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.

About Vince Giuliano

Being a follower, connoisseur, and interpreter of longevity research is my latest career, since 2007. I believe I am unique among the researchers and writers in the aging sciences community in one critical respect. That is, I personally practice the anti-aging interventions that I preach and that has kept me healthy, young, active and highly involved at my age, now approaching 91. I am as productive as I was at age 45. I don’t know of anybody else active in that community in my age bracket. In particular, I have focused on the importance of controlling chronic inflammation for healthy aging, and have written a number of articles on that subject in this blog. In 2014, I created a dietary supplement to further this objective. In 2019, two family colleagues and I started up Synergy Bilherbals a dietary supplement company that is now selling this product. In earlier reincarnations of my career. I was founding dean of a graduate school and a university professor at the State University of New York, a senior consultant working in a variety of fields at Arthur D. Little, Inc., Chief Scientist and C00 of Mirror Systems, a software company, and an international Internet consultant. I got off the ground with one of the earliest PhD's from Harvard in a field later to become known as computer science. Because there was no academic field of computer science at the time, to get through I had to qualify myself in hard sciences, so my studies focused heavily on quantum physics. In various ways I contributed to the Computer Revolution starting in the 1950s and the Internet Revolution starting in the late 1980s. I am now engaged in doing the same for The Longevity Revolution. I have published something like 200 books and papers as well as over 430 substantive.entries in this blog, and have enjoyed various periods of notoriety. If you do a Google search on Vincent E. Giuliano, most if not all of the entries on the first few pages that come up will be ones relating to me. I have a general writings site at www.vincegiuliano.com and an extensive site of my art at www.giulianoart.com. Please note that I have recently changed my mailbox to vegiuliano@agingsciences.com.
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