Unmasking malnutrition through soluble RAGE: A biomarker-guided insight from FRASNET

Description

Rationale: to identify circulating biomarkers for malnutrition in elderly. Background: Malnutrition is a prevalent geriatric syndrome, with multifactorial etiology and consequences for health and independence. Inflammation contributes to nutritional decline, yet conventional inflammatory markers often lack sensitivity for identifying malnutrition risk. The soluble receptor for advanced glycation end-products (sRAGE), a modulator of inflammatory responses, has emerged as a biomarker of disease risk and adverse outcomes in various conditions. Objectives: to evaluate the association between circulating sRAGE levels and nutritional status in community-dwelling older adults. Methods: This prospective observational study was conducted within the FRASNET cohort. Fifty-two community-dwelling older adults underwent multidimensional geriatric assessments during two time periods: 2017–2020 and 2023–2024. Serum sRAGE levels were measured at both timepoints. Nutritional status was assessed using the Mini Nutritional Assessment Short Form (MNA-SF). Associations between sRAGE and clinical parameters were evaluated through linear regression models adjusted for age and sex. The diagnostic performance of sRAGE in identifying malnutrition was assessed using ROC curve analysis. Results: Higher baseline sRAGE levels were significantly associated with lower BMI (β = –0.003, p = 0.036), reduced calf circumference (β= –0.002, p = 0.04), and poorer nutritional status as revealed by MNA-SF scores (β= –0.001, p = 0.03) at follow-up. Associations were more pronounced in women. ROC analysis indicated good diagnostic accuracy for identifying malnutrition risk, with an AUC of 0.85. The optimal sRAGE cut-off value for malnutrition risk was 1,362.5 pg/mL. Conclusions: Higher sRAGE levels were prospectively associated with poorer nutritional outcomes in older adults, particularly in women. sRAGE may aid early identification of inflammation-related malnutrition risk.

Steps to reproduce

The Frailty and Sarcopenia Network (FRASNET) is a multicenter observational cohort including community-dwelling and institutionalized older adults. The study was approved by the San Raffaele Scientific Institute (24/INT/2017), and all participants provided written informed consent. Recruitment occurred between April 2017 and October 2020. To ensure population homogeneity, institutionalized individuals were excluded. Between 2023 and 2024, participants were re-contacted within two projects approved by the San Raffaele Ethics Committee: Age-It (CET 88-2024) and PNRR-MAD-2022-12376672 (CET: 161/INT/2022). These calls assessed survival and willingness to attend follow-up visits. Eligible individuals underwent in-person reassessment. Follow-up evaluations included functional status (ADL, IADL), fall risk (Tinetti), frailty (CFS, FI, modified Frailty Phenotype), physical activity (PASE), cognition (MMSE), mood (GDS-15), and sarcopenia risk (SARC-F). Sarcopenia diagnosis included bioelectrical impedance analysis (BIA), handgrip strength, and SPPB. Nutritional status was assessed using MNA-SF, classifying participants as malnourished (≤7), at risk (8–11), or well-nourished (12–14). Comorbidity was evaluated using the SNAC-K index. Within the Age-It project, biomarkers were selected through a Delphi consensus process involving multidisciplinary experts; sRAGE was chosen among candidate markers. Of 1,250 initial participants, by November 2024, 65 had died, 511 declined follow-up, 400 were unreachable, and 46 missed visits; 228 completed follow-up. Biomarker analyses were performed in 52 participants, selected based on sample availability and assay costs. This subgroup was representative of the cohort. sRAGE levels were measured using the ELLA™ platform on biobanked samples collected at baseline (2017–2020) and at follow-up. Statistical analysis: a post-hoc GPower analysis (n=52, α=0.05) indicated 80% power to detect a medium effect (f²=0.16). Continuous variables were expressed as mean±SD or median (IQR), categorical as N (%). Paired t-test or Wilcoxon test assessed longitudinal changes; chi-square tested categorical differences. Group comparisons used Mann–Whitney U test. Associations were evaluated using Spearman correlation and linear regression adjusted for age and sex; sex-stratified analyses were also performed. Additional covariates were limited to avoid overfitting. BMI was excluded in models with MNA-SF due to overlap. ROC analysis assessed sRAGE discrimination for malnutrition, with cut-offs defined by the Youden Index. AUC values indicated low (>0.5–0.7), moderate (>0.7–0.9), or high (>0.9) accuracy.

Institutions

• IRCCS Ospedale San Raffaele

  Lombardy, Milan

Categories

Funders

• European Union - Next Generation EU - NRRP M6C2 - Investment 2.1 Enhancement and strengthening of biomedical research in the NHS.

  Grant ID: PNRR-MAD-2022-12376672, CUP C43C22001310007

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