Identifying frail elderly subjects is of paramount importance in order to conduct a tailored care. The characterization of frailty status is currently based on the collection of clinical data and on the use of various tools such as Fried’s criteria, which constitutes a difficult and time-consuming process. Up to now, no biological markers have been described as reliable tools for frailty characterization. We tested the hypothesis that a link between frailty and protein molecular aging existed. This study aimed therefore at determining whether post-translational modification derived products (PTMDPs), recognized as biomarkers of protein aging, were associated with frailty status in elderly subjects.
Frailty status was determined according to Fried’s criteria in 250 elderly patients (>65 years old) hospitalized in a short-term care unit. Serum concentrations of protein-bound PTMDPs, including carboxymethyllysine (CML), pentosidine, methylglyoxal-hydroimidazolone-1 and homocitrulline (HCit), were determined by liquid chromatography coupled with tandem mass spectrometry, and tissue content of advanced glycation end-products was assessed by skin autofluorescence (SAF) measurement. Associations between PTMDPs and frailty status were analyzed using logistic regression models.
Frail patients had significantly (p<0.01) higher CML, HCit, and SAF values compared to non-frail and pre-frail subjects. By multivariate analysis, only HCit concentrations and SAF values remained associated with frailty status (p=0.016 and p=0.002, respectively), independently of age, comorbidities, renal function, C-reactive protein and albumin concentrations.
HCit and SAF are significantly associated with frailty status in elderly subjects. This study suggests that PTMDPs constitute promising biomarkers for identifying frail patients and guiding personalized patient care.
The authors thank all the participants of this study, the staff of the Department of Internal Medicine and Geriatrics, the staff of the Department of Biochemistry of Reims University Hospital, and especially Mrs. Tatiana Decampos Dos Santos and Isabelle Flandre.
Author contributions: All the authors contributed significantly to the study (conception, design, and interpretation of the data, critical revision of the manuscript for important intellectual content, and approval of the final version). In addition, Rachid Mahmoudi, Stephane Jaisson, and Philippe Gillery contributed to the analysis strategy and wrote the article.
Research funding: This study was funded by the University of Reims Champagne-Ardenne and the Reims University Hospital through the “Projet Hospitalo Universitaire VIeillissement protéique et VAsculaire (PHU-VIVA)” program.
Employment or leadership: None declared.
Honorarium: None declared.
Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.
1. Fried LP, Tangen CM, Walston J, Newman AB, Hirsch C,Gottdiener J, et al. Frailty in older adults: evidence for a phenotype. J Gerontol A Biol Sci Med Sci 2001;56:M146–56.10.1093/gerona/56.3.M146Search in Google Scholar PubMed
2. Eeles EM, White SV, O’Mahony SM, Bayer AJ, Hubbard RE. The impact of frailty and delirium on mortality in older inpatients. Age Ageing 2012;41:412–6.10.1093/ageing/afs021Search in Google Scholar PubMed
3. Song X, Mitnitski A, Rockwood K. Prevalence and 10-year outcomes of frailty in older adults in relation to deficit accumulation. J Am Geriatr Soc 2010;58:681–7.10.1111/j.1532-5415.2010.02764.xSearch in Google Scholar PubMed
4. Cesari M, Prince M, Thiyagarajan JA, De Carvalho IA, Bernabei R, Chan P, et al. Frailty: an emerging public health priority. J Am Med Dir Assoc 2016;17:188–92.10.1016/j.jamda.2015.12.016Search in Google Scholar PubMed
5. Romera-Liebana L, Orfila F, Segura JM, Real J, Fabra ML, Moller M, et al. Effects of a primary-care based multifactorial intervention on physical and cognitive function in frail, elderly individuals: a randomized controlled trial. J Gerontol A Biol Sci Med Sci 2018;73:1688–74.10.1093/gerona/glx259Search in Google Scholar PubMed PubMed Central
7. Rockwood K, Song X, MacKnight C, Bergman H, Hogan DB, McDowell I, et al. A global clinical measure of fitness and frailty in elderly people. CMAJ 2005;173:489–95.10.1503/cmaj.050051Search in Google Scholar PubMed PubMed Central
