An Interview with Irina and Michael Conboy on Blood Factors in Aging
Here is a lengthy interview with researchers Irina and Michael Conboy on their work with parabiosis. This involves joining the circulatory systems of an old and a young mouse, and studies have shown that this reverses some measures of aging in the old mouse. Researchers have so far largely focused on the possible effects of signal molecules present in young blood, but the most recent work from the Conboy lab provides fairly compelling evidence to suggest that the more interesting benefits are instead produced by a dilution of harmful signals in old blood. This is reinforced by the possible identification of one of those signals by another research group. In the bigger picture, this means that initiatives involving blood transfusions are probably going to fail, and would explain why transfusions in mice didn't produce noteworthy outcomes. One alternative approach suggested by this new research is plasmapheresis, a class of existing therapy in which blood plasma is replaced in volume, and which would hopefully also dilute harmful signals in the process.
Dan Pardi: 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: 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 telomeres 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, called the 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. Then if you figure that there are proved ways to reawaken stem cells 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: 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.
Irina Conboy: 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. 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. 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 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.
Dan Pardi: 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?
Michael Conboy: At the time we also 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. 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?
Irina Conboy: 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 a 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. 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 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.
Dan Pardi: For humans 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: We have clinical trials under development with our colleague Professor Dobri Kiprov from San Francisco Blood Apheresis Clinic. Who is doing blood exchange in people for 35 years. 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 advanced. You just see if the same or slightly modified protocol can be used. 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 are many, many parameters that we can study. How much improvement can we expect from our process or approach where we take person's blood and it goes through the plasmapheresis machine in the approved process?
This work is excellent and addresses altered intercellular communication, a hallmark of aging. Thanks for posting this.
So, how much of this benefit can be gained by simply donating a pint of blood every eight weeks?
@gwood: About zero, I'd imagine.
I wonder what happened to Irina's work on rejuvenating aging stem cell populations. That was a line of research I was much more interested in but, I suppose this is good as well.
I should've read the article first I suppose.
So now the theory is starting to shift to - senescent cells and the soma are impacting regeneration and stem cells aren't actually "exhausted"?
It's definitely more economically viable if it is true.
Getting replacement stem cells for all of your tissues would prove to be quite the luxury for most people, in the foreseeable future anyway. So even as a stopgap there is merit in this if it does work as advertised.
@Anonymoose - there was the below recent paper on stem cell exhaustion for white blood cells:
It is paywalled, but I'm sure you can get past that in the usual way.
I'm sure you've seen the research - including the Conboys' own extensive work - showing how tissue stem cells that seem to have ceased functioning are able to function again after some kind of metabolic manipulation - whether via parabiosis, or pharmacological or genetic manipulation of some pathway (such as inhibition of p38α/β MAPK in muscle stem cells), or the now largely discounted GDF-11 findings, or oxytocin, or whatever. However, these aren't senescent cells, but rather functional cells that are being prevented somehow from being activated.
It's important to note that the evidence for the existence of such "reversibly quiescent" tissue stem cells comes from studies in "younger-old" mice (18-22 mo old) - or 24 mo old ones, if you're willing to grasp at the most elaborate metabolic mousetrap (muscle stem cell biopsy, followed by small-molecule p38α/β MAPK inhibition, followed by exposure to an actual or simulated young niche, followed by re-transplantation).
By contrast, such interventions fail in truly old (28-32 mo) mice's muscle stem cells once they have suffered sufficient DNA damage to progressed into a state of truly irreversible sensescence ("geroconversion"), making the point ultimately moot.
Of course, even senescence programming can in principle be overrriden (and was, in the above case), but in this case you'd be playing with rather serious fire, allowing cells with genetic and other kinds of damage to begin proliferating again. Real rejuvenation entails removing the damaged cells and then replacing them with pristine, youthful ones.
I love the Conboy's work in this area and I hope you will feature them often in your blog.
Several questions based on the above interview:
1) Can someone point me to the URL of the published study based on their newer modified parabiosis work? I don't understand the study design based on their description? They take blood from old and young mice and mix that outside of their bodies. That blood is then NOT re-infused until many months later?
2) Do they have an entry on clinicaltrials for the new plasmapheresis study? I want to understand the basic protocol they are proposing for that. Are they just filtering out the patient's plasma and then returning it to the patient, or are they replacing the patient's plasma with plasma from young patients?
Here is the newer Conboy work on transfusing old/young blood between mice:
I am interested in this subject and would like to meet or have the opportunity to write directly to scientists Irina and Michael Conboy ... I can invest and support their research with my personal funds.
skype contact : stefano.pepe1
Here is where you can get her address and contact : http://vcresearch.berkeley.edu/faculty/irina-conboy