Leader: Patrizia Rovere-Querini, Simone Cenci (UNISR); Other collaborator(s): Annamaria Martone (UNICATT)
Integrated multidimensional biomarkers of musculo-skeletal decline. Osteoporosis and fragility fractures, modifications in body composition (sarcopenia and increased fat mass) and low-grade inflammation are frequent in the elderly. Although single specific hormones (e.g. sex hormones, GH, cortisol) have been implicated in osteoporosis or sarcopenia, an all-encompassing analysis of biochemical, molecular, radiological and clinical evaluation has never been conducted so far. We plan to integrate canonical and novel biomarkers of cellular inflammation and endocrine-metabolic dysfunction to predict bone fragility and muscle loss in obese and non-obese elderly and disclose relationships between inflammation and bone and muscle health.
Brief description of the activities and of the intermediate results: In a cohort of 100 community dwelling older people previously enrolled in the FRASNET study we are assessing integrated multidimensional biomarker of musculo-skeletal decline. These individuals who were evaluated and biobanked in 2016 and 2017 will were called to assess their availability to be evaluated again. Body composition, muscle and bone status though BIA and DEXA are under assessment and new blood samples are being collected.
Drafting and projecting of a national event on HL, foreseen at the end of September, to share results, methodology and insights between all the members of Spoke 3 upon HL.
Main policy, industrial and scientific implications: Better definition of possible targets of novel therapeutic and preventive interventions
Body composition, muscle and bone status though BIA and DEXA and blood samples collection are being performed.
In the blood sample biobanked and in the de novo blood sample we are going to assess markers of low-grade inflammation (high sensitivity CRP, ferritin) and novel biomarkers of metabolic dysfunction to assess the ability of these to predict bone fragility and muscle loss in obese and non-obese older patients and disclose relationships between inflammation and bone and muscle health.
Integrated biomarkers of musculoskeletal decline are being evaluated in a cohort of 100 community-dwelling older individuals from the FRASNET study.
In a cohort of 100 community-dwelling older individuals previously enrolled in the FRASNET study, we evaluated integrated biomarkers of musculoskeletal decline. Due to budget constraints, we did not measure inflammation and metabolic dysfunction markers as initially planned. Instead, we assessed whether biomarkers selected within the context of WP3 (GDF-15, FGF21, sRAGE) predicted fragility fractures and muscle mass loss in addition to other clinical characteristics assessed during the geriatric visits. Fragility fractures were assessed during the geriatric visits.
The dosage of the biomarkers through the Ella Automated Immunoassay System was completed. Statistical analyses to assess the above mentioned associations are ongoing.
Data collection from follow-up visits of participants from the FRASNET cohort has been conducted and it is still ongoing.. The measurement of biomarkers defined in WP3 (GDF-15, FGF-21, NFL, and sRAGE) was completed using biobanked samples. The preliminary design of an assessment tool integrating these biomarkers with other multidimensional factors was carried out, leading to the discovery of correlations between the mentioned biomarkers and measures of physical performance, muscle parameters, and frailty.
The evaluation of a subgroup of community-dwelling older individuals previously enrolled in the FRASNET study has been completed. Biomarker levels of GDF-15, FGF21, and sRAGE were measured using the Ella Automated Immunoassay System. We are currently assessing whether these biomarkers can predict muscle mass loss, alongside other clinical characteristics.
Biomarkers reflecting mitochondrial stress neurodegeneration and chronic inflammation were found to serve as valuable tools for early identification of individuals at risk of malnutrition. Moreover, NfL levels were 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. 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.
Between April and July 2025, the research team made significant progress in disseminating findings related to emerging biomarkers for age-related conditions, particularly malnutrition, sarcopenia, and frailty.
An abstract entitled “GDF-15, sRAGE, FGF21, and NfL: Novel Biomarkers in Malnutrition” was prepared and submitted for the International Congress on Sarcopenia, Cachexia and Wasting Disorders. The work highlights the potential role of specific circulating biomarkers in the early detection of malnutrition in older adults, based on findings from the FRASNET cohort. This marks an important step toward integrating molecular profiling into clinical risk stratification tools.
