The Aged Adaptive Immune System is Strange
The adaptive immune system of an older person is a very different beast in comparison to that of the younger self. It has lost the supply of new T cells due to atrophy of the thymus, and the remaining population of T cells becomes ever more damaged, misconfigured, strange, and different. The immune system as a whole is complex enough to still be hiding many unexplored details, even in this era of biotechnology. Here, researchers outline a novel discovery in the immune function of supercentenarians. It seems that at very advanced ages, some T cells start to undertake radical shifts in function in order to compensate somewhat for the growing lack of capacity. It remains to be seen whether or not this only occurs to a significant degree in a minority of the population, and is thus a feature of supercentenarians because it increases the odds of survival.
Supercentenarians, people who have reached 110 years of age, are a great model of healthy aging. Their characteristics of delayed onset of age-related diseases and compression of morbidity imply that their immune system remains functional. Here we performed single-cell transcriptome analysis of 61,202 peripheral blood mononuclear cells (PBMCs), derived from 7 supercentenarians and 5 younger controls. We identified a marked increase of cytotoxic CD4 T cells as a signature of supercentenarians. This characteristic is very unique to supercentenarians, because generally CD4 T cells have helper, but not cytotoxic, functions under physiological conditions. Furthermore, single-cell T cell receptor sequencing of two supercentenarians revealed that cytotoxic CD4 T cells had accumulated through massive clonal expansion, with the most frequent clonotypes accounting for 15-35% of the entire CD4 T cell population.
The cytotoxic CD4 T cells exhibited substantial heterogeneity in their degree of cytotoxicity as well as a nearly identical transcriptome to that of cytotoxic CD8 T cells. This indicates that cytotoxic CD4 T cells utilize the transcriptional program of the CD8 lineage while retaining CD4 expression. Indeed, cytotoxic CD4 T cells extracted from supercentenarians produced IFN-γ and TNF-α upon ex vivo stimulation. Our study reveals that supercentenarians have unique characteristics in their circulating lymphocytes, which may represent an essential adaptation to achieve exceptional longevity by sustaining immune responses to infections and diseases.
Hi there! Just a 2 cents,
''Indeed, cytotoxic CD4 T cells extracted from supercentenarians produced IFN-γ and TNF-α upon ex vivo stimulation.''
My take is that supercentenarians have a heightened response compare to old seniors that are younger than them (but in a less healthy state), which means a preserved immunity. Because, oftenly, older seniors (in the 80-90 years old bracket) die of immunity related diseases/viral diseases (oftenly, after a short bout of infectious/bacterial disease). At that age, the immune system is just much sluggish to combat the pathogens/cancer cells. This was shown in a woman of 115 years old with small telomeres in her leukocytes WBC; meaning she was at the end of immunity (immunosenescence due to short telomeres causing instability of the immunity/reaching its hayflick); but she had toughed to 115...which is not nothing. This means she was (mostly) in good health and had preserved in immune system all this time. While, other elders, die younger of immune related disease (or complications..from the diseases, not necessarily, directly, from the diseases itself). This also means she had higher telomerase Activity or lower oxidative stress (by maintaining immune redox; immune cells rely on the redox and telomerase). It is interesting that the supercentenarians' cells are very active; demonstrating that the 'load' of viral/bacterial diseases rises with age as the immune system weakens (with age too); but, that, in their cells; they compensate and are still very active (even if supercentenarian); thus, they are behave more like Younger immune systems (of Young adults...not elders); even though they are supercentenarians. If they were compromised, they wouldn't produce INF/TNF; INF/TNF are causal to inflammation yet are important for immunity (to destroy cancer/bacteria/pathogens), because they help to produce ROS (that destroy such invaders); but we all know ROS are a double-edged sword. Signaletic yet Oxidative; a carefully made balance (like everything else in the body)). Thus, ROS/INF/TNF must be dosed and for specific tasks (like Controlled immunity), in that case are good; otherwise, it is Uncontrolled immunity and causes Chronic Inflammation/oxidative stress (from the immune system/INF/TNF (tumore necrosis factor is to destroy cancers/suppress tumors - it does so via ROS, while cancers strive from chronic inflammation but not the point of Killing them (for ROS kill tumors - at a certain point/certain emission; but medium-ROS is perfect environment for tumors; just enough chaos to strive but not too much to end them either (cancers highjack telomerase and the redox (they turn it to their favor/using GSH as a quenchingshield for them against ROS) to 'overcome' ROS blast from the immune system INF/TNF-a/WBC); leading to the diseases (thus a vicious circle/a balance) in the first place. It's why therapies that have boosted ROS (via chemotherapy or radiation) have had effect (albeit, not always, because tumors can find workarounds (ALT) and overporuction of ROS destroys the healthy tissues) by increasing ROS production directly in the tumor to kill it/must be centered in it only to spare the healthy surrounding cells (this is done by the immune system (including NK-cells/T-cells/macrophages)).
Just a 2 cents.