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
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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.
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Circulating MDV-derived NDUFS3 may be a novel predictor of sarcopenia.
“Circulating MDV-derived ubiquinone oxidoreductase subunit S3 (NDUFS3), the reduced form of nicotinamide adenine dinucleotide, may be a novel predictor of sarcopenia (100).”
From From mitochondria to sarcopenia: role of 17β-estradiol and testosterone (2023) · cites this paper as [100]
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Picca, A., Triolo, M., Wohlgemuth, S. E., Martenson, M. S., Mankowski, R. T., Anton, S. D., Marzetti, E., Leeuwenburgh, C., & Hood, D. A. (2023) · Cells · doi:10.3390/cells12010183 · Cited by 23 · see citing works
Self-citationMolecular routes to sarcopenia and biomarker development: per aspera ad astra
Picca, A., Calvani, R., Sirago, G., Coelho‐Júnior, H. J., & Marzetti, E. (2021) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2021.02.006 · Cited by 21 · see citing works
The biological roots of the sex-frailty paradox
Arosio, B., & Picca, A. (2024) · Experimental Gerontology · doi:10.1016/j.exger.2024.112619 · Cited by 19 · see citing works
Mitochondria Transplantation from Stem Cells for Mitigating Sarcopenia
Tian, X., Pan, M., Zhou, M., Tang, Q., Chen, M., Hong, W., Zhao, F., & Liu, K. (2023) · Aging and Disease · doi:10.14336/ad.2023.0210 · Cited by 18 · see citing works
Associations of Serum CXCL12α and CK Levels with Skeletal Muscle Mass in Older Adults
Chen, Z., Laurentius, T., Fait, Y., Müller, A., Mückter, E., Bollheimer, L. C., & Nourbakhsh, M. (2023) · Journal of Clinical Medicine · doi:10.3390/jcm12113800 · Cited by 16 · see citing works
Iron Metabolism and Muscle Aging: Where Ferritinophagy Meets Mitochondrial Quality Control
Lorenzo, R. D., Marzetti, E., Coelho‐Júnior, H. J., Calvani, R., Pesce, V., Landi, F., Leeuwenburgh, C., & Picca, A. (2025) · Cells · doi:10.3390/cells14090672 · Cited by 17 · see citing works
Low, S. K., Wang, J., Moh, A. M. C., Ang, S. F., Ang, K., Shao, Y. M., Ching, J., Wee, H. N., Lee, L. S., Kovalik, J., et al. (2022) · Diabetes Research and Clinical Practice · doi:10.1016/j.diabres.2022.109803 · Cited by 15 · see citing works
Mitochondrial pathways and sarcopenia in the geroscience era
Marzetti, E., Calvani, R., Coelho‐Júnior, H. J., & Picca, A. (2024) · The journal of nutrition health & aging · doi:10.1016/j.jnha.2024.100397 · Cited by 14 · see citing works
Exploring the metabolomics profile of frailty- a systematic review
Shekarchian, A., Bandarian, F., Hadizadeh, A., Amirsardari, Z., Sharifi, Y., Ayati, A., Varmaghani, M., Shandiz, A. F., Sharifi, F., Ghadery, A. H., et al. (2024) · Journal of Diabetes & Metabolic Disorders · doi:10.1007/s40200-023-01379-y · Cited by 13 · see citing works
Mitochondria: between aging, frailty and sarcopenia
Davin, A., Ferrari, R. R., & Pansarasa, O. (2023) · Aging · doi:10.18632/aging.204998 · Cited by 13 · see citing works
Integrating Mitochondrial Biology into Innovative Cell Therapies for Neurodegenerative Diseases
Ore, A., Angelastro, J. M., & Giulivi, C. (2024) · Brain Sciences · doi:10.3390/brainsci14090899 · Cited by 13 · see citing works
Marzetti, E., Coelho‐Júnior, H. J., Calvani, R., Girolimetti, G., Corato, R. D., Ciciarello, F., Galluzzo, V., Mario, C. D., Tolusso, B., Santoro, L., et al. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26031224 · Cited by 16 · see citing works
Guerra, F., Ponziani, F. R., Cardone, F., Bucci, C., Marzetti, E., & Picca, A. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25094783 · Cited by 9 · see citing works
The mitochondrial side of frailty
Marzetti, E., Lorenzo, R. D., & Picca, A. (2025) · Current Opinion in Clinical Nutrition & Metabolic Care · doi:10.1097/mco.0000000000001175 · Cited by 7 · see citing works
Ginevičienė, V., Pranckevičienė, E., Kilaitė, J., Mastavičiūtė, A., Dadelienė, R., Jamontaitė, I. E., Letukienė, A., Ahmetov, I. I., & Alekna, V. (2024) · Frontiers in Medicine · doi:10.3389/fmed.2024.1326764 · Cited by 7 · see citing works
Multisystem derangements in frailty and sarcopenia: a source for biomarker discovery
Picca, A., Calvani, R., & Marzetti, E. (2022) · Current Opinion in Clinical Nutrition & Metabolic Care · doi:10.1097/mco.0000000000000828 · Cited by 7 · see citing works
Longitudinal changes in blood-borne geroscience biomarkers: results from a population-based study
Picca, A., Nguyen, N. V., Calvani, R., Dale, M., Fredolini, C., Marzetti, E., Calderón-Larrañaga, A., & Vetrano, D. (2025) · GeroScience · doi:10.1007/s11357-025-01666-x · Cited by 6 · see citing works
Marzetti, E., Lorenzo, R. D., Calvani, R., Coelho‐Júnior, H. J., D’Argento, E., Pesce, V., Landi, F., Bucci, C., Guerra, F., & Picca, A. (2026) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2026.112167 · Cited by 6 · see citing works
What role do extracellular vesicles play in developing physical frailty and sarcopenia?
