Reversing dermal aging by inhibiting NFκB

The transcription factor NF-κB has been well studied in its role as an inflammatory signaling factor, and more recently in the context of aging. In the context of inflammatory lung disease, NF-κB is downregulated by SIRT1, a pro-longevity protein. Furthermore, a focused analyses of its role in inflammaging have revealed that NF-κB expression is regulated by FOXO transcription factors, which are also involved in longevity assurance.

Fine; we know what sorts of factors can prevent NF-κB from wreaking its havoc in the first place — but what about havoc that has already been wrought? Knowing what might have inhibited NF-κB in the past is all well and good, but it’s cold comfort for individuals whose bodies are already undergoing its inflammatory ravages.

Happy news, then, from Adler et al., who report that genetic knockdown of NF-κB can actually reverse inflammatory damage in the skin of aged mice:

Reversal of aging by NFκB blockade

Genetic studies in model organisms such as yeast, worms, flies, and mice leading to lifespan extension suggest that longevity is subject to regulation. In addition, various system-wide interventions in old animals can reverse features of aging. To better understand these processes, much effort has been put into the study of aging on a molecular level. In particular, genome-wide microarray analysis of differently aged individual organisms or tissues has been used to track the global expression changes that occur during normal aging. Although these studies consistently implicate specific pathways in aging processes, there is little conservation between the individual genes that change. To circumvent this problem, we have recently developed a novel computational approach to discover transcription factors that may be responsible for driving global expression changes with age. We identified the transcription factor NFκB as a candidate activator of aging-related transcriptional changes in multiple human and mouse tissues. Genetic blockade of NFκB in the skin of chronologically aged mice reversed the global gene expression program and tissue characteristics to those of young mice, demonstrating for the first time that disruption of a single gene is sufficient to reverse features of aging, at least for the short-term.

Could NFκB inhibitors be used to turn back the clock in age-damaged skin, or in other organs? At the moment, the state of the art is decidedly not up to the task. Our own lab uses a wide range of pharmaceutical NFκB inhibitors for a variety of purposes, and the consensus is that these compounds make cells very unhappy (though we don’t know whether that is because of a direct effect on NFκB signaling or some off-target effect on other pathways). Beyond that, NFκB is actually useful in contexts where inflammation is useful, as when the immune system is fighting off infections (and some tumors).

What would be nice is if we could specifically turn off the transcription of NFκB in cells or tissues of interest, perhaps using therapeutic small RNAs or some other approach — but this is pie-in-the-sky assumption of a can opener; if we could turn off specific genes in specific cells we could basically do anything in biology. Then again, even decades before the technology becomes available, it doesn’t hurt to start compiling a prioritized list of the things we’d do with it.



  1. Might it be possible to at least remove any extra-cellular NFκB by a extra-corporeal process similar to dialysis? If serum can be pumped past a filter that preferentially binds to NFκB, then we might be able to intermittently reduce its systemic signaling effects.

  2. we’d have to figure out which extracellular signal(s) were rate limiting in this (and possibly each) case. I could hazard an educated guess here: advanced glycation endproducts have been shown to activate NFkB through the RAGE receptor.
    As far as direct inhibition of NFkB, it might not be a complete “pie in the sky”. The siRNAi companies seem to be flying along with their treatments and doing a lot on the chemistry of stabilizing siRNAs for in vivo applications. The skin would seem to be a very accessible target – the obvious challenge being cellular uptake (ie in vivo transfection), but there is a lot of money going into solving that problem right now.

  3. A quick literature search indicates that aspirin (+ other salicylates), some polyphenols, and periodic heat shock, curcumin (+ some other herbs) reduce NFkB expression. Could some combination of these be beneficial.

    Also, how closely coupled are NFkB and TNF-alpha expression?

  4. tnf-alpha stimulates NFkB activation (nuclear localization). I don’t know that they impact each others’ expression.

  5. As Nf-kB is redox regulated and as oxidative stress is connected to skin aging, may be useful to understand the background of NF-kB activation. Actually there are many commercial products used for dermal aging containing antioxidants. May be this is the right way.

  6. Ashwagandha extract blocks activation of NFκB via multiple mechanisms and likely lacks the toxicity and side effects while actually fighting cancer and has also shown benefit for infection.

    Mol Cancer Ther. 2006 Jun;5(6):1434-45.

    Withanolides potentiate apoptosis, inhibit invasion, and abolish
    osteoclastogenesis through suppression of nuclear factor-kappaB (NF-
    kappaB) activation and NF-kappaB-regulated gene expression.

    Ichikawa H, Takada Y, Shishodia S, Jayaprakasam B, Nair MG, Aggarwal

    Cytokine Research Laboratory, Department of Experimental Therapeutics,
    The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe
    Boulevard, Houston, TX 77030, USA.

    The plant Withania somnifera Dunal (Ashwagandha), also known as Indian
    ginseng, is widely used in the Ayurvedic system of medicine to treat
    tumors, inflammation, arthritis, asthma, and hypertension. Chemical
    investigation of the roots and leaves of this plant has yielded
    bioactive withanolides. Earlier studies showed that withanolides
    inhibit cyclooxygenase enzymes, lipid peroxidation, and proliferation
    of tumor cells. Because several genes that regulate cellular
    proliferation, carcinogenesis, metastasis, and inflammation are
    regulated by activation of nuclear factor-kappaB (NF-kappaB), we
    hypothesized that the activity of withanolides is mediated through
    modulation of NF-kappaB activation. For this report, we investigated
    the effect of the withanolide on NF-kappaB and NF-kappaB-regulated
    gene expression activated by various carcinogens. We found that
    withanolides suppressed NF-kappaB activation induced by a variety of
    inflammatory and carcinogenic agents, including tumor necrosis factor
    (TNF), interleukin-1beta, doxorubicin, and cigarette smoke condensate.
    Suppression was not cell type specific, as both inducible and
    constitutive NF-kappaB activation was blocked by withanolides. The
    suppression occurred through the inhibition of inhibitory subunit of
    IkappaB alpha kinase activation, IkappaB alpha phosphorylation,
    IkappaB alpha degradation, p65 phosphorylation, and subsequent p65
    nuclear translocation. NF-kappaB-dependent reporter gene expression
    activated by TNF, TNF receptor (TNFR) 1, TNFR-associated death domain,
    TNFR-associated factor 2, and IkappaB alpha kinase was also
    suppressed. Consequently, withanolide suppressed the expression of TNF-
    induced NF-kappaB-regulated antiapoptotic (inhibitor of apoptosis
    protein 1, Bfl-1/A1, and FADD-like interleukin-1beta-converting enzyme-
    inhibitory protein) and metastatic (cyclooxygenase-2 and intercellular
    adhesion molecule-1) gene products, enhanced the apoptosis induced by
    TNF and chemotherapeutic agents, and suppressed cellular TNF-induced
    invasion and receptor activator of NF-kappaB ligand-induced
    osteoclastogenesis. Overall, our results indicate that withanolides
    inhibit activation of NF-kappaB and NF-kappaB-regulated gene
    expression, which may explain the ability of withanolides to enhance
    apoptosis and inhibit invasion and osteoclastogenesis.

    PMID: 16818501 [PubMed – indexed for MEDLINE]

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