Just this past Spring, Tony Wyss-Coray of Stanford demonstrated that infusions of blood plasma from young mice can make old mice grow new brain tissue. Others have demonstrated benefits for muscle and liver health. The old mice are healthier, smarter, better healers for the infusion of hormones and dissolved factors (not blood cells) from the younger mice. Leapfrogging over years of animal tests and investigations, Wyss-Coray is about to test plasma infusions in people.
(I’m grateful to Adrian Crisan and a reader who identifies himself only as “Quandry” for alerting me to this story. This is not what I had planned to write about today, but I’m pumped.)
I have argued that much of our age-state may be coded in gene expression—the choice of which genes are active and which are idle. We go through life with the same 46 chromosomes we got from our parents, the same DNA, the same genes. But different genes are turned on and off in different tissues, at different ages. This is “epigenetics”, and it determines everything about a cell’s behaviors and activities.
The epigenetic state of a chromosome is programmed by several different kinds of decorations to the DNA. The decorations include methylation, acetylation, and states of tight-winding and unwinding of DNA about molecular spindles called histones.
Does epigentics also determine age? In other words, would a young person whose DNA state was epigenetically re-programmed to look like an old person’s actually become old? Could the body of an old person fix itself up to look like that of a young person if its DNA was reprogrammed? I think it’s a good bet that this will work.
A separate question is whether it works by a local or a whole-body mechanism. Does changing the epigenetic programming of a single cell make that one cell younger, or does it contribute to a hormone environment that makes the whole body a tiny bit younger? DNA expression creates proteins that do the cell’s work at home within the cell, and others that circulate through the body as signals, commonly known as “hormones”. Hormones can affect the decoration of DNA, changing the epigenetics. But hormones are also a product of epigenetics. Cause, effect, and cause and effect. Perhaps this is the basis of a clock, a biological clock that can time development, maturity, puberty and aging. It’s an idea I find intriguing.
Up until Sunday, I thought that this idea would be explored at a leisurely pace, indirectly as a result of research with a different conceptual basis. I was delighted to learn from this New Scientist article of trials soon to begin that will test to what extent young hormones can make a person young. Here is an interview with Wyss-Coray that contains more details.
History of Parabiosis and Plasma Transfusions
About ten years ago, Tom Rando and several students at Stanford picked up and rejuvenated an experimental paradigm that had been used and abandoned in the past. They sewed together a young mouse and an old mouse so that they shared a common blood supply. [See my previous blog, and another]. Of course, the arrangement was hard on both mice, and they didn’t live long. But they lived long enough to determine that the older mouse was receiving benefits from the younger blood: faster healing, tissues that looked younger under the microscope, enhanced growth of new nerve and muscle cells.
There were many directions to take this research:
- What were the blood factors that gave the benefit? (Not just beneficial blood factors, but others as well that we have too much of as we age.)
- What tissues and processes are affected?
- Aside from the surgery, what are the costs and risks?
- The big question: does the youthful blood profile have the power to reprogram cells epigenetically, so that the body remains in a youthful state and produces its own youthful blood profile?
Wyss-Coray’s Bold Experiment
Plasma transfusions are old technology. Donor blood is separated centrifugally (apheresis) into cells and liquid (plasma) and the cells are returned to the donor’s body. Because there are no cells, there is no issue of blood type compatibility or immune attack. A lot of the usual regulatory hurdles are avoided, and Phase I safety studies are bypassed.
This is a small trial, less than 20 Alzheimer’s patients, conducted at Stanford but privately funded by Alkahest, Inc. (I can’t find a web site for them. Perhaps they are very new.) It sounds from the article as though they plan on only one transfusion for each patient. They will measure cognitive performance sensitively, and hope to see a bump in a few days, perhaps lasting a few weeks or months.
If it is true that they’re planning only one transfusion, this is disappointing. I’m tempted to say something stronger than “disappointing”, like “what could they be thinking?” They’re not giving these patients new brain cells, after all. They’re signaling the body in a way that is likely to stimulate growth of new cells and offer other benefits as well. But this could take weeks or months, and require a youthful hormonal environment that is sustained over that time. If I were designing the experiment, I would opt for 10 weekly transfusions to 2 patients, rather than a single transfusion for each of 20 patients.
The Future of Blood Factors
I predict that Wyss-Coray’s experiment will work marginally or not at all without repeated treatments. I hope they see enough success to warrant extended trials in a follow-up. I think that with ongoing treatment, it has the potential to work spectacularly well, and that over a few months’ time we will see patients becoming younger in a number of ways. If this happens, it will precipitate a rush of interest and new research in the area. Patients, too, will be clamoring for treatments. Old people will feel an entitlement to the blood plasma of young donors.
