Age-related trends and sexual dimorphism in inflammaging: Insights from the ATTICA study

Since the hallmarks of aging precede clinical manifestations, we investigated whether inflammaging is present at younger ages than previously thought and exhibits sexual dimorphism, through cross-sectional analysis across age groups.

Circulating interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α), fibrinogen, high-sensitivity C-reactive protein (hs-CRP) and ImmActScore, an aggregate score of IL-6, TNF-α and fibrinogen, were quantified in 1,825 community-dwelling adults aged 18-89 years without cancer, cardiovascular and chronic inflammatory disease from the ATTICA study. The functional form of the relationship and the association between age and biomarkers were evaluated using restricted cubic splines/fractional polynomial models and multivariable linear regression, respectively.

In both sexes fibrinogen and IL-6 demonstrated linear increases across the age range, hs-CRP remained relatively stable, ImmActScore followed a sigmoidal curve relative to age, while TNF-α exhibited a late-life acceleration in females. Significant sex-by-age interactions were observed for TNF-α, hs-CRP and ImmActScore, indicating sex-specific shape in the age curves. Chronological age was independently associated with elevated mean circulating levels of IL-6, TNF-α and fibrinogen, but not hs-CRP. Comparison across age groups demonstrated that the transition from an immune activation-free to an activated state, as assessed by ImmActScore, was detected at approximately 35 years of age for females and 26 years for males.

Changes in established biomarkers of immune activation reflecting inflammaging are detectable during the 30s, with males reaching transition threshold earlier than females. Prompt recognition of inflammaging may offer opportunities for chronic diseases prevention, potentially reducing the period of morbidity and promoting healthy longevity.