Transfusing Youth: The Epigenetic Aging Clock Hypothesis

mice

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, Tony 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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This post originally appeared in Josh’s blog here: http://joshmitteldorf.scienceblog.com/2014/09/02/transfusing-youth-the-epigenetic-aging-clock-hypothesis-is-about-to-be-tested/