Parabiosis: Reverse Aging With Young Blood? Podcast with Irina and Michal Conboy

Can we stave off the aging process by transfusing young blood into old people? The idea that youthful blood might have rejuvenating properties has lingered in popular imagination for centuries. It sounds like science fiction to most people now, but various companies have become interested in this proposition. A startup (aptly named Ambrosia) in Monterey has even launched a clinical trial that is transfusing the blood of young people into older individuals… provided they’re willing to pay $8,000 for the opportunity. Much of the interest in this came from studies of parabiosis – I’ll come back to what this is shortly.

Now, animals vary considerably in their ability to regenerate. Salamanders, for example, can regrow entire limbs and organs with enviable ease. Sadly, humans are much more limited. But one commonality across species is that we all experience considerable declines in regenerative capacity as we age.

So, why specifically does this happen?

And can we do something about it?

In this episode of humanOS radio, I speak with Drs. Michael and Irina Conboy of the Department of Bioengineering at UC Berkeley. Their lab investigates the process of tissue repair throughout the body and is trying to determine why damaged tissue is not productively repaired as the body ages.

Their early work in this area used a fascinating technique called heterochronic parabiosis. In this experimental model, two mice – one old and one young – are joined together surgically so that the animals share a circulatory system. They found that the older animals benefit from this fusion – their muscle tissue becomes functionally younger. However, Irina was reluctant to attribute the health improvements entirely to the young blood. She points out that the older animal in this arrangement also benefits from having younger organs and immune systems, which would also enhance health and vitality.

The Conboy team eventually figured out a way to isolate the effects of the blood itself. In their most recent study, they used a pump to continuously circulate and mix together blood between two different mice – one very young and one very old.

After just five days, changes were evident. The older mice experienced some improvements, as we might expect. However, Conboy noted that the biggest changes by far occurred in the younger mice in response to the old blood. They became weak and decrepit, like their elderly counterparts.

Their study suggests that it may not be factors in young blood that have regenerative properties – just giving young blood to old animals may not make them much younger. Rather, the findings suggest that certain attributes of old blood – perhaps inhibitory molecules within that blood – may be responsible for the notable declines in tissue repair associated with the aging process.

Therefore, a more fruitful approach might be to figure out which specific molecules in the old blood are interfering with the regenerative process, ultimately finding a way to clear them. This could have profound implications, not just for slowing down aging, but also for the treatment of conditions like Parkinson’s disease, osteoporosis, sarcopenia, and others.

Listen below to hear about the Conboys’ remarkable research, and its potential future implications for the prevention of aging and degenerative diseases!

On Soundcloud, iTunes, Google Play, Stitcher, and YouTube.

Image: http://tinyurl.com/jzba5m2

Irina Conboy - 00:06: If we were funded better, we could have combated all of the horrible, incurable, devastating pathologies of aging. Such as Alzheimer's, and Parkinson's, and Type II Diabetes at once. Pretty much like Penicillin combats bacterial infections.

Kendall Kendrick - 00:24: HumanOS. Learn. Master. Achieve.

Dan Pardi - 00:34: Irina and Mike Conboy, thank you so much for joining humanOS Radio. So you two are married and have been doing work together for many years. Tell me about your story. How you guys met, and the type of work you do together now.

Michale Conboy - 00:44: Sure.

Irina Conboy - 00:44: It's a very romantic story. We have recently celebrated our silver anniversary.

Dan Pardi - 00:50: Congratulations.

Michale Conboy - 00:51: I met Irina after graduating from college. I was working in a lab just as a technician. I came into lab one day and there was Irina sitting on my bench.

Irina Conboy - 01:00: Next couple of years we had long distance dating. Then we got married.

Dan Pardi - 01:04: A lot of the work that you guys have done has been in stem cells. Before we launch into that, for those who are unfamiliar, what are stem cells? Why are they so interesting?

Irina Conboy - 01:13: Stems cells are cells which can make more of themselves. Also, make any tissue that we need. For example, in adults there are stem cells in our brains which can make new neurons. Specifically, they can make new neurons in the part of the brain which is responsible for memory and learning. For example, if people want to learn new language, for example Greek, right now. In the beginning it will be very, very difficult. With time it will be easier and easier as they practice. There are many mechanisms but one of the is that we start making new neurons. The neurons connect with each other and therefore allow us to speak Greek.