We will quickly run out of donors. The best thing that could come from this is an intensive effort to test different components of the blood that vary with age. I predict that the optimum blood environment will be obtained by re-balancing components. rather than just adding a few magic ingredients. Some hormones will have to be dialed up, others dialed down in order to make old blood young. We may hope that there are just a handful of important factors, and not many hundreds or thousands. It will not be terribly difficult to create the recipe once we know which hormones are the important ones and how much to add or remove.
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As you know I”ve been saying this for years (I wish someone would cite me). You are correct about the insufficiency of the response – a single ‘transfusion’ and on demented patients (for me, the horse has already left the barn in that case – but there’s hope. What worries me is that this insufficient response, if it doesn’t succeed may nix future efforts – but not to worry, Corey-Wyss may no be the only party testing this hypothesis.
Would the requisite blood factors have to be human or simply mammalian ?
If simply mammalian, couldn’t we harvest them from slaughtered food stock until we can manufacture them in vats ?
Or is this view too simplistic ?
That’s a really good idea, Mike. We know that young human blood plasma has rejuvenating effects in a mouse. Would a cow or a pig’s blood plasma work in humans? It’s certainly worth finding out.
Maybe CaliCo will pick up on GDF11 as a rejuvenation therapy?
Harvesting from “slaughtered animals” could be some thing (that honestly
I’m not excited about, since we have to kill some beings …), but how about producing
synthetic/artificial blood plasma? Anybody can comment on why that is not achievable?
We won’t have to “kill some beings” because we already do kill some (millions of) beings… we just have to collect yet another piece of them which goes mostly to waste anyways (AFAIK).
And it would be temporary, as Mike said, until we figure how to produce those factors in a vat. =)
Alchahest was founded in July 2014 by Karoly Nikolich.
http://www.linkedin.com/pub/karoly-nikolich/4/47a/305
Whilst I am excited by the prospect of young plasma transfusions to potentially reverse the symptoms of aging, I like many, would ask the question: How did the “old epigenetic state” come about in the first place ?
To me, with my very limited knowledge, the answer appears to be Telomere shortening. As telomeres shorten, the expression of the genome changes becoming older and as they are lengthened they revert to a younger expression state, this view was supported by this study. http://www.sciencedaily.com/releases/2010/10/101003205928.htm
So while the epigenetic state of the cell is an interesting and appealing target for regenerating the human body at least in the short term, I don’t see how it can work long term.
The above study shows that extending telomeres can create a more youthful epigenetic state, but unfortunately I have never seen anything to indicate that changing DNA’s epigenetics would cause the telomeres to lengthen.
I think that for this process to work we would need to apply in conjunction with youthful signalling factors, otherwise very short term reversions using up valuable telomere length and putting us into a worse position than before.
If you have time, would you please reply.
Mike
Mike – You might be right. I think of telomere state and epigenetic state as two different aging clocks, probably cross-linked. I would be surprised if one had absolute control over the other, but I’ve been surprised before. For the record, my two favorite approaches to anti-aging research are epigenetic reprogramming and telomerase expression.
– Josh
I have seen recently this article:
“GHK and DNA: Resetting the Human Genome to Health” by Loren Pickart et al.
http://www.hindawi.com/journals/bmri/2014/151479/
Loren Pickart’s web site is:
http://www.skinbiology.com/
Is this something that goes along with GDF-11 & Oxytocin research that was published recently about rejuvenation?
Any comments on this?
thanks.
Thanks for the links and the information, Adrian. I had not known about GHK, but it seems to be an example of just the kind of epigenetic changes that I have talked about (here) — signals that we need for healing or maintenance decline with age.
Josh –
that is why I mentioned the paper since there are similar effects with GDF-11/Oxytocin for rejuvenation. (if I interpreted the paper correctly)
In their article they say:
“GHK was discovered during studies comparing the effect of human plasma from young persons (age 20–25) to plasma from older persons (age 50–70) on the functioning of incubated slices of human hepatic tissue.”
Would be nice if Mr. Harold Katcher can make some comments on this and connect it (if possible) with his work.
thanks.
Response from Dr Harold Katcher:
Dear Adrian,
The question was to comment on the apparent rejuvenating factors, GDF-11. oxytocin and GHK (which affects bone stromal cells as GDF-11 affect cardiomyocytes formation and neurogenesis and oxytocin affects skeletal muscle). So it’s really very simple – different cell types have different inputs that determine their age phenotypes. We know the substances that rejuvenate some sorts of tissue – but there are many other sorts that we have no idea about. There is an interaction between cells and organs that helps determine the age-phenotype of the body. To attribute aging as a property of cells or a property of the body are both incomplete – the aging program is carried neither by the cells, nor in the body but results from the interactions between body, its cells and its environment (in the broadest sense); like all developmental processes.