8. Cesari M, Vellas B, Hsu FC, Newman AB, Doss H, King AC, et al. A physical activity intervention to treat the frailty syndrome in older persons – results from the LIFE-P study. J Gerontol A Biol Sci Med Sci 2015;70:216–22.10.1093/gerona/glu099Search in Google Scholar PubMed PubMed Central
9. Wang J, Maxwell CA, Yu F. Biological processes and biomarkers related to frailty in older adults: a state-of-the-science literature review. Biol Res Nurs 2019;21:80–106.10.1177/1099800418798047Search in Google Scholar PubMed
10. Gillery P, Jaisson S. Usefulness of non-enzymatic post-translational modification derived products (PTMDPs) as biomarkers of chronic diseases. J Proteomics 2013;92:228–38.10.1016/j.jprot.2013.02.015Search in Google Scholar PubMed
11. Jaisson S, Gillery P. Evaluation of nonenzymatic posttranslational modification-derived products as biomarkers of molecular aging of proteins. Clin Chem 2010;56:1401–12.10.1373/clinchem.2010.145201Search in Google Scholar PubMed
12. de Vos LC, Noordzij MJ, Mulder DJ, Smit AJ, Lutgers HL, Dullaart RP, et al. Skin autofluorescence as a measure of advanced glycation end products deposition is elevated in peripheral artery disease. Arterioscler Thromb Vasc Biol 2013;33:131–8.10.1161/ATVBAHA.112.300016Search in Google Scholar PubMed
15. Verzijl N, DeGroot J, Oldehinkel E, Bank RA, Thorpe SR, Baynes JW, et al. Age-related accumulation of Maillard reaction products in human articular cartilage collagen. Biochem J 2000;350 Pt 2:381–7.10.1042/bj3500381Search in Google Scholar
16. Jaisson S, Pietrement C, Gillery P. Carbamylation-derived products: bioactive compounds and potential biomarkers in chronic renal failure and atherosclerosis. Clin Chem 2011;57:1499–505.10.1373/clinchem.2011.163188Search in Google Scholar PubMed
17. Gorisse L, Pietrement C, Vuiblet V, Schmelzer CE, Kohler M, Duca L, et al. Protein carbamylation is a hallmark of aging. Proc Natl Acad Sci USA 2016;113:1191–6.10.1073/pnas.1517096113Search in Google Scholar PubMed PubMed Central
18. Sell DR, Lane MA, Johnson WA, Masoro EJ, Mock OB, Reiser KM, et al. Longevity and the genetic determination of collagen glycoxidation kinetics in mammalian senescence. Proc Natl Acad Sci USA 1996;93:485–90.10.1073/pnas.93.1.485Search in Google Scholar PubMed PubMed Central
20. Katz S, Ford AB, Moskowitz RW, Jackson BA, Jaffe MW. Studies of illness in the aged. The index of adl: a standardized measure of biological and psychosocial function. JAMA 1963;185:914–9.10.1001/jama.1963.03060120024016Search in Google Scholar PubMed
21. Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis 1987;40:373–83.10.1016/0021-9681(87)90171-8Search in Google Scholar
22. Folstein MF, Folstein SE, McHugh PR. “Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12:189–98.10.1016/0022-3956(75)90026-6Search in Google Scholar
23. D’Ath P, Katona P, Mullan E, Evans S, Katona C. Screening, detection and management of depression in elderly primary care attenders. I: the acceptability and performance of the 15 item Geriatric Depression Scale (GDS15) and the development of short versions. Fam Pract 1994;11:260–6.10.1093/fampra/11.3.260Search in Google Scholar
24. Vellas B, Guigoz Y, Garry PJ, Nourhashemi F, Bennahum D, Lauque S, et al. The Mini Nutritional Assessment (MNA) and its use in grading the nutritional state of elderly patients. Nutrition 1999;15:116–22.10.1016/S0899-9007(98)00171-3Search in Google Scholar
25. Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro 3rd AF,Feldman HI, et al. A new equation to estimate glomerular filtration rate. Ann Intern Med 2009;150:604–12.10.7326/0003-4819-150-9-200905050-00006Search in Google Scholar PubMed PubMed Central
26. Stevens PE, Levin A, Kidney Disease: Improving Global Outcomes Chronic Kidney Disease Guideline Development Work Group M. Evaluation and management of chronic kidney disease: synopsis of the kidney disease: improving global outcomes 2012 clinical practice guideline. Ann Intern Med 2013;158:825–30.10.7326/0003-4819-158-11-201306040-00007Search in Google Scholar PubMed
27. Jaisson S, Souchon PF, Desmons A, Salmon AS, Delemer B, Gillery P. Early formation of serum advanced glycation end-products in children with type 1 diabetes mellitus: relationship with glycemic control. J Pediatr 2016;172:56–62.10.1016/j.jpeds.2016.01.066Search in Google Scholar PubMed