01:56: Meanwhile, each cell does not just make a neuron. It also makes another stem cell. This process can continue for many, many decades. Pretty much the same happens in muscle, and bone, and skin. Everywhere that we looked in every single organ in our bodies. They think that there is potential to repair and restructure the organ throughout our adult life. Those are adult stems cells. There is of course embryonic stem cells which is entirely different thing.

Dan Pardi - 02:27: Right. In my conversation with Aubrey de Grey, he was optimistic of stem cells being one area in which we can effect aging itself. If we have these stem cells that regenerate and then can become new tissue, what does happen with aging to stem cells?

Irina Conboy - 02:44: What we believe and we found is that, interestingly, stem cells remain relatively young in a person who is 80, 85 years old. You are like a mosaic of cells. Many of your cells are old, decrepit. They have damaged DNA and short tumors and what not. But stem cells are actually pretty healthy, and young, and functional. They are inhibited. They are pretty much blocked by their surrounding tissue. It's called niche. It's like they live in their little niche. That niche blocks them from performing any work. The cells that we know work just like keep sleeping and do not repair the tissue. Then, because of that, when there is tissue damage and stem cells are sleeping, they are not activated. Then the damage is not regenerated. Instead you have fibrosis. It's like your plan B. You now make fibrous tissue, and depose fat tissue to replace the damage. Then gradually the time, you just turn into this big scar and big fat blob.

Dan Pardi - 03:53: Well that would certainly describe what is visible when somebody ages. They lose their muscle. They become less functional. That is a primary reason why that's happening. These stem cells, although they remain young, their surrounding environment gets in the way of them become healthy, new muscle cells. Therefore, overall, the organism start to have less and less muscle, more and more fat and fibrous tissue. It's less functional.

Irina Conboy - 04:17: It's not just in muscle. The same happens in liver. There is liver fibrosis and liver adiposity, or fat liver. Even in brain, right? You don't maybe necessarily have fibrous tissue in brain but certainly you have less neurons and more kind of connective supportive tissue in brain with age. That is actually promising. The alternative, if we simply physically lost our stem cells, would be much worse because cell transplantation really doesn't work. Since we still have them, maybe there is a little bit less of them, but whatever 10%, 20%. We still have enough of them that if we rewaken the cells which you have already, they just start making new young tissue. They're pretty much actually, interestingly, most of our adult or tissue stem cells are in the state of hibernation. They are kind of sleeping all of the time. They're waking up only when there is a signal from surrounding tissue to tell them that the tissue is damaged. You need to wake up, repair tissue and then go back to sleep.

05:22: If you can imagine, you know, there was this sci-fi movies that if people sleep for a long time they remain young. Meanwhile hundreds of years have passed and they wake up. It's kind of similar analogy of the tissue stem cells. They sleep most of the time. Most likely because of that they remain relatively young and capable of making new tissue. That's promising because then if you figure that there are proved ways to reawaken them then 70 year old, 80 year old person will start regenerating. All of the organs as if they are 20 year old. Gradually, not only you prevent all these bad diseases to happen but perhaps start getting even younger.

Dan Pardi - 06:06: The regeneration of all of our tissues, whether it's brain or muscle or liver, whatever, requires these stem cells to be woken up. Turned into healthy new tissue. What is it about getting older? What happens in that microenvironment of the stem cells that prevents the signals from waking them up?

Irina Conboy - 06:22: Basically, again, best way I can present it for your audience is a metaphor or analogy. If you imagine that there are a bunch of old bureaucrats working. They just don't want to be replaced by any new employees in the company. They kind of put all of the things that they have on top of the years to prevent new hiring and prevent their own retirement. That's a perfect analogy to what happens in our tissues. You know that we go through life. We are exposed to all kind of stresses. UV rays from sun. Reactive oxidative species just simply from eating. We damage ourselves. Interestingly, those damaged cells which you call differentiated cells which cannot divide anymore. All they can do is just either perform their function or die.

07:14: Interestingly, they produce chemicals in their environment which prevent stem cells from replacing them with the new tissue. Those chemicals help the differentiated cells that are damaged to survive. They maintain their life. At the same time, they inhibit stem cells from waking up and replacing damaged tissue with the new one. It's like they are clinging onto the life for the bitter end. Then ultimately, when they cannot cling on anymore and big chunks of liver start dying, the whole organism then is compromised.

