Abstract
Although interest in biomarkers of biological aging is growing, consensus on reliable, non-invasive indicators remains limited. Endotrophin, a bioactive fragment released during collagen type VI formation, reflects fibroblast activation and extracellular matrix remodeling and has been linked to chronic diseases, metabolic dysfunction, and inflammation. Whether circulating endotrophin also captures aging-related phenotypes and mortality risk in older adults remains unclear. We quantified serum endotrophin by the PRO-C6 assay in 1) acutely hospitalized Older patients ( n = 121) at admission (T -1 ), one-month post-discharge (T 0 ), and after 12 months (T 12 ); 2) Older controls ( n = 52) at T 0 (inclusion) and T 12 ; and healthy Young controls ( n = 59) at T 0 and one-month follow-up (T 1 ). Group differences and longitudinal trajectories were analyzed using linear mixed-effects models, and mortality associations were evaluated using Cox regressions. At T 0 , endotrophin levels were significantly elevated in Older patients compared to Older controls, while Young controls displayed substantially lower levels. Endotrophin remained stable over 12 months in Older controls, while Older patients showed a modest but significant overall increase. Higher endotrophin at T 0 correlated with markers of inflammation, frailty, and reduced physical function. Among Older patients, elevated endotrophin levels at T -1 and T 0 were associated with all-cause mortality, independent of demographic and clinical factors, though adjustment for inflammatory biomarkers attenuated the associations. These findings suggest that circulating endotrophin reflects disease burden, frailty, and prolonged physiological stress in acutely hospitalized older adults, while potentially overlapping with pathways of biological aging. Further studies in larger and more diverse cohorts are needed to establish its predictive and clinical utility.