GeroScience study identifies circulating endotrophin as a biomarker for inflammaging and mortality risk in older adults

A prospective cohort study published in GeroScience demonstrates that circulating endotrophin, a collagen type VI-derived peptide, correlates with inflammaging and frailty, and independently predicts long-term all-cause mortality in older adults.

Researchers quantified serum endotrophin levels using the PRO-C6 assay in a longitudinal cohort consisting of 121 acutely hospitalized older patients, 52 age- and sex-matched older controls, and 59 healthy young controls.

Circulating endotrophin levels were significantly elevated in older controls compared to young controls, and were further elevated in hospitalized older patients compared to age-matched controls.

Elevated circulating endotrophin correlated strongly with established inflammatory markers, including GDF15 (rho = 0.63), suPAR (rho = 0.62), TNF-alpha (rho = 0.55), and IL-6 (rho = 0.43), as well as with a clinical frailty index (rho = 0.54) and measures of kidney function.

Cox proportional hazards regression revealed that a doubling of circulating endotrophin at 1-month post-discharge was associated with an unadjusted hazard ratio of 2.55 for all-cause mortality, which remained statistically significant at 2.43 after adjusting for age, sex, and traditional risk factors (BMI, smoking, cystatin C, HbA1c) over an 8-year follow-up period.

Traditional inflammatory markers such as IL-6 and TNF-alpha fail to fully capture the structural deterioration of tissues that occurs during biological aging.

Endotrophin, as a bioactive byproduct of collagen type VI formation, reflects active fibroblast activation, extracellular matrix (ECM) remodeling, and tissue stiffening across multiple organs.

The findings suggest that endotrophin bridges systemic inflammaging and organ-level functional decline, functioning as a prospective indicator of physiological frailty and chronic disease burden.

The attenuation of the endotrophin-mortality association when adjusted for GDF15, suPAR, and TNF-alpha suggests that endotrophin is integrated into a shared pathological network of cellular senescence, secretory phenotypes (SASP), and subsequent tissue remodeling.

The clinical validation of the PRO-C6 assay in an aging cohort highlights the potential for extracellular matrix-remodeling biomarkers to improve risk-stratification in clinical trial design.

Drug developers working on senolytic therapies, anti-fibrotic drugs, or anti-inflammatory compounds can utilize endotrophin as a non-invasive surrogate endpoint to evaluate treatment efficacy on structural tissue health.

Combining endotrophin with complementary markers of cellular stress (GDF15) and immune activation (suPAR) could facilitate the creation of multi-marker biological age assessment panels for commercial longevity and clinical testing.

Further longitudinal evaluation in larger, non-hospitalized aging cohorts to establish standardized clinical reference ranges and cutoffs for circulating endotrophin.

Clinical studies exploring whether therapeutic interventions targeting cellular senescence or systemic chronic inflammation can systematically reduce circulating endotrophin levels.