Archive for the ‘CREB’ Category

Cinematicode wall
Image by Smeerch via Flickr

As far as science movies go, the new movie, “To Age or Not To Age” seems like a lot of fun.  The interview with Dr. Leonard Guarente suggests that the sirtuin genes play a starring role in the film.  Certainly,  an NAD+ dependent histone deacetylase – makes for a sexy movie star – especially when it is able to sense diet and metabolism and establish the overall lifespan of an organism.

One comment in the movie trailer, by Aubrey de Grey, suggests that humans may someday be able to push the physiology of aging to extreme ends.  That studies of transgenic mice over-expressing SIRT1 showed physiological properties of calorie-restricted (long lived) mice – even when fed ad libitum – suggests that something similar might be possible in humans.

Pop a pill and live it up at your local Denny’s for the next 100 years?  Sounds nice (& a lot like grad school).

Just a few twists to the plot here.  It turns out that – in the brain – SIRT1 may not function as it does in the body.  Here’s a quote from a research article “Neuronal SIRT1 regulates endocrine and behavioral responses to calorie restriction” that inactivated SIRT1 just in the brain:

Our findings suggest that CR triggers a reduction in Sirt1 activity in hypothalamic neurons governing somatotropic signaling to lower this axis, in contrast with the activation of Sirt1 by CR in many other tissues. Sirt1 may have evolved to positively regulate the somatotropic axis, as it does insulin production in β cells, to control mammalian health span and life span in an overarching way. However, the fact that Sirt1 is a positive regulator of the somatotropic axis may complicate attempts to increase murine life span by whole-body activation of this sirtuin.

To a limited extent, it seems that – in the brain – SIRT1 has the normal function of promoting aging.  Therefore, developing “pills” that are activators of SIRT1 would be good for the body, but somehow might be counteracted by what the brain would do.  Who’s in charge anyway?  Mother Nature will not make it easy to cheat her! Another paper published recently also examined the role of SIRT1 in the brain and found that – normally – SIRT1 enhances neuronal plasticity (by blocking the expression of a  micro-RNA miR-134 that binds to the mRNA of, and inhibits the translation of, synaptic plasticity proteins such as CREB).

So, I won’t be first to line up for SIRT1 “activator” pills (such as Resveratrol), but I might pop a few if I’m trying to learn something new.

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Angry face
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Indeed, learning how to manage one’s response to the negative emotions of others and stay out of trouble is an important life skill. At some point, most of us learn to just avoid angry, mean or melodramatically negative people and save ourselves the strife. Roy Perlis and colleagues, in their recent paper, “Association of a Polymorphism Near CREB1 With Differential Aversion Processing in the Insula of Healthy Participants“, show how the transcriptional regulator CREB might exert an influence on this learning process. By having subjects view images of various facial expressions, the investigators found that individuals with the TT genotype at rs4675690 (C/T) showed less negative activation in the left insula, a brain region that is known to activate when subjects feel disgust, but not happiness, desire or fear. Subjects with the TT genotype have been shown to require more effort in the management of negative emotions and are at greater risk for suicide when being treated for depression. In the Perlis et al., study, TT subjects showed less of an effort (as measured in key presses) to avoid viewing emotionally distressing pictures. The known role of CREB in neural plasticity suggests that this gene may facilitate neural changes associated with memory. Unfortunately, 23andMe does not cover this SNP, so I’ll just have to hope that (during the upcoming election) my insula keeps me on the path to enlightenment.

Update: Thanks so very much Brian for the info on rs7591784. This explains a lot – I’m a GG here, which means I’m a TT at rs4675690 – and have always had difficulty handling it when folks are rude to me.

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