Biomarkers for Sarcopenia: Predicting Muscle Mass and Function Decline Through GDF-15, FGF21, sRAGE, and Neurofilaments

Sarcopenia is a major public health concern that significantly impacts the quality of life, morbidity, and mortality among older adults. Given the complex mechanisms underlying its development, recent efforts to enhance diagnostic approaches have increasingly focused on utilizing multiple blood-based biomarkers for screening. Through a Delphi consensus involving biologists and physicians from various Italian universities, we identified a panel of key biomarkers: FGF21 and GDF15, both mitokines released in response to mitochondrial stress; sRAGE, a soluble form of the receptor for advanced glycation end products (RAGE), generated through the shedding of membrane-bound RAGE, which acts as a decoy receptor by competitively inhibiting RAGE-ligand interactions and attenuating downstream inflammatory responses; and NfL, a marker of axonal damage. This biomarker panel was selected to enhance the prediction of sarcopenia in community-dwelling older adults in Italy. This research was conducted as part of the Age-It project, a national initiative advancing aging studies in Italy. Funded by the National Recovery and Resilience Plan. Participants were recruited from the FRASNET cohort which enrolled healthy community-dwelling volunteers in 2017-2019 with the aim of investigating renal aging, frailty, and sarcopenia. Participants underwent multidimensional assessments, including anthropometric evaluations, bioelectrical impedance analysis, frailty measurements, and blood sampling. Collected blood samples were subsequently bio-banked for future analyses. Follow-up assessments were conducted between 2023 and 2024. Despite the challenges posed by the COVID-19 pandemic, only 65 of the 1,250 originally enrolled participants had died, highlighting the resilience of the cohort. However, the majority of individuals declined to attend follow-up visits or did not respond to telephone outreach. During follow-up, participants who attended underwent repeated multidimensional evaluations, and additional blood samples were collected and bio-banked. Selected biomarkers were measured in samples of 52 individuals. The median age of this subgroup was 76 years, with 38.5% being male. The median Body Mass Index was 26.7, and the prevalence of frailty was 21%, with a median frailty index of 0.13. Cognitive performance in this group was generally high, with a median Mini-Mental State Examination score of 29, while nutritional status was good, indicated by a median Mini Nutritional Assessment Short Form score of 14. The figure illustrates the distribution of body composition classes within the sample. Among participants, 54.55% were classified as robust, 13.5% as pre-sarcopenic, and 4.55% as sarcopenic and obese. Blood biomarker determination was conducted using the ELLA method. No significant sex-based differences were observed in biomarker levels, except for sRAGE in the samples collected and biobanked during 2017–2019. NfL levels were found to be cross-sectionally associated with higher scores on the Fatigue Severity Scale, aligning with the established understanding that fatigue is elevated in individuals with sarcopenia. Additionally, NfL levels demonstrated a prospective association with both the risk of sarcopenia—assessed using the SARC-F questionnaire—and the decline in physical performance, measured by the Short Physical Performance Battery. FGF21 levels were found to be both cross-sectionally and longitudinally associated with lower physical activity levels in older adults. Additionally, FGF21 levels demonstrated a longitudinal association with reduced muscle mass. sRAGE levels were found to be longitudinally associated with reduced calf circumference. Previous studies have also linked elevated sRAGE levels to malnutrition and increased inflammatory markers. It is hypothesized that sRAGE levels may rise as a compensatory response to heightened inflammation, which contributes to muscle deterioration and functional decline over time. GDF15 levels were found to be cross-sectionally associated with an increased risk of physical frailty (as defined by the frailty phenotype), greater fatigue, and poorer physical performance at baseline. Additionally, during follow-up visits, GDF15 levels were cross-sectionally associated with poorer balance and lower physical activity levels in older adults. Longitudinally, elevated GDF15 levels were linked to an increased risk of sarcopenia, lower physical activity levels, and poorer physical performance. In a population of community-dwelling Italian older adults, we confirmed that NfL, GDF15, FGF21, and sRAGE serve as valuable biomarkers of age-related sarcopenia. These biomarkers predict distinct aspects of sarcopenia progression, facilitating the early identification of individuals at risk. The observed heterogeneity in biomarker associations may reflect the involvement of distinct pathophysiological mechanisms underlying sarcopenia, including mitochondrial dysfunction, inflammation, and axonal damage. These findings support the potential use of these biomarkers for the early prediction of sarcopenia risk in aging populations and for guiding personalized preventive interventions aimed at mitigating functional decline.