Michale Conboy - 07:47: I have a slightly different rewording of that. Entrenched bureaucrat asleep at their desk would be that there is growth and then there is differentiating. Stems cells, when you're young, which stem cells are getting a lot of growth signals. Your whole body is getting a lo of growth signals. The stem cells get regenerative cells which perforate a lot. There's relatively less differentiated cells and differentiation signals compared with later in life. When you lose the growth signals, and you're fully grown and fully mature. All that remains, I guess, is more of a differentiation signal environment. Then the cells perceive that and that tends to tell stem cells to stay asleep and not wake up and perforate.

08:30: There is also this phenomenon. I guess the term is inflammaging. Inflammatory signals that increase with age. The aging body in general has a lot more signals of kind of persistent and chronic inflammation. Those tend to be pro differentiative also. If I were to lump those molecules of signals into a, are they on the growth side or differentiation side? I'd put them on the differentiation side.

Dan Pardi - 08:52: Okay. You've got a diminution of growth signals that happen naturally as we age. You've got then an increase in these inflammatory signals that prevent the stem cells from differentiating. All together that leads to loss of tissue function. One publication that got a lot of attention is one where you did this parabiosis experiment where you had blood exchanged from an old rat to a young rat. Tell us a little bit about that one. Then we can talk about the more recent one, which was not parabiosis but had highly controlled blood exchange.

Irina Conboy - 09:22: Thanks. The first one, Mike did most of the surgeries if not all of the surgeries there, you simply staple skins of two mice together. If you imagine there are those sleeping bags that you can unzip and then zip together to make a bigger sleeping bag. It's exactly like that. Then you wait for like a week or so for capillaries. Small blood vessels to grow between the skin. Then blood starts to exchange or flow between two animals. It's of course, kind of, very rudimentary. Not very precisely controlled experiment because different animals might have different amount of capillaries growing through them. Therefore the blood exchange could be different between pairs. Then you wait a month or so and mice are running together. They are eating together. Sleeping together. Then you see what happens to their organs and tissues.

10:16: In this experiment we found that old animal becomes much younger, with respect to muscle degeneration, formation of new neurons in the brain. Also, liver regeneration. All of these molecules which were responsible for making animal younger were also rejuvenated. It was not just a fluke. There was also fundamental mechanism of how they became younger. The young animals suffered from this connection. Became older, particularly in liver and in brain. Back in 2005 we did studies. Actually we started in 2003, 2004. We did studies with all three tissues. Muscle, liver and brain. But for brain the Nature reviewer who reviewed our paper was very vicious. He gave us many suggestions for additional experiments which would have taken years.

11:14: I now already had position at Berkeley. Editors of Nature really wanted to publish this findings. As a compromise, we just removed our brain results from the paper. We published only on muscle and liver. We shared our findings. We showed this results to Tony Whyss-Coray from Stanford who was at the time new assistant professor studying how inflammation induces Alzheimer's Disease. You shared it with Tony and then Tony published identical results. Also extrapolated them six years later on brain. Fortunately the brain data was not abandoned. In that respect we could have published these findings back in 2005 as well.

11:57: From that time on, people kind of became obsessed with the stories about vampires and that young blood holds the secret to health, and youth, and so forth. It was really strange to me. It was surprising that that was such a simplistic interpretation of our findings. Which we did not intend our findings to be interpreted like that. Also, that how much, I guess, interest it got. It really absorbed all of the funding in the area. As a result there was not enough funding to do any alternative work, which in my opinion was the most important work to do.

12:32: Anyways, if you want we can explain to you why we think that it was simplistic interpretation? That young blood will solve the problem.

Michale Conboy - 12:40: That's right. Let me interject a historical correction there. In that paper, it was actually Amy Wager from Irving Weissman's lab who did most of those surgeries.

Irina Conboy - 12:49: That's right.

Michale Conboy - 12:50: I did plenty of surgeries, but not for that particular paper.

Irina Conboy - 12:52: Yeah.

Dan Pardi - 12:53: Got it.

Irina Conboy - 12:53: That was her contribution. Our third author on the paper is Amy Wagers. Who at the time was connecting two young mice together for totally different question. She told us how to staple mouse skins. Also she stapled a bunch of mice for us. That was her contribution. Then from then on, she continued with this stapling of mice for many other research papers trying to see if heart becomes better, bones become better. In general, the whole field kind of confirmed and extrapolated our findings that, yes, if you connect young mice with old mice you see positive effects on a number of old tissues. We also see inhibitor effects on a number of young tissues. That's kind of the overall conclusions.

