Sci will admit that I just finished reading Batwoman: Elegy recently. I thought it was great. It's the kind of story that you read, put down, and then put back up again. It leaves you with a pile of unanswered questions and keeps you going back, trying to figure out if there were clues you missed that can piece it together. Also, the split between the two types of art REALLY highlighted the divide in the worlds to me. Good stuff.

And also, the villain quotes a LOT of Lewis Carroll (this, and all the goth that has been infused into Alice in Wonderland have kind of ruined the amusing whimsy the book used to have for me, but oh well), and so that is what I was thinking about when I read this paper: "One side will make you grow taller, and the other side will make you grow shorter."

Except in this case, one injection may make your cells act older, and the other one...well who knows?

And so I present this paper to you.

Begin at the beginning and go on till you come to the end; then stop.

Villeda et al. "The ageing systemic milieu negatively regulates neurogenesis and cognitive function" Nature, 2011.

And also, we're going to learn about PARABIOSIS, which is something that I, as a scientist, thought was either really rare or didn't even EXIST...until today. And it is CRAZY. SCIENCE, dudes. SCIENCE.

There are a lot of changes that take place as the body ages. Obviously there are the ones we can see: the wrinkles, grey hairs, the joint issues, and then there are the ones we CAN'T. One of them in neurogenesis. I write a lot about neurogenesis and it's mostly because it's something that still just boggles my mind. We used to think that you were born with all the neurons you would ever have or need, but now we know that neurogenesis, the birth of new neurons, occurs throughout life. We are also coming to realize what a delicately balanced process it is, and how many different things can change it. Depression, formation of memory, stress, aging, all of these things are thought to involve neurogenesis. In particular (for today's topic), as we get older neurogenesis decreases, and people think that this is related to some of the cognitive declines that come with getting older.

But HOW does the neurogenesis get the signal to decrease? We (scientists who study the brain, anyway) generally think of these signals as coming from within the brain, from local signals or from other brain areas. But recently we have come to realize that signals affecting neurogenesis can come from all over the body. But of course, the signals have to get to the brain...and so these authors decided to look at the blood.

The authors in this study started with a large group of older mice. These mice had decreased neurogenesis, decreased neuronal plasticity (a very popular term lately, which basically means the neurons can grow and adapt to change very well), and didn't do well on mouse tests of cognitive ability, like mazes. The authors hypothesized that something in the blood of the old mice was contributing to the behavioral and brain effects of aging.

And so they hooked them up to YOUNG mice. In an experiment that makes me think forcibly of Holly Tucker's book Blood Work (which is both a fun and interesting read, unfortunately I didn't have the time to write up a review, but I liked it very much!), a young mouse and an old mouse were yoked together in what's called parabiosis, where their blood systems are joined, as well as the membranes surrounding the organs in the body. They paired up young mice to young mice, old mice to old mice, and old mice to young mice. This allowed them to see the effect that the factors borne in the blood had on the BRAINS of the young mice.

And what they found was that, when paired up, young mice began to look a lot like OLD mice. When they exposed young mice to older mouse blood, the young mice ended up with decreased neurogenesis. This didn't happen young mice hooked up to young mice, or old mice hooked up to old, and presumably was the result of factors associated with aging in the blood of the old mouse. Not only that, while the neurogenesis in the young mice suffered from the presence of the old mice, the old mice showed the opposite effect, with small increases in neuron birth when exposed to young mouse blood.

To isolate this effect to the blood, the authors then took plasma from old mice and put it in to young mice (with plasma from young mice going into young mice as a control).

You can see here (starting from the top), that injecting old mouse plasma into young mice decreased their neurogenesis in the hippocampal slices. At the bottom, you can see that it ALSO increased the number of errors they made in a behavioral task, showing that the neuron loss you can see in the brain has functional consequences.

All this is very cool, but this is where you have to start asking the hard questions. WHAT is the "factor" (or factors) in the blood that is causing the decreases in neurogenesis and the changes in behavior? We can just start bathing in the blood of young virgins to increase our neurogenesis. So the authors of this study did a measure of various proteins in the blood that changed during aging, and also during parabiosis.

They found several cytokines (proteins associated with inflammation and cellular injury response) that increased in the blood both during aging and during parabiosis, and they settled on one of them, CCL11 (others are not shown, but usually they end up "settling" on one specific molecule or another either because there is a good back up in previous scientific literature showing that one is more likely...or because they tested the rest and they didn't work. In this case, they had literature to back them up, as well as observations that aging HUMANS showed increases in CCL11). When they injected CCL11 specifically into young mice (no plasma or parabiosis this time), they saw decreases in neurogenesis, just like with plasma or parabiosis, and this could be blocked by using an antibody to stop CCL11. And the CCL11 also affected the ability of the young mice to perform in behavioral tests like fear conditioning.

So what does it all mean? It means that blood borne factors, particularly cytokines related to inflammation, increase during aging (which we knew), and can have effects on your brain (which we didn't know). And it narrows down these factors to CCL11 (though others may also be involved), showing that higher amounts of it in aging mice contribute to decreased neurogenesis and cognitive decline. And it means that we may be able to look at cytokines, and maybe decreasing cytokines, as a way to combat some of the cognitive effects in aging.

But don't start bathing in the blood of virgins just yet. It's going to take more than one cytokine, and far more than one series of experiments (and more than experiments in mice) to show which cytokines are involved, and exactly what they are doing to decrease neurogenesis and affect behavior. And of course, they didn't do all of the reverse experiments, to see if decreasing levels of CCL11 specifically could increase neurogenesis and make old mice perform better. But it's still very fascinating to see, even in a mouse, that one injection can make you "older", and another can make you "younger"...

Villeda SA, Luo J, Mosher KI, Zou B, Britschgi M, Bieri G, Stan TM, Fainberg N, Ding Z, Eggel A, Lucin KM, Czirr E, Park JS, Couillard-Després S, Aigner L, Li G, Peskind ER, Kaye JA, Quinn JF, Galasko DR, Xie XS, Rando TA, & Wyss-Coray T (2011). The ageing systemic milieu negatively regulates neurogenesis and cognitive function. Nature, 477 (7362), 90-4 PMID: 21886162