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.