Sincerely,
Harold
Dr. Harold Katcher & Josh – thanks for you reply!
I had a busy week and even though I red you reply, I had no time to post back.
I got the big picture from your short and concise explanation – thanks.
I wonder if there is an “intelligent map” that we can create (as of now – I hope that Josh can create mind-maps for something like this and post on his blog) with connections and results based on current reseacrh that shows which factor, rejuvenates what type of cells/organs.
I wonder if there is a way to “trick” the age-phenotype of cells/organs, making them younger? There should be a way.
On a side note, I red at one time that you encountered problems funding such research for GDF-11 and rejuvenation. Did you think about using crowd-funding? or use web resources like kickstarter.com or indiegogo.com (or similar)?
I’m pretty much sure you can get your test/trial funded that way. If I recall correct, recently there was a company that got the funds for testing C-60 in mice and they got the funds in couple days supported by Longecity community. I believe you will get lots of support from interested people around the world.
Also reading about GDF-11 and rejuvenation, it was mentioned that the rejuvenation effect is temporary. Do you know anything about this “temporary” effect?
Thanks for all your comments and looking forward to your new papers researching these fascinating things on rejuvenation.
This is very interesting though I am concerned the trial won’t be thorough enough. Josh can we get Berkley to investigate too? Afterall transfusion is an accepted practice so won’t require safety approval. I am interested in seeing the extent of organs it can rejuvenate.
I recall reading in one experiment GDF11 on mice it rejuvenated muscle and some organs but led to no increase in lifespan. However there are likely a number of factors in young blood that are contributing. I know Amy wagers is planning trials of GDF11 In a few years but I think the results will not be astounding using a single factor.
Also I think the effects on humans could be potentially a lot more impressive in humans. I wonder if combined with restoration of telomere length it would extend life greatly
We urgently need to progress telomere extension in vivo. I know of only one group planning an offshore human test using htert to that end.
One team in Palo Alto Longevity prize (FOUNTAIN OF YOUTH team) is using GDF-11:
http://paloaltoprize.com/team/fountain-of-youth/
While Team Futicon (Irina Conboy, PhD) is using Oxytocin:
http://paloaltoprize.com/team/futicon/
I was hoping that David Sinclair with NAD+ as well as Ronald DePinho with telomerase activators, to be on the teams.
Let’s hope interesting results come out of this, and yes we need a lot more prizes like this one to ignite longevity and age reversal field. I wonder where all entrepreneurs with future vision are and why they do not fund such research?
This seems to be looking at aging within a particular species. Why is a mouse average life expectancy 4 years and a rabbit 9 years? Are telomeres half as long on a mouse? Or are methyl and acetyl tags that cause gene expression for age phenotype moving by some influence at twice the speed in the mouse? Is the epigenome where ageing is controlled?
It is not know why closely-related species can have very different life spans. Bats live 40-50 years, mice live 2, naked mole rats live 30. They’re all rodents, about the same size.
Their telomere lengths don’t explain it. See this paper by Vera Gorbunova.
Michael Fossel makes a strong case that it is relative telomere length that is important, but he’s not completely clear on the details – relative to what?
I believe that some, maybe most epigentic markers can be reset when telomere length is extended, but I’d be surprised if resetting telomeres does the whole job.
Unless of course Telomere length increases through exposure to youthful blood factors as a side effect. There are a number of ways Telomeres can lengthen not just via direct hTERT use.
It could be plasma contrains signals that initiate this but to my knowledge no one has measured Telomere changes when exposed to blood from a younger person.
There is some evidence that youthful blood factors will increase telomerase expression. There is also evidence that increased telomere length will promote a more youthful profile of blood factors.
Maybe to the two treatments will be syngergistic. We will only know when we try it.
The TERRA mechanic is a possible pathway to increasing Telomere length. I think it is highly likely signals in young plasma would encourage Telomeres to lengthen.
Also I am somewhat surprised that Tony Wyss-Coray is quoated in interviews that they do not know where GDF-11 is produced. The Endocrine system namely the Spleen, Thymus, Liver and a few others all produce that factor. They are talking about focusing on where its made to help the body produce its own. Odd they are not aware that the Endocrine system does this.
Do you have any links to studies indicating telomere length is influenced by youtful serum in old bodies?