Physical frailty and sarcopenia (PF&S) is a prototypical geriatric condition characterized by reduced physical function and low muscle mass. The aim of the present study was to provide an initial selection of biomarkers for PF&S using a novel multivariate analytic strategy. Two-hundred community-dwellers, 100 with PF&S and 100 non-physically frail, non-sarcopenic (nonPF&S) controls aged 70 and older were enrolled as part of the BIOmarkers associated with Sarcopenia and Physical frailty in EldeRly pErsons (BIOSPHERE) study. A panel of 74 serum analytes involved in inflammation, muscle growth and remodeling, neuromuscular junction damage, and amino acid metabolism was assayed. Biomarker selection was accomplished through sequential and orthogonalized covariance selection (SO-CovSel) analysis. Separate SO-CovSel models were constructed for the whole study population and for the two genders. The model with the best prediction ability obtained with the smallest number of variables was built using seven biomolecules. This model allowed correct classification of 80.6 ± 5.3% PF&S participants and 79.9 ± 5.1% nonPF&S controls. The PF&S biomarker profile was characterized by higher serum levels of asparagine, aspartic acid, and citrulline. Higher serum concentrations of platelet-derived growth factor BB, heat shock protein 72 (Hsp72), myeloperoxidase, and α-aminobutyric acid defined the profile of nonPF&S participants. Gender-specific SO-CovSel models identified a “core” biomarker profile of PF&S, characterized by higher serum levels of aspartic acid and Hsp72 and lower concentrations of macrophage inflammatory protein 1β, with peculiar signatures in men and women.
SO-CovSel analysis allowed identifying a set of potential biomarkers for PF&S. The adoption of such an innovative multivariate approach could help address the complex pathophysiology of PF&S, translate biomarker discovery from bench to bedside, and unveil novel targets for interventions.
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Data analyzed in the current study are available from the corresponding author on reasonable request.
Andrae J, Gallini R, Betsholtz C. Role of platelet-derived growth factors in physiology and medicine. Genes Dev. 2008;22:1276–312. https://doi.org/10.1101/gad.1653708.
Bano G, Trevisan C, Carraro S, Solmi M, Luchini C, Stubbs B, et al. Inflammation and sarcopenia: a systematic review and meta-analysis. Maturitas. 2017;96:10–5. https://doi.org/10.1016/j.maturitas.2016.11.006.
Berghella AM, Contasta I, Marulli G, D’Innocenzo C, Garofalo F, Gizzi F, et al. Ageing gender-specific “Biomarkers of Homeostasis”, to protect ourselves against the diseases of the old age. Immun Ageing. 2014;11:3. https://doi.org/10.1186/1742-4933-11-3.
Biancolillo A, Måge I, Næs T. Combining SO-PLS and linear discriminant analysis for multi-block classification. Chemom Intell Lab Syst. 2015;141:58–67. https://doi.org/10.1016/J.CHEMOLAB.2014.12.001.
Biancolillo A, Marini F, Roger JM. SO-CovSel: a novel method for variable selection in a multi-block framework. J Chemom. 2020;34:e3120. https://doi.org/10.1002/cem.3120.
Biancolillo A, Naes T. The sequential and orthogonalised PLS regression (SO-PLS) for multi-block regression: theory, examples and extensions. In: Cocchi M, editor. Data fusion methodology and applications, vol. 31. Amsterdam, Netherlands: Elsevier Inc.; 2019. p. 157–77.
Breuillard C, Cynober L, Moinard C. Citrulline and nitrogen homeostasis: an overview. Amino Acids. 2015;47:685–91. https://doi.org/10.1007/s00726-015-1932-2.
Brzeszczyńska J, Meyer A, McGregor R, Schilb A, Degen S, Tadini V, et al. Alterations in the in vitro and in vivo regulation of muscle regeneration in healthy ageing and the influence of sarcopenia. J Cachexia Sarcopenia Muscle. 2018;9:93–105. https://doi.org/10.1002/jcsm.12252.
Busti F, Campostrini N, Martinelli N, Girelli D. Iron deficiency in the elderly population, revisited in the hepcidin era. Front Pharmacol. 2014;5:83. https://doi.org/10.3389/fphar.2014.00083.
