A further update on NF-kappaB

As time rolls on and new research studies roll in, there appears to be more and more evidence for key role of the nuclear binding factor NF-kappaB in aging.  I have listed some updates on this subject in a previous blog post and treat it in my Anti-Aging Firewalls treatise under the Programmed epigenomic changes theory of aging.  I provide some additional thoughts and research citations on this important subject in this post.

First of all, a bit of additional clarification on what NF-kappaB is.  NF-kappaB  is not a single molecular substance but is “a collective name for inducible dimeric transcription factors composed of members of the Rel family of DNA-binding proteins that recognize a common sequence motif”(ref).  What these proteins share in common is a motif, e.g. a characteristic DNA binding sequence.  In simple language NF-kappaB is a collection of proteins that can profoundly affect the transcription of DNA, that is the production of messenger RNA and the subsequent productions of proteins encoded by DNA.  It can target over 200 human genes in different kinds of cells.  It has positive roles in maintaining health and also can create disease conditions and accelerate aging.

According to a key study, the gene sequence motif most closely associated with aging is that of NF-KappaB.   “NF-kappaB is found in essentially all cell types and is involved in activation of an exceptionally large number of genes in response to infections, inflammation, and other stressful situations requiring rapid reprogramming of gene expression(ref). It is a very rapidly-acting substance, a “first responder” to harmful cellular stimuli.  NF-kappB tends to be plentiful in cells of older people. 

Normally, NF-kappaB lives in the cytoplasm of cells where it is bound up and kept out of the nucleus by a family of substances called IkB (inhibitor of kappaB).  When a harmful extracellular stimulus is perceived, the IkB inhibitor molecules are modified by a process called ubiquitination and destroyed by cellular processes known as proteolysis(ref).  The result is that the NF-kappaB is freed to translocate into the nucleus where it can bind to a variety of genes, activate them and produce a variety of impacts including vicious pro-inflammatory ones.  These processes are in fact quite complex involving many proteins, adapter, promoter and co-activator factors.

“Recently, considerable progress has been made in understanding the details of the signaling pathways that regulate NF-kappaB activity, particularly those responding to the proinflammatory cytokines tumor necrosis factor-alpha and interleukin-1(ref).”   NF-kappaB plays a wide variety of roles going far beyond control of inflammation.  The aging process appears to involve changes in immune regulation and, among other things, NF-kappaB appears to be the master regulator of both the adaptive and the innate immune systems(ref). 

There is a large amount of research going on, basically focused on how inhibiting the expression of NF-kappaB can be used to prevent or control cancers, cardiovascular diseases and other inflammatory-related disease processes.  On a molecular level, there seems to be three possible strategies: 1 prevent the unbinding of NF-kappaB from IkB, 2, inhibit the translocation of NF-kappaB into the nucleus of cells, and 3.  prevent the activated NF-kappaB from binding onto and activating genes.  In a previous post I described an important experimental substance DHMEQ which acts through the second approach to inhibit the expression of NF-kappaB.  The third approach generally involves histone deacetylation.  That is, it involves coiling up the DNA in the neighborhood of genes so that those genes are not accessible for activation by the NF-kappaB. This appears to be the main mechanism used by curcumin, resveratrol and other dietary polyphenols for inhibition of gene activation by NF-kappaB(ref). 

I remind my reader that 39 of the supplements in my Anti-Aging Firewalls regimen are inhibitors of NF-kappaB expression.  Most of them work through this third mechanism.

One key challenge is finding therapeutic interventions that distinguish between the component NF-kappaB transcription factors: p50, p52, p65 (RelA), c-Rel, and RelB.  The research literature related to NF-kappaB is rapidly growing and increasingly difficult to follow.  A recent and excellent review and synthesis article can be found here.