The Durk Pearson & Sandy Shaw®
Life Extension NewsTM
Volume 13 No.
2 • April 2010
Chronic Activation of NF-kappaB, the Master Regulator of Inflammation,
A new paper reports on how NFkappaB signaling plays an important role in aging by its regulatory function in apoptosis, autophagy, and tissue atrophy, and how chronic activation of NF-kappaB can induce senescence.
As reported in paper #1, a meta-analysis of age-related expression profiles of 27 datasets from mice, rats, and humans, the most common age-related genetic signature involved the overexpression of inflammation and immune response genes and also genes associated with the lysosomal system (which breaks down cell garbage, as in autophagy). This combination of age-associated changes is often called inflamm-aging. An earlier study by the authors of paper #1 reported that the DNA-binding capacity of the NFkappaB complex was significantly increased in all old rat and mouse tissues they studied as compared to young rat and mouse tissues. “This age-related constitutive activation of NF-kappaB system has been verified later by several other research groups ...”
“The NFkappaB system is a cytoplasmic sensor in particular in immune attacks but also to a wide array of external and internal danger signals such as oxidative stress, hypoxia, and genotoxic stress.”
Chronic activation NFkappaB is importantly involved in loss of muscle mass as occurs in cachexia and in age-associated muscle loss (sarcopenia). “Recent studies have convincingly demonstrated that the NFkappaB pathway is the major signaling mechanism, which can induce muscle atrophy.” Moreover, NFkappaB signaling potently inhibits autophagy by activating the mTOR/Raptor complex in response to TNFalpha (tumor necrosis factor alpha) and exposure to insulin. Conversely, SIRT1 (induced, for example, by caloric restriction or by resveratrol) and FoxO3, two longevity factors that inhibit NFkappaB signaling, powerfully enhance autophagy. Resveratrol and curcumin also inhibit NFkappaB signaling. As the authors note, it would be harmful to inhibit the entire NFkappaB signaling pathway, as they illustrate with thalidomide, an NFkappaB inhibitor that was associated with severe birth defects. Hence, the safe NFkappaB inhibitors only moderately reduce NFkappaB signaling.
Other natural substances that inhibit NFkappaB expression include, for example, quercetin, lutein, EGCG, cinnamaldehyde (the major constituent of cinnamon bark oil) and alpha lipoic acid. On the other hand, high glycemic index carbohydrate (bread, glucose) were reported to increase NFkappaB activation in mononuclear cells of young, lean healthy subjects.
It is also interesting to note that NFkappaB has been found to be a critical mediator of stress-impaired neurogenesis and depressive behavior, thus linking inflammation in the brain to cognitive and emotion regulation dysfunction. The authors of paper #8 report that these findings are consistent with human studies, which show increased NFkappaB signaling in social stress/anxiety.
- Salminen and Kaarniranta. NF-kappaB signaling in the aging process. J Clin Immunol 29:397-405 (2009).
- Min et al. Quercetin inhibits expression of inflammatory cytokines through attenuation of NF-kappaB and p38 MAPK in HMC-1 human mast cell line. Inflamm Res 56:210-5 (2007).
- Kim et al. The non-provitamin A carotenoid, lutein, inhibits NFkappaB-dependent gene expression. ... Free Radic Biol Med 45:885-96 (2008).
- Giakoustidis et al. Inhibition of intestinal ischemia/reperfusion induced apoptosis and necrosis via down regulation of NFkappaB, c-Jun and caspace-3 expression by epigallocatechin-3-gallate administration. Free Radic Res 42(2):180-8 (2008).
- Kim et al. Suppression of age-related inflammatory NF-kappaB activation by cinnamaldehyde. Biogerontology 8:545-54 (2007).
- Bierhaus et al. Advanced glycation end product-induced activation of NF-kappaB is suppressed by alpha-lipoic acid in cultured endothelial cells. Diabetes 46:1481-90 (1997).
- Dickinson et al. High-glycemic index carbohydrate increases nuclear factor-kappaB activation in mononuclear cells of young, lean healthy subjects. Am J Clin Nutr 87:1188-93 (2008).
- Koo et al. Nuclear factor-kappaB is a critical mediator of stress-impaired neurogenesis and depressive behavior (study done in rats). Proc Natl Acad Sci USA 107(6):2669-74 (2010).