the research and there's been a few things come out in the last month that have got potential implications for how we grow old, and how we can do it better.

So the very first paper that we'll talk about today, the title is: Beta Hydroxybutyrate Prevents Vascular Senescence Through HNRNP A1 Mediated Up Regulation of Oct4. Sounds kind of frightening, but basically we're going to talk a little bit about how ketones can affect aging in the body.

The next paper we'll talk about is called: Quantitative Analysis of NAD Synthesis Breakdown Fluxes. This is more looking at how the cells make energy and the role of the essential co-factor called NAD.

Finally, we're going to go a little bit more off the wall. This isn't actually a recent article, but it's something that features quite widely and on the news every now and again, when people want to make an example of crazy things happening in Silicon Valley. This is about young blood. The paper here is called: Young Blood Reverses Age Related Impairments In Cognitive Function And Synaptic Plasticity In Mice. So this paper is about linking up the circulations of young and old animals, and looking at the effects on aging.

Beta Hydroxybutyrate Prevents Vascular Senescence Through HNRNP A1 Mediated Up Regulation of Oct4

Okay, let's talk about the first paper. This was published in molecular cell. And it's looking at the role of ketones in vascular aging. Aging is a pretty complex process. And actually all of the systems of the body age in different ways. But it's quite important when we think about our cardiovascular system. With the cardiovascular system, inflammation plays a key role. Inflammation is linked to the balance between two processes called senescence and quiescence. So senescence is irreversible arrest of the cell cycle, so that means that the cells, they stop dividing and they can't divide anymore again. That is offset by the process called quiescence, which is reversible arrests of the cell cycle. And so that means that the cell goes into kind of a pause. It doesn't divide anymore, but it can start dividing again in the future. And so that's really important for making sure that we can age healthily, because when your cells get senescent, they can't divide anymore and keep your circulatory system healthy. That said, there are important roles for senescence. So for example, in cancer or fibrosis, you don't want those cells to be continuing to divide, but it does exacerbate age related diseases.

There are many different molecular signaling pathways that regulate the balance between senescence and quiescence. With quiescence linked to kind of the property called stemness. So it's like where the cells are more like stem cells and they can divide multiple times and produce new cells. So one important protein or transcription factor that regulates this process is called Oct-4. And people have found that when you activate Oct-4 it's protective against cardiovascular disease such as atherosclerosis, which is where your arteries have a plaque that can cause a stiffening and damage. So beta hydroxybutyrate has been found to have anti aging signals in the brain. But it's unknown if this also affects the vascular system. So in this paper, the authors used cell cultures of vascular stem cells, and they subjected them to stress, using a molecule called hydrogen peroxide. And when they did this, the cells became senescent. However, if they added in beta hydroxybutyrate, but not, interestingly enough, Image result for Image result for acetoacetate, then senescence went down and quiescence went up. They also looked at the expression of inflammatory proteins. So remember, inflammation is a bad thing in excess that contributes to aging. And they found that when you add beta hydroxybutyrate, you get less inflammatory marker expression, and you also decrease markers of damage to the DNA. And it's important to protect the DNA from damage so that the cells can continue dividing and keeping us healthy.

What's more interesting though is that they found that ketones elevated the expression of the transcription factor Oct-4. Meaning, the cells are sort of more able to divide healthily and keep the vascular system ready to go. The authors then used genetic modifications to the mice to knock out the gene related to Oct-4. So this means that in the cells of these mice, there was no Oct-4. This caused senescence, and it meant that when they added BHB, they did not see the protective effect. So, that this demonstrated that Oct-4 is a crucial part of the BHB signaling effect on vascular health. So moving on from cells and then on a knockout animals, they then looked at healthy animals injected with beta hydroxybutyrate. So mice injected with beta hydroxybutyrate saw an increase in Oct-4 expression. And this lasted up to 72 hours after they'd been injected.

The final set of experiments look to see if having chronically elevated beta hydroxybutyrate was able to have the same effect rather than just acute one off injections. And so here they found that the higher the beta hydroxybutyrate concentrations in the blood of the mice, the higher the expression of Oct-4, and the lower the expression of inflammatory markers. So this suggests that there's a direct correlation or some kind of relationship between having elevated levels of ketones, and decreased inflammation, and increased markers of vascular stem cell kind of potency. All in all, suggesting that ketones could help to signal and keep our cardiovascular systems healthy. In the conclusion to this paper, the authors write, therefore Oct-4 is a potential therapeutic target, and beta hydroxybutyrate is a potent treatment for anti aging, or age related vascular disease.

Brianna's Thoughts on BHB for Aging

So what do I make of this paper? Well, firstly, it's really exciting to see more research come out around hydroxybutyrate, especially with our product H.V.M.N. Ketone. We're always very interested in the ways that the beta hydroxybutyrate molecule can affect health and performance. I'd certainly say this is a long way off any conclusive evidence in humans, but obviously the research has to start with the animals before we can start unpicking the mechanisms and understanding the implications for humans. And there's a lot more research to be done before we really understand if taking exogenous beta hydroxybutyrate would help to slow down vascular aging. But that said, this is very compelling evidence adding to an already growing body of evidence, showing that beta hydroxybutyrate can decrease inflammation, and act as a very powerful signal, as well as just a fuel source for our body. So I'm very excited to see where this research goes in the future.

