When immunity starts to harm. Inflammaging, CXCL9, and faster biological aging

May 20, 2026

A new study links chronic inflammation, the interferon pathway, and selected epigenetic clocks with faster biological aging and multimorbidity.

When immunity starts to harm. Inflammaging, CXCL9, and faster biological aging

Why this study matters

The aging of the immune system has a paradoxical nature. On one hand, the body often maintains a low-grade, chronic inflammatory state. On the other hand, immune cells may become less effective when a real pathogen appears. This state is often described as inflammaging — the inflammatory background of aging.

A new paper published in Cell Genomics connects this process with epigenetic aging, measured using several established biological clocks. One signal stands out in particular: CXCL9, a protein linked to the interferon pathway and inflammatory immune responses.

The key point is not that “inflammation is bad.” The more important message is more precise: specific patterns of chronic immune activation may be linked to faster biological aging, multimorbidity, and weaker immune cell function.

Study details

Publication title: Interferon-related inflammaging links epigenetic age acceleration to multimorbidity.
Authors: Zhaoli Liu, Athanasios Ziogas, Yihan Zhang, Manoj Kumar Gupta, Konstantin Föhse, Esther Taks, Elisabeth Dulfer, Andrei Sarlea, Lorenzo Ventriglia, Büsra Geckin, Mohamad Ballan, Nienke van Unen, Leonie Helder, Stephanie Trittel, Peggy Riese, Simone Moorlag, Charlotte de Bree, Valerie Koeken, Vera Mourits, Martin Jaeger, Frank Pessler, Carlos A. Guzmán, Leo A. B. Joosten, Yang Li, Cheng-Jian Xu, Mihai G. Netea.
Publication date: April 17, 2026.
Journal: Cell Genomics.
Identifiers: DOI: 10.1016/j.xgen.2026.101218; PMID: 41999740.
Links: full publication in Cell Genomics, PubMed, publication summary by ImmunoSensation.
Study type and design: an analysis of the relationship between the inflammatory proteome, epigenetic clocks, multimorbidity, and immune cell responses; the authors also used Mendelian randomization to assess potential causal links.
Population and sample: data came from four independent cohorts including people of different ages and health status.
Exposure: circulating inflammatory proteins, especially those related to the interferon pathway, including CXCL9, CXCL10, CCL11, and IL-18.
Main outcome: health- and disease-related epigenetic clocks, especially GrimAge and PhenoAge, were more strongly associated with inflammatory proteins, frailty, and multimorbidity than the Horvath and Hannum clocks.
Methodological context: the study strengthens the hypothesis that inflammaging may be not only a marker of aging, but also a potential contributor to some age-related processes.

These details matter because the authors were not analyzing a single simple inflammation marker. They examined a broader relationship between immunity, DNA methylation, and the clinical state of the body.

What epigenetic clocks show

Epigenetic clocks estimate biological age based on DNA methylation patterns. However, not all clocks measure the same thing. Some are more closely tied to chronological age, while others are more strongly linked to health, disease risk, and mortality.

The study analyzed four established clocks: Horvath, Hannum, PhenoAge, and GrimAge. GrimAge and PhenoAge were especially interesting because they showed stronger associations with inflammatory proteins, frailty, and multimorbidity.

This has several important implications:

Not every biological clock responds to the same signals. The Horvath and Hannum clocks are more closely related to chronological age, while GrimAge and PhenoAge appear more sensitive to health status and disease burden.
Inflammation may be more closely related to the “quality of aging” than to time itself. This distinction matters because two people of the same chronological age may have very different inflammatory profiles and different epigenetic risk patterns.
Multimorbidity was especially strongly linked to GrimAge. This suggests that some clocks may better capture the biological consequences of accumulated health burden.

This does not mean that a single epigenetic clock result should be treated as a diagnosis. Rather, the study suggests that epigenetic age may offer a useful window into the relationship between immunity, inflammation, and clinical-metabolic health.

CXCL9 and the interferon pathway

The strongest signal in the study involved CXCL9, a chemokine associated with inflammation and the interferon pathway. The authors found that higher CXCL9 levels were linked to faster epigenetic aging, particularly according to GrimAge and PhenoAge.

