Imagine you’re a mad scientist who wants to figure out if there’s something in young peoples’ blood that can be transplanted into old people (some “youth serum” that you could package and sell) to improve their health. You might go about it by harvesting vast quantities of blood from young people, and transfusing it (or different components of it) into old people; running tests on muscle tone, energy, and cognitive function to see if and what components reversed the aging process in old people.
This experiment isn’t feasible in humans—it’s hard to find two people who have compatible blood and tissue types, and even if you did, you wouldn’t be able to ethically harvest enough blood to make the experiment work. However, this experiment can be performed in mice—thanks to the fact that mouse strains are so inbred that mice of the same strain can exchange organs (or blood) with minimal immune response. Using a surgical procedure called “parabiosis”, researchers can connect two mice and create a surgical version of conjoined twins. These mice now share a circulatory and immune system—as well as any mysterious components that might be present in their blood. The surgery involves joining the skin and peritoneum on complementary sides of the animals, and suturing their legs together so they can move properly. Performed correctly, the procedure is no more harmful to the mice (in survival and lifespan terms) than any other surgical procedure.
A decade ago a molecule that made fat mice thin (leptin) was discovered largely through parabiotic experiments that joined obese mice with normal mice that had been performed back in the 70s. These parabiotic joinings have been a staple of medical research for a long time—they were critical to understand antibody-based immunity, organ rejection, diabetes, and blood pressure regulation earlier in the 20th century. All these studies joined diseased mice to normal mice to show how factors present in blood could either promote disease in healthy mice or improve disease in diseased mice.
For the last few decades these experiments have been less popular in the literature—probably because they’re technically difficult and a bit icky. Recently, though, this is has changed–work by three groups early this year (Lee Rubin and Amy Wagers at Harvard, and the Villeda/Wyss-Coray groups at UCSF/Stanford) have established how this old technique in combination with modern stem cell and whole-genome analysis techniques can be a powerful tool for investigating molecular processes involved in aging. This is part of a larger parabiosis revival in biomedical research, which started about a decade ago with work by Irina Conboy, Thomas Rando, and Irving Weissman at Stanford University which began to investigate the theory that factors in young blood could restore the function of stem cells in old animals.
The most recent work by the Rubin/Wagers/Villeda/Wyss-Coray groups used sets joining young and old mice in every combination (young-young, young-old, and old-old; a “complete parabiotic set”) to understand the effects of young blood on muscle and brain function in old mice. These young-old (heterochronic) pairs showed dramatic reversals in age-related declines in muscle and neural (brain) stem cell populations, which doubled in old mice exposed to young blood. This was shown to improve muscle healing after injury and their ability to detect an odorant (goes downhill in aged mice). It is thought that these results are related to the ability to generate new muscles and neurons in aged mice. More excitingly, the Rubin and Wagers groups demonstrated that both effects (muscle regeneration and odorant detection) could be reproduced by simply injecting mice daily with a single growth factor—GDF11.
The effects of young blood administration went far beyond just effects on stem cell populations. When the Villeda/Wyss-Coray groups examined the hippocampi (memory-consolidating centers) in brains of heterochronic old mice, they saw that even mature neurons began to look more like young neurons: their spine density (number of connections with nearby neurons–a feature that declines in old neurons) increased, and they developed gene expression profiles similar to young neurons. Inspired by this result, they tried to reproduce the effect by injecting aged mice with plasma (blood minus cells) from young mice—and observed the same cellular and gene expression effects seen in the parabionts. Even more remarkably, the old mice injected with young plasma showed genuinely improved memory—performing similarly to young mice when required to remember a fear stimulus. The authors connected this effect to a transcription factor named Creb, which produced the same effects when they used a virus to deliver it to the hippocampi in old mouse brains.
Taken together, both these studies show that components in young blood can improve the function of aged cells and regenerate populations of neural and muscle stem cells needed for resilience to normal injuries. Importantly, these factors appear to be proteins present in serum that could be engineered to give to patients the same way growth hormone and therapeutic antibodies currently are. While the Villeda group was unable to identify the factor that upregulated Creb in their studies, the fact that it’s present in serum means its identification is only a matter of time. In the meantime, studies on GDF11 administration will likely be a particularly hot topic in clinical aging research, as the ability to reduce aging-related muscle dysfunction holds great promise for treating a wide variety of cardiovascular problems, as well as improving day-to-day quality of life for elderly with reduced muscle tone.