Sirtuins are involved in longevity assurance in organisms as evolutionarily diverse as yeast, worms, and mice. All members of the family have homology to histone deacetylases (HDACs), but each protein has unique characteristics as well. Individual family members have distinct tissue expression profiles, subcellular localization, and substrate specificity. Over the past few years, we’ve begun to learn a great deal about the specific targets and interactions of each sirtuin, and how these interaction contribute to their functions in prolonging lifespan.

The SIRT6 protein, one of seven sirtuins encoded by mammalian genomes, came onto biogerontologists’ radar with a report from Katrin Chua‘s group that its histone H3K9 deacetylase activity is required to maintain telomeric chromatin in a healthy state. Furthermore, SIRT6 is required for the proper localization of the Werner’s syndrome protein, WRN, to telomeres: in the absence of SIRT6, the WRN-telomere association becomes unstable, recapitulating several of the cellular phenotypes of Werner’s progeria. (SIRT6 isn’t the only sirtuin involved in WRN biology: SIRT1, the most well-studied member of the family, appears to directly deacetylate WRN).

A second association between SIRT6 and aging has been revealed by a new study from the Chua lab: SIRT6 associates with the transcription factor NF-κB and deacetylates histones at NF-κB-bound promoters, causing them to become less active. Genetic suppression studies suggest that SIRT6’s influence on lifespan might be primarily mediated by NF-κB. Kawahara et al.:

SIRT6 Links Histone H3 Lysine 9 Deacetylation to NF-κB-Dependent Gene Expression and Organismal Life Span

Members of the sirtuin (SIRT) family of NAD-dependent deacetylases promote longevity in multiple organisms. Deficiency of mammalian SIRT6 leads to shortened life span and an aging-like phenotype in mice, but the underlying molecular mechanisms are unclear. Here we show that SIRT6 functions at chromatin to attenuate NF-κB signaling. SIRT6 interacts with the NF-κB RELA subunit and deacetylates histone H3 lysine 9 (H3K9) at NF-κB target gene promoters. In SIRT6-deficient cells, hyperacetylation of H3K9 at these target promoters is associated with increased RELA promoter occupancy and enhanced NF-κB-dependent modulation of gene expression, apoptosis, and cellular senescence. Computational genomics analyses revealed increased activity of NF-κB-driven gene expression programs in multiple Sirt6-deficient tissues in vivo. Moreover, haploinsufficiency of RelA rescues the early lethality and degenerative syndrome of Sirt6-deficient mice. We propose that SIRT6 attenuates NF-κB signaling via H3K9 deacetylation at chromatin, and hyperactive NF-κB signaling may contribute to premature and normal aging.

NF-κB has been widely implicated in the aging process, especially in the context of inflammatory transcription resulting in “inflammaging.” Indeed, a very recent study has suggested that knocking down NF-κB activity is sufficient to reverse the effects of chronological aging in the skin, at least at the level of gene expression, possibly by blocking inflammatory transcription and allowing the tissue’s natural regenerative capacity to proceed without obstacle.

As with the WRN story, this isn’t the first time a sirtuin has been implicated in regulating the activity of NF-κB — but also as with WRN, the mechanisms of sirtuin action are distinct. Studies of chronic obstructive pulmonary disease have revealed that SIRT1 directly deacetylates NF-κB, reducing its activity. In contrast, SIRT6 appears to associated with NF-κB but then exploit this interaction to “follow” the transcription factor to promoters, where it deacetylates histone H3K9 and facilitates formation of a closed or inactive chromatin state. Kind of a neat team: SIRT1 directly deacetylates proteins of interest, while SIRT6 acts in the same location but operates on chromatin. Working together, the proteins may well have greater than additive impact.

Thus, there is partial redundancy of ultimate function, even though the proteins operate via different mechanisms. This might actually make it easier to intervene favorably in the affected processes, if separate agonists of SIRT1 and SIRT6 end up having a synergistic effect at target promoters (and telomeres).

(There’s also a nice preview/summary piece in the same issue of Cell, by Gioacchino Natoli.)


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.

Two of the great scourges of old age are insulin resistance (often leading to late-onset diabetes) and frailty (a suite of symptoms that may have their roots in runaway inflammatory signaling). A review by Paolisso and Abbatecola investigates the possible connections between the two:

Is There A Relationship Between Insulin Resistance and Frailty Syndrome?

