Parabiosis: A Murky Fountain Of Youth

4. October 2017

Parabiosis has made a comeback in ageing research. Studies showed: the sewing together of two differently aged mice has rejuvenating effects on the body of the older mouse. A new anti-ageing strategy? Some companies are already offering blood transfusions.

About 150 years ago the French physiologist Paul Bert made an amazing discovery: the scientist removed two strips of skin from two rats and then sewed the animals together at that location. After a short time the blood vessels of the two rodents had fused. Blood circulation had formed there. By injecting fluids into the veins of one of the animals, Bert was able to show that the blood of the one rat also flowed through the veins of the other one. He received the Paris Academy of Sciences Prize two years later for his work.

Parabiosis is the name of this phenomenon, in which two organisms are fused together. Living beings can either be linked from birth, such as Siamese twins, or they can be sewn together using a surgical procedure.

Results at any price?

Aspects of ageing were first investigated using parabiotics in 1956. The biochemist and gerontologist Clive McCay from Cornell University in New York sewed an old rat to a young rat. The rats remained united in this arrangement for several months – to the advantage of the older animal, as its bone density improved. A few years later, in 1972, scientists from the University of California also published a study on the topic “young blood in older animals”. The American researchers found that elderly rats which shared blood with younger ones lived four to five months longer than those which did not. However, these results have until now not as yet been reproduced.

As fascinating as the results are, for the animals these experiments were nonetheless anything other than pleasant and also associated with a high risk of death: rats that were not used to each other bit each other to death. In addition, 11 of the 69 rodent pairs died from parabiotoid disease, in which presumably the immune system of the one animal fights against the blood of the other.

Older mice benefit from young blood

By the end of the seventies interest in parabiotics had diminished. Nowadays however the topic is back in the media as part of ageing research. This is because in almost all areas of the body of older mice “young blood” seems to have a rejuvenating effect, not only on bone density. In 2005 a research team led by Thomas Rando, at the time assistant professor at Stanford University School of Medicine, showed how the blood of young mice affects ageing muscles. He combined pairs of mice for a period of six to seven months, one being two to three months old and the other between 19 and 26 months old. After five weeks the scientist injured the muscles at each mouse’s hind paw. Five days later the injury to the older animals had healed as well as the younger one’s. This was probably due to the stem cells of the older animal being stimulated to divide. However, if the older mouse was bound to a rodent of the same age the injury healed much worse – in a way that would be normal with non-parabiotic older animals.

From this time on many different publications appeared on the subject. Young blood can repair damaged spinal cord tissue or support the formation of new neurons in the brain and the olfactory system, thickened heart muscles can be induced to regress. The effect also works with human plasma. In April this year Tony Wyss-Coray from the Stanford University School of Medicine showed that the memory and learning ability of old mice improves through human umbilical cord plasma. This involved the research team injecting the plasma every four days over two weeks.

More animal friendly approach

Since the 1970s, much has changed for the welfare of animals. In order that these animals suffer less, mice of the same sex and the same size are accustomed to each other at least two weeks before the surgery. They are anaesthetised for the operation. In order to reduce the mortality rate of the test animals, nowadays only genetically identical animals are connected. This is because they do not then seem to suffer from parabiosis illness. In addition doses of antibiotics reduce the risk of infection. After the surgical procedure, the connected animals behave normally and they can be successfully separated again later.

Unknown mechanism of action

The question of how exactly “young blood” works on the older body is still unclear. It is assumed that certain components of the blood positively affect the older stem cells. One possible explanation for the positive effects of the young blood could be the protein GDF11 (growth differentiation factor 11), the concentration of which decreases in blood the older an individual becomes. Researcher at Havard University in Cambridge administered the protein over four weeks to older mice with cardiac hypertrophy, after which the enlarged heart regressed. In addition the protein TIMP2 (tissue inhibitor metalloprotease) is suspected of having a positive effect by improving the function of the older hippocampus, the hormone oxytocin is thought to delay ageing processes. Both are found at elevated levels in young blood.

Nevertheless there is not always common opinion. The biotechnology company Novartis for example was not able to reproduce the positive effect of GDF11. The problem is that GDF11 resembles the protein myostatin and the Havard scientists were not able to differentiate between these two substances, it is believed. Myostatin inhibits muscle growth and its concentration in the blood increases in age. In fact, GDF11 levels would also increase with ageing, something which Novartis wants to demonstrate using other reagents. The research team from Havard University replied that there might possibly be several forms of GDF11 and the tests conducted by Novartis would not be comparable due to some deviations.

The cause of the rejuvenating effect of parabiosis could however be the sharing of organs by the connection animals. In order to get to the bottom of this question, Irina Conboy developed a device using which she could exchange the blood of young and old mice. It was shown that the inhibitory effect of the old blood on young mice was significantly more pronounced than the use of the young blood on old mice. The reason for the observed positive effects in old mice could, according to the researchers, also be explained by the fact that the old blood was diluted.

Rejuvenation costs 8,000 dollars

Although the mechanism of action of the young mouse blood on older tissue is still unclear, some companies have begun their own studies of humans. In contrast to animal experiments however, parabiosis is dispensed with. After all, who wants to be sewn together voluntarily with another person? Instead, the trial participants receive blood donated by younger people.

One of these companies is the start-up Ambrosia out of Monterey in California. Company founder Jesse Karmazin is currently still searching for participants for the study. The prerequisite is that you are at least 35 years old, not pregnant and healthy. If one has the necessary pocket money, namely $8,000, nothing stands in the way of the rejuvenation treatment: one then receives a one-time plasma infusion from a donor, who is a maximum of 25 years old. A control group does not exist – no one would want to spend 8,000 dollars on a placebo. Instead, the blood of the participants is examined for different biomarkers before and after the infusion. Speaking to a specialist magazine the company founder assured that the fee was necessary to cover, among other things, the costs of the plasma, the approval of the ethics committee and the laboratory tests.

Another such company is Alkahest. The private company from San Carlos in California was founded by Wyss-Coray and launched a randomised placebo-controlled double-blind study in September together with Stanford University. 18 Alzheimer patients over 50 years of age received four infusions from young donors over four weeks. The primary endpoint is safety. In addition, the scientists are looking for changes in the brain or blood. The study is expected to be completed by the end of the year.

What’s more, a hospital in South Korea has launched a randomised placebo-controlled clinical study. 64 subjects who are 55 years or older receive either fresh umbilical cord blood, frozen umbilical cord blood, frozen plasma, or a placebo. In addition to testing for safety, the study also aims to investigate the effects of blood or plasma on ageing.

Beware of unnecessary blood transfusions

At present there is no data that proves a life-prolonging effect of blood transfusions. Treatments for life prolongations are therefore not advisable. On top of that, blood transfusions, although already medically routine, cannot be taken lightly. In addition to the transmission of infections, immune reactions can occur even with a well-suited donor. In an extreme case the receiver can even suffer anaphylactic shock.

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