13:40: The main secret there is that mice share more than blood when you staple them. When they live together for like an entire month, then old mouse now has access to young heart. The blood pressure becomes better. Young lungs, so now you have better oxygenation of blood. Red blood cells now are more oxygenated. Also, you have young red blood cells going into an old animal. Also, you have young liver. You have much better metabolism. You have young immune system. You have much better wind clearing and less inflammation. It is not, you know, those secret proteins in blood. It is simple things like how much oxygen does your brain get. That was completely overlooked. Then millions of dollars were spent on a fractionation of blood. Which in our perspective could not have led to anything significant and it didn't. Also, you know, injecting small volumes of young blood into old mice or old people. Which the jury is still out there but in my opinion based on just the basic biology knowledge that doesn't seem likely to work.

Dan Pardi - 14:48: I see.

Irina Conboy - 14:50: That was kind of the conclusions of the parabiosis.

Dan Pardi - 14:54: The summary, if I may, a young mouse and an old mouse. Circulations were tied together.

Irina Conboy - 14:58: It was not circulations. That would have been better. Their skins were sutured. Right? Nobody did vascular surgery on them.

Dan Pardi - 15:06: Okay. What you found is that the older mouse all of a sudden started to appear younger. It had better oxygenation of the blood. There was a variety of different things but it was hard to attribute what those benefits were due to. But because it was a seemingly simple solution it stimulated a lot of other research. Even a field of saying, hey, this can be a way to prevent or effect aging in people by injecting, you know, young blood. That stimulated that hypothesis. People ran with it. It was a little suspect to you. You thought there was probably other things that were taking place besides just the blood. What did you think was going on? What was your next experiment that took it a step further to identify really what was going on?

Michale Conboy - 15:45: Right. At the time we also had some data that we did. We call in vitro in a petri dish. Where we would take cells and grow them in culture. Usually when you do that you add some amount of serum to that. That's the liquid fraction of blood. You spin out the cells. If you grow the cells in young serum, they grow very well. If you grow them in old serum, they grow poorly. What was interesting was if we mixed young serum and old serum together, the cells grew poorly. That indicated that there was something that was in the old serum that was suppressing the growth and was also dominate over whatever was in young serum.

16:19: That got us thinking that what was growing on in parabiosis must be more along on the lines of the young animals filtering some old, inhibitory stuff out of the old mouse. Maybe more than it's adding young positive factors to the mix. That got Irina thinking that there's got to be something that circulates, that's inhibitory, and what could it be? She did a screen that I like to call in biblio. It's not in vitro or in vivo or in silico. It's sitting on a computer and going into PubMed. Looking up papers and reading them.

Dan Pardi - 16:54: Right. In biblio.

Irina Conboy - 16:55: I think that all the secrets of the universe are already uncovered on PubMed.

Dan Pardi - 16:59: Right.

Irina Conboy - 16:59: There are millions of papers. If any one person understood all of them then there would be no secrets left. That's one of my favorite things I do. [inaudible 00:17:09] by screening PubMed first.

Dan Pardi - 17:12: Right. That's smart. Isn't there a saying, an hour in the library saves a month in the lab.

Michale Conboy - 17:16: Exactly.

Irina Conboy - 17:16: Absolutely. Very few people still do it unfortunately.

Dan Pardi - 17:19: Yeah.

Michale Conboy - 17:20: Yeah. Anyway. More funding. Get more funding. We'll have more time and sit and actually read papers instead of scrambling to rewrite and write grants.

Dan Pardi - 17:27: Right.

Michale Conboy - 17:27: To get back to the screen. She thought of, okay, what circulates? Could potentially increase with age? Is probably part of a gene family? So you don't find long lived or well regenerating mutants because they picked up, gained a functional mutation or something in the one member of the family, right? It was probably necessary for proper function at some dose. She could a short list of molecules. We then tested them in the lab.

17:51: Then TGF beta was one that kind of rose to the top as having a robust inhibitory effect on our cell growth and culture. If she blocked it in cultures with old serum she was able to restore the growth of the cells. That sparked a whole set of years of investigation into transforming growth factor beta. Then got a bunch of publications on that. The up side of that was that in the mice, if they were injured the old mouse, if you added an inhibitor of TGF beta ... These are pharmaceuticals that are available off the shelf. Some are in clinical trials against various cancers or something like that. For a short dose, short duration you could improve the muscle regeneration dramatically-

Dan Pardi - 18:30: Incredible.