Quantitative Analysis of NAD Synthesis Breakdown Fluxes

Next up, this paper was published in cell metabolism. And the title is Quantitative Analysis of NAD Synthesis Breakdown Fluxes. Now, NAD is a very hot topic right now. NAD refers to nicotinamide adenine dinucleotide. And it's what's called a redox co-factor. Basically that means that it plays a central role in cellular energy generation. Because it carries electrons from the degenerated, when we break down metabolic substrates, and it delivers them to a special place in the mitochondria where they can be used for a process called oxidative phosphorylation. Which is how cells make ATP. Energy is depleted with aging. And so there's been a lot of interest in how it's made and how it's broken down, so that we can look to maintain levels of NAD, and thus maybe slow down aging. So how can we make NAD? In our cells, NAD is made from tryptophan, nicotinic acid, nicotinamide riboside, and nicotinamide. These are all precursors that can be converted into NAD. Now, nicotinamide riboside and another called nicotinamide mononucleotide, these have been actively pursued as oral supplements, because they can be converted into NAD without passing through a gating enzyme for its conversion into NAD. So in theory, these nutraceuticals could boost NAD levels more than consuming NAM, and therefore prevent the effects of aging.

Up until now there's been a pretty limited understanding of NAD and metabolism. And so we've been relying on measuring its concentration, rather than actually directly tracking where it goes. Now this paper is very interesting as they were able to isotopically label NAD so that they could follow its metabolism in the body. Now, before we dive into this paper, I think it's important to set the scene and know that there's been quite extensive animal work in the past that's used NAD precursors such as nicotinamide riboside, which is called NR, and NMN, nicotine mononucleotide. And these are precursors to NAD, and they've shown promise for several hallmarks of aging. So people have studied their effects on cardiovascular function, liver function, eye function, and seen that supplementing with these precursors can have some beneficial effect. So in a way, the results of this paper are little bit counter to some of this earlier evidence. So, in the first round of experiments, the researchers used a variety of cancer cell lines, and used isotopically labeled nicotinamide. Nicotinamide found to be the main source of NAD in the cell lines. After they'd pinned down how NAD was being formed, they also looked at the processes involved in its breakdown. And they found that conversion of NAD to another co factor called NADP was one of the biggest contributors, as well as consumption from proteins called P pause and situtions.

Each of these latter two accounting for about one third of the consumption of NAD. After that they've done the cell experiments, they used a similar technique looking at NAD metabolism in vivo. In contrast to the cell lines were nicotinamide or NAM was the most important contributor to NAD production, in vivo, NAD was made from tryptophan. And this was mainly occurring in the liver which then excreted nicotinamide or NAM. So rather than NAM being used itself, tryptophan is being used here. So we have cell lines NAD being made from nicotinamide, and in vivo NAD being made from tryptophan. So what happens now, if we look at their more common precursors that are used in supplements? Nicotinamide riboside or nicotine mononucleotide. If either of these precursors were given IV, they were delivered intact to multiple tissues, but if you took them orally, they were actually broken down by the liver into nicotinamide. So each of these two precursors have received attention for their ability to elevate tissue NAD. However, in this paper they did not find that either compound was able to enter the circulation in tact.

So therefore, this nearly complete first pass metabolism of both nicotinamide riboside, an nicotinamide mononucleotide means that these compounds likely have a very similar effect to taking nicotinamide. Which is much cheaper and easier to get hold of.

Brianna's Thoughts on NAD for Aging

In summary, this paper is demonstrating a really exciting new technique. And I think that especially with the growing interest around supplements containing nicotinamide riboside, and nicotinamide mononucleotide, it will be interesting to see whether actually using isotope measurements to actually follow where these things go inside the body will be really important for us to understand, if they're working, and how they're working. But from this paper, it looks like if you take these supplements that your liver is metabolizing it into something else altogether, that is cheaper and easier to buy. So at the moment it's a bit of a toss up as to whether you would buy the expensive precursors, or whether you could go with something that's a little bit cheaper, and whether you be getting the same effect. But this paper certainly doesn't look at any outcomes of aging, or anything like that. And it is in contrast to some of the earlier findings. So watch this space. There's a lot of research to be done here. And I think it could have interesting applications for aging in the future. Because NAD plays such a vital role in how our cells make energy and stay healthy.

