Young Blood

Dr.  Harold Katcher of the University of Maryland believes that signals in our blood tell our stem cells how old to act, and that some key disabilities of old age might be reversed by serial transfusions of blood plasma from a young donor.  Plasma transfusion is a routine medical procedure, established to be safe for humans, but remarkably, its potential for rejuvenation has never been tested in humans or even in animals.

In a 2005 experiment that would make anyone with the least sensitivity to animal welfare cringe, Irina and Michael Conboy of UC Berkeley surgically joined pairs of mice so that they shared a common blood supply.  One old mouse and one young mouse became artificial Siamese twins.  For control, Conboy also paired two old mice and two young mice.

After the surgery, they injured one mouse from each pair, and monitored the healing process at a cellular level.  As expected, the young mice recovered from injury much more efficiently than old mice. The surprise was that old mice that were paired with young mice healed as if they were young.  “Importantly, the enhanced regeneration of aged muscle was due almost exclusively to the activation of resident, aged progenitor cells, not to the engraftment of circulating progenitor cells from the young partner.” In other words, it was not young cells that implanted themselves in the old mice; it was signal proteins in the blood that told the old mouse tissue to go ahead and heal as if it were young.  Something in the young blood was signaling the satellite cells of the old mice to divide and grow efficiently, as if they were young.

The Conboys went on from muscle cells to study the livers of their test animals.  The liver is constantly regenerating, and in livers of old animals this regrowth slows way down.  They found that livers of old mice exposed to young blood had rejuvenated potential for growth.

 

Some background

Satellite cells are partially-differentiated stem cells.  A pluripotent stem cell can produce daughter cells capable of taking on any role in the body – nerve, muscle, bone, blood, etc.  At the other extreme, the terminally differentiated cells of the body perform their functions but never divide to create new cells.  A satellite cell is an in between stage.  It is derived from a pluripotent stem cell, and its job is to divide and create a supply of new muscle cells only.  The Conboys found that satellite cells from older mice were rejuvenated by exposure to blood from the young mouse.  Blood is best known as white and red corpuscles, but the fluid (plasma) is important as well.  Blood plasma contains dissolved hormones, tiny quantities of powerful signal proteins.  One class of signal molecules effects notch signaling.

Notch signaling is a mechanism by which cells can respond to external signals without allowing the signal molecule to enter the cell.  It’s a lock-and-key mechanism where the key inserted from outside controls a latch inside the house.  There are four types of notch proteins, which span the cell membrane, head in the cell and tail extending outside.  The tail contains a receptor for specific signal molecules, and when one of these finds its way to the receptor, the entire molecule changes conformation along its length, reconfiguring the head which is inside the cell.  The Conboy study identified a notch signal molecule called Delta that was present in the young mouse blood, but missing in older mice.  Responding to the Delta signal, old satellite cells were reprogrammed to act young.

(In case you don’t find this to be bizarre, go back and read it again.  Old cells become dysfunctional not because there’s something wrong that can’t be repaired.  All they need is a messenger protein commanding them to Be Young!)

 

From mouse to human

The Conboys with colleague Morgan Carlson went on to explore the biology of aging stem cells in humans.  After a disappointing response to their ad seeking young volunteers to be surgically joined to genetically-matched old fogeys, they wisely decided to work instead with cell cultures.  They were able to rejuvenate old, inactive stem cells by treatment with young blood plasma.  They identified another notch signal protein that make this happen: TGF-β (“Transforming Growth Factor”).  Using TGF-β, cells drawn from a 70-year-old human were made to behave and function like cells from a 20-year-old.

 

Katcher’s Proposal

Katcher’s new paper presents a lot of background

  • debunking the idea that bodies simply  wear out with age
  • tracing the reasoning that led him to the conclusion that aging is a
    genetic program, a continuation of the developmental program
  • citing the Conboys’ work in detail
  • and continuing to present other experiments that suggest that
    senescent tissues might be capable of rejuvenation in response to
    signals in the blood.

For example, “when an aged, involuted thymus gland is placed in a young body, it is rejuvenated and regains full functionality, even though it was originally in a senescent state.” (ref)

Katcher’s paper culminates in a proposal for whole-body rejuvenation that might be practical in the near term.  Fortuitously, its safety in humans has already been established, so people might be willing to try it if a course of animal experiments shows promise.  The idea is simply to transfuse older subjects with blood plasma from a young donor, repeated often enough to sustain levels of signaling proteins that control gene expression.There is a mature medical technology for blood separation.  A fine physical filter separates cells from plasma. Red and white blood cells can be returned to the donor, with the result that the donor can safely give blood plasma up to twice weekly.  The plasma includes dissolved hormones, including notch signal proteins.

