GDF11: A hormonal candidate for rejuvenation

I did a series last fall [1, 2, 3] on the thesis that aging is a program of self-destruction, executed under the control of hormonal signals in the blood.  If we can re-balance those signals appropriately, we will be able to revert the body to a younger age.  Maybe.  Yesterday, just in one day, three papers appeared in major journals reporting on blood factors that can reverse aging.

All three papers come from a line of research called parabiosis.  Circulatory systems of a young mouse and an old mouse are surgically joined so that the blood circulating in the veins of the old mouse comes half from the young mouse.  The finding from the Conboy Lab in 2005 is that the old mouse is rejuvenated in significant ways.  Research since then has sought to separate which factors in the blood are responsible for this effect.  Irina Conboy told me last month she has identified 6 key molecules, some of which need to be added, others either removed or de-activated.

Paper #1: (out of Stanford and UCSF and the Palo Alto Center for Regenerative Medicine) “Here we report that exposure of an aged animal to young blood can counteract and reverse pre-existing effects of brain aging at the molecular, structural, functional and cognitive level.”  Exactly which chemical compounds was not determined, but the benefit was seen both in growth of new neurons in the brain, and also in oberved behavioral changes and improvements in learning among the older animals.  The mechanism was traced to biochemical effects in the hippocampus, part of the old mammalian brain that is the first to be damaged in Alzheimer’s disease.  In case you’re wondering how you measure cognitive behaior in a surgically-creaed Siamese twin, the answer is that the group was able to see the cognitive benefits when small amounts of the young mouse blood were injected intravenously into the old mouse, eliminating the need for surgerical pairing.

The other two papers were announced in on-line news from Science Magazine, but the original papers are embargoed until Friday.  Both involve GDF11, (for “Growth-Differentiating Factor”), which is a hormone common to mice and humans.  “GDF11 is naturally found in much higher concentration in young mice than in older mice, and raising its levels in the older mice has improved the function of every organ system thus far studied.” [Doug Melton of Harvard, quoted in Science Daily]

Paper #2: (from Lee Rubin’s group at Harvard) Improvement in l earning behavior and increase in new neurons were both noted with injections of GDF11. “Regardless of the age of the old brain . . . young blood is still able to rejuvenate the aged brain.”  “We do think that, at least in principle, there will be a way to reverse some of the cognitive decline that takes place during aging, perhaps even with a single protein. It could be that a molecule like GDF 11, or GDF 11 itself, could” reverse the damage of aging.” [quoted in Science 2.0]

Paper #3: (from Amy Wager’s group at Harvard) also used GDF11, and demonstrates improvements in healing and in muscle growth and strength. “Injections of GDF11 can reduce the thickening of the heart that typically comes with aging in mice…GDF11 works nearly as well as parabiosis in helping aging mice recover from a muscle injury and boosts their performance on running and grip strength tests.”

When dramatic results like this, indicating that some simple intervention is capable of turning back the aging clock, the question everyone avoids asking is, “Why isn’t the body doing this on its own?”  The answer, of course, is that the body doesn’t want to.  The body is programmed in its genes to age and die, but to acknowledge this is to precipitate a revolution in our understanding of the fundamental mechanisms of evolutionary biology.

 

51 thoughts on “GDF11: A hormonal candidate for rejuvenation

  1. I told everyone about this (young blood being able to restore youth) quite a long time ago (http://protein.bio.msu.ru/biokhimiya/contents/v78/pdf/bcm_1061.pdf). I don’t think a single protein is responsible for aging or for youth, if there were a mutant lacking or overproducing it (or continuing to produce it throughout life at the same level), it would give rise to abnormalities, like living forever or dying of old age at a very young one (like the progerias, but there’s never been a progeria associated with GDF 11). It is well known that the same cytokine (a sort of hormone that cells use to talk among themselves of which GDF 11 is one) has different effects on different tissues, so it seems unlikely that GDF11 will affect all tissues the same way (nice if it were true, and GDF11 by itself might be useful in fighting the disease of old age called ‘sarcopenia’ (muscle wasting). I still believe that my technique of HPE (in the article I gave reference to) – is the penultimate answer – penultimate because I think that we will be able at some point to produce ‘rejuvenating’ blood plasma synthetically or use modified animal plasma for this purpose. Be aware everyone that you are just now seeing mankind enter into a new phase of development – where the promises of the ‘Enlightenment’ (and of the Bible) that Man, immortal moves into the Heavens will be fulfilled. That is if we don’t destroy each other first or become overwhelmed by the surge of violent irrationality that seems to be sweeping over the “religious” people of this world, people like the murderous Boku Haram who would like to tear down everything they don’t understand and reduce the world to their own stupidity and ignorance.