Michale Conboy - 18:31: Also, a grad student in the lab, Hanadie Yousef, found that if you injected that you not only improved the muscle regeneration but you'd also improve neurogenesis.

Irina Conboy - 18:38: In the same old animal.

Michale Conboy - 18:40: Right. In the same old animal.

Dan Pardi - 18:41: Ah! It's not necessarily tissue specific, but you can have a broad effect throughout the body.

Michale Conboy - 18:45: Right.

Irina Conboy - 18:45: Exactly.

Dan Pardi - 18:46: Yeah.

Irina Conboy - 18:46: Then unfortunately that was overlooked because people were obsessing at the time about GDF11. Which later on turned out to be problematic and irreproducible. Our paper was published not in a high impact journal. In what a reputable, good journal but not in Science. I think that because of that really the benefits to people who are suffering for degenerative pathologies were limited. Again, that is only because we don't have enough funding to pursue multiple directions and see how they contrast and compare. Everybody just jump into one direction. GDF11 is great! Then, oh, no, sorry it doesn't work. Meanwhile the work that was published in parallel is not big news because it was published back in 2015.

Dan Pardi - 19:35: Right. In science you've got to go where it's hot because that's where the funding might be. Everybody is doing the same thing and it slows everything down.

Irina Conboy - 19:42: Yeah. Then if there is big hoopla and so many press releases then private investors also tend to gravitate over those exciting news. Often times because they are exaggerated nothing good comes out of it.

Dan Pardi - 19:56: Yeah. Right.

Irina Conboy - 19:57: That's with like specific things. Then, we were thinking about the clear experiment. A proof of principal which we will once and for all discriminate between whether young blood is good or whether we need to remove old blood inhibitors. That's how we switched to the blood exchange. Which is much more difficult to set up than parabiosis. It is much better experimental set up to answer many questions. In blood exchange, in fact, we do exchange only blood. There are small catheters which are inserted into mouse veins. You can imagine, mice are very little, how tiny their veins are. You need to be very, very skilled to be able to catheterize mouse veins. Then there is tilted pump that pretty much mixes the blood from young mouse with an old mouse to equilibrium. Which is identical to parabiosis. There is no loss of blood. There is no gain of blood. They are mixed in exactly the same way.

20:57: That happens in one day. Then mice are not living together for one month anymore. They do not share organs. You exchange their blood. Then that's it. They are separate. Young mouse and old mouse. Then very quickly you can study what happens with their organs and tissues. Most surprising findings that you have from this experiment is that, yes, blood exchange without any organ sharing or adaptation does have effect on youth and aging. The effect is almost instantaneous. It implies completely different set of mechanisms as compared to when mice are sutured and running together. The effect is almost like it takes place for some organs in one day after blood exchange.

Dan Pardi - 21:39: Wow.

Irina Conboy - 21:40: The most predominant effect is that you have inhibition or premature again of young animal because now it has old blood.

Dan Pardi - 21:50: Interesting. The excitement with the parabiosis studies is that young blood could make an older mouse younger. What this study showed was actually the opposite. That older blood makes a younger mouse older.

Irina Conboy - 22:01: Exactly.

Michale Conboy - 22:02: I wouldn't-

Irina Conboy - 22:02: No. Yeah.

Michale Conboy - 22:02: Exactly phrase it as opposite. There's definitely good stuff in young blood. We'll see what happens to the studies that people are doing now. Where they are injecting young blood into old people and pursuing those types of experiments in mice. Just what this shows is that relatively there's a bigger negative bang of the old blood. Then there is of a positive boost from the young blood.

Irina Conboy - 22:22: Or like to paraphrase what Mike said, is that if you neutralize and remove inhibitors of old blood. That by itself will be therapeutic without adding anything young. If you do that, then any other positive thing that you might find in young blood or otherwise, will work better or actually work.

Dan Pardi - 22:41: Right so the old blood, is you could be adding these inhibitory factors. Which, Mike, I remember you saying earlier when you're doing an in vitro. When you added a mixture of the old and the young blood. It seemed like the older blood was having a greater impact. Those inhibitory factors were there, but there could be a positive impact from the younger blood being added to dilute the inhibitory factors that are present?