Butcher S, Chahel H, Lord JM. Review article: ageing and the neutrophil: no appetite for killing? Immunology. 2000;100:411–6. https://doi.org/10.1046/J.1365-2567.2000.00079.X.
Calabrese EJ, Dhawan G, Kapoor R, Iavicoli I, Calabrese V. What is hormesis and its relevance to healthy aging and longevity? Biogerontology. 2015;16:693–707. https://doi.org/10.1007/s10522-015-9601-0.
Calabrese EJ, Mattson MP. How does hormesis impact biology, toxicology, and medicine? NPJ Aging Mech Dis. 2017;3:13. https://doi.org/10.1038/s41514-017-0013-z.
Calvani R, Marini F, Cesari M, Tosato M, Anker SD, von Haehling S, et al. Biomarkers for physical frailty and sarcopenia: state of the science and future developments. J Cachexia Sarcopenia Muscle. 2015;6:278–86. https://doi.org/10.1002/jcsm.12051.
Calvani R, Marini F, Cesari M, Buford TW, Manini TM, Pahor M, et al. Systemic inflammation, body composition, and physical performance in old community-dwellers. J Cachexia Sarcopenia Muscle. 2017;8:69–77. https://doi.org/10.1002/jcsm.12134.
Calvani R, Picca A, Marini F, Biancolillo A, Cesari M, Pesce V, et al. The “BIOmarkers associated with Sarcopenia and PHysical frailty in EldeRly pErsons” (BIOSPHERE) study: rationale, design and methods. Eur J Intern Med. 2018a;56:19–25. https://doi.org/10.1016/j.ejim.2018.05.001.
Calvani R, Picca A, Marini F, Biancolillo A, Gervasoni J, Persichilli S, et al. A distinct pattern of circulating amino acids characterizes older persons with physical frailty and sarcopenia: results from the BIOSPHERE study. Nutrients. 2018b;10:1691. https://doi.org/10.3390/nu10111691.
Calvani R, Rodriguez-Mañas L, Picca A, Marini F, Biancolillo A, Laosa O, et al. Identification of a circulating amino acid signature in frail older persons with type 2 diabetes mellitus: results from the MetaboFrail study. Nutrients. 2020;12:199. https://doi.org/10.3390/nu12010199.
Cesari M, Landi F, Calvani R, et al. Rationale for a preliminary operational definition of physical frailty and sarcopenia in the SPRINTT trial. Aging Clin Exp Res. 2017a;29:81–8. https://doi.org/10.1007/s40520-016-0716-1.
Cesari M, Marzetti E, Calvani R, et al. The need of operational paradigms for frailty in older persons: the SPRINTT project. Aging Clin Exp Res. 2017b;29:3–10. https://doi.org/10.1007/s40520-016-0712-5.
Chaleckis R, Murakami I, Takada J, Kondoh H, Yanagida M. Individual variability in human blood metabolites identifies age-related differences. Proc Natl Acad Sci U S A. 2016;113:4252–9. https://doi.org/10.1073/pnas.1603023113.
Chavez AO, Molina-Carrion M, Abdul-Ghani MA, Folli F, DeFronzo RA, Tripathy D. Circulating fibroblast growth factor-21 is elevated in impaired glucose tolerance and type 2 diabetes and correlates with muscle and hepatic insulin resistance. Diabetes Care. 2009;32:1542–6. https://doi.org/10.2337/dc09-0684.
Chew J, Tay L, Lim JP, Leung BP, Yeo A, Yew S, et al. Serum myostatin and IGF-1 as gender-specific biomarkers of frailty and low muscle mass in community-dwelling older adults. J Nutr Health Aging. 2019;23:979–86. https://doi.org/10.1007/s12603-019-1255-1.
Chung J, Nguyen A-K, Henstridge DC, Holmes AG, Chan MHS, Mesa JL, et al. HSP72 protects against obesity-induced insulin resistance. Proc Natl Acad Sci. 2008;105:1739–44. https://doi.org/10.1073/pnas.0705799105.
Cohen AA, Legault V, Fuellen G, Fülöp T, Fried LP, Ferrucci L. The risks of biomarker-based epidemiology: associations of circulating calcium levels with age, mortality, and frailty vary substantially across populations. Exp Gerontol. 2018;107:11–7. https://doi.org/10.1016/j.exger.2017.07.011.