  2. I read Harold Katcher’s article this weekend, and needless to say, it was very interesting. Now this news is gaining traction in CRsociety. Looks like parabosis is gaining traction.

    On one hand I’m glad, since this anti-aging intervention looks serious, Katcher’s paper is pretty convincing. On the other hand if finally proven its utility it’s one of the most awful ways from an ethycal point of view. It will be only available for the rich, and probably not very good for the youth and fetus….

    • Santiago: if you read my article then you see that I use plasma, not blood to translate what would be a very expensive procedure to one that would be affordable to most people and could be accommodated by having teens storing their own plasma for that purpose or some system like social security where the plasma of young people (voluntarily) is collected for use by seniors (for at least their first renewal) – the same for each subsequent generation. I don’t think that would be necessary however. I believe with modification (the work’s already been done) animal plasma may take the place of human plasma – and an animal, like a cow or pig can provide large amounts of plasma without harming the animal. Ultimately all of the factors that contribute to signalling cells to age or to be young (because it’s all controlled by the cells environment, at least up to a point) and their concentrations will be known and totally artificial plasma will be made to perform the same functions. All that I’m saying is that when we first used electricity to light our homes, no one knew what an electron was – but we used it for light, transportation etc. Right now we know that blood plasma can do the job (and what will be its effects on the diseases of aging – Alzheimer’s, cardiovascular disease,cancer?), we don’t know, but we don’t have to know to use it.
      Of course as Josh says, we’ll have to re-think much of what we think we know about basic biology, but that’s happening already.

  3. It’s been said that with aging there are decreases in levels of coq10, gluthathione, collagen synthesis, among other factors and also as seen in this article detrimental changes in blood composition.

    I believe that such detrimental changes do suggest an underlying program. I agree that it is likely to involve several genes. Recently a new factor that may promote the evolution of such an aging program was found, the selective advantage of some detrimental mutations in male reproductive cells in an age dependent manner(which would mean that without aging, the mutation load in the population could increase without bound overtime leading to declining fitness of the whole population.).

    • This is an interesting hypothesis but (like all aging theories) problematic in its own peculiar way. First, since mutation level in the population at large is a group trait, it would be discounted as a mechanism by most evolutionary biologists (though not by me), because they believe quite crudely that cost to the individual always trumps benefit to the group. More questionable from my vantage is that I believe mutation rates to be under tight genetic control, so if the mutation rate became problematic, the evolutionary process could dial up a lower rate in short order.

      • “More questionable from my vantage is that I believe mutation rates to be under tight genetic control, so if the mutation rate became problematic, the evolutionary process could dial up a lower rate in short order.”

        Well the finding was that there are certain mutations that cause both advantage in cell division as well as being detrimental to progeny, The advantage in cell reproduction causes these cell lines to outcompete healthier reproductive cells. It’s similar phenomenon to cancer, only it affects progeny health rather than the individual themself.

        Been connected with the father age dependent increase in probability of unhealthy progeny.

        In theory if the father did not age, this phenomenon would cause an increase in subtle defects reducing fitness of progeny over time even with low mutation rate.

        In my opinion, it is clear that mechanisms to protect quality of progeny can and are actually implemented such as the westermarck effect, which affects progeny genetic quality but not the individual themselves.

  4. So basically what you are all are saying is that there is a good chance that simple transfusions of young blood plasma could reverse aging effects. Transfusions of blood plasma is allready quite common for other reasons and it is deemed quite safe.

    So why doesnt everybody run to the nearest privatly owned clinic and order up som plasma transfusion?

