Physical frailty and sarcopenia (PF&S) is a prototypical geriatric condition characterized by reduced physical function and low muscle mass. The multifaceted pathophysiology of this condition recapitulates all hallmarks of aging making the identification of specific biomarkers challenging. In the present study, we explored the relationship among three processes that are thought to be involved in PF&S (i.e., systemic inflammation, amino acid dysmetabolism, and mitochondrial dysfunction). We took advantage of the well-characterized cohort of older adults recruited in the “BIOmarkers associated with Sarcopenia and Physical frailty in EldeRly pErsons” (BIOSPHERE) study to preliminarily combine in a multi-platform analytical approach inflammatory biomolecules, amino acids and derivatives, and mitochondrial-derived vesicle (MDV) cargo molecules to evaluate their performance as possible biomarkers for PF&S. Eleven older adults aged 70 years and older with PF&S and 10 non-sarcopenic non-frail controls were included in the analysis based on the availability of the three categories of biomolecules. A sequential and orthogonalized covariance selection—linear discriminant analysis (SO-CovSel–LDA) approach was used for biomarkers selection. Of the 75 analytes assayed, 16 had concentrations below the detection limit. Within the remaining 59 biomolecules, So-CovSel–LDA selected a set comprising two amino acids (phosphoethanolamine and tryptophan), two cytokines (interleukin 1 receptor antagonist and macrophage inflammatory protein 1β), and MDV-derived nicotinamide adenine dinucleotide reduced form:ubiquinone oxidoreductase subunit S3 as the best predictors for discriminating older people with and without PF&S. The evaluation of these biomarkers in larger cohorts and their changes over time or in response to interventions may unveil specific pathogenetic pathways of PF&S and identify new biological targets for drug development.

身体虚弱和肌肉减少症（PF＆S）是一种典型的老年病，其特征是身体机能降低和肌肉质量低下。这种情况的多方面病理生理学概括了衰老的所有特征，从而使鉴定特定生物标志物具有挑战性。在本研究中，我们探讨了被认为与PF＆S有关的三个过程之间的关系（即系统性炎症，氨基酸代谢异常和线粒体功能障碍）。我们利用了“老年痴呆症中与肌肉减少症和身体虚弱相关的生物标志物”（BIOSPHERE）研究中招募的特征鲜明的队列，将炎症生物分子，氨基酸和衍生物初步整合到了多平台分析方法中，和线粒体来源的囊泡（MDV）货物分子，以评估其作为PF＆S可能的生物标记物的性能。根据三类生物分子的可用性，将11名70岁及以上的PF＆S老年人和10名非肌肉少的非脆弱对照纳入分析。顺序和正交协方差选择-线性判别分析（SO-CovSel-LDA）方法用于生物标志物的选择。在分析的75种分析物中，有16种的浓度低于检测极限。在剩余的59种生物分子中，So-CovSel-LDA选择了一组包含两种氨基酸（磷酸乙醇胺和色氨酸），两种细胞因子（白介素1受体拮抗剂和巨噬细胞炎性蛋白1β）以及MDV衍生的烟酰胺腺嘌呤二核苷酸还原形式的一组：泛醌氧化还原酶亚基S3是区分有和没有PF＆S的老年人的最佳预测指标。对较大人群中这些生物标志物的评估以及它们随时间的变化或响应干预措施的变化，可能揭示PF＆S的特定致病性途径，并确定药物开发的新生物学靶标。