Circulating Mitochondrial-Derived Vesicles, Inflammatory Biomarkers and Amino Acids in Older Adults With Physical Frailty and Sarcopenia: A Preliminary BIOSPHERE Multi-Marker Study Using Sequential and Orthogonalized Covariance Selection – Linear Discriminant Analysis

Abstract

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 Marzetti et al. Physical Frailty and Sarcopenia Biomarkers 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.

Specific Metabolites Involved in Antioxidation and Mitochondrial Function Are Correlated With Frailty in Elderly Men

“…In the "BIOmarkers associated with Sarcopenia and Physical frailty (PF&S) in EldeRly pErsons" (BIOSPHERE) study, 11 elderly adults aged 70 years and older with PF&S and 10 non-frail and non-sarcopenic controls were included. The results of that study showed that a decline in tryptophan was one of the best predictors for discriminating older people with and without PF&S (46). Our data support those previous studies.…”

Cell Death and Inflammation: The Role of Mitochondria in Health and Disease

“…Cells harboring only mild mitochondrial defects shuttle functional mitochondria within MDVs to rescue aerobic respiration, thereby indicating a link between mitochondrial defects and EV endocytosis [ 75 , 76 , 77 , 78 ]. Mitochondrial constituents have also been found to be displaced within MDVs in age-related conditions characterized by altered cell’s quality control mechanisms [ 79 , 80 , 81 ]. MDV generation, orchestrated by mitochondrial–lysosomal crosstalk, has also been recognized as a candidate mechanism linking cellular dyshomeostasis with systemic inflammation in the context of aging and associated conditions [ 2 , 80 , 81 ].…”

Mitochondrial Quality Control in Sarcopenia: Updated Overview of Mechanisms and Interventions

“…Moreover, mitochondrial derived vesicles (MDVs) function as important mediators in the vesicle transport between mitochondria and lysosomes, which was regarded as an Drp1-independent mitophagy pathway [ 120 ]. And MDV-derived nicotinamide adenine dinucleotide may become a novel biomarker for sarcopenia [ 121 ].…”