Inflammation as a Biomarker of Mortality

Inflammation and epigenetics may lead to mortality in different ways.


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In a paper published in Geroscience, researchers have developed a metric of systemic inflammation and used it to estimate mortality, finding that it performs better than epigenetic clocks.

Evaluating a danger

This paper begins with familiar discussions about inflammaging and epigenetic clocks, tools that use DNA methylation to estimate biological age. These clocks are also used to measure age acceleration: the difference between biological and chronological age [1].

These researchers note that while immune cells are used for both epigenetic and inflammatory clocks, only a small number of studies have evaluated this connection [2]. Some of this previous research has shown that the two are largely independent [3]. This work builds upon its predecessors with an attempt at building a latent variable built upon known inflammatory biomarkers.

Latent variables and their analysis

After curation, this study used data from 3,311 participants in the Health and Retirement Study, a sample of people from across the United States. All participants were at least 50 years old.


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A latent variable is one that cannot be directly observed but has observable effects. In this case, that variable is systemic inflammation as a whole, which was combined from analyzing C-reactive protein (CRP), three different interleukins, tumor necrosis factor (TNF), insulin growth factor (IGF-1), and the neutrophil-to-lymphocyte ratio.

The researchers mathematically determined the relationships of these biomarkers to the latent inflammation variable. The relationships were not linear, and in the case of IGF-1, it was inverse: more IGF-1 was correlated with less inflammation.

A great many covariates were included in this study, including such standards as age, sex, and ethnicity along with cytomegalovirus (CMV) infection, alcoholism, obesity, and smoking. Multimorbidity, which was defined as having at least two of eight known risk factors, was also included.

This analysis compared systemic inflammation to several age acceleration measurements gleaned from epigenetic clocks, including GrimAge, Hannum, Levine, the Methylation Pace of Aging (MPOA, based on a Dunedin clock), and the original Horvath clock.

Significant correlations

Even after adjustment for all of the various comorbidities, inflammaging was found to be heavily correlated with 4-year mortality risk and significantly correlated with multiple epigenetic clocks. While a couple of lesser-known clocks were not correlated, and the magnitude of the associations was not particularly strong, GrimAge, MPOA, and many others were found to be significantly associated, and the power of this expansive cohort resulted in small p-values. The researchers note that their inflammation variable has stronger associations with clocks that are more geared towards mortality than chronological age.


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However, the most crucial finding from this study was that systemic inflammation is more strongly correlated with mortality than any of the epigenetic clocks are. In accordance with previous research [3], the authors hold that inflammation and epigenetic aging may represent independent processes that lead to mortality. Of course, this is only an association study, and in this paper, the authors did not attempt any biological understanding of the underlying processes.

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[1] Levine, M. E., Lu, A. T., Quach, A., Chen, B. H., Assimes, T. L., Bandinelli, S., … & Horvath, S. (2018). An epigenetic biomarker of aging for lifespan and healthspan. Aging (albany NY), 10(4), 573.

[2] Irvin, M. R., Aslibekyan, S., Do, A., Zhi, D., Hidalgo, B., Claas, S. A., … & Arnett, D. K. (2018). Metabolic and inflammatory biomarkers are associated with epigenetic aging acceleration estimates in the GOLDN study. Clinical epigenetics, 10, 1-9.

[3] Cribb, L., Hodge, A. M., Yu, C., Li, S. X., English, D. R., Makalic, E., … & Dugué, P. A. (2022). Inflammation and epigenetic aging are largely independent markers of biological aging and mortality. The Journals of Gerontology: Series A, 77(12), 2378-2386.

About the author
Josh Conway

Josh Conway

Josh is a professional editor and is responsible for editing our articles before they become available to the public as well as moderating our Discord server. He is also a programmer, long-time supporter of anti-aging medicine, and avid player of the strange game called “real life.” Living in the center of the northern prairie, Josh enjoys long bike rides before the blizzards hit.