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.
some intrguing thoughts
progerin is a gene that gets expressed more in case of progeria patients.
FTIs are new class of cancer drugs that are expermented successfully in animal models of progeria.
Can we assume normal expression of progerin gene is the cause of normal aging?
If so FTIs would help stave of the normal aging too?
“Taken together, the results of these experiments provide a new window into the biology behind the clinical features of HGPS. They may also hold relevance for understanding the biology of normal aging. â€œProgerin is present at low levels in the cells of healthy people,â€ said Misteli. â€œOne could envision a scenario in which progerinâ€™s effects on the Notch pathway and, by extension, on adult stem cells could, over time, lead to many of the tissue changes we commonly associate with the aging process.â€
I think progerin as the main underlying principle behind the aging process is conceivable.
The progerin affected cells have a irregular shape. They have similar characteristics in the progeria (young) patients and the old people. FTIs restore the shape of the cells.
While I have not seen any tests that were conducteed on actual old mice with the FTIS to restore their youth, it is a distinct possiblity. (May be someone is doing that)
The clinical trials on the progeria patients will be completed in 2009 and results published in 2010. May be we will have an answer that time.
Res: I have started looling into the whole progeria-related complex of findings you put me in touch with: altered-LMNA/progerin/farsyltransferase inhibitor therapy, etc. I am amazed to find so much that could be highly relevant to normal aging. I had a hard look at progeria a few years back but put the subject aside and have missed this whole progerin-related thread. In fact, a dozen years ago I wrote an action-adventure screenplay about discovering a telomerase cure for Hutchinson Gildford disease that also reversed aging. So:
– Res, you are possibly right, there could be a new theory of aging and new therapeutic interventions connected with progerin.
– There is a lot of research material in this area that is new for me that could be quite important. I want to study the research publications in much more depth and think about this angle on aging.
– Possibly I will update the Anti-Aging Firewalls treatise with this material. Either that or I will post a long entry on this blog.
All this is to say you probably won’t hear from me about this for a few days until I can get my mind around it. Please stand by.
See the above recent study
Progerin RNA expression slowly builds up in the normal cells as they age