How Inflammaging Is Linked to Epigenetic Aging

A paper in Cell Genomics has described how age-related systemic inflammation (inflammaging) is related to epigenetic aging as measured by four established clocks.

Tying together two well-known aspects of aging

Chronic Inflammation

Chronic inflammation refers to a persistent, low-grade buzz of immune activity that settles into the body without the drama of an infection or obvious injury. In the world of aging, this slow, smoldering fire is often called inflammaging, a term coined by Claudio Franceschi to capture the systemic, hard-to-detect inflammation that creeps in with advancing years.
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These researchers note that inflammatory problems have been repeatedly linked to aging, both in inflammaging and in the immune system’s failure to properly respond to threats (immunosenescence). Very often in older people, chronic inflammation is linked to internal factors that have no link to pathology; however, these researchers cite one study that noted the downstream benefits of eliminating hepatitis C, finding that it had beneficial effects on epigenetic aging [1].

Epigenetic Alterations

Epigenetic alterations are age-related changes in gene expression that harm the fundamental functions of cells and increase the risk of cancer and other age-related diseases. One of the proposed reasons we age is the changes to gene expression that our cells experience as we get older; these are commonly called epigenetic alterations. These alterations harm the fundamental functions of our cells and can increase the risk of cancer and other age-related diseases.
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The authors of this study decided to investigate this relationship further, looking into the relationship between inflammaging and epigenetic aging as measured by four established clocks: Horvath and Hannum, which are based on chronological age; PhenoAge, a clock that is more closely tied to healthspan; and GrimAge, another healthspan-based clock that is a strong predictor of all-cause mortality. The researchers also included the versions of these clocks that measure the rate of increase (epigenetic aging acceleration, EAA).

A morbid link

For their first analysis, the researchers used data from the BCG-PRIME cohort, whose participants had at least one comorbidity known to worsen length or quality of life. Frailty was one of these comorbidities, and unsurprisingly, frailty was linked to every clock except the EAA_Hannum and EAA_Horvath clocks. Frailty appeared to be even more strongly linked to GrimAge than to chronological age.

Similar results were found in a multimorbidity analysis. Unsurprisingly, the number of various morbidities was strongly linked to GrimAge, although there were significant results among the other clocks. These results were maintained even after adjusting for smoking, which is known to cause both epigenetic damage and COPD, one of the morbidities that was also strongly linked to GrimAge.

The researchers then went to the heart of their study. They performed an analysis that compared these four clocks and their EAA versions to 64 inflammatory biomarkers that were considered to be measurable enough by a quality control analysis. While the EAA versions of Hannum and Horvath failed to have any significant connections, both of their regular versions showed associations with many of these proteins.

GrimAge and PhenoAge had stronger connections. Many CCLs, members of an inflammatory cytokine family of proteins, were associated with these clocks and their EAA variants. Hepatocyte growth factor (HGF) was another hit, as was another well-known inflammatory factor, tumor necrosis factor (TNF), which was more strongly associated with these clocks than with chronological age.

CXCL9 causes faster epigenetic aging

The strongest relationship was between GrimAge and CXCL9, a chemokine with well-established links to inflammation, and a link to age acceleration was found as well. Using a Mendelian randomization analysis, this link was found to be causal: people with more circulating CXCL9 were found to be epigenetically older, and epigenetically aging more quickly, than people with less. This causal link was also established for PhenoAge. Even after multiple statistical correction methods, this association persisted, and both TNF and CXCL10 were found to be casually associated with faster aging according to EAA_GrimAge.

Similarly, these inflammatory factors were found to be linked with multimorbidity, leading the authors to conclude that inflammaging indeed is a driver of age-related diseases.

The researchers then broke their results down by sex. Men and women had very few differences, none of which reached statistical significance. The effects of CXCL9, in particular, appeared to be completely unaffected by sex.

Their next experiment involved testing cells derived from the 500FG and BCG-PRIME cohorts against well-known pathogens. Unsurprisingly, cells that were epigenetically older according to the various clocks did not perform as well against these attacks; despite having more overall inflammation, they failed to properly respond to genuine threats with IFN-γ and IL-22.

This study was only an association study that investigated causal links through statistical methods. While the researchers noted that the strongest hits were related to the interferon pathway (IFN) and that this pathway has been previously linked to stem cell aging [2], this research did not involve any investigation into the mechanisms of action. Future work will need to determine why CXCL9 and related proteins increase with age and if anything can be done to halt this increase.

Literature

[1] Oltmanns, C., Liu, Z., Mischke, J., Tauwaldt, J., Mekonnen, Y. A., Urbanek-Quaing, M., … & Cornberg, M. (2023). Reverse inflammaging: long-term effects of HCV cure on biological age. Journal of hepatology, 78(1), 90-98.

[2] Demerdash, Y., Kain, B., Essers, M. A., & King, K. Y. (2021). Yin and Yang: The dual effects of interferons on hematopoiesis. Experimental hematology, 96, 1-12.