Wang, L.-X., Zhang, X., Guan, L.-J., & Pen, Y. (2022) · Zeitschrift für Gerontologie und Geriatrie · doi:10.1007/s00391-022-02150-3 · Cited by 5 · see citing works
Wen, B., Wei, S., Huang, D., Zhang, C., Wang, H., Liu, S., & Wu, X. (2025) · Archives of Gerontology and Geriatrics · doi:10.1016/j.archger.2025.105774 · Cited by 4 · see citing works
Liu, L., Cai, Y., Liu, D., Fang, R., Huang, H., Zou, M., Chen, B., Peng, J., & Hao, L. (2026) · Biomaterials Science · doi:10.1039/d5bm01061f · Cited by 3 · see citing works
The Frailty Puzzle: Searching for Immortality or for Knowledge Survival?
Govoni, S. M., Fagiani, F., Lanni, C., & Allegri, N. (2022) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2022.838447 · Cited by 3 · see citing works
Exploring Mitochondrial Quality in Aging and Neurodegenerative Diseases
Jiao, X., Li, M., Na, D., Meng, M., Zhang, G., & Guo, Y. (2024) · Neurochemical Journal · doi:10.1134/s1819712424700016 · Cited by 2 · see citing works
Extracellular vesicles for therapeutic and diagnostic applications
Ramani, P., Padinjarathil, H., Dattilo, S., & Drago, C. (2025) · Elsevier eBooks · doi:10.1016/b978-0-443-23891-8.00012-3 · Cited by 1 · see citing works
Mitochondrial Alterations and Signaling in Aging, Frailty, and Sarcopenia: An Integrated View
Picca, A., González‐Freire, M., Anton, S. D., Marzetti, E., & Leeuwenburgh, C. (2024) · Springer eBooks · doi:10.1007/978-3-031-57361-3_14
Imaging Biomarkers of Cognitive Impairment in Sarcopenia: A Narrative Review
Lei, W.-X., Zhu, J., Jiang, Y.-T., Peng, X., Sun, H. Y., Tan, J., Zhou, X.-H., Huang, M., Lei, H., & Zhao, H. (2026) · International Journal of General Medicine · doi:10.2147/ijgm.s601894
- Authors
- Marzetti, E., Guerra, F., Calvani, R., Marini, F., Biancolillo, A., Gervasoni, J., Primiano, A., Coelho-Júnior, H. J., Landi, F., Bernabei, R., Bucci, C., & Picca, A.
- Affiliations
- Università Cattolica del Sacro Cuore (IT)
- University of Salento (IT)
- Agostino Gemelli University Polyclinic (IT)
- Sapienza University of Rome (IT)
- University of L'Aquila (IT)
- Corresponding author
- Calvani, Riccardo
- ORCID
- Venue
- Frontiers in Cell and Developmental Biology
- Publisher
- Frontiers Media SA
- Published
- 2020-09-22
- Volume
- 8
- Pages
- 564417-564417
- ISSN
- 2296-634X (ISSN-L)
- PMC
- PMC7536309
- OpenAlex
- W3089036665
- Cited by
- 45
- References
- 61
- Citations by year
- 2026: 4 · 2025: 6 · 2024: 11 · 2023: 9 · 2022: 9 · 2021: 6
- FWCI
- 3.61
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Frontiers in Cell and Developmental Biology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- IRIS Research product catalog (Sapienza University of Rome) (submittedVersion, cc-by-nc-nd)
- Archivio Istituzionale della Ricerca - Università degli Studi dell Aquila (submittedVersion, cc-by-nc-nd)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- AIRUS (submittedVersion)
- PubliCatt (Università Cattolica del Sacro Cuore) (submittedVersion, cc-by)
- Funders
- Innovative Medicines Initiative
- Associazione Italiana per la Ricerca sul Cancro
- Ministero dell’Istruzione, dell’Università e della Ricerca
- Università Cattolica del Sacro Cuore (D3.2 2013)
- Topics
- Health Sciences › Medicine › Physiology › Nutrition and Health in Aging
- Health Sciences › Medicine › Geriatrics and Gerontology › Frailty in Older Adults
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Keywords
- physical frailty, sarcopenia, mitochondrial-derived vesicles, inflammatory markers, mitochondrial dysfunction, older adults, phosphoethanolamine, tryptophan, interleukin-1 receptor antagonist, macrophage inflammatory protein-1β, biomarker selection, linear discriminant analysis
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