Irina Conboy - 23:00: I don't think so. In our experiments we pretty much removed 50% of the old blood and replaced it with 50% of the young blood. It is a huge amount. As you probably know it is impossible to do or to do frequently in people because of the immune rejection and horrible side effects like lung collapse, and anaphylactic shock. Our mice are pretty much younger clones or younger twins of the older mice. They're all genetically identical. In people it would be impossible to do. We removed incredible amount of this old inhibitor blood, 50%. We added 50% of the young blood. Similar to when mice were sutured. Still we had no, zero positive effects on brain. Zero. We did have positive effects on muscle and on livers. Mike was accurate. This is again proof of principal experiment which is not possible to directly translate to people. We have some ideas of how that could be translated to people. How our findings could be translated.

Dan Pardi - 24:03: The small molecule that you mentioned, that is being currently tested in some cancer trials was very interesting. This transforming growth factor beta one does seem to increase with age and all body tissue. Not very present when you're younger. It's more ubiquitous in some tissues when you're older. This is actually inhibiting those stem cells. This small molecule, however, that is available. This actually can block the receptor of TGF beta one. Then that will decrease the pathway activity. That's really exciting. That feels like it's a much more direct approach. Even if there was some effect of diluting the blood from an older person with a younger person blood this seems more powerful and targeted.

Irina Conboy - 24:42: Yes. The one caution with that is that TGF beta one is really important thing that we cannot simply remove. If we do remove too much of it we become very sick.

Dan Pardi - 24:52: Right. You want to get it right. You got to-

Irina Conboy - 24:54: You want to get it right. Exactly. Right now, for example, we are working on this ... What's it called? Immunoaffinity modules or next generation blood exchange with our bioengineering colleagues where you can take blood from an old person. Which is now FDA approved process, so blood exchange. Then you can filter out specifically access of TGF beta one. Measuring precisely what are the young levels that you need. Then we can return that rejuvenated blood back to the same person without any side effect because it is his own or her own blood.

Dan Pardi - 25:33: Right!

Irina Conboy - 25:33: Now it is not inhibitor anymore. In fact we know that it can be done sustainably. There is no immune reaction and there is no negative effects on anything.

Dan Pardi - 25:43: That is interesting.

Irina Conboy - 25:43: That is kind of one approach. Right? If you start injecting inhibitor of key signaling that is really needed for many cells in the body, it's really easy to get it off a little bit. Then we start developing horrible side effects. If you actually precisely measuring, pretty much FDA approved protocol which could be repositioned to achieve now, number of degenerative pathologies. Then it could be done sustainably and safely. That's one of our ideas for the future.

Dan Pardi - 26:13: That is pretty exciting. It would be like a dialysis situation. Now you have to just figure out, how frequently? How much needs to be removed and put back in?

Irina Conboy - 26:23: Then the second point is that we don't think it could be single prone or silver bullet type therapy. There are probably three to five things which we need to normalize to young levels. Those are the key things. We don't need to work on hundreds of molecules. We need to do really well with three or five to make blood. Therefore stem cell responses younger and healthier for long time. Also, do it safely. You know? It's not simply that you have toxins and you filter out in dialysis. Those are molecules without which we cannot live. They just become deregulated ether too much or too low. You need to return them to their normal levels.

27:03: It's possible to do. We have clinical trials under development with Professor Dobri Kiprov at San Francisco in collaborations with UC Berkeley engineers. That's one of the huge directions. Which I think actually has a hope to succeed [inaudible 00:27:21] to injecting blood of virgin teenagers into old people.

Dan Pardi - 27:25: Do you still that some investigation into these small molecules drugs has potential or is it a little bit too risky?

Irina Conboy - 27:32: Our colleague professor Dobri Kiprov from San Francisco Blood Apheresis Clinic. Who is doing blood exchange in people for 35 years. He's an expert. Currently practicing physician. He contacted us because of reading our papers. Make him interested in can this be repositioned. Repositioning is when you already have FDA approved procedure and your clinical trial therefore are much more advance. You just see if the same or slightly modified protocol can be used. Instead of what immunity can be used to create Parkinson cells, Type II Diabetes, Osteoporosis, muscle wasting and other pathologies of aging. We are working with him on that. Basically we envision precision medicine approach because we do not age identically to each other.

28:21: Even if you think of normalizing the levels of TGF beta. Another positive molecule that we found that diminishes with age which is called oxytocin. It might be different from person to person. In one person you need to drop it down by two fold but another person by five fold. Therefore you need the precision medicine process and good sensors to measure completely and accurately the levels of those candidates. Before and after. It would be in the nature, I think, of the clinical trials. It matters that we raise funds for that. Again, funding has been very scarce and diluted into multiple directions.

