Leader: Patrizia Rovere-Querini (UNISR); Other collaborator(s):
DAMPs as novel targets to interfere with aging trajectories. The investigation of sarcopenia, a multifactorial determinant of age-related morbidity, and of underlying inflammaging circuits may disclose pathomechanisms and tools for risk stratification. Damage-associated molecular patterns (DAMPs), released by damaged/dying cells, are key mediators of sterile inflammation that hold potential as novel biomarkers, e.g., HMGB1, implicated in muscle waste in cancer patients, but still unexplored in age-related sarcopenia. We plan to study DAMPs as serum biomarkers, in association with functional and imaging-related correlates to stratify clinical phenotypes and predict sarcopenia, disability and frailty in a large cohort of geriatric patients.
Brief description of the activities and of the intermediate results: In November and December 2023 we participated in coordination meetings with the other Spoke 3 partners. Organization of the activities. Performance of the multidimensional geriatric evaluations and blood biobank. From January we performed the multidimensional geriatric evaluations and biobank of the community dwelling volunteers previously enrolled in the FRASNET study. This is the cohort in which we are going to study the biomarkers of inflammation.
Main policy, industrial and scientific implications: Better definition of targets that could interfere with ageing trajectories.
Due to budget constraints, we shifted from the initial plan to measure damage-associated molecular patterns (DAMPs) for stratifying aging trajectories. Instead, we will measure GDF-15 in conjunction with multidimensional geriatric evaluations to stratify clinical phenotypes and predict sarcopenia, disability, and frailty in a large cohort of older individuals.
We continue to perform multidimensional geriatric evaluations (including blood sample collection and biobanking) in a large cohort of geriatric and neurologic patients.
We continue to perform multidimensional geriatric evaluations (including blood sample collection and biobanking) in a large cohort of geriatric and neurologic patients. We have now completed 222 visits of participants previously enrolled in the FRASNET study and 51 patients affected by cognitive impairment.
We have started the dosage of GDF15 though the Ella method in 144 patients.
We continue to perform multidimensional geriatric evaluations (including blood sample collection and biobanking) in a large cohort of geriatric and neurologic patients.
We have completed the dosage of GDF15 though the Ella method in both geriatric and neurologic patients.
The dosage of GDF-15 was performed in a group of 52 individuals whose samples were collected in both 2017-2019 and 2023-2024. 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. Among participants, 54.55% were classified as robust, 13.5% as pre-sarcopenic, and 4.55% as sarcopenic and obese. GDF15 determination was conducted using the ELLA method. No significant sex-based differences were observed in GDF-15 levels.
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.
These findings support the potential use of GDF-15 for the early prediction of sarcopenia risk in aging populations and for guiding personalized preventive interventions aimed at mitigating functional decline.
From April to July 2025, the team made steady progress in advancing the scientific validation and dissemination of emerging GDF15 as biomarker associated with aging-related conditions, particularly frailty, sarcopenia, and malnutrition. In April 2025 the team prepared an abstract titled “GDF-15, sRAGE, FGF21, and NfL: Novel Biomarkers in Malnutrition” for submission to the International Congress on Sarcopenia, Cachexia and Wasting Disorders. This work highlights the relevance of specific circulating biomarkers—identified within the FRASNET study—in detecting malnutrition among older adults, and underscores the potential clinical utility of molecular profiling in geriatric risk stratification. In June 2025 results from this line of research were also presented at the national level, during the 13th Congresso I.S.Mu.L.T., held in Milan. The oral presentation, titled “Biomarkers per la sarcopenia: come prevenire il declino della massa e della funzione muscolare”, was aimed at a clinical and scientific audience, with the goal of translating biomarker research into practical insights for preventing muscle loss and functional impairment in older adults.
The recruitment of the patients has been concluded.
Sarah Damanti performed the oral presentation "“Plasma Neurofilaments as Biomarkers of Frailty and Sarcopenia: Insights from the Prospective and Cross-Sectional FRASNET Study” at the 21st EuGMS Congress, Reykjavik, Iceland on 25th September.
