Researchers publishing in Aging have used Mendelian randomization to conclude that the inflammatory factor IL6 causes increased mortality and that its circulating receptor, IL6R, decreases it.
Looking for a proof of danger
Chronic, age-related inflammation (inflammaging) is very well-known to be closely connected to negative age-related outcomes, to the point that it has been addressed by the Hallmarks of Aging authors [1]. However, as these researchers note, proving causation in this case is particularly difficult; inflammation often comes with a large variety of confounding factors, and reverse causation must also be ruled out [2].
To accomplish that, the researchers turned to Mendelian randomization, a technique that uses large genomic datasets derived from very large groups of people, to discover the effects of various conditions in a way that is far less prone to confounding and reverse causation. They chose the well-studied inflammatory factor IL6, along with its soluble receptor IL6R, which leads this inflammatory factor down a different and possibly contradictory pathway [3].
Ruling out other factors
This study found that increases in IL6R cause increased longevity and protected against a variety of conditions. While Alzheimer’s and kidney diseases were unaffected, increases in IL6R were found to be protective against lung cancer, diabetes, stroke, and coronary artery disease. People with more circulating IL6R had less all-cause mortality.
Similarly, increases in IL6 were found to cause more overall mortality, and genetic propensities for the various conditions that cause mortality, such as heart disease, were not connected to this increase in IL6, meaning that reverse causality was not a factor. C-reactive protein and GDF15, two other inflammation-related compounds frequently studied in aging, were not found to have any effects.
The researchers noted that, because very few genes are associated with increased inflammation, they had to use only those genes that were very significantly and strongly associated in order to avoid creating data from weak instruments. Additionally, by using repeated leave-one-out analyses, the researchers made sure that the associations that they discovered stood on their own. None of the individual genes responsible for the IL6 increase was found to be the cause; instead, the cause was, indeed, the increased IL6.
A cardiovascular focus
The researchers noted that most of the causes of increased mortality linked to IL6 were cardiovascular in nature. They note that IL6R is not abundant in the walls of blood vessels or heart tissue, and therefore, increases in this anti-inflammatory factor throughout the bloodstream bring it to where it is needed. By binding to and taking away IL6, the researchers reason, IL6R prevents this inflammatory compound from worsening various cardiovascular conditions, such as thrombosis and dysfunction of the endothelium, providing a “clear mechanistic pathway” for its beneficial effects.
The researchers sum up their findings simply: “Taken together, the results of the current mendelian randomization study strengthen the rationale for IL6R antagonism as a potential strategy to reduce cardiovascular disease and associated mortality.” Fortunately, an IL6R antagonist already exists in the clinic: tocilizumab is already approved by the FDA and has been found to reduce mortality in both the contexts of COVID-19 [4] and giant cell arteritis [5].
However, this approach still needs to be examined carefully. Experiments will need to be performed in animals and people to determine if artificially increasing circulating IL6R through tocilizumab or other methods is a viable method of reducing overall cardiovascular disease risk.
Literature
[1] López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2023). Hallmarks of aging: An expanding universe. Cell, 186(2), 243-278.
[2] Emerging Risk Factors Collaboration. (2010). C-reactive protein concentration and risk of coronary heart disease, stroke, and mortality: an individual participant meta-analysis. The Lancet, 375(9709), 132-140.
[3] Interleukin-6 Receptor Mendelian Randomisation Analysis (IL6R MR) Consortium. (2012). The interleukin-6 receptor as a target for prevention of coronary heart disease: a mendelian randomisation analysis. The Lancet, 379(9822), 1214-1224.
[4] Rosas, I. O., Bräu, N., Waters, M., Go, R. C., Hunter, B. D., Bhagani, S., … & Malhotra, A. (2021). Tocilizumab in hospitalized patients with severe Covid-19 pneumonia. New England Journal of Medicine, 384(16), 1503-1516.
[5] Stone, J. H., Tuckwell, K., Dimonaco, S., Klearman, M., Aringer, M., Blockmans, D., … & Collinson, N. (2017). Trial of tocilizumab in giant-cell arteritis. New England Journal of Medicine, 377(4), 317-328.
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