Conte M, Ostan R, Fabbri C, Santoro A, Guidarelli G, Vitale G, et al. Human aging and longevity are characterized by high levels of mitokines. J Gerontol A Biol Sci Med Sci. 2019;74:600–7. https://doi.org/10.1093/gerona/gly153.
De Santa F, Vitiello L, Torcinaro A, Ferraro E. The role of metabolic remodeling in macrophage polarization and its effect on skeletal muscle regeneration. Antioxid Redox Signal. 2019;30:1553–98. https://doi.org/10.1089/ars.2017.7420.
Drey M, Sieber CC, Bauer JM, Uter W, Dahinden P, Fariello RG, et al. C-terminal Agrin Fragment as a potential marker for sarcopenia caused by degeneration of the neuromuscular junction. Exp Gerontol. 2013;48:76–80. https://doi.org/10.1016/j.exger.2012.05.021.
Franceschi C, Garagnani P, Parini P, Giuliani C, Santoro A. Inflammaging: a new immune–metabolic viewpoint for age-related diseases. Nat Rev Endocrinol. 2018;14:576–90. https://doi.org/10.1038/s41574-018-0059-4.
Funai K, Lodhi IJ, Spears LD, Yin L, Song H, Klein S, et al. Skeletal muscle phospholipid metabolism regulates insulin sensitivity and contractile function. Diabetes. 2016;65:358–70. https://doi.org/10.2337/db15-0659.
Furman D, Campisi J, Verdin E, Carrera-Bastos P, Targ S, Franceschi C, et al. Chronic inflammation in the etiology of disease across the life span. Nat Med. 2019;25:1822–32. https://doi.org/10.1038/s41591-019-0675-0.
Gehrig SM, van der Poel C, Sayer TA, Schertzer JD, Henstridge DC, Church JE, et al. Hsp72 preserves muscle function and slows progression of severe muscular dystrophy. Nature. 2012;484:394–8. https://doi.org/10.1038/nature10980.
Goron A, Lamarche F, Blanchet S, Delangle P, Schlattner U, Fontaine E, et al. Citrulline stimulates muscle protein synthesis, by reallocating ATP consumption to muscle protein synthesis. J Cachexia Sarcopenia Muscle. 2019;10:919–28. https://doi.org/10.1002/jcsm.12435.
Guralnik JM, Simonsick EM, Ferrucci L, Glynn RJ, Berkman LF, Blazer DG, et al. A short physical performance battery assessing lower extremity function: association with self-reported disability and prediction of mortality and nursing home admission. J Gerontol. 1994;49:M85–94. https://doi.org/10.1093/geronj/49.2.m85.
Henstridge DC, Bruce CR, Drew BG, Tory K, Kolonics A, Estevez E, et al. Activating HSP72 in rodent skeletal muscle increases mitochondrial number and oxidative capacity and decreases insulin resistance. Diabetes. 2014;63:1881–94. https://doi.org/10.2337/db13-0967.
Irino Y, Toh R, Nagao M, Mori T, Honjo T, Shinohara M, et al. 2-Aminobutyric acid modulates glutathione homeostasis in the myocardium. Sci Rep. 2016;6:36749. https://doi.org/10.1038/srep36749.
Johnson JD, Fleshner M. Releasing signals, secretory pathways, and immune function of endogenous extracellular heat shock protein 72. J Leukoc Biol. 2006;79:425–34. https://doi.org/10.1189/jlb.0905523.
Justice JN, Ferrucci L, Newman AB, Aroda VR, Bahnson JL, Divers J, et al. A framework for selection of blood-based biomarkers for geroscience-guided clinical trials: report from the TAME Biomarkers Workgroup. GeroScience. 2018;40:419–36. https://doi.org/10.1007/s11357-018-0042-y.
Jylhävä J, Pedersen NL, Hägg S. Biological age predictors. EBioMedicine. 2017;21:29–36. https://doi.org/10.1016/J.EBIOM.2017.03.046.
Kaeberlein M. Translational geroscience: a new paradigm for 21st century medicine. Transl Med Aging. 2017;1:1–4. https://doi.org/10.1016/J.TMA.2017.09.004.