The reason this technique has been tested and developed as a medical technology is that it has been found useful for patients whose blood does not clot.  Hemophiliacs and others who are in danger of excessive bleeding routinely receive plasma transfusions, which include the clotting factors they need.  Katcher stresses that plasma transfusions have already been approved as safe for humans, so that we are ready to try the additional twist of transfusing plasma from young donors into old recipients.

 

What can we expect?

I wrote in this space last month that aging may be primarily a matter of gene expression, controlled by chemical signals.  Signals are of two kinds: intra-cellular and inter-cellular.  The former may be difficult to reprogram.  But we can intercept and replace the body’s inter-cellular signals without even a detailed understanding of what signals are necessary. Katcher’s proposal is a way to bypass many years of study, disentangling a hierarchy of chemical signals, and simply transfuse the entire complement of youthful blood factors into an older patient.

I have tentatively adopted a paradigm in which DNA methylation is the body’s aging clock, controlling gene transcription.  The choice of which genes to transcribe both governs the body’s metabolic state (including aging) and also includes signals that feed back to advance the cellular “methylation clock”.

Viewed from this perspective, Katcher’s proposal is not the holy grail of directly manipulating the methylation state of the cell. But it is a promising shortcut, addressing the inter-cellular but not intra-cellular signals that govern the “methylation clock”. We don’t know to what extent the inter-cellular signals by themselves might be able to turn back the clock, but Katcher’s proposal is exciting because it is expected to be safe and practical in the near term, and because experiments support optimism that there will like be some rejuvenation benefit.

In the most optimistic scenario, signals from the blood will change gene expression in ways that not only engender a more youthful phenotype, but also feed back again to methylation patterns, creating an even more youthful gene expression profile. In the pessimistic scenario, it will turn out that telomere attrition is far more important in humans than in mice, and that blood factors fail to produce a significant benefit because they don’t address cellular senescence.

Most speculation about anti-aging mechanisms and candidate treatment modalities is quite abstract, and cannot easily be verified.  The beauty of Katcher’s proposal is that it could be tried now in animals, and the required procedure are already approved as safe for humans.  What are we waiting for?

I’ll not be posting next week, not because it’s Easter, but because I’m moving.
See you April 7.

22 thoughts on “Young Blood

  1. Imagine the social consequences if this should pan out and some subset of older people wants very much to avail themselves of it. It might require treatments every few days that only wealthy people can afford. Insurers will make sure it’s not covered. Specialized clinics will spring up in major cities, like dialysis centers at present.

    It might require 8-10 pints of plasma for a transfusion, whereas donors can give only 2 pints a week. 20 healthy, genetically-matched donors would be needed to maintain one older person in his prime. Very shortly, older wealthy people will offer substantial financial incentives, bidding up the reward for donating plasma. An international market will grow up, with armies of young, healthy Africans whose earning potential is $1 / day being paid a month’s wages for donating a pint of plasma. Stories of “medical slavery” will emerge, and round denials will be issued. Older patients won’t want to know the details of where their blood plasma comes from, until a wave of HIV infections sends a scare through the community.

    It could be the largest generational transfer of wealth in history, coupled with a huge new reason for the 99% to be resentful of the 1%, and a major new income source for the Third World.

    • Seems like you’re jumping to the most dystopian possible outcome. I would bet that if this does work, within a few years, pessimistically a decade, we’d understand why and be able to synthesize the necessary materials.
      By the way, do you know that if anyone is planning to try this in animals? You’re right that it does have the huge appeal of being an easy way around some potentially time consuming problems (epigenetics, etc).

    • If this treatment works it will be a huge boost for everybody – young and old (we all grow old and die right now). And it seems that the treatment will definitely have some benefits: the full extent of them needs more research, but there’s enough evidence already to suggest that they will be considerable.

      As for the process, it depends on the results of the research, but there’s nothing to suggest that patients will need a continuous supply of new plasma. Plus if the benefits of the treatment include increased levels of signaling proteins (younger blood) then you could have a co-op sort of arrangement where you receive the treatment and then donate your plasma to the next recipient.

    • There could be huge infectious disease risks unless you have a specific donor. Remember a majority of receiving hemophiliacs in some areas developed HIV/AIDS before the virus could be characterized. A similar outbreak of a new virus would be a catastrophe for people receiving from multiple donors. There are also many viral diseases that are poorly characterized because they produce subclinical illness. If you get pooled plasma that is not sterilized, expect to get them all.

  2. Rita Levi-Contini just died at102, having attributed her longevity to daily eye drops of NGF, Nerve Growth Factor, which she had developed in her research work.
    Dr Rita Levi-Montalcini is the correct spelling; an Italian MD.
    Perhaps her work is relevant to this discussion.

  3. I had some of those same thoughts…….right out of a Stephen King or Matheson (RIP) novel of the old harvesting the young……

    I think the most likely scenario is production of blood from embryonic stem cells.
    Advanced Cell Technology is able to create stem cell lines without the destruction of the embryo and has been able to produce red blood cells and platelets. They are gearing up for a platelet IND trial with the FDA.

