November 13, 2011 | 2
Collette et al. “Chronic Alpha-1A adrenergic receptor stimulation increases lifespan and reduces the overall incidence of cancer in mice” Saturday, Nov 12, 2011, 55.10.
It’s time to kick off this neuroblogging experience with something that you might not initially think is associated specifically with neuroscience: lifespan and cancer. Here’s a post from yesterday’s (Saturday’s) poster session.
We’ll start with the alpha1a and alpha1b adrenergic receptors. Adrenergic receptors are receptors which bind the neurotransmitters epinephrine and norepinephrine. That might sound a little odd, until you recall that epinephrine and adrenaline are just wildly different spellings of basically the same thing. When I usually think of epinephrine, I usually think of that scene from pulp fiction where Ume Thurman ODs and they stab a syringe into her heart full of adrenaline. Completely fiction, but you WILL remember (you CAN use adrenaline to treat cardiac arrest, but stabbing direct into the heart like that…eh…).
And there are lots of adrenergic receptors in the heart. But there are also adrenergic receptors in the brain, in the vasculature, in the liver, in the prostate (alpha 1 a adrenergic antagonists are in fact used to treat prostate hyperplasia).
In an effort to determine how various receptors affect our behavior and our bodies, scientists use different animal models. Some of these are knockouts, where you knockout a gene, making sure its products are not expressed, by making the genetic sequence gibberish. And some, like the ones used in this project, are “knockins”, or in this case, mice which OVERexpress your gene that you are interested in. Scientists can put a promoter sequence of DNA in front of the DNA they are interested in, and this promoter will cause more of the DNA to get transcripted to RNA, and then translated to protein. In this case, they promoted a form of the alpha 1 a adrenergic receptor that is always active, resulting in a lot more receptor activity than you would get in a normal mouse. In another set of mice they did the same thing with an alpha 1 b adrenergic receptor.
The net result is a change in the activity of these receptors, where the mice act like they have been treated with alpha 1a or alpha 1b adrenergic agonists, which is a bit more subtle than overexpressing something to 100 times it’s normal concentration. And these mice have many behavioral alterations. Mice with constantly active alpha 1 a adrenergic receptors are less anxious than normal mice, show less depressive-like activity in mouse depression tests, and showed increases in new neuron birth in the hippocampus. The animals even show protection from cardiac problems like ischemia. On the other hand, constantly active alpha 1 b adrenergic receptor mice have rather opposite effects, with more cardiac issues, and an increase in neurodegeneration.
With all these seemingly positive effects of alpha 1 a mice, and possibly negative effects of alpha 1 b mice, the authors of this poster wanted to know whether the lifespans of these mice differed. And do find this out, they do something very simple. You walk through the mouse colony once a day, checking on all your mice. See who’s died, and what they died from. It’s a morbid job but someone’s got to do it.
Now, you might think that mice don’t generally live very long. There you’d be wrong, laboratory mice can live two to three YEARS without any problems (though they do get little grey hairs!). So after what must have been a very long experiment, the authors of this study had enough animals to look at whether constantly active alpha1a adrenergic receptors, or constantly active alpha 1b andrenergic receptors changed lifespan.
And it looks like they did. The mice with constantly active alpha 1a receptors lives significantly longer, and the mice with constantly active alpha 1b receptors lived SHORTER lives that normal mice. Not only that, the preliminary data indicates that constantly active alpha 1 a receptor mice have a trend (p=0.07) toward decreased CANCER incidence.
Now this is kind of odd, because both alpha 1a and alpha 1b receptors are thought to be “protooncogenes” meaning that both of them are thought to be permissive toward tumor formation. Right now the authors hypothesize that differences in these two receptors may be in the way they interactive with downstream proteins, in particular p21, a cell cycle regulator. And that’s where they are going to look next, to try and find the mechanism behind why these two sets of mice lead such wildly different lives (or at least, wildly different in length). These studies into basic mechanisms can go a long way into determining how the many tiny parts of our bodies come together, and what happens when things go wrong, and may be able to provide information on lifespan and cancer incidence in the future.