Kirkwood TBL. Systems biology of ageing and longevity. Philos Trans R Soc Lond Ser B Biol Sci. 2011;366:64–70. https://doi.org/10.1098/rstb.2010.0275.
Kouchiwa T, Wada K, Uchiyama M, Kasezawa N, Niisato M, Murakami H, et al. Age-related changes in serum amino acids concentrations in healthy individuals. Clin Chem Lab Med. 2012;50:861–70. https://doi.org/10.1515/cclm-2011-0846.
Landi F, Calvani R, Lorenzi M, Martone AM, Tosato M, Drey M, et al. Serum levels of C-terminal agrin fragment (CAF) are associated with sarcopenia in older multimorbid community-dwellers: results from the ilSIRENTE study. Exp Gerontol 2016. 2016;79:31–6. https://doi.org/10.1016/j.exger.2016.03.012.
Le Plénier S, Walrand S, Noirt R, et al. Effects of leucine and citrulline versus non-essential amino acids on muscle protein synthesis in fasted rat: a common activation pathway? Amino Acids. 2012;43:1171–8. https://doi.org/10.1007/s00726-011-1172-z.
López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell. 2013;153:1194–217. https://doi.org/10.1016/j.cell.2013.05.039.
Lorenzi M, Lorenzi T, Marzetti E, Landi F, Vetrano DL, Settanni S, et al. Association of frailty with the serine protease HtrA1 in older adults. Exp Gerontol. 2016;81:8–12. https://doi.org/10.1016/j.exger.2016.03.019.
Maggini S, Wintergerst ES, Beveridge S, Hornig DH. Selected vitamins and trace elements support immune function by strengthening epithelial barriers and cellular and humoral immune responses. Br J Nutr. 2007;98:S29–35. https://doi.org/10.1017/S0007114507832971.
Mangoni AA, Rodionov RN, Mcevoy M, et al. New horizons in arginine metabolism, ageing and chronic disease states. Age Ageing. 2019;48:776–82. https://doi.org/10.1093/ageing/afz083.
Martone AM, Lattanzio F, Abbatecola AM, Carpia D, Tosato M, Marzetti E, et al. Treating sarcopenia in older and oldest old. Curr Pharm Des. 2015;21:1715–22. https://doi.org/10.2174/1381612821666150130122032.
Marzetti E. Identification of predictors of physical frailty and sarcopenia through a new multi‐marker approach. FASEB J. 2020;34:1–1. https://doi.org/10.1096/fasebj.2020.34.s1.09628.
Marzetti E, Calvani R, Landi F, Hoogendijk EO, Fougère B, Vellas B, et al. Innovative medicines initiative: the SPRINTT project. J Frailty Aging. 2015;4:207–8. https://doi.org/10.14283/jfa.2015.69.
Marzetti E, Calvani R, Lorenzi M, Marini F, D'Angelo E, Martone AM, et al. Serum levels of C-terminal agrin fragment (CAF) are associated with sarcopenia in older hip fractured patients. Exp Gerontol. 2014a;60:79–82. https://doi.org/10.1016/j.exger.2014.10.003.
Marzetti E, Cesari M, Calvani R, Msihid J, Tosato M, Rodriguez-Mañas L, et al. The “Sarcopenia and Physical fRailty IN older people: multi-componenT Treatment strategies” (SPRINTT) randomized controlled trial: case finding, screening and characteristics of eligible participants. Exp Gerontol. 2018;113:48–57. https://doi.org/10.1016/j.exger.2018.09.017.
Marzetti E, Landi F, Marini F, Cesari M, Buford TW, Manini TM, et al. Patterns of circulating inflammatory biomarkers in older persons with varying levels of physical performance: a partial least squares-discriminant analysis approach. Front Med. 2014b;1:27. https://doi.org/10.3389/fmed.2014.00027.
Marzetti E, Picca A, Marini F, Biancolillo A, Coelho-Junior HJ, Gervasoni J, et al. Inflammatory signatures in older persons with physical frailty and sarcopenia: the frailty “cytokinome” at its core. Exp Gerontol. 2019;122:129–38. https://doi.org/10.1016/j.exger.2019.04.019.
Matsuo Y, Greenberg DM. Metabolic formation of homoserine and alpha-aminobutyric acid from methionine. J Biol Chem. 1955;215:547–54.
