Abstract
Objectives
Apelin and GDF-15 have been proposed as biomarkers of age-related sarcopenia but evidence in human models is scarce. This study aimed to explore the associations between blood apelin and GDF-15 with sarcopenia incidence and the evolution of sarcopenia components over two years in older adults >70 years.
Design
Secondary longitudinal analysis of the Multidomain Alzheimer Preventive Trial.
Participants
Older adults (>70 years) attending primary care centers in France and Monaco. Setting. Community.
Measurements
Serum Apelin (pg/mL) and plasma GDF-15 (pg/mL) were measured. Outcomes included sarcopenia defined by the European Working Group on Sarcopenia in Older People (EWGSOP) and its determinants (appendicular lean mass [ALM] evaluated through a Dual-energy X-ray Absorptiometry (DXA) scan, handgrip strength (HGS) and the 4-meter gait speed) measured over 2 years. Linear mixed models and logistic regression were used to explore the longitudinal associations.
Results
We included 168 subjects from MAPT (median age=76y, IQR=73–79; 78% women). Serum apelin was not significantly associated with sarcopenia incidence (OR=1.001;95%CI=1.000,1.001;p-value>0.05 in full-adjusted models) nor with ALM (β=−5.8E-05;95%CI=−1.0E-04,2.12E-04;p>0.05), HGS (β=−1.1E-04;95%CI=−5.0E-04,2.8E-04;p>0.05), and GS (β=−5.1E-06;95%CI=−1.0E-05,2.0E-05;p>0.05) in fully adjusted models. Similarly, plasma GDF-15 was not associated with both the incidence of sarcopenia (OR=1.001,95%CI=1.000,1.002,p>0.05) and the evolution of its determinants ([ALM, β=2.1E-05;95%CI=−2.6E-04,3.03E-04;p>0.05], HGS [β=−5.9E-04;95%CI=−1.26E-03,8.1E-05; p>0.05] nor GS [β=−2.6E-06;95%CI=−3.0E-05, 2.3E-05;p>0.05]) in fully adjusted models.
Conclusions
Blood apelin and GDF-15 were not associated with sarcopenia incidence or with the evolution of sarcopenia components over a 2-year follow-up in community-dwelling older adults. Well-powered longitudinal studies are needed to confirm or refute our findings.
Similar content being viewed by others
References
Cruz-Jentoft AJ, Sayer AA (2019) Sarcopenia. Lancet 393:2636–2646. https://doi.org/10.7861/clinmedicine.14-2-183
Angulo J, El Assar M, Rodríguez-Mañas L (2016) Frailty and sarcopenia as the basis for the phenotypic manifestation of chronic diseases in older adults. Mol Aspects Med 50:1–32 https://doi.org/10.1016/j.mam.2016.06.001
Locquet M, Beaudart C, Hajaoui M, Petermans J, Reginster J-Y, Bruyère O (2018) Three-Year Adverse Health Consequences of Sarcopenia in Community-Dwelling Older Adults According to 5 Diagnosis Definitions. J Am Med Dir Assoc. https://doi.org/10.1016/j.jamda.2018.06.004
Laosa O, Alonso C, Castro M, Rodriguez-Manas L (2014) Pharmaceutical interventions for frailty and sarcopenia. Curr Pharm Des 20:3068–3082. https://doi.org/10.2174/13816128113196660705
Kwak SE, Cho SC, Bae JH, Lee J, Shin HE, Di Zhang D, Lee Y-I, Song W (2019) Effects of exercise-induced apelin on muscle function and cognitive function in aged mice. Exp Gerontol 127:110710. https://doi.org/10.1016/j.exger.2019.110710
Liu H, Huang Y, Lyu Y, Dai W, Tong Y, Li Y (2021) GDF15 as a biomarker of ageing. Exp Gerontol 111228. https://doi.org/10.1016/j.exger.2021.111228
Rai R, Ghosh AK, Eren M, et al (2017) Downregulation of the Apelinergic Axis Accelerates Aging, whereas Its Systemic Restoration Improves the Mammalian Healthspan. Cell Rep 21:1471–1480. https://doi.org/10.1016/j.celrep.2017.10.057
Guerville F, De Souto Barreto P, Ader I, et al (2020) Revisiting the Hallmarks of Aging to Identify Markers of Biological Age. J Prev Alzheimers Dis 7:56–64. https://doi.org/10.14283/jpad.2019.50
