CCL11 found in aged but not young blood inhibits adult neurogenesis

Portion of Fig. 1 from Villeda et al. (2011, doi: 10.1038/nature10357) describing the parabiosis procedure. Basically, under complete anesthesia, the peritoneal membranes and the skins of the two mice were sutured together. The young mice were 3–4 months (yellow) and old mice were 18–20 months old (grey).

My last post was about parabiosis and its sparse revival as a technique in physiology experiments. Parabiosis is the surgical procedure that joins two living animals allowing them to share their circulatory systems. Here is an interesting paper that used the method to tackle blood’s contribution to neurogenesis.

Adult neurogenesis, that is the birth of new neurons in the adult brain, declines with age. This neurogenesis has been observed in some, but not all brain regions, called neurogenic niches.

Because these niches occur in blood-rich areas of the brain, Villeda et al. (2011) wondered if, in addition with the traditional factors required for neurogenesis like enrichment or running, blood factors may also have something to do with neurogenesis. The authors made a young and an old mouse to share their blood via parabiosis (see pic.).

Five weeks after the parabiosis procedure, the young mouse had decreased neurogenesis and the old mouse had increased neurogenesis compared to age-matched controls. To make sure their results are due to something in the blood, they injected plasma from an old mouse into a young mouse and that also resulted in reduced neurogenesis. Moreover, the reduced neurogenesis was correlated with impaired learning as shown by electrophysiological recordings from the hippocampus and from behavioral fear conditioning.

So what in the blood does it? The authors looked at 66 proteins found in the blood (I don’t know the blood make-up, so I can’t tell if 66 is a lot or not ) and noticed that 6 of these had increased levels in the blood of ageing mice whether linked by parabiosis or not. Out of these six, the authors focus on CCL11 (unclear to me why that one, my bet is that they tried the others too but didn’t have enough data). CCLL11 is a small signaling protein involved in allergies. So the authors injected it into young mice and Lo and Behold! there was decreased neurogenesis in their hippocampus. Maybe the vampires were onto something, whadda ya know? Just kidding… don’t go around sucking young people’s blood!

This paper covers a lot of work and, correspondingly, has no less than 23 authors and almost 20 Mb of supplemental documents! The story it tells is very interesting and as complete as it gets, covering many aspects of the problems investigated and many techniques to address those problems. Good read.

Reference: 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. (31 Aug 2011). The ageing systemic milieu negatively regulates neurogenesis and cognitive function. Nature. 477(7362):90-94. doi: 10.1038/nature10357. Article | FREE Fulltext PDF

By Neuronicus, 6 January 2016

Your blood is better than my blood

Siamese tomatoes. Taken from here.

Parabiosis is a surgical procedure that lets two animals to share the same blood; it’s a case of reverse conjoined twins restricted to the circulatory system.

The procedure is over 150 years old and is a useful technique in physiology, though rarely used, probably due to the perceived cruelty towards the animals, although today is performed under anesthesia and aseptic condition. It delivered good data; for example, it was a parabiosis experiment with rodents that showed is not the sugar in the blood that causes cavities but the sugar in the mouth. Similarly, parabiosis has been proven useful in cancer, diabetes, and ageing research.

Scudellari (2015) wrote a News piece for Nature describing some advancements in the ageing field using the parabiosis technique. Namely, by joining the circulatory systems of a young and an old mouse, researchers have observed that the old mouse is faster, smarter, with rejuvenated muscles and glossier fur. Now the race is to find out what in the blood does it. Researchers caution that the young blood is not effectively reversing ageing, but may have factors circulating in it that promote tissue repair. Already a muscle-rejuvenating protein has been identified.

I am not going through the original papers themselves as I usually do (they are provided as links in the Reference paper). Instead, I am featuring the news piece by Scudellari because in addition of looking at parabiosis and ageing result, it also provides a nice historical account of the use of parabiosis. Enjoy!

Reference: Scudellari, M. (22 Jan 2015). Ageing research: Blood to blood. Nature, 517: 426-429. Article | FREE Fulltext PDF

By Neuronicus, 4 January 2015