Meister A, Anderson ME. Glutathione. Annu Rev Biochem. 1983;52:711–60. https://doi.org/10.1146/annurev.bi.52.070183.003431.
Naes T, Tomic O, Mevik B-H, Martens H. Path modelling by sequential PLS regression. J Chemom. 2011;25:28–40. https://doi.org/10.1002/cem.1357.
Nakamura E, Miyao K. Sex differences in human biological aging. J Gerontol A Biol Sci Med Sci. 2008;63:936–44. https://doi.org/10.1093/gerona/63.9.936.
Newman AB, Simonsick EM, Naydeck BL, Boudreau RM, Kritchevsky SB, Nevitt MC, et al. Association of long-distance corridor walk performance with mortality, cardiovascular disease, mobility limitation, and disability. JAMA. 2006;295:2018–26. https://doi.org/10.1001/jama.295.17.2018.
Newman JC, Milman S, Hashmi SK, Austad SN, Kirkland JL, Halter JB, et al. Strategies and challenges in clinical trials targeting human aging. J Gerontol Ser A Biol Sci Med Sci. 2016;71:1424–34. https://doi.org/10.1093/gerona/glw149.
Ogawa K, Kim H, Shimizu T, Abe S, Shiga Y, Calderwood SK. Plasma heat shock protein 72 as a biomarker of sarcopenia in elderly people. Cell Stress Chaperones. 2012;17:349–59. https://doi.org/10.1007/s12192-011-0310-6.
Oost LJ, Kustermann M, Armani A, Blaauw B, Romanello V. Fibroblast growth factor 21 controls mitophagy and muscle mass. J Cachexia Sarcopenia Muscle. 2019;10:630–42. https://doi.org/10.1002/jcsm.12409.
Ostan R, Monti D, Gueresi P, Bussolotto M, Franceschi C, Baggio G. Gender, aging and longevity in humans: an update of an intriguing/neglected scenario paving the way to a gender-specific medicine. Clin Sci (Lond). 2016;130:1711–25. https://doi.org/10.1042/CS20160004.
Owen OE, Kalhan SC, Hanson RW. The key role of anaplerosis and cataplerosis for citric acid cycle function. J Biol Chem. 2002;277:30409–12. https://doi.org/10.1074/jbc.R200006200.
Pansarasa O, Castagna L, Colombi B, Vecchiet J, Felzani G, Marzatico F. Age and sex differences in human skeletal muscle: role of reactive oxygen species. Free Radic Res. 2000;33:287–93. https://doi.org/10.1080/10715760000301451.
Papadia C, Osowska S, Cynober L, Forbes A (2017) Citrulline in health and disease. Review on human studies. Clin Nutr 37:1823–1828. https://doi.org/10.1016/j.clnu.2017.10.009.
Patel D, Witt SN. Ethanolamine and phosphatidylethanolamine: partners in health and disease. Oxidative Med Cell Longev. 2017;2017:4829180–18. https://doi.org/10.1155/2017/4829180.
Pavlova NN, Hui S, Ghergurovich JM et al (2018) As extracellular glutamine levels decline, asparagine becomes an essential amino acid. Cell Metab 27:428–438.e5. https://doi.org/10.1016/j.cmet.2017.12.006.
Perreault K, Courchesne-Loyer A, Fortier M, Maltais M, Barsalani R, Riesco E, et al. Sixteen weeks of resistance training decrease plasma heat shock protein 72 (eHSP72) and increase muscle mass without affecting high sensitivity inflammatory markers’ levels in sarcopenic men. Aging Clin Exp Res. 2016;28:207–14. https://doi.org/10.1007/s40520-015-0411-7.
Picca A, Ponziani FR, Calvani R, Marini F, Biancolillo A, Coelho-Júnior HJ, et al. Gut microbial, inflammatory and metabolic signatures in older people with physical frailty and sarcopenia: results from the BIOSPHERE study. Nutrients. 2020;12:65. https://doi.org/10.3390/nu12010065.
Pitkänen HT, Oja SS, Kemppainen K, et al. Serum amino acid concentrations in aging men and women. Amino Acids. 2003;24:413–21. https://doi.org/10.1007/s00726-002-0338-0.
