Nonuniversality of inflammaging across human populations[?]

That is the title of a recent Nature Aging article (the question mark is my addition) led by teams from the University of Sherbrooke and Columbia University reporting on their analysis of biomarkers of inflammation vs. age in 4 different populations, 2 they describe as “industrialized” (IPs) and 2 as “non-industrialized” (NIPs). In a nutshell, the study found that cytokine signatures are markedly different between IPs and NIPs. Inflammatory markers in IPs were consistent with the “inflammaging” model, increasing with age and associated with the usual chronic diseases of aging (blood pressure, diabetes, etc.). In NIPs, the measured biomarkers of inflammation, unfortunately a small subset of the ones measured in IPs, behaved very differently, showing very little correlation with age and no association with the usual chronic diseases.

That’s the interesting part: although there is a constant level of inflammation in NIPs, it is not the same “type” as in IPs, leading the authors to conclude (or very strongly suggest) that inflammaging is not universal across human populations. One hypothesis they put forward is that sources of inflammation are different: differences in the “exposomes”, e.g., environment and diets, lead to different inflammatory markers. For example, an “industrialized” diet leads to typical inflammaging and its attending chronic diseases, while NIPs are constantly exposed to infections that trigger a different type of immune response.

For anyone interested in chronic low-grade inflammation, that is an intriguing result, one that questions inflammaging as a universal correlate, or hallmark, of aging.

I beg to differ.

There are a lot of caveats that come with the study.

One is the very small set of markers of inflammation measured in the NIPs, which restricts the comparison to a tiny set of overlapping markers. The authors do recognize the need to standardize the measurements and to include, for example, the inflammation clock biomarker CXCL9.

The second is the dramatic differences in the age distributions of the populations: for example, 67.8±15.9 yrs in one of the IPs compared to 40.6±15.2 in one of the NIPs. Confidence intervals would have been useful when comparing the rate of change of the “inflammaging factor score”, as one would not expect a lot of 80 yr-olds in the NIP with an average age of 40.6.

Which leads to another question: are there enough “old” participants in the NIPs to draw conclusions about inflammaging? And what are the main causes of mortality in the NIPs?

In conclusion, the article presents some intriguing but limited evidence that the long-term dynamics of inflammation does not have a unique signature and may be driven by the exposome more than by age itself. I would argue that even in our industrialized world, inflammaging is the result of a constant pressure on our immune systems, which over time leads to chronic age-related diseases: it is not that age is the driver so much as the accumulation over time of a low grade immune challenge, damaging both the immune system and multiple organs.