28:57: We do plan to study in those clinical trials how much younger do people become? Do they become younger in their epigenetics for example? Do they become younger in their lack of predisposition to cancer? There is many, many parameters that we can study. How much improvement can we expect from our process or approach where we take persons blood and it goes through the machine in the approved process? Then we return blood back but in much rejuvenated state. Is this systemic rejuvenation applied to cells, and to molecules, to DNA? That would be good.

Dan Pardi - 29:34: Pretty much everything that happens to every single person as we get older. If we address some of the core mechanism then we can basically address everything at once. Aging itself there's a major lack in funding. Particularly with the importance of being able to solve so many things at once, potentially. What's the current state of funding? What do you think needs to happen in order for more dollars to go toward these really important research?

Michale Conboy - 29:55: This paper costs about half a million dollars. We got funding from Calico. We got a little bit of funding from NH and a few other sources. What really nucleated that and made that happen was Aubrey de Grey. He came up with the funding to get it going. He also found the expertise. He knew Justin Rebo from previous work through SENS who had the expertise of being able to do the catheterization. Getting this miniaturized [inaudible 00:30:15] computer controlled pump. Justin's friend, Keith, to put all that stuff together. I'm sure it wouldn't happen at that time if it wasn't for Aubrey and his interest to not just aging but thinking-

Dan Pardi - 30:24: Spreading the gospel.

Irina Conboy - 30:26: Yeah. What I know on my part, is that a couple of months ago very famous scientists including Murando, Judy Campisi, myself and others, Tony Whyss-Coray, wrote a letter to the director of National Institutes of Health asking to provide more funding for aging research. Saying that really we're underfunded. If we were funded better we could have combated all of the horrible, incurable, devastating pathologies of aging. Such as Alzheimer's, and Parkinson's, and Type II Diabetes. At once. Pretty much like Penicillin combats bacterial infections. Regardless of whether it is Tuberculosis or Meningitis. That was the nature of our petition. Unfortunately, I don't think that it's going to happen because we had similar appeal a couple of years ago. Had a whole symposium dedicated to that. As a result nothing good happened. Again, aging research which I think is instrumental to biomedicine is sorely underfunded.

Dan Pardi - 31:28: Well getting funding from NIH is a wonderful thing and it should happen. We also have organizations like SENS Research Foundation, which anybody who is listening, can go there and donate. You can directly help people like Conboy's to do their work. Go to SENS. Make a small donation. If enough of us do that it can actually lead to pretty meaningful results. For example, the Conboy's can get funding to do the next step. Which could actually have a benefit within our lifetime.

Irina Conboy - 31:53: There is Open Philanthropy which is a different foundation.

Dan Pardi - 31:57: Yes.

Irina Conboy - 31:58: They are looking at the proposals that were not funded by NIH. They are reviewing the value of the proposal. If it's a good proposal and exciting work they're thinking of funding it. That was done as a model with respect to cancer research recently. With very big success. It got funded independently by philanthropy they have led to this immunotherapy against cancer which turned out to be actually working.

32:27: Open Philanthropy wants to do the same with a broad range of scientific endeavors. So Open Philanthropy would be another place, I think, where people could contribute. Then we will have better chances to get funding. Additionally, somebody can just give gifts to UC Berkeley or Conboy Laboratory for a specific idea project.

Michale Conboy - 32:45: Tax deductible.

Irina Conboy - 32:46: Tax deductible. What I want also to mention is that currently at NIH or other major funding agencies it's winner takes all. All of the kind of funding has accumulated in very limited laboratories. We don't have this kind of help from, you have more heads and you have better outcomes. You have only a couple of brains which now have millions of dollars of funding to do whatever they want to do. We still have no cures. It doesn't seem like we are going in the right direction. Even spreading the funding around better so now more of us can contribute would be significant improvement.

Dan Pardi - 33:25: We've got SENS. We've got Open Philanthropy. You can make a donation to UC Berkeley or specifically to the Conboy Lab.

Irina Conboy - 33:31: Exactly.

Dan Pardi - 33:32: Those are just some ways to continue the funding in aging. Bypassing the limited ability of the NIH to reach all the labs that need too. To help the research that needs to happen.

Kendall Kendrick - 33:45: Thanks for listening and come visit us soon at humanOS.me.