Ponziani FR, Bhoori S, Castelli C, Putignani L, Rivoltini L, del Chierico F, et al. Hepatocellular carcinoma is associated with gut microbiota profile and inflammation in nonalcoholic fatty liver disease. Hepatology. 2019;69:107–20. https://doi.org/10.1002/hep.30036.
Ponziani FR, Putignani L, Parini Sterbini F, et al. Influence of hepatitis C virus eradication with direct-acting antivirals on the gut microbiota in patients with cirrhosis. Aliment Pharmacol Ther. 2018;48:1301–11. https://doi.org/10.1111/apt.15004.
Prior RL, Crim MC, Castaneda C, Lammi-Keefe C, Dawson-Hughes B, Rosen CJ, et al. Conditions altering plasma concentrations of urea cycle and other amino acids in elderly human subjects. J Am Coll Nutr. 1996;15:237–47. https://doi.org/10.1080/07315724.1996.10718594.
Roger JM, Palagos B, Bertrand D, Fernandez-Ahumada E. CovSel: variable selection for highly multivariate and multi-response calibration: application to IR spectroscopy. Chemom Intell Lab Syst. 2011;106:216–23. https://doi.org/10.1016/J.CHEMOLAB.2010.10.003.
Sarwar G, Botting HG, Collins M. A comparison of fasting serum amino acid profiles of young and elderly subjects. J Am Coll Nutr. 1991;10:668–74. https://doi.org/10.1080/07315724.1991.10718185.
Scully D, Naseem KM, Matsakas A. Platelet biology in regenerative medicine of skeletal muscle. Acta Physiol. 2018;223:e13071. https://doi.org/10.1111/apha.13071.
Scully D, Sfyri P, Verpoorten S, Papadopoulos P, Muñoz-Turrillas MC, Mitchell R, et al. Platelet releasate promotes skeletal myogenesis by increasing muscle stem cell commitment to differentiation and accelerates muscle regeneration following acute injury. Acta Physiol. 2019;225:e13207. https://doi.org/10.1111/apha.13207.
Selathurai A, Kowalski GM, Mason SA, Callahan DL, Foletta VC, Della Gatta PA, et al. Phosphatidylserine decarboxylase is critical for the maintenance of skeletal muscle mitochondrial integrity and muscle mass. Mol Metab. 2019;27:33–46. https://doi.org/10.1016/j.molmet.2019.06.020.
Sierra F. The emergence of geroscience as an interdisciplinary approach to the enhancement of health span and life span. Cold Spring Harb Perspect Med. 2016;6:a025163. https://doi.org/10.1101/cshperspect.a025163.
Soga T, Baran R, Suematsu M, Ueno Y, Ikeda S, Sakurakawa T, et al. Differential metabolomics reveals ophthalmic acid as an oxidative stress biomarker indicating hepatic glutathione consumption. J Biol Chem. 2006;281:16768–76. https://doi.org/10.1074/jbc.M601876200.
Soysal P, Stubbs B, Lucato P, Luchini C, Solmi M, Peluso R, et al. Inflammation and frailty in the elderly: a systematic review and meta-analysis. Ageing Res Rev. 2016;31:1–8. https://doi.org/10.1016/j.arr.2016.08.006.
Sprott RL. Biomarkers of aging and disease: introduction and definitions. Exp Gerontol. 2010;45:2–4. https://doi.org/10.1016/j.exger.2009.07.008.
Stephan A, Mateos JM, Kozlov SV, Cinelli P, Kistler AD, Hettwer S, et al. Neurotrypsin cleaves agrin locally at the synapse. FASEB J. 2008;22:1861–73. https://doi.org/10.1096/fj.07-100008.
Studenski SA, Peters KW, Alley DE, Cawthon PM, McLean RR, Harris TB, et al. The FNIH sarcopenia project: rationale, study description, conference recommendations, and final estimates. J Gerontol A Biol Sci Med Sci. 2014;69:547–58. https://doi.org/10.1093/gerona/glu010.
Tezze C, Romanello V, Sandri M. FGF21 as modulator of metabolism in health and disease. Front Physiol. 2019;10:419. https://doi.org/10.3389/fphys.2019.00419.
van der Veen JN, Kennelly JP, Wan S, Vance JE, Vance DE, Jacobs RL. The critical role of phosphatidylcholine and phosphatidylethanolamine metabolism in health and disease. Biochim Biophys Acta Biomembr. 2017;1859:1558–72. https://doi.org/10.1016/j.bbamem.2017.04.006.