Due to the fact that the percentage of aged subjects in the populations of industrialized countries is dramatically increasing, the scientific community has been obligated to focus their attention on age related disease states and peculiar consequences of aging such as, frailty. Frailty is defined as a syndrome of decreased reserve and resistance to stressors and is clinically expressed as muscle weakness, poor exercise tolerance, factors related to body composition, sarcopenia, and lower extremity mobility. Some biochemical markers of frailty in older persons, including pro-inflammatory markers, hormones and free radicals have been suggested. However, there is growing evidence that a rise in insulin resistance [IR] occurs as individuals age and IR is not only considered a simple metabolic finding, but has been identified as a major risk factor for many age-related diseases due to altered lipid metabolism, increased inflammatory state, impaired endothelial functioning, pro-thrombotic status and atherosclerosis. Considering that IR is related to many of the clinical features of frailty such as, skeletal muscle weakness, lower extremity mobility disability, cognitive decline and body composition changes, we will analyze the relationships among IR and such individual components while highlighting potential pathophysiologic mechanisms of IR on the activation of the downward spiral of the frailty syndrome in older persons. In particular, we will address the issue that IR may also be considered a pivotal biological component of some clinical aspects of the frailty syndrome in aging individuals.

Resveratrol decreases tobacco-induced inflammation in the lungs of smokers, suggesting that SIRT1 is involved in regulating the inflammatory response to cigarette smoke. Further evidence for a role for sirtuins in this process comes from Rajendrasozhan et al., in a study that confirms and extends the results of previous work.

The authors show once again that SIRT1 levels are low in the lungs of smokers, and that these levels diminish further in response to cigarette smoke. Smoke-exposed lung cells and macrophages exhibited increased inflammatory signaling (assayed primarily by looking at IL-8), as do cells in which SIRT1 has been artificially knocked out. Consistent with this, the RelA subunit of the master inflammation regulator NF-κB is hyperacetylated — recall that SIRT1 is a deacetylase — and consequently more active. Conversely, overexpression of SIRT1 decreases inflammatory cytokine production, echoing earlier results that described SIRT1 activation by resveratrol treatment.

Thus, a key longevity-assurance gene is also involved in restricting inflammation, which is a risk factor for some of smoking’s worst complications — chronic obstructive pulmonary disease (COPD) — as well as tumorigenesis. Tobacco is a major public health issue, so it’s not surprising that SIRT1 is getting attention in this context, but there is reason to believe that the phenomenon is general to organs other than the lung — e.g., see this review from Salminen et al., which describes how signaling from SIRT1 and FoxO transcription factors (mammalian homologs of the worm longevity gene DAF-16) can inhibit NF-κB signaling in a variety of systems. The authors close the circle by discussing the connection between longevity assurance and the mitigation of one specific age-related phenotype, inflammaging.

COPD is a leading cause of death worldwide, and it arises not only in smokers but in members of their households, as well as people exposed to environmental pollutants. A host of other inflammatory diseases, such as arthritis, beset the elderly and decrease quality of life. Increasing evidence that SIRT1 activity could mitigate the health harms of runaway inflammation point to even more potential uses for the new class of sirtuin-activating drugs that are currently under consideration as therapies against diabetes and metabolic syndrome.

“Inflammaging” (a term we owe to Claudio Franceschi and co-workers) is defined as “a global reduction in the capacity to cope with a variety of stressors and a concomitant progressive increase in proinflammatory status” over the course of the aging process. High levels of inflammatory cytokines in aging tissues have been implicated in immunological dysfunctions and frailty in the very old. What causes this age-related upregulation of inflammation?

From Kim et al., we learn of a connection between two “usual suspects” that might help explain the phenomenon. They propose that NF-kappaB (the no-brainer go-to candidate transcription factor for inflammatory responses) is activated by phosphorylation of FOXO (a key transcription factor in an evolutionarily ancient longevity assurance pathway), which increases with age.

Furthermore, calorie restriction (CR) may protect the animal by decreasing overall levels of insulin (and insulin-like growth factor) signaling: less insulin/IGF means less FOXO phosphorylation, leading to reduced oxidative stress. This in turn reduces nuclear translocation of NF-kappaB and a relative diminution of inflammatory cytokine production.

While the molecular connections between all the moving parts could certainly be bolstered by focused study, I like where this is going: toward a broader integration of formerly disparate aspects of biogerontology. Also note the increased explanatory power of IGF/FOXO, one of the core longevity control pathways — and, for that matter, another gold star for CR, which lately seems like it could use one.