Association of an inflammaging score based on IL-6, IL-10 and CXCL9, and frailty with long-term mortality in hospitalized older adults

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Abstract Background Aging is accompanied by chronic low-grade inflammation ("inflammaging"), which contributes to increased morbidity and mortality in older adults. This study evaluated the prognostic value of circulating inflammatory biomarkers, i.e. interleukin-6 (IL-6), interleukin-10 (IL-10), and CXCL9, and their integration with frailty for long-term risk stratification. Methods We analyzed 1,009 patients (median age, 84 years) hospitalized in acute care wards of three Italian geriatric hospitals as part of the ReportAGE cohort. Frailty was assessed using a deficit accumulation–based Frailty Index (FI), and serum cytokines were measured by immunoassay. Cytokine-specific risk categories were combined into a composite I3 score (range, 3–9). Cox proportional hazards models adjusted for age, sex, comorbidity burden, polypharmacy, and laboratory variables were used to assess associations with 10-year mortality. In a subset of 237 patients, DNA methylation–based estimates of cytokine levels were also analyzed. Results Higher I3 scores were independently associated with increased mortality (hazard ratio [HR] 2.42, 95% CI 1.74–3.37 for high vs. low scores), with CXCL9 as the strongest individual predictor (HR 1.69, 95% CI 1.30–2.19). The I3 score improved risk prediction beyond FI alone, and their combination identified four distinct risk groups, with the highest mortality observed among patients with both elevated FI and I3 scores. The integrated model (Clinical variables + FI + I3) achieved the greatest discrimination during the first seven years of follow-up. Serum IL-6 and CXCL9 correlated with their DNA methylation–based estimates, supporting an epigenetic contribution to chronic inflammation. Conclusions The I3 score complements frailty assessment and enhances long-term mortality prediction in hospitalized older adults.

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