    What is preventing the common man from just trying this? We dont really have to wait 5-10 years for human trials to start at research institutes?

    • I think that transfusions will not be practical for a number of reasons. Transfusions are expensive and uncomfortable. You might need one a month. If this worked and made people younger, then every old person would want to get his hands on the blood of a young person. There will be a bidding war for blood.

      I think it makes more sense to do a modest amount of research on animals before trying it on people. Working with mice, it might be possible to find out if it works at all, and how many transfusions are needed, and what time intervals would be optimal. Better yet, I think there is a good chance that a handful of hormones and blood factors will be identified that can be manufactured without need for a human donor, and with much less expense and discomfort than a transfusion.

      On the other hand, I agree completely that this is too exciting and too important to just wait for some scientist somewhere to find the answers for us. The labs that were in the news Sunday were at Harvard and UCSF. The people I know best in the field are at UC Berkeley. All these groups have some funding, but not nearly enough to go full forward with their program. I’m actively looking for funding for the Berkeley folks. If you have investment connections, that would be most valuable. Perhaps there is a rich 80-year-old somewhere who would be willing to put up a few million dollars in exchange for being the first person to try blood plasma therapy.

      • I’m always shocked with the huge number of rich aroung of the world, who are so deeply stupid that are unable to invest a small portion of their fortunes in their own health.

        • My first response was to say “Amen”, but I’m thinking that if they truly knew and believed this work they’d be more interested in supporting it. Of course maybe having the best of it, they still conclude that ‘life sucks’ (how many celebrities commit suicide or become druggies?) and are hoping for a Heaven where it doesn’t. Still it’s probably the wish of most people to extend their lifespan (somewhat) and definitely their healthspan – which these techniques should almost certainly do.

          • I think people would do allmost anything if they belived this to be a real possibility. Funding would be no problem. It is true that most people don’t invest enough in their health but this is because people are lazy and not disciplined enough to exercise regulary and eat a healthy diet….but if it was merly a matter of money.
            You write that rich famous people commit sucide. Isnt this because they have gotten old and are not able to do what they became famous for and their carrier has stranded? They feel old and useless and the spot light gets turned around to somebody younger?
            What we need is a visual proof of this concept, because right now it is just to good to be true.
            And it seems we are in luck because the nature of this discovery could allow for a low cost and low risk experiement?
            Wouldn’t it be possible to do an experiment where different test persons received young plasma for a period of time just to prove the concept? This would not require the paperwork for testing a new drug? I know this would not be the best or final solution but it could prove that it actually worked?

      • I do realize that this is not the most practical solution, and that methodical research should be done to pinpoint the exact proteins and the optimal amount. But one also has to consider that we could be on the verge of the greatest discovery in history.
        You say you are looking for funding. What if you could give visual proof of this concept. What if an experiment were conducted with a few subjects and different amount of young blood plasma were transfused for 6 months or a year. This would be low risk and low cost and would should not require much paperwork for approval since you would not be testing a new drug, but merely giving a person blood plasma which is already approved. What if the subjects started getting their hair back, were able to read without glasses? I think that would get everyones attention. I don’t think funding for a more practical solution would be a problem after this.

        • At one point (I can’t really say more) we had two physicians and one billionaire who were willing to undertake this procedure (my HPE procedure) – but at the last minute the billionaire ‘chickened out’ (with the advice of his own physician). At this point (about three years later), that same individual is non compos mentis – lost in the world of Alzheimer’s disease. Personally I would rather be dead (those people who think that all of this is motivated by the fear of death are wrong – I have none). He missed his chance. With time running out for the “baby boomers” who else will miss their opportunity? I don’t disagree with human experimentation (though it think it would be imprudent to begin with it), and I do agree that we’re not talking about an experimental procedure that requires years of development, this procedure is already approved and currently used across the globe. It would be nice to see animal studies done first, and they will be necessary if we want to find out all of the various cytokines, RNAs, etc. that control the aging process at a systemic level, but we can start without that knowledge. Also we’d like to know how old the potential donor should be – how old the potential candidate can be (and there is a fear that past a certain point some cells at least may become refractory to rejuvenation). I think it would be possible to proceed directly to human trails, but that might not be the best alternative. On the other hand though, time is running out for millions of people. Imagine that we could push the clock back for millions of retirees who then rather than requiring services could provide them? Yes it could be the greatest scientific discovery ever.

