NF-κB Inhibition Extends Life in Flies

NF-κB is associated with a range of interesting mechanisms: "Aging is associated with NF-κB-dependent pro-inflammation. Here we demonstrated that inhibition of NF-κB with pyrrolidine dithiocarbamate increases the median lifespan (13-20%) and the age of 90% mortality (11-14%) in Drosophila melanogaster females and males, respectively. ... NF-κB controls the expression of genes involved in innate immunity, inflammation and apoptosis. Such age-dependent pathologies as tissue inflammation and atrophy are caused by over-activation of the NF-κB signaling with age. ... Recent studies suggest that the NF-κB transcription factor controls age-dependent changes in inflammation genes expression. Donato et al showed that an increase of NF-κB dependent genes in human endothelium with age is primarily linked to [decreased] NF-κB inhibition. Age-associated expression of NF-κB-dependent genes cause progression of atherosclerosis in rat. Furthermore, selective inhibition of NF-κB activity in blood vessel endothelial cells prevents atherosclerosis progression. Genetic blockade of NF-κB in the skin of chronologically aged mice reverses the global gene expression program and tissue characteristics to those of young mice ... However, the effect of NF-κB inhibition on the lifespan was not studied before."

Link: http://www.impactaging.com/papers/v3/n4/full/100314.html

Comments

This simple intervention seems to pose problems for "wear and tear" theories.

Are mutations that reduce NF-kappaB expression examples of antagonistic pleiotropy? - i.e., do they reduce mobility, fertility or some other measure of fitness in early life?

It would also be interesting to see how additive this effect is with CR, mTOR reduction, etc.

Posted by: Lou Pagnucco at April 19th, 2011 11:04 AM

Merely this example "Genetic blockade of NF-κB in the skin of chronologically aged mice reverses the global gene expression program and tissue characteristics to those of young mice" is a very very interesting and possibly a significant "clue"... Certain genes start "drifting" from the optimal state due to lack of pressure from a natural selection, a cellular mess begins, you restore some of that to it's former state - voila, tissue goes back to "young". That's a great proof of the regulation of gene expression relation to the "aging state" of a tissue, and quite probably - a whole organism (I'm not educated enough to speculate how possible it would be to affect a whole epigenome of a mice and "bring it back" to the one it was when a mice was young, if that's possible at all, but I'd bet that would translate in the same effect - overall "age reversal".)..
Key words - "Gene expression program".

Posted by: Regular-reader at April 20th, 2011 5:54 AM

@Regular-reader: Not quite so simple, I'm afraid. There's damage and then there's the way in which cells react to that damage. Changing gene expression in the skin does nothing to remove, for example, the harmful build up of AGEs.

Posted by: Reason at April 20th, 2011 6:27 AM

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