During May, the team focused on the development of a full scientific manuscript titled “Mitokine Signatures of Aging: GDF-15 and FGF21 Predict Frailty, Sarcopenia, and Malnutrition in the FRASNET Study”, which was submitted to the journal Mechanisms of Ageing and Development. The article explores the prognostic value of the mitokines GDF-15 and FGF21, showing their strong associations with key geriatric syndromes. These results may inform future biomarker-driven approaches to aging-related clinical care.
In June, preliminary results were publicly presented at the 13th Congresso I.S.Mu.L.T. (Italian Society of Muscles, Ligaments and Tendons), held in Milan. The oral presentation, titled “Biomarkers per la sarcopenia: come prevenire il declino della massa e della funzione muscolare”, addressed an audience of clinicians and researchers, raising awareness on the clinical relevance of GDF-15, FGF21, and NfL in predicting muscular decline in the aging population. A detailed update was prepared for the Spoke 3 – WP4 July progress meeting, summarizing all dissemination and scientific output related to Task 4.5.
Preparation and submission of the papers "Circulating Mitokines GDF-15 and FGF21 Predict Frailty, Sarcopenia, and Malnutrition in Older Adults: Evidence from the FRASNET Study" for Mechanisms of Aging and Development, "FGF21 predicts Depressive Symptoms in Older Adults: Evidence from the FRASNET Cohort" for Frontiers in Psychiatry, "Unmasking Malnutrition Through soluble RAGE: A Biomarker-Guided Insight from FRASNET" for Experimental Gerontology.
Activities within task 4.5 are progressing toward the development of a pragmatic, multidimensional assessment tool for early identification of musculoskeletal decline in community-dwelling older adults, integrating circulating biomarkers with clinical, functional, and anthropometric determinants collected during comprehensive geriatric visits. The work leverages a cohort of approximately older individuals enrolled in FRASNET in 2017-2020 who underwent standardized follow-up evaluations in 2023-2024, enabling the construction of predictive models grounded in real-world geriatric assessment workflows.
Due to budget constraints, the biomarker plan has been streamlined, and the current strategy prioritizes a biologically informed panel selected within WP3—GDF-15, FGF21, and sRAGE—chosen because they capture complementary mechanisms relevant to muscle and nutritional vulnerability (mitochondrial stress, metabolic stress signaling, and chronic inflammation-related pathways). Evidence already generated in FRASNET supports the feasibility and clinical relevance of this targeted approach. In longitudinal analyses, higher baseline GDF-15 was associated with poorer nutritional status at follow-up (lower MNA-SF) and increased vulnerability across geriatric domains including the risk of sarcopenia, while both GDF-15 and FGF21 demonstrated excellent discrimination of malnutrition risk, suggesting utility for early nutritional risk stratification within an integrated tool.
In parallel, sRAGE emerged as a biomarker linked to malnutrition-related body composition changes: higher baseline sRAGE predicted poorer nutritional outcomes at follow-up, including lower BMI, reduced calf circumference, and lower MNA-SF scores, with good diagnostic accuracy for malnutrition risk.
Overall, the task is now focused on translating these FRASNET-derived associations into an operational assessment framework that integrates: (i) WP3 biomarker panel (GDF-15, FGF21, sRAGE), (ii) nutritional metrics (MNA-SF and anthropometry), and (iii) functional and frailty-related measures from geriatric visits. This approach aims to maximize predictive value while ensuring feasibility, scalability, and alignment with AGE-IT objectives for early risk stratification and prevention of musculoskeletal decline.
Oral presentation at the ICFSR in Toulouse “Biomarkers for Sarcopenia: Predicting Muscle Mass and Function Decline Through GDF-15, FGF21, sRAGE, and Neurofilaments”
Oral presentation, titled “Biomarkers per la sarcopenia: come prevenire il declino della massa e della funzione muscolare” at the13th Congresso I.S.Mu.L.T. (Italian Society of Muscles, Ligaments and Tendons), held in Milan