          • This topic is still hot in the media. Why not go public with the intension of conducting the experiement? Give a couple of interviews as an follow up article to the countless “vampire research”-headlines we have seen in the media these last few days. Get people to really understand that this does not have to be so far into the future that they shouldnt care. That this could be done with plasma which can be donated without risk and stored for a long time. That plasma can be transferred using a well known and safe procedure. Talk about your vision about storing plasma as young and use when you get older. I think it would make a great story! We need people to wake up and start caring about things that really matter and stop wasting their valuable time on fashion, celebrities etc etc.

            Remeber to send me the link for the interview!

          • Feel slightly out of my depth on the science although reading about artificially made blood for transfusions becoming nearer coupled with this article does make things sound like they may come together nicely at some point hopefully sooner rather than later.
            http://haemo2.com/

            You’ve probably considered it already but just encase not. I have a bit of a background in charity fundraising, nothing this scale though. But we’d always look for people who could gain as well as be generous when we needed to raise money for a project and or find partners. If you haven’t already looked at the SENS website there maybe famous folk there on the ‘what ageing means to me’ pages who have the profile you want to get media attention, motive and means to fund such a project. And would probably be contactable by SENS if not directly. The TA 65 testimonial page may also be useful. While there are numerous people in the public spotlight who make their living being men or women of action but time is running against who I could imagine would be tempted by anything that could extend their careers. Some of which are known for the large amounts of money they give to causes, some of which are quite ‘interesting’ to say the least.

    • A simple transfusion would not be enough – in the experiments tried you would have to replace about half of your blood with young blood – but it might work to an extent. There’s a better way though.

    • Safe and an approved technique for the treatment of many conditions plasma exchange (and establishing a schedule of exchanges sufficient to “fix” the body at a prior life stage). I’ve applied for a patent on the technique (since I published it less than a year ago) – and I believe it will revolutionize medicine. I’m trying to get together some money to do human experiments – and I’m pretty certain I can get positive results. So if there are any physicians out there with a bit of courage and a desire to change all of human history (for the better) please contact me. Josh will give you my name – also any investors would be appreciated. The risks are great but the rewards are unimaginable.

      • The GRG could potentially be interested in funding this, I will check with them and see if we can get the ball rolling. Also Logencity is doubling grants for research at the moment if you wish to propose your study to them.

  5. Great commentary Josh. I look forward to the research described by these three articles providing the impetus to the development of an effective longevity treatment.

  6. Do you now wether currently is a doible option to conserve one’s blood in a blood’s bank, and re-use it one or two decades later?. That would not be perfect, but one’s decade ahead we’ll look back at our current body with envy.

    I ask this because I believe there are blood’s banks used by Jehovah’s Witnesses. They might be a good human group to study this theory.

    Best.

    • Storing blood for long periods is not feasible – blood contains living cells and therefore has a ‘shelf-life’ (except for cryogenic storage in liquid nitrogen). However, plasma, which may have all of the factors needed for rejuvenation (there’s no evidence that any cellular components are required and some evidence that they are not) is easily stored indefinitely (can even be dehydrated and stored as a powder). Of course we don’t know yet whether plasma contains all the factors needed or if plasma stored under a variety of conditions retains its rejuvenating ability – but that’s why it’s called ‘research’. Your vision Santiago is much the same as mine – young people can store their plasma until needed. The ease and safety of plasma donation (that the fact that young people can give plasma on a weekly basis without ill effects) would make this very simple and affordable to all. If the procedure works, at some point replacement of natural plasma by artificial or modified animal plasma will occur.