Wagenmakers AJ. Protein and amino acid metabolism in human muscle. Adv Exp Med Biol. 1998a;441:307–19. https://doi.org/10.1007/978-1-4899-1928-1_28.
Wagenmakers AJ. Muscle amino acid metabolism at rest and during exercise: role in human physiology and metabolism. Exerc Sport Sci Rev. 1998b;26:287–314. https://doi.org/10.1249/00003677-199800260-00013.
Wang H, Liu H, Liu RM. Gender difference in glutathione metabolism during aging in mice. Exp Gerontol. 2003;38:507–17. https://doi.org/10.1016/s0531-5565(03)00036-6.
Wang L, Ahn YJ, Asmis R. Sexual dimorphism in glutathione metabolism and glutathione-dependent responses. Redox Biol. 2020;31:101410. https://doi.org/10.1016/j.redox.2019.101410.
Wang X, Liu Y, Wang S, Pi D, Leng W, Zhu H, et al. Asparagine reduces the mRNA expression of muscle atrophy markers via regulating protein kinase B (Akt), AMP-activated protein kinase α, toll-like receptor 4 and nucleotide-binding oligomerisation domain protein signalling in weaning piglets after lipopolysaccharide challenge. Br J Nutr. 2016;116:1188–98. https://doi.org/10.1017/S000711451600297X.
Westerhuis JA, Hoefsloot HCJ, Smit S, Vis DJ, Smilde AK, van Velzen EJJ, et al. Assessment of PLSDA cross validation. Metabolomics. 2008;4:81–9. https://doi.org/10.1007/s11306-007-0099-6.
Westerhuis JA, Kourti T, Macgregor JF. Analysis of multiblock and hierarchical PCA and PLS models. J Chemom. 1998;12:301–21. https://doi.org/10.1002/(SICI)1099-128X(199809/10)12:53.0.CO;2-S.
Wilson D, Jackson T, Sapey E, Lord JM. Frailty and sarcopenia: the potential role of an aged immune system. Ageing Res Rev. 2017;36:1–10. https://doi.org/10.1016/J.ARR.2017.01.006.
Yahiaoui L, Gvozdic D, Danialou G, Mack M, Petrof BJ. CC family chemokines directly regulate myoblast responses to skeletal muscle injury. J Physiol. 2008;586:3991–4004. https://doi.org/10.1113/jphysiol.2008.152090.
Zhang X, Yeung DC, Karpisek M, et al. Serum FGF21 levels are increased in obesity and are independently associated with the metabolic syndrome in humans. Diabetes. 2008;57:1246–53. https://doi.org/10.2337/db07-1476.
This study was supported by the Fondazione Roma (NCDs Call for Proposals 2013 to A.P., E.M., F.L., R.B., and R.C.), the Innovative Medicines Initiative – Joint Undertaking (IMI-JU 115621 to A.P., E.M., F.L., M.C., R.B., and R.C.), the nonprofit research foundation “Centro Studi Achille e Linda Lorenzon” (A.P, E.M., and R.C.), intramural research grants from the Università Cattolica del Sacro Cuore (Linea D3.2 2013 and D3.2 2015 to F.L.), and by a scholarship from the Brazilian federal government to H.J.C.-J. (Coordenação de Aperfeiçoamento de Pessoal de Nivel Superior; 001).
A.P., E.M., F.L., M.C., and R.C. are partners of the SPRINTT consortium, which is partly funded by the European Federation of Pharmaceutical Industries and Associations (EFPIA).
E.M. served as a consultant for Abbott, Biophytis, Nutricia, and Nestlè. R.C. served as a consultant for Abbott and Nutricia. M.C. served as a consultant for and/or received honoraria for scientific presentations from Nestlé and received a research grant from Pfizer.
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Calvani, R., Picca, A., Marini, F. et al. Identification of biomarkers for physical frailty and sarcopenia through a new multi-marker approach: results from the BIOSPHERE study. GeroScience (2020). https://doi.org/10.1007/s11357-020-00197-x
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