With an aging population globally, prevention of frailty and sarcopenia will become a public health priority. Growth Differentiation Factor-15 (GDF-15), a stress-responsive cytokine of the TGF-β superfamily, has emerged as a promising biomarker linking mitochondrial dysfunction, cellular senescence, and systemic inflammation to biological and phenotypic aging. This systematic literature review systematically synthesizes the clinical evidence on GDF-15 as a biomarker of frailty, sarcopenia, and physical function, highlighting patterns, gaps, and the biological plausibility of its role as a predictive marker and therapeutic target. Following PRISMA guidelines, we searched CENTRAL, Embase, MEDLINE, and PubMed up to February 2026. Studies involving adult human participants with measured serum GDF-15 levels and assessments of frailty or sarcopenia were included. Data were extracted and grouped thematically by population type, study design, and outcome domains. Narrative synthesis was used to compare findings and explore heterogeneity. From 1027 records, 35 studies were included, spanning community-dwelling adults, hospitalized patients, and individuals with cardiovascular, metabolic, gastrointestinal, and respiratory diseases. Elevated GDF-15 levels were consistently associated with poorer physical performance and greater frailty severity. Longitudinal studies suggested predictive value for future functional decline, although associations with sarcopenia were less consistent. Sex-specific variations and methodological heterogeneity, including assay techniques and diagnostic criteria, were key sources of variability. Interventional studies demonstrated limited modulation of GDF-15 levels through physical activity alone. These findings support the integration of GDF-15 into precision geriatric care, though further longitudinal and interventional studies, including those evaluating the incremental value of adding GDF-15 to existing screening tools for frailty, sarcopenia, and functional status, are required to establish its clinical utility. • GDF-15 is associated with age-related functional decline and frailty severity across diverse populations. • Longitudinal studies suggest GDF-15 may predict future frailty and mobility loss, though causal pathways remain unclear. • Sex-specific differences in GDF-15 levels and associations with physical function highlight the need for stratified analyses. • Methodological heterogeneity including assay techniques and frailty definitions limits cross-study comparability. • GDF-15 shows promise as a biomarker for risk stratification, early intervention, and potential gerotherapeutic targeting.
Lee et al. (Sun,) studied this question.