In the magazine Immunity an article with an obscure title was published on October 9, 2026. It was titled “Single-cell analyzes of global cohorts describe determinants of immune aging and link the ratio of GZMK+ to Tem GZMB+ cells to health trajectories.“, which I think is one of the worst titles I have ever seen for, ironically, one of the most important articles in the science of aging. I still don’t understand why authors and journal editors use or allow such obscure titles!
In this edition of Ground Truths, I will reveal the extraordinary work carried out by the team led by Maxim Artyomov. This takes our understanding of how our immune system ages – both healthily and unhealthy – to a new level with practical implications for determining its status and promoting our health.
It turns out to be a story of two cells – different subtypes of memory T cells – that contain distinct types of granules resulting in divergent functions. And above all, major consequences on health.
Some very impressive statistics on who was studied and what was done:
—8 international cohorts, 2,609 individuals, 12,394,834 white blood cells
—aged 18 to 98
-59 types of immune cells resulting from the harmonization of scRNA sequences
The story begins with the thymus, whose involution begins early in life and accelerates after puberty., after which there is a progressive loss of naive T cells and recent thymic emigrants (RTE) with age. This decline was the strongest predictor of chronological age in the study. The problem is not so much the decline of naive T cells, the “newbies,” but what happens, as the immune system adapts, to replace them: the “veterans.”
Until this study, prior cell sorting (flow cytometry) or grouped sequencing methods did not allow differentiation of CD8+ effector memory T lymphocytes. This was only possible by obtaining large-scale single-cell transcriptomes.
The 2 types of veterans are effector memory T cells (Tem) which are primarily K or B granzymes. You may think of B as “bad” because these cells are leaky, exhausted, and spillage of their granules leads to matrix dissolution, tissue disruption, macrophage activation, and inflammation. This profile of terminally differentiated GZMB+ cells was characterized from experiments on mice. Bifurcation (Figure below) is influenced toward GZMB+ by exposure to cytomegalovirus (CMV) and chronic diseases, such as cardiovascular disease (CVD) or metabolic disease (such as type 2 diabetes).
Performing large-scale single-cell RNA sequencing to correlate with clinical findings or to develop a clinically useful blood test is impractical, not to mention expensive. Instead, using the Olink test of thousands of plasma proteins in 4 independent cohorts (of the 8 used in phase 1) percent TemB+ (Tem stands for T effector memory cell) is the best correlation with single cell GZMB+ data (using a LASSO computer model). This protein signature was closely correlated with single-cell RNA sequencing work, as seen below in each of the 4 cohorts.
Note: Throughout this article, please acknowledge the interchangeability of established terms between GZMB+ and TemB+, or GZMK” and TemK+.
Next, TemB+ was validated for its clinical outcomes in the UK Biobank in 48,620 participants with 17 years of follow-up, using both cellular protein data. As you can see below, individuals with high TemB+% had significantly higher all-cause mortality than those with low TemB+% or the average group, categorized into tertiles. The x-axis represents the years of follow-up.
%TemB+ was predictive of several specific health outcomes, as shown below.
Conversely, note the absence of predictive correlation with neurodegenerative diseases and macular degeneration: Alzheimer’s disease, Parkinson’s disease, dementia and age-related macular degeneration.
To highlight the contribution of viral exposure and inflammation, CMV-seropositive individuals had higher GZMB+ and those with higher C-reactive protein had higher %TemB+.
Here is a simplified dichotomy of clinical findings and inflammation based on a high percentage of Tem B+ (or GZMB+).
Of course, there are many limitations. Patients in the multiple cohorts were primarily of European and Asian ancestry, leaving some uncertainty as to whether the results will be extrapolated to those of African ancestry. The window into immune cell aging was only through blood cells and not through tissues. “TemB+ was measured at one time point, so we do not know how it progresses in a person, or whether reducing it changes the risk. It is important to note that the dichotomy between ‘good’ and ‘bad’ TemK+ and TemB+ cells, respectively, is an oversimplification, as we know that K cell granules can also promote inflammation. CD*+ T cell counts were not available in the UK Biobank and therefore had to be imputed with a model. None of this work is about establishing causality. I haven’t gotten into the “weeds” of the report, which is a beast to read and untangle, and there is much more on different cell types, other mouse experimental data, type 2 immunity remodeling, and so on.
This is a seminal paper, the most comprehensive assessment of white blood cells across the human lifespan, tracking immune cell aging and its relationship to survival and multiple adverse health outcomes. Let me summarize the key points:
Primacy of the thymus. The study identified the decline of naive T cells and recent thymic emigrants as the basis of the aging clock, predicting chronological age.
It’s not just that we lose naive T cells during thymus involution, but it’s also about type of cells that replace them. And it turns out that there is a critical bifurcation between TemK+ and TemB+ cells. The difference in the granules of these cells may explain the instigation or enhancement of inflammation. Further characterization of mouse TemB+ cells showed their propensity to leak, become exhausted, and disrupt tissues.
Viral exposure, particularly through CMV blood positivityaffects the bifurcation pathway to promote TemB+ cells. The other main influence on the promotion of TemB+ instead of TemK+ was chronic diseases, particularly cardiovascular and metabolic.
Discovery in work using single cell RNA sequencing in more than 12 million white blood cells from the bifurcation and the link to the results might not have been established with traditional cell sorting, flow cytometry or batch sequencing methodologies. This is another reinforcement of the “granular” nature (no pun intended with granules) when it comes to learning from single-cell data.
A new protein blood test appears from this body of work, the percentage of TemB+, or the ratio of TemB+ to TemK+. This could be considered a main indicator of unfavorable aging of the immune system. This could lead to a simple and inexpensive window into a person’s immune status and the researchers in the current study are indeed pursuing this goal. For people with poor immune status, we know of ways to ameliorate the problem through lifestyle factors and vaccines, and much more will be done in the coming years to find other ways.
Here at the end of 2026, we have no way to assess a person’s immune system in the clinicas I already wrote on “Why we need an immune system. Ironically, we have so many ways to control the immune system, by releasing its brakes (tconsider immune checkpoint inhibitors and ten other classes of interventions) and B cell depletion or “reverse” vaccines to induce tolerance in autoimmune diseases. We can increase it or decrease it, but we can’t measure it!
In recent months, we have seen 2 new practical ways to arrive at this crucial assessment: (1) AI analyzes the thymus from a low-resolution chest CT scan (see “Your thymus and your health”) and (2) Proteomic clocks of the immune system and immune cells (see “Medicine is moving from calendars to clocks”) from a blood test. Both of these immune system assessments are now on their way to commercialization. The current study represents a 3rd avenue. In short, we’re getting there!
NB. I wrote this post. I used AI to generate four of the figures as shown above to help the reader visualize what I was writing about. I have no conflict of interest related to this topic or post.
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