During this trimester, AGE-IT–related research activities focused on the analysis and interpretation of longitudinal data aimed at identifying circulating biomarkers associated with major geriatric syndromes and mental health outcomes in older adults. The work leveraged previously collected biological samples and comprehensive geriatric assessments, integrating them within the AGE-IT translational framework to generate novel evidence on biological ageing, frailty, sarcopenia, malnutrition, and depression.
Specifically, AGE-IT activities advanced the investigation of inflammatory, metabolic-stress, and neurodegenerative biomarkers as predictors of adverse outcomes in community-dwelling older adults.
One line of activity examined plasma neurofilament light chain (NfL) as a longitudinal biomarker of ageing-related functional decline. Baseline NfL levels, measured several years prior to follow-up, emerged as a strong predictor of multiple adverse geriatric outcomes assessed longitudinally, including poorer physical performance, impaired balance, increased frailty, higher risk of sarcopenia, and worse nutritional status, independent of age and sex. NfL also demonstrated high discriminative accuracy in identifying individuals at elevated risk of falls, frailty, and malnutrition. These findings support the concept that neuroaxonal damage represents a central biological substrate linking neuromuscular decline and nutritional vulnerability in ageing and position NfL as an integrated biomarker within the AGE-IT framework.
A second line of activity focused on fibroblast growth factor-21 (FGF21), a stress-induced hepatokine involved in metabolic and inflammatory regulation, and its relationship with affective symptoms in older adults. Longitudinal analyses showed that higher baseline FGF21 levels were prospectively associated with depressive symptoms at follow-up, independent of age, sex, and body mass index. Although FGF21 concentrations tended to decline over time in the overall population, they remained consistently higher in individuals with clinically relevant depressive symptoms. These results suggest that FGF21 reflects chronic metabolic-inflammatory stress pathways that are particularly relevant to late-life depression and support its role as a biomarker of affective vulnerability in ageing.
An additional AGE-IT–related line of activity investigated circulating mitokines as biomarkers of mitochondrial stress and biological ageing, with a specific focus on growth differentiation factor-15 (GDF-15) and fibroblast growth factor-21 (FGF21). These biomarkers were selected for their established roles in metabolic regulation, inflammation, energy balance, and muscle–mitochondrial crosstalk, all of which are central mechanisms in the development of frailty, sarcopenia, and malnutrition in older adults.
Longitudinal analyses showed that higher baseline GDF-15 levels identified individuals at increased risk of developing frailty and malnutrition over time and were associated with poorer physical performance, higher fall risk, and worse nutritional status at follow-up. GDF-15 demonstrated high discriminative accuracy for identifying older adults at risk of frailty, malnutrition, and falls, supporting its role as a robust marker of vulnerability related to mitochondrial dysfunction and catabolic stress.
FGF21, while showing an overall decline over time at the population level, was also associated with nutritional vulnerability and adverse geriatric outcomes. Elevated FGF21 levels identified individuals at increased risk of malnutrition and reflected chronic metabolic stress pathways relevant to ageing-related functional decline. Together, these findings support the integration of mitokines into AGE-IT strategies aimed at early risk stratification and prevention of major geriatric syndromes, reinforcing the link between mitochondrial stress, muscle dysfunction, and nutritional impairment.
A further AGE-IT–related research activity addressed the relationship between kidney function and frailty in older adults, exploring both glomerular and tubular parameters as determinants of biological vulnerability. This line of work responded to the growing recognition that age-related decline in renal function may contribute to frailty beyond the presence of overt chronic kidney disease.
Analyses demonstrated a strong association between reduced estimated glomerular filtration rate (eGFR) and frailty status, particularly in older individuals. Importantly, results suggested the existence of a clinically relevant eGFR threshold below which the risk of frailty markedly increases, even in the absence of advanced kidney disease. In older participants, kidney function emerged as a key determinant of frailty, whereas in younger-old individuals, comorbidity burden and obesity played a more prominent role.
In addition, markers of tubular function, including indicators of sodium handling, showed progressive alterations across frailty categories, suggesting that subclinical tubular dysfunction may contribute to frailty pathophysiology. These findings highlight kidney ageing as a multidimensional process involving both glomerular and tubular components and support the inclusion of renal function assessment within AGE-IT frameworks for frailty risk stratification and personalized prevention strategies.
Publications
Dissemination