#SfN14: A "how-to" guide to finding the Fountain Of Youth


Nanosymposium: Castellano JM, Wyss-Coray T et al. Factors present in young plasma enhance neuronal function in old mice. Stanford U, Palo Alto.

You've probably seen the headlines: "Young blood may hold key to reversing aging." In a series of remarkable studies published last year, researchers hooked up the circulation system of young and old mice in a century-old experimental preparation called heterochronic parabiosis. Incredibly, the blood of young mice acted on multiple bodily systems in their paired elderly counterparts – skeletalbrainimmune – and restored their biological functions to that of healthy young adults. The researchers saw similar results when they gave old mice daily injections of serum (the liquid part of blood), suggesting that blood cells weren't working the magic.

But then what is?

In an earlier experiment, researchers found that when they heated up the serum it lost its regenerative ability. This tells us that the "youth factors" are sensitive to heat – so most likely large peptides or proteins. With thousands of different protein factors circulating in the blood, how do we narrow it down?

In a talk presented at the Society for Neuroscience annual conference, researchers from Stanford University described their pocket-map to finding the fountain(s) of youth.

The key is to setup a robust system that screens for strong candidate youth factors with few mistakes. Scientists harvested the blood from three different models: normal mice aging, human aging and the mice parabiosis model. The idea is to use a technique called protein microarray, which assesses changes in the levels of thousands of proteins at the same time, and to look for overlapping candidate factors across all three models. By looking for factors that decrease with age, the researchers would be able to narrow the candidates down to a tenable amount for further research. After finding these potential "hits", researchers can then directly deliver each candidate protein to aged mice and see if the treatment improves learning and memory.

Luckily, medical collaborators donated three types of human blood to the researchers: that from umbilical cords, 20 year olds and 65 year olds. A quick microarray assay revealed that the umbilical cord harboured many factors not present in "aged" blood. Many such proteins declined with age – perfect candidates for future study.

The next question is how to evaluate the effects of these candidates in mice. Due to species differences, human plasma can't be directly injected into mice: the resulting immune response would most likely kill the recipient. Instead, researchers turned to a strain of immunodeficient mice called NSG. With age, NSG mice gradually loose their ability to retain new information, and the neurons in their hippocampus show less activation.

The team injected aged NSG mice with the plasma from human umbilical cords for 14 days straight, and then tested the mice on a spatial memory task and gene expression. This treatment increased the number of activated neurons in the hippocampus, and rescued a type of electrical coupling in neurons called long-term potentiation (LTP). Put simply, LTP is the leading mechanism for the learning principle "fire together, wire together", and is often impair in aged mice. Thus it seems that cord plasma increases the ability of old neurons to form connections that support new learning and memory. In fact, when trained and tested on two different memory tasks, cord plasma-treated mice showed significant improvements over controls.

Now that researchers are confident human plasma works in aged mice, they went on to directly test a candidate pro-youth factor called CSF2. They directly injected this protein into aged mice for four days, and again saw enhanced hippocampal neuron activation and better spatial learning in a maze – although the effect wasn't as strong as treatment with the whole plasma. Researchers think this is likely because there are many other types of rejuvenating factors present in plasma – most still waiting to be discovered.

PS.  The "young blood rejuvenates old brain" study is up for nomination at Science for Breakthrough of the year! Go check out the other incredible findings across multiple disciplines, and if you think the study's worth it give it a vote.