28. Jaisson S, Kazes I, Desmons A, Fadel F, Oudart JB, Santos-Weiss IC, et al. Homocitrulline as marker of protein carbamylation in hemodialyzed patients. Clin Chim Acta 2016;460:5–10.10.1016/j.cca.2016.06.009Search in Google Scholar PubMed
29. Meerwaldt R, Graaff R, Oomen PH, Links TP, Jager JJ, Alderson NL, et al. Simple non-invasive assessment of advanced glycation endproduct accumulation. Diabetologia 2004;47:1324–30.10.1007/s00125-004-1451-2Search in Google Scholar PubMed
30. Desmons A, Jaisson S, Pietrement C, Rieu P, Wynckel A, Gillery P. Homocitrulline: a new marker for differentiating acute from chronic renal failure. Clin Chem Lab Med 2016;54:73–9.10.1515/cclm-2015-0398Search in Google Scholar PubMed
31. Koeth RA, Kalantar-Zadeh K, Wang Z, Fu X, Tang WH, Hazen SL. Protein carbamylation predicts mortality in ESRD. J Am Soc Nephrol 2013;24:853–61.10.1681/ASN.2012030254Search in Google Scholar PubMed PubMed Central
32. Wang Z, Nicholls SJ, Rodriguez ER, Kummu O, Horkko S, Barnard J, et al. Protein carbamylation links inflammation, smoking, uremia and atherogenesis. Nat Med 2007;13:1176–84.10.1038/nm1637Search in Google Scholar PubMed
33. Whitson HE, Arnold AM, Yee LM, Mukamal KJ, Kizer JR, Djousse L, et al. Serum carboxymethyl-lysine, disability, and frailty in older persons: the cardiovascular health study. J Gerontol A Biol Sci Med Sci 2014;69:710–6.10.1093/gerona/glt155Search in Google Scholar PubMed PubMed Central
34. Meerwaldt R, Links T, Zeebregts C, Tio R, Hillebrands JL, Smit A. The clinical relevance of assessing advanced glycation endproducts accumulation in diabetes. Cardiovasc Diabetol 2008;7:29.10.1186/1475-2840-7-29Search in Google Scholar PubMed PubMed Central
35. Drenth H, Zuidema SU, Krijnen WP, Bautmans I, Smit AJ, van der Schans C, et al. Advanced glycation end products are associated with physical activity and physical functioning in the older population. J Gerontol A Biol Sci Med Sci 2018;73:1545–51.10.1093/gerona/gly108Search in Google Scholar PubMed
36. Pilleron S, Rajaobelina K, Tabue Teguo M, Dartigues JF, Helmer C, Delcourt C, et al. Accumulation of advanced glycation end products evaluated by skin autofluorescence and incident frailty in older adults from the Bordeaux Three-City cohort. PLoS One 2017;12:e0186087.10.1371/journal.pone.0186087Search in Google Scholar PubMed PubMed Central
37. Carracedo J, Merino A, Briceno C, Soriano S, Buendia P, Calleros L, et al. Carbamylated low-density lipoprotein induces oxidative stress and accelerated senescence in human endothelial progenitor cells. FASEB J 2011;25:1314–22.10.1096/fj.10-173377Search in Google Scholar PubMed
38. Speer T, Owala FO, Holy EW, Zewinger S, Frenzel FL, Stahli BE, et al. Carbamylated low-density lipoprotein induces endothelial dysfunction. Eur Heart J 2014;35:3021–32.10.1093/eurheartj/ehu111Search in Google Scholar PubMed
39. Gautieri A, Passini FS, Silvan U, Guizar-Sicairos M, Carimati G, Volpi P, et al. Advanced glycation end-products: Mechanics of aged collagen from molecule to tissue. Matrix Biol 2017;59:95–108.10.1016/j.matbio.2016.09.001Search in Google Scholar PubMed
40. Jaisson S, Lorimier S, Ricard-Blum S, Sockalingum GD, Delevallee-Forte C, Kegelaer G, et al. Impact of carbamylation on type I collagen conformational structure and its ability to activate human polymorphonuclear neutrophils. Chem Biol 2006;13:149–59.10.1016/j.chembiol.2005.11.005Search in Google Scholar PubMed
41. Semba RD, Nicklett EJ, Ferrucci L. Does accumulation of advanced glycation end products contribute to the aging phenotype? J Gerontol A Biol Sci Med Sci 2010;65:963–75.10.1093/gerona/glq074Search in Google Scholar PubMed PubMed Central
42. Buta BJ, Walston JD, Godino JG, Park M, Kalyani RR, Xue QL, et al. Frailty assessment instruments: Systematic characterization of the uses and contexts of highly-cited instruments. Ageing Res Rev 2016;26:53–61.10.1016/j.arr.2015.12.003Search in Google Scholar PubMed PubMed Central
43. Loomis SJ, Chen Y, Sacks DB, Christenson ES, Christenson RH, Rebholz CM, et al. Cross-sectional analysis of AGE-CML, sRAGE, and esRAGE with diabetes and cardiometabolic risk factors in a community-based cohort. Clin Chem 2017;63:980–9.10.1373/clinchem.2016.264135Search in Google Scholar PubMed PubMed Central
The online version of this article offers supplementary material (https://doi.org/10.1515/cclm-2018-1322).
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