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.
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 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?
This post originally appeared here: http://joshmitteldorf.scienceblog.com/2013/03/25/young-blood/