    • We don’t yet know if storage is a possibility – there are some components that are lost with freezing (but how about liquid nitrogen storage – we just don’t know. That is one possible goal however to have people bank their own plasma (and perhaps sell some as a price for the former) and use it when they need a renewal. There are blood components that two years ago were unknown, for example exosomes containing miRNA. It first took the discovery of miRNAs to know that these membrane-bound containers of short RNA molecules were not simply degradation products – that they could be powerful modulators of cellular behaviors. Now we know that these exosome are taken up by other cells and that they do modify the behavior of the new hosts (by changing the production rates of the proteins each miRNA type controls)- so do these also figure in to blood-borne factors? Of course – are they important players? We’ll see. Again from a purely genetic viewpoint if a single factor (protein, hormone, cytokine), controlled aging – such that it’s decrease resulted in aging – there would have been mutants such that there was increased production of that factor which would make for an immortal individual. Since such people, or mammals in general, don’t exist we can assume that there is no single factor that controls aging.
      There’s so much to do and no one is doing anything!!! (Except the Stanford group under Tom Rando and Tony Wyss-Coray – but I wish they’d acknowledge me.)

  7. Hi Josh,

    interestingly researchers have found that Trichostatin A, which belongs to a class of drugs called HDAC inhibitors, up-regulates the gene encoding GDF-11 and increases the amount of GDF-11 protein:

    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC419886/

    I wonder if supplements like sodium butyrate could have a similar effect and I am also curious about prebiotics like potato starch and short-chain fructo-oligosaccharides; which can increase colonic production of butyrate.

    http://onlinelibrary.wiley.com/doi/10.1046/j.1365-2672.2003.01836.x/pdf
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2579941/figure/F4/
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2579941/figure/F3/

    Best regards,

    Sven Cornelssen

    • Pardon my naievty, but David Sincliar and Leny Guarante has made a career out of the theory that sirtuins (especially Sirt 1) which is a lysine deacetylase and also a type III histone deacetylase reverses some of the aging traits associated with the epigenetic changes introduced by acetylatoin of histones. Sinclair proposes that epigenetic changes associated with aging promoted by acetylation of histone III can be reversed by Sirt ! activation. I was wondering how Trichostatin, which is an INHIBITOR of histone deacetylase (the opposite of resveratrol) could counter the action of Sirt1? Can anyone throw some light on this?

  8. Just to clarify, that last two citations look at “GDNF” not “GDF-11”, but since both are influenced by H3 acetylation, this gives an interesting comparison of the effectiveness of various HDAC inhibitors. Sodium butyrate seems to hold up surprisingly well.

    Best regards,

    Sven Cornelssen

  9. I’m not a doctor or expert so I’m not qualified to give advice on the safety of these drugs/compounds, but I do want to discuss them out of academic interest. While I am not aware of any clinical trials involving trichostatin A, a structurally similar synthetic hydroxamic acid called SAHA (vorinostat) has undergone clinical trials. I found this journal interesting, it reviews recent clinical trials involving various HDAC inhititors: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3587473/

    Na butyrate is sold as a food supplement supplement in many countries, as with every supplement you should seek independent medical advice before taking it.

    Butyrate is actually an endogenous short chain fatty acid and it is possible to raise butyrate levels by consuming more fiber. Some people also supplement resistant potato starch and fructo-oligosaccharides to boost colonic production.

    Best regards,

    Sven Cornelssen

    • These are great leads, Sven. More testing needs to be done before I would recommend either of these compounds as a dietary supplement. It looks as though both trichostatin and SAHA are classed as “De-acetylace inhibitors”. This means that they tend to keep genes from being turned off. Of course, it’s the balance between the right genes being turned on and the wrong ones turned off at the right time in the right place that keeps our bodies functioning. I see no indication as yet how specific these two agents are to gene expression just for GDF11.

  10. Hello –

    one question/suggestion: isn’t the artificial blood going to impact in a positive way this process?

    I mean is the new research done in creating “blood” using stem cell a viable option to create “new” blood that mimics all the characteristics required for a successful process as described by the teams of researchers above.

    For example

    Roslin Cells to manufacture blood cultured from stem cells

    http://roslincells.com/latest-news/2014/4/15/roslin-cells-to-manufacture-blood-cultured-from-stem-cells.html

    • Adrian – This isn’t about blood or stem cells that produce blood cells. It’s about hormones – molecules, not cells found in the blood that signal the metabolism and potentially control a cascade of biochemical events.