Last up, a paper that was actually published back in 2014 in Nature Medicine. And the title of the paper, as I said earlier, is Young Blood Reverses Age Related Impairments In Cognitive Function And Synaptic Plasticity In Mice. This paper is one of a series of papers that came out around about this time, looking at what happens when you join the circulations of young and old mice. So, it all sounds kind of spooky and vampirish. But the scientists call the process heterochronic parabiosis. And what that really means is you have two animals of different ages and you surgically joined their circulatory systems so that they share a blood supply. And it might sound all a little bit futuristic, but there's actually records of this process dating back into the 1800s. So in 1864, a scientist called Paul Bert invented this process. And perhaps not surprisingly, it fell out of favor, due you too mysterious deaths with a parabiotic disease. So after a bit of time where this was not being investigated, it kicked off again in Stanford University in 2005. And since then a number of papers were published, looking at the effects of heterochromatic parabiosis on muscle and liver regeneration and proliferative capacity. The fact that the circulatory systems are joined means that there is a systemic.

So, throughout the whole system, something mysterious, perhaps that's controlling the aging process. So it's not just a local effect or an effect of what's going on in the specific cell or tissue. It's system wide. Now another interesting thing to note with this field in general, that there is some history of data manipulation. And quite famously one of these papers was retracted. This wasn't the Stanford Group. Their research group was in Harvard, but they had to retract one of the science papers for manipulating one of the images. Whilst there are definitely some ethical concerns in this field, not just from the ethics of the research itself, but also the ethics of the publishing of the research, it's certainly interesting, and a topic that always receives a lot of attention in the media. So I thought that we would discuss one of the papers here that looked at the effect of young blood on the brain.

So in this paper, the authors decided to use a mouse model and to focus on an area of the brain called the hippocampus. This is involved with memory formation, and it's particularly vulnerable to aging. It exhibits downregulation of plasticity related genes, so this means the ability to form new connections. This results in impairments in cognitive function and new memory formation. So in this experiment, they're comparing young mice joined to old mice, and old mice join two other old mice. So, age matched mice. An old mouse that was joined to young mouse had very different gene expression inside the hippocampus. And there were very much up regulated levels of genes involved with synaptic plasticity. So again, the ability to form new memories. Once they looked at gene expression in the old mice conjoined to a young mouse, they then looked at physiological measurements. So they looked at a property called longterm potentiation, or LTP. LTP is crucial in the ability to form new memories. And they found the LTP in the old mice who had been joined to young mice was maintained above baseline throughout the recording. Indicating that synaptic plasticity again is enhanced by exposure to the young blood. Given the LTP is a functional correlate to learning and memory, they hypothesized that exposure to young blood could enhance cognitive processes.

So they actually tested the behavior of mice in fair conditioning, and water maze experiments to see whether the cognition was actually improved, and whether the age related impairments in hippocampal dependent learning and memory were protected. So when they looked at the behavior of the aged mice, given young plasma, these mice demonstrated enhanced learning and memory, and they did not see any difference between untreated aged mice, and aged mice treated with aged plasma. So really highlighting that the young plasma was crucial for the effect here. So the authors conclude in this paper that their data demonstrates the exposure to young blood can counteract aging at the molecular, structural, functional, and cognitive levels in the aged hippocampus. They did note however, that it is important to consider that the results are currently limited to aged mice. But they suggest that future studies are warranted in aged humans, and potentially those suffering from age related neurodegenerative disorders.

Brianna's Thoughts on Youngblood for Aging

Now, once I'd finished reading this paper, I had a lot of thinking to do. Because I mean I've seen on Silicon Valley, the idea of parabiosis, and it's all kind of somewhat fantastical. But if this worked, would it be something that would be practical? So I looked up what these investigators had done since this paper was published, and actually I found a record on the clinical trials registry of young plasma being used in a clinical trial for Alzheimer's disease. So it does look like this work has progressed. And whilst it might not be as grotesque as we imagine, with a young person surgically patched onto an older person and having to follow them around, there is a possibility that receiving transfusions with young plasma could be used in the clinics in the future. So not only are there clinical trials underway, but typically it's being accelerated and is actually coming to market. There was a headline in Rolling Stone magazine published the end of September, so just last week, saying, clinic to offer young blood transfusions. And so if you're based in New York, you will soon be able to have blood of a 16 to 25 year old transfused directly into their body. So whilst all the evidence that we've been discussing today is quite promising, in this Rolling Stone article, the experts that were interviewed were not convinced. One of the key researchers in some of the early work in animals called Tony Whisk Coray of Stanford, who actually was the lead author on the paper we just read, he told the magazine, "there's just no clinical evidence that the treatment will be beneficial, and you're basically abusing people's trust and the public excitement around this". And he actually called the company offering the service immoral and compared them to climate change deniers. Whilst it might sound all great when you read the science literature, there's definitely a long way to go before it's translatable into humans. And if the lead author on this paper is going as far as to call the company immoral, I'd definitely think twice before signing up for this. But maybe keep an eye out and see where the science goes in the future. So there's still quite a long way to go before we understand the philosopher's stone, elixir of life, fountain of youth, but certainly some areas to look out for. But just be wary of being oversold any particular strategy.

Parting Words

That's it for this week! I hope you've enjoyed listening in and learned something. And I hope that if you did enjoy it, you'll reach out and let us know. Let us know if there's any topics that you're interested for us to cover. As ever, I'll be following the research between now and next month, and look forward to seeing you again on the H.V.M.N. Research Roundup.

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