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.
Discussion
52 reader comments
Imported threads are marked Archive. New comments are welcome and moderated for spam.
Josh,
It would appear that limited trials with Humans and blood transfusion may be going ahead at Stanford already to treat AD. GDF11 may be a component of any rejuvenation seen but likely not the only factor. I wonder if the results will show any improvement elsewhere in the body?
https://www.sciencenews.org/article/year-review-young-blood-aids-old-brains
There is also further info about the research here which indicates some DNA damage was also repaired which is interesting.
http://www.biosciencetechnology.com/articles/2014/12/reversing-aging-processes-one-protein-2014-breakthrough
Hello,
I apologise in advance for my non-intention to reply your comment.
I am contacting to ask you about the ALS trial with GDF11, which you mentioned on February 20, 2015 at 1:11 pm. I am very much interested in this study, I could not find anything in the web.
Could you please give provide some source of information, link?
Thank you very much in advance.
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.
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
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".
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.
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.
That's sounds like a fair assessment Josh, thanks for your input.
That* - excuse the poor grammar, the comment was sent from my phone.
Looks good, but what would an effective dose be, and what about side effects?
Mike
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
This is great information - perhaps we don't have to wait for GDF-11 to filter through the research pipeline into commercial products.
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?
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.)
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.