    • While reading the literature (scientific) on an unrelated issue I came across a paper that described GDF11 negative mice – there was no mention of their lifespan being shorter than other mice’s. So let’s not imagine that GDF11 is some sort of elixir vitae (the liquid that bring eternal life) – its a growth factor, a member of the transforming growth factor beta (TGF-beta) family – a cytokine like hundreds of others that control growth in a variety of different tissues.
      Secondly – Blood cannot be produced by means of activating hematopoietic stem cells. To begin with, the majority of blood proteins are made in the liver (only the IgG fraction results from blood cells) – and the hundreds or thousands of different compounds (some of which may cause aging or rejuvenation) are supplied to the blood by cells or organs (cytokines, hormones, etc.). So those are not possibilities.

      • I’ve been trying to tell people this for a time. Everyone is looking for “the” anti-aging factor. Now we know it’s in the blood – we can try every factor in the blood that decreases with aging and try to get rid of every factor in the blood that increases with aging Only we don’t know all the factors and missing some might make all the difference between rejuvenation or not. So do we want to wait until we (think) know every blood component and its concentration in the blood as a function of age and try to bring the old patient’s blood to those levels (and how expensive would that be?) or do it the easy way?

        • GDF-11 alone is definatly not going to cut it, the plasma needs the entire youthful package with correctly identified and balanced factors. I saw a list of known factors somewhere which compared young and old blood and the differences.

          Now if one could balance those factors you could restore youthful tissue function, this has been shown in mice by Wagers, Convoy etc…

          The ideal would be filtering a patients blood, removing the bad factors and balancing the good and returning it to the body. This could be done via a Dialysis style intervention.

          If you could remove Senescent cells too as you do this that would be a major boost. SENS-RF is developing such a T-Cell Scrubber.

          • I agree that several blood factors will have to be re-balanced to fully restore youth. It may be just a handful, it may be hundreds if we’re not lucky. I’m not sure that we won’t be able to get a boost in longevity from just one or two.

            The problem with the dialysis-style approach is that these blood factors don’t have a long half-liife in the blood. They last for minutes, and are constantly being renewed by internal secretion. That means that the source has to be re-configured, and the source is in the epigenetic programming of the endocrine cells.

          • Currently there is a study underway with blood transfusions with ALS patients to see if they benefit. Its a small study though and personally I feel that the heart would have been a better and easier to measure improvement in target for the study.

            I am hearing also there is indication that some factors need turning up, some down or off and some on for a while but if left on could be dangerous.

            I would like to see a study done for heart diesease though as that would quickly show possitive results if they were similar to the mice studies.

  11. Josh – thanks for reply.

    I was thinking more in a line of thought like this:

    if there is a technology right now that can produce “new” blood using stem cells, then at a different sub-scale, “same” procedure can be applied to produce plasma proteins to carry the needed/required (GDF11 & Co) hormones.
    So the result will rely on “artificial blood/plasma”.

  12. It would also be fair to hypothesize that the “youth factors” in blood decline in either quality or quantity with age, either of which should be attributed to environmental effects. One area of interest would be to find out how the environment influences these youth factors to the point that they are not able to keep up with the maintaining the body’s youthful composition.
    One key environmental factor to consider would be diet.

    • Of course we want to attribute it to “environmental factors”. None of us wants to think it’s an inside job, our own bodies betraying us. But the evidence is overwhelming if you step back and look at it. One piece of that evidence is that environmental stressors often lead to longer life.
      -JJM

  13. Josh, I really like your write up. Also the comments discourse is quite illuminating and generally high quality.

    Do you have any write up or paper references you could share about the environmental stressors have been shown to lead to a longer life are.

    Of the top of my head I can only think of “starvation/fasting diets” of which there have been many papers on.

    • Toxins, radiation, pathogens, heat and cold have all been observed to provoke a hormetic response. If you search Google Scholar for hormesis reviews, you’ll find several good ones. Luckey and Calabrese are the most prominent names. You can start with this and this.

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