Centenarians Better Regulate the Chronic Inflammation of Aging

People who reach extreme old age do so because they managed to be less damaged and dysfunctional at every age than their now deceased peers. Why is this the case? A great deal of effort is devoted to answering that question, and I have mixed feelings on whether it is all that useful as a focus for the research community. For example, if genetic variants explain some of the survival of centenarians, then they don't have to be all that good. All it takes is a few percentage points of lowered mortality risk year after year provided by a given variant, and people at very advanced ages will largely have that variant. But a few percentage points are not worth chasing with large-scale investment into the development of drugs that mimic the effects of that variant.

More interesting is whether or not centenarian biochemistry confirms the importance of aspects of aging thought to be influential on mortality, such as the chronic inflammation that is characteristic of old age. The immune system runs down in later life, and a part of that dysfunction is the unresolved, harmful inflammation that is provoked by the signaling of senescent cells, by the DNA debris present in aged tissues, and by other, similar issues. The burden of inflammation varies widely by lifestyle choice and other less well explored characteristics of the individual. In today's open access paper, researchers discuss the evidence for centenarians to exhibit an immune system configuration that acts to suppress inflammation. Why this configuration arises in some people and not others is an open question.

Centenarians Alleviate Inflammaging by Changing the Ratio and Secretory Phenotypes of T Helper 17 and Regulatory T Cells

Inflammaging is suggested to be one of the major contributory factors leading to the increased morbidity and mortality of older adults; however, the inflammaging status, especially the subsets of CD4+ T cells in centenarians is not clearly understood. Herein, it was found that centenarians had unique levels of inflammatory cytokines and reduced Th17/Treg levels. CD4+ T cells in centenarians tended to differentiate into pro-inflammatory cells with decreased secretory function. These results suggested the presence of a mechanism in centenarians that alleviated inflammaging. This may be through the reversal of the imbalance of Th17/Treg cells and the reduction of pro-inflammatory cytokines.

Associated with immune dysregulation, inflammaging has been attributed to a combination of age-related defects. One of the most evident characteristics of inflammaging is high blood levels of pro-inflammatory mediators, including CRP, TGF-β, TNF-α, IFN-γ, IL-1, and IL-6, in the absence of evident triggers. The levels of these pro-inflammatory mediators have an important relationship with the processes of longevity and aging-related diseases and are positively correlated with mortality. In this study, we detected the levels of inflammation-related factors in the plasma of centenarians and demonstrated that many pro-inflammatory factors, namely, CRP, IL-12, TNF-α, IFN-γ, and IL-6, were elevated in centenarians. Intriguingly, other proinflammatory cytokines, such as IL-17A, IL-1β, and IL-23, were reduced in centenarians. This evidence suggested that centenarians partly alleviated inflammaging by affecting the secretion of these cytokines.

In vitro T cell cultures from different ages provided controversial results. We found that naive T cells of centenarians tended to differentiate into Th17 cells instead of Tregs, which was demonstrated in previous studies. Studies have shown that naive CD4+ T cells from aged animals differentiate into Th17 effectors more readily than T cells from young animals. This tendency of Th17 polarization seems to be an inherent characteristic of naive CD4+ T cells from older individuals. Furthermore, we demonstrated that they secreted fewer proinflammatory cytokines and relatively more anti-inflammatory cytokines. This was consistent with previous studies, and this phenomenon may be associated with altered metabolic activity.

Previous studies have found that CD4+ T cells in centenarians have a senescent pro-inflammatory phenotype. This study showed that centenarians had very specific changes in CD4+ T cell populations, which were manifested by an elevated Th17/Treg ratio in vivo, as well as a changed secretory phenotype. Although the T cells of centenarians cannot resist the aging-related expression of proinflammatory genes, their secretory phenotype was altered, explaining the relatively low level of inflammation in centenarians. These results suggested the presence of a mechanism to ameliorate inflammaging in centenarians. This may be achieved by reversing the imbalance of Th17/Treg cells and reducing pro-inflammatory cytokines.

Comment Submission

Post a comment; thoughtful, considered opinions are valued. New comments can be edited for a few minutes following submission. Comments incorporating ad hominem attacks, advertising, and other forms of inappropriate behavior are likely to be deleted.

Note that there is a comment feed for those who like to keep up with conversations.