    Look at slide 36 of this presentation…..http://www.advancedcell.com/documents/0000/0443/act-corporate-presentation—bio-ceo-feb-2013.pdf

    At any rate the future will be interesting; thanks for the article.

  4. It doesn’t seem like there is any reason a year long study couldn’t be done right now. 100 plasma donors matched with 10 recipients. The study protocol would have to be carefully designed, especially the tests and measurements to be taken to document the effects. Anyone have experience costing such a study?

      • I would suggest using the Horvath test to confirm DNAm changes and Histone coding changes from the young plasma. Couple that with a Telomere test to see if that changes too (Androgens have been shown to change Telomere length as do some DNAm processes) as the two have crossover and we will have a fair few answers.

        Honestly I think Plasma and a TERT combination are likely required to fully reset cell age and this is why when either has been used we are not seeing dramatic lifespan increase. We are seeing significant increases in some cases but not massive.

        I have just been informed the cost of the Horvath test is around 250-280 dollars so cost is hardly a barrier as this is probably an experiment we would crowd source easy enough.

        The question is can we afford not to test this because it could reveal so much for so little?

          • I could suggest the idea though I imagine we may need to get the community to fund raise to cover the $250 or so per Horvath test. Apparently that’s what the rough assay cost is according to Johnny.

  5. You guys keep talking about humans. I am thinking of million dollar race horses being rejuvenated by some young horses worth a thousand dollars each. The old race horse does not even have to race, he just has to keep breeding.

  6. PRP (platelet rich plasma) and SCT (stem cell therapy) are currently being used clinically for a variety of conditions, including osteoarthritis, tendon and muscle injury. As Science Based Medicine points out, there is no ‘evidence’ that these therapies work. There are in vitro and vivo (animal), with a variety of human studies, but recent review articles conclude that there insufficient evidence to conclude that these therapies are effective in humans over placebo. In fact one review paper last year, of the studies which were included, not more than two of the studies used the same protocol for PRP. To my knowledge, neither insurance companies or CMS will pay for these therapies. Both PRP and SCT (which adds PRP to the infusion) both use autologous (one’s own) blood and stem cells. With respect to osteoarthritis, the literature notes that in people with extensive cartilage damage and age over 55 have see less improvement from these therapies. For the most part this is a redundant statement as osteoarthritis IS primarily a ‘disease’ of the aged, as opposed to RA (an auto-immune disease). The suggestion is, that people with cartilage damage are likely to be suffering from the diminished replacement of cartilage, caused by lack of ‘factors’ that activate their extant mesenchymal stem cells. Using autologus blood in older people seems to present a problem in that the ‘factors’ in the blood that are necessary have likely diminished concentrations (by demonstration), and that concentrating the plasma is, for the most part insufficient to get the levels necessary to cause new cartilage to be formed, especially in older (more aged) people. As this is a degenerative process which happens over an extended period in an area that is circulation deficient, the use of autologus blood is always likely to get patient biological age dependent results. Also, it is patient dependent, and while it appears that as people age almost everyone exhibits some degree of osteoarthritis, only in some meaningful percentage of people does it reach clinical significance to the extent that a hip or knee replacement is necessary. I believe the reason that PRP has been combined with STC is an attempt to amplify those ‘factors’ so as to make the STC more effective. Since the ‘factors’ are unknown at this time, I would suggest that experimenting with ‘young blood’ instead of autologous blood for the generation of the PRP infusion may be effective in improving the outcome of these procedures, especially for osteoarthritis in the elderly.

  7. Thanks for the great article. I just realized this was written more than 2 years ago. I became interested in this topic after watching the recent TED talk https://www.ted.com/talks/tony_wyss_coray_how_young_blood_might_help_reverse_aging_yes_really?language=en.

    It seems that clinical trials are well under way and there seem to be some early positive outcome. I also think there is a certain risk of medical slavery and other social consequences as described above, but I believe we should be able to manufacture those rather soon. Besides, we might obtain benefits from pig plasma, or perhaps someone will come up with those plasma factors in a pill form.

    • Last I spoke to Tony was in August 2015, and the human trials had not yet begun.
      I don’t think there’s danger of millions of young humans being recruited for their blood, because we will learn before we get to that stage what chemicals in the plasma are the important ones, and we will manufacture them.

  8. I have been on it for 5 years for atypical depression. The emotional factors in my life are still difficult. But I have taken up hiking (after being too depressed for 6 years to go out), lost 50 lbs last year spending 14 weekends climbing mountains with snowshoes, sometimes breaking the whole trail.
    My gp doc says my blood work is incredible

    Clearly increased exercise extends life, too.

  9. I was researching on this and had a question Will this also work if Body generates its own new blood. I mean, for example, post blood donation, the body has to generate new blood including RBC’s , plasma etc. Can the results be similar ( may be at a small scale)?

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