Aging, Immunity, and the Final Chapter

New study demonstrated an association between individual immune cell subsets and mortality in a nationally representative sample of older adults (> 55 years) in the United States. Adaptive immune subsets (total T cells), innate subsets (NK cells (CD56LO) and neutrophils) were associated with 4-year mortality even after adjustment for biological age and chronic subclinical inflammation.

An increase in the percentage of total T cells, certain CD4+ T cells (called Tn), and a specific subset of natural killer cells (NK LO) was linked to a reduced risk of death.

Another type of immune cell subset (DC-M) showed a potential decrease in mortality risk, but this finding wasn't statistically significant.

On the other hand, an increase in CD4+ Tem cells, IgD- Mem B cells, and neutrophils was associated with an increased risk of death.

After adjusting for multiple comparisons, the associations that remained statistically significant were total T cells, NK LO cells, and neutrophils.

NK LO cells are the first line of defense, always vigilant against invaders. With their high cytotoxicity, they act like skilled archers on the castle walls, vigilant and precise, distinguishing friend from foe and protecting the kingdom from harm. Neutrophils, on the other hand, are like swift-footed messengers in the kingdom. Quick to respond, they rush to the scene when danger approaches. Unfortunately, they may be a bit inflammatory, although their sheer numbers and speed make them essential foot soldiers, standing ready to counter any threat to the castle. 

The Jedi T cells play a crucial role in orchestrating the immune response. While CD4+ T cells (Tn) are like novice Jedi Masters, in the early stages of their magical training, CD4+ Tem cells are like battle-ready warriors that have completed extensive training wielding their weapons to fend off enemies. Tn may take a bit longer to mobilize and coordinate the defense, but Tem, with their battle-hardened skills and memory, can swiftly engage in the magical skirmish. Yet, Tn are adaptable to new challenges, while Tem are specialists, excelling in scenarios they've encountered before. IgD- Mem B cells are akin to resilient defenders armed with magical shields. These memory B cells with reduced clonal expansion ensure the castle's protection but may pose some challenges. 

Several previous studies have shown a positive association between neutrophils and mortality and the new study confirmed these previous findings. The number of neutrophils are preserved in older adults though their phagocytic ability is impaired. Since neutrophils are pro-inflammatory, higher numbers of neutrophils in older adults may increase the odds of mortality. NK cells cytotoxicity and IFN-γ production decreases in old age, and low cytotoxicity is associated with increased morbidity and mortality. NK LO cells have significantly higher cytotoxicity than NK Hi cells. The absolute count of T cells decreases with age, and this decrease especially affects naïve subset (Tn). This alters the T cell repertoire, compromising their ability to mediate effective immune responses, and thus increasing the odds of mortality. A higher percentage of myeloid subset of dendritic is also associated with reduced mortality. As B cell senescence is characterized by increase in apoptotic resistant memory B cells with reduced clonal expansion that leads to impaired antibody functioning and decreased opsonizing capabilities, the direction of association in the new study is consistent with a previous study that showed that memory B cells were positively associated with cardiovascular mortality.

Systemic chronic inflammation contributes to a wide range of age-related health conditions such as ischemic heart disease, stroke, and cancer that remain the predominant causes of age-related morbidity and mortality. Though canonical markers of inflammation (IL-6, TNF-α, and CRP) have previously been shown to be associated with higher mortality in supercentenarians and COVID-19 patients, there is an intricate interplay between immune cells and cytokine secretion. Other functions of immune cells independent of their ability to secrete various cytokines may be important mechanisms through which immunosenescence affects mortality odds. The new findings indicate that the association between immune cell distribution and mortality is not influenced by biological aging, co-morbidities, and age-related inflammation. A major strength of this study was the adjustment for covariates including a multi-dimensional aging construct (KDM-BA), co-morbidities, and inflammatory biomarkers. A major limitation of this study is the short follow up time. Another limitation was that only all-cause mortality was evaluated. 


Seshadri G, Vivek S, Prizment A, Crimmins EM, Klopack ET, Faul J, Guan W, Meier HCS, Thyagarajan B. Immune cells are associated with mortality: the Health and Retirement Study. Front Immunol. 2023 Oct 20;14:1280144. doi: 10.3389/fimmu.2023.1280144. PMID: 37928548; PMCID: PMC10623116.


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