A Review of the Recent History of Parabiosis Research

Today, a history of parabiosis studies, albeit one rather biased towards the idea that signals present in young blood might be used to produce benefits in the old. It is possibly a little early to be taking firm sides on that question given the contradictory research results to date. Parabiosis is the name given to linking the circulatory systems of two individuals in order to compare the effects on both sides. Of late it has been used in aging research, joining a young mouse and an old mouse in search of answers regarding the degree to which aging is influenced by a changing balance of signals in the bloodstream. This influence should be a secondary or later consequence in the chain of cause and effect that drives aging: signal and other molecules are secreted by cells, and changes in the mix of these molecules are a reaction to the current state of the cells and their tissues. In the case of age-related change, it is a reaction to underlying molecular damage in cells and their surroundings.

Changing the levels of various signaling molecules carried in the fluids suffusing tissues can have potent effects. Think of most present stem cell therapies, for example: comparatively small numbers of transplanted cells can produce a period of enhanced regeneration and reduced inflammation simply by changing the balance of signals for a short time before they die. This is an essentially compensatory strategy, one that doesn't address root causes, but tries to ameliorate some of their consequences for at least a little while. Far more members of the research community work on this sort of approach than are striking at the root, more is the pity.

Parabiosis is a starting point on the road to identifying which of the signaling changes in blood and tissues are most important, or at the very least, most easily mapped and manipulated. Goals include most of the same outcomes found in stem cell therapies: dampening chronic inflammation; increasing stem cell activity and tissue regeneration; boosting organ function. One might think of parabiosis, stem cell therapy, and a few other related lines of research as parallel roads heading at some pace to the same future destination, which is the ability to directly deliver or block signal molecules to produce the same or greater benefits presently observed in simple stem cell transplants. To adjust the operation of metabolism to disable as much as possible of the harmful further reaction to initial age-related damage. This will probably be a diverse and widespread form of medicine two decades from now, but it is nonetheless second fiddle to the primary goal of repairing the root cause damage of aging. Fix the root cause, and much of the rest of the problem fixes itself.

The Fountain of Youth: A tale of parabiosis, stem cells, and rejuvenation

The claim that blood can rejuvenate our organs has been revitalized by one research group at the Stanford University School of Medicine in 2005 and 2010. These studies stemmed out from observations which show that tissue regenerative capacity declines with age. In tissues such as muscle, blood, liver, and brain this decline has been attributed to a diminished responsiveness of tissue-specific stem and progenitor cells. However, aged muscle successfully regenerates when grafted into muscle in a young host, but young muscle displays impaired regeneration when grafted into an aged host.

Either local or systemic factors could be responsible for these reciprocal effects. In order to test whether systemic factors can support the regeneration of tissues in young animals and/or inhibit regeneration in old animals, the the paper by Conboy and colleagues of 2005 reported an experimental setup in which - in contrast to transplantation - regenerating tissues in aged animals are exposed only to circulating factors of young animals, and vice versa. Thus, they established parabiotic pairings between young and old mice (heterochronic parabioses), with parabiotic pairings between two young mice or two old mice (isochronic parabioses) serving as controls. In parabiosis, two mice are surgically joined, such that they develop a shared blood circulation with rapid and continuous exchange of cells and soluble factors at physiological levels through their common circulatory system.

Parabiosis was invented in 1864 by the physiologist Paul Bert in order to see whether a shared circulatory system was created. Clive McCay, a biochemist and gerontologist at Cornell University in Ithaca, New York, was the first to apply parabiosis to the study of ageing, but this technique fell out of favour after the 1970s, likely because many rats died from a mysterious condition termed parabiotic disease, which occurs approximately one to two weeks after partners are joined, and may be a form of tissue rejection. Only at the beginning of the 21st century, Irving Weissman and Thomas A. Rando at the Stanford University brought parabiosis back to life, to study the movement and fate of blood stem cells.

The Stanford group investigated muscle regeneration and liver cell proliferation in the parabiosis setting. Notably, parabiosis with young mice significantly enhanced the regeneration of muscle in old partners. The regeneration of aged muscle was almost exclusively due to the activation of resident, aged progenitor cells, and not to the engraftment of circulating progenitor cells from young partners. In the case of liver studies, and as in muscle, parabiosis to a young partner significantly increased hepatocyte proliferation in aged mice. As also in muscle, the enhancement of hepatocyte proliferation in aged mice was due to resident cells and not the engraftment of circulating cells from young partners.

From that start, the paper walks through more recent years of work, including the ongoing debate over whether GDF11 is or is not important in the effects of parabiosis, and the beginning of human trials of blood transfusion from young donors. It omits last year's findings that suggest dilution of harmful factors in old blood is the more important mechanism in parabiosis studies, possibly because it was written prior to that point. Papers can take a long time to make it through peer review to publication. Results from human transfusion studies are so far entirely unspectacular, which at the outset seemed to me a likely outcome given disappointing results in mice. Transfusion is quite different from parabiosis, but we should at least think that this might be telling us something about which mechanisms are more plausible.

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