A key element of the study was Mendelian randomization. This statistical method uses genetic variants as tools to assess whether an observed relationship may have a causal character. In this case, the findings suggested that higher concentrations of selected cytokines related to the interferon pathway may contribute to accelerated epigenetic aging.

Several proteins stood out in the results:

CXCL9 emerged as one of the strongest signals connecting inflammaging with epigenetic age and age acceleration.
CXCL10 also belongs to the interferon-related inflammatory pathway and was linked with accelerated aging in selected analyses.
CCL11 and IL-18 appeared as additional molecules whose levels increased with age and may be connected with epigenetic age acceleration.
TNF was also associated with health-related epigenetic clocks, which fits its broader role in chronic inflammatory responses.

The most interesting point is that the study does not present inflammaging as one general “inflammatory state.” Instead, it suggests that specific immune pathways, especially those related to interferons, may be particularly important.

Inflammation does not mean better immunity

At first glance, it might seem that a more active immune system should offer better protection. In aging, however, something more problematic often happens: the body maintains a chronic inflammatory background while losing the ability to mount a precise response to real infections.

The authors also analyzed immune cell responses to known pathogens. Cells from people who were epigenetically older responded less effectively, even though their bodies showed greater inflammatory activation.

This paradox can be described in a few ways:

More inflammation does not mean better protection. Chronic immune activation can resemble an alarm that rings all the time, making the body less responsive when a real threat appears.
An epigenetically older immune system may be less flexible. Cells may produce appropriate cytokines less effectively in response to microbial stimulation, suggesting impaired function rather than just elevated inflammation.
Inflammaging and immunosenescence may occur together. The body can be more inflamed and, at the same time, less effective at responding to specific pathogens.

This is an important lesson for interpreting inflammatory markers. The goal is not to “turn off” immunity, but to keep it in a state where it can respond precisely, proportionally, and only when needed.

What this means for longevity

The study does not show that simply lowering CXCL9 would slow aging. It also does not provide a ready-made intervention protocol. Its importance is more fundamental: it strengthens the view that biological aging is not only metabolic, hormonal, or genetic, but also immunological.

In the context of longevity, three conclusions are especially important:

Chronic inflammation should be treated as a central area of health monitoring. This is not only about standard CRP, but also about the broader picture of immunity, chronic infections, inflammatory diseases, sleep, stress, body composition, and recovery.
Epigenetic clocks may be more useful when interpreted alongside clinical context. A biological age result without information about inflammation, disease burden, lifestyle, and health history may lead to oversimplified conclusions.
The interferon pathway may become an important direction in aging research. If future studies confirm the role of CXCL9, CXCL10, and related proteins, inflammaging may be analyzed more precisely than as a generic “high inflammation” state.

For health practice, the safest interpretation is cautious: it makes sense to support the lifestyle factors that help regulate chronic inflammation and immune balance — sleep, physical activity, healthy body composition, a low-inflammatory dietary pattern, treatment of chronic infections, and control of metabolic disease.

Limitations

This study is important, but it does not close the topic. The authors analyzed strong biological associations and used statistical methods that support causal interpretation, but this was not a clinical trial testing a specific anti-inflammaging intervention.

The main limitations should be taken seriously:

The study does not show a ready-made therapy. The results point to potential biological targets, but they do not show how to safely and effectively modify CXCL9 or other parts of the interferon pathway in humans.
The mechanism still requires further research. The authors point to the interferon pathway, but they do not fully explain why CXCL9 and related proteins increase with age or how exactly they affect DNA methylation and cell function.
Epigenetic clocks are research tools, not simple diagnostic tests. Their results can be valuable, but they should be interpreted within the full health context, not as a single number defining the state of the body.
Inflammaging is not one single process. Different sources of chronic inflammation — infections, visceral obesity, autoimmune disease, stress, poor sleep, or vascular aging — may produce similar markers but require very different responses.

The best interpretation is therefore measured: the study strengthens the importance of precise immune profiling in aging, but it does not justify rushed interventions targeting a single cytokine.