Durk Pearson & Sandy Shaw’s®
Life Extension NewsTM
Volume 14 No. 5 • November 2011

Centenarians Have Preserved Immune Functions But a Lower Expression of Genes Inducing Inflammation

Yet more evidence emerges supporting the hypothesis that excess inflammatory gene activity is a major causative factor in aging.

While inflammatory pathways are a critical part of immune function, adequate regulatory control to prevent excessive inflammation is important in the prevention of chronic inflammation-associated diseases such as atherosclerosis and diabetes. Recent studies indicate that human centenarians are able to maintain immune function while avoiding excessive inflammatory activity.1 In fact, “older humans and mice show higher levels of inflammation and oxidative stress in their leukocytes [white blood cells], coincident with the impaired immune responses.”1

A recent paper1 investigated the relationship between preserved immune functions and controlled oxidative stress in successful aging using a natural long-lived mouse model. NF-kappaB (nuclear factor kappa B) is an important mediator of the effects of inflammation and oxidative stress on immune function. The activity of this factor is increased in many chronic inflammatory diseases, including multiple sclerosis and sepsis. It is also reported to be downregulated by glutathione precursors such as N-acetylcysteine, which can prevent excessive oxidative stress and inflammation in animal models. However, these authors wanted to look at specific models of long-lived animals (animals living naturally long periods of time as compared to others of their species, analogously to human centenarians) to assess the degree of NF-kappaB activity in leukocytes in old individuals. They chose to look at Mus musculus, a type of mouse that can be extremely long lived (for a mouse), with 7–10% of the females reaching 125 ± 4 weeks of age.

A recent paper2 reviewed the effects of NF-kappaB signaling in the aging process. Here, the authors explain that chronic activation of NF-kappaB signaling “has the capacity to induce the senescent phenotype associated with aging. Interestingly, several longevity genes such as SIRT1, SIRT6, and FoxOs can clearly suppress NF-kappaB signaling and in this way delay the aging process and extend lifespan.”2 Of particular interest, they report that “… de Magalhaes et al [see ref 3] performed a meta-analysis of age-related expression profiles of 27 datasets from mice, rats, and humans. The most common age­related genetic signature involved the overexpression of inflammation and immune response genes and also the genes linked to the function of lysosomal system. This indicates that the entropy [disorganization] related to aging process activates the innate immunity system. This process is called inflammaging … .” The NF-kappaB system responds, not only to immune attacks, but to other signals such as oxidative stress, hypoxia, and genotoxic stress.2 Not unsurprisingly, caloric restriction studies in organisms ranging from yeast to mammals can prevent the appearance of the age-related proinflammatory gene expression profile.4

The response of the lymphocytes to stimulation by the T-cell mitogen Con A was preserved in the extreme long-lived as compared with adults, whereas old animals had a significantly decreased response.1 Phagocytosis, an important function of macrophages, was reduced in old and very old animals as compared to adults. However, the peritoneal macrophages from the extreme long-lived animals had intact phagocytic function.

Importantly, the levels of GSSG (oxidized form of glutathione) in peritoneal leukocytes from old animals was increased compared to adult levels, but there was no such increase in the extreme long-lived animals, indicating that they had superior antioxidative capacities.1

“The results show a low level of basal NF-kappaB activation in cells from adult and extreme long-lived animals. However, leukocytes from both old and very old animals showed greater activation of NF-kappaB compared with the adult animals, suggesting chronic activation of this transcription factor in resting leukocytes with aging, but not in those animals that achieved extreme old age.” “… persistent high NF-kappaB activation in basal conditions could be deleterious and has been related to a wide range of aging-related diseases, such as atherosclerosis.”1,10

Most of the mice, however, never made it to extreme old age just as few people live to 100 and beyond. “… only 1 of 10 individuals analyzed from the old and very old age groups ultimately achieved extreme longevity (138 and 132 weeks, respectively), and interestingly these two mice were the ones showing controlled NF-kappaB activation in their leukocytes.” “Importantly, extreme long-lived mice maintained their NK [natural killer] cytotoxic activity, a finding also reported for human centenarians.”

One recent paper5 suggests that, inhibition of NF-kappaB, activated in influenza-infected lung epithelial cells and playing a key role in the inflammatory response to influenza infections, could be part of a practical strategy to improve survival during flu epidemics. One way that NF-kappaB increases inflammatory activity is to promote the transcription of a number of proinflammatory cytokines.3

NF-kappaB as a Mediator of Stress

Finally, it is interesting to note that NF-kappaB is identified as a “critical mediator of stress-impaired neurogenesis and depressive behavior.”5b Hence, it may be particularly helpful during these stressful times to take supplements that inhibit NF-kappaB signaling.

Modulation of NF-kappaB Levels with Supplements

Supplements that have been reported to inhibit NF-kappaB include metabolites of omega-3 fatty acids (called resolvins and protectins).6 quercetin,7 EGCG,8 the amino acid cysteine,9 and others.


1. Arranz et al. Preserved immune functions and controlled leukocyte oxidative stress in naturally long-lived mice: possible role of nuclear factor kappa B. J Gerontol A Biol Sci Med Sci 65A(9):941-50 (2010).
2. Salminen and Kaarniranta. NF-kappaB signaling in the aging process. J Clin Immunol 29:397-405 (2009).
3. De Magalhaes et al. Meta-analysis of age-related gene expression profiles identifies common signatures of aging. Bioinformatics 25:875-81 (2009) doi:10.1093/bioinformatics/btp073.
4. Weindruch et al. Microarray profiling of gene expression in aging and its alteration by caloric restriction in mice. J Nutr 131:918S-23S (2001).
5. McCarty et al. Practical strategies for targeting NFkappaB and NADPH oxidase may improve survival during lethal influenza epidemics. Med Hypotheses 74:18-20 (2010).
5b. Koo et al. Nuclear factor-kappaB is a critical mediator of stress-impaired neurogenesis and depressive behavior. Proc Natl Acad Sci USA 107(6):2669-74 (2010).
6. Kaarniranta and Salminen. NF-kappaB signaling as a putative target for w-3 metabolites in the prevention of age-related macular degeneration (AMD). Exp Gerontol 44:685-8 (2009).
7. Min et al. Quercetin inhibits expression of inflammatory cytokines through attenuation of NFkappaB and p38 MAPK in HMC-1 human mast cell line. Inflamm Res 56:210-5 (2007).
8. Giakoustidis et al. Inhibition of intestinal ishemia/reperfusion induced apoptosis and necrosis via down-regulation of the NF-kappaB, c-Jun, and caspace-3 expression by epigallocatechin-3-gallate administration. Free Radic Res 42(2):180-8 (2008).
9. Mihm et al. Inhibition of HIV-1 replication and NF-kappaB activity by cysteine and cysteine derivatives. AIDS 5:497-503 (1991).
10. Spencer et al. Constitutive activation of NF-kappaB in an animal model of aging. Int Immunol 9(10):1581-8 (1997).

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