Vinel C, Lukjanenko L, Batut A, et al (2018) The exerkine apelin reverses age-associated sarcopenia. Nat Med 24:1360–1371. https://doi.org/10.1038/s41591-018-0131-6
Chen Y-Y, Chiu Y-L, Kao T-W, Peng T-C, Yang H-F, Chen W-L (2021) Cross-sectional associations among P3NP, HtrA, Hsp70, Apelin and sarcopenia in Taiwanese population. BMC Geriatr 21:192. https://doi.org/
Jang I-Y, Lee S, Kim JH, Lee E, Lee JY, Park SJ, Kim DA, Hamrick MW, Park JH, Kim B-J (2020) Lack of association between circulating apelin level and frailty-related functional parameters in older adults: a cross-sectional study. BMC Geriatr 20:420. https://doi.org/10.1186/s12877-021-02146-5
Luan HH, Wang A, Hilliard BK, et al (2019) GDF15 Is an Inflammation-Induced Central Mediator of Tissue Tolerance. Cell 178:1231–1244.e11. https://doi.org/10.1016/j.cell.2019.07.033
Bao X, Borné Y, Xu B, Orho-Melander M, Nilsson J, Melander O, Engström G (2021) Growth differentiation factor-15 is a biomarker for all-cause mortality but less evident for cardiovascular outcomes: A prospective study. Am Heart J 234:81–89. https://doi.org/10.1016/j.ahj.2020.12.020
Hassanpour Golakani M, Mohammad MG, Li H, Gamble J, Breit SN, Ruitenberg MJ, Brown DA (2019) MIC-1/GDF15 Overexpression Is Associated with Increased Functional Recovery in Traumatic Spinal Cord Injury. J Neurotrauma 36:3410–3421. https://doi.org/10.1089/neu.2019.6421
Kleinert M, Clemmensen C, Sjøberg KA, Carl CS, Jeppesen JF, Wojtaszewski JFP, Kiens B, Richter EA (2018) Exercise increases circulating GDF15 in humans. Mol Metab 9:187–191. https://doi.org/10.1016/j.molmet.2017.12.016
Han E-S, Muller FL, Pérez VI, et al (2008) The in vivo gene expression signature of oxidative stress. Physiol Genomics 34:112–126. https://doi.org/10.1152/physiolgenomics.00239.2007
Budui SL, Rossi AP, Zamboni M (2015) The pathogenetic bases of sarcopenia. Clin Cases Miner Bone Metab 12:22–26. https://doi.org/10.11138/ccmbm/2015.12.1.022
Kim H, Kim KM, Kang MJ, Lim S (2020) Growth differentiation factor-15 as a biomarker for sarcopenia in aging humans and mice. Exp Gerontol 142:111115. https://doi.org/10.1016/j.exger.2020.111115
Semba RD, Gonzalez-Freire M, Tanaka T, Biancotto A, Zhang P, Shardell M, Moaddel R, CHI Consortium, Ferrucci L (2020) Elevated Plasma Growth and Differentiation Factor 15 Is Associated With Slower Gait Speed and Lower Physical Performance in Healthy Community-Dwelling Adults. J Gerontol A Biol Sci Med Sci 75:175–180. https://doi.org/10.1093/gerona/glz071
Patel MS, Lee J, Baz M, et al (2016) Growth differentiation factor-15 is associated with muscle mass in chronic obstructive pulmonary disease and promotes muscle wasting in vivo: GDF-15 promotes muscle atrophy in COPD. Journal of Cachexia, Sarcopenia and Muscle 7:436–448. https://doi.org/10.1002/jcsm.12096
Alcazar J, Frandsen U, Prokhorova T, Kamper RS, Haddock B, Aagaard P, Suetta C (2021) Changes in systemic GDF15 across the adult lifespan and their impact on maximal muscle power: the Copenhagen Sarcopenia Study. J Cachexia Sarcopenia Muscle. https://doi.org/10.1002/jcsm.12823
Rosenberg B, Hirano M, Quinzii C, Colantuoni E, Needham DM, Lederer DJ, Baldwin MR (2019) Growth differentiation factor-15 as a biomarker of strength and recovery in survivors of acute respiratory failure. Thorax 74:1099–1101. https://doi.org/10.1136/thoraxjnl-2019-213621
Hofmann M, Halper B, Oesen S, et al (2015) Serum concentrations of insulin-like growth factor-1, members of the TGF-beta superfamily and follistatin do not reflect different stages of dynapenia and sarcopenia in elderly women. Exp Gerontol 64:35–45. https://doi.org/10.1016/j.exger.2015.02.008
Kim M, Walston JD, Won CW (2021) Associations between elevated growth differentiation factor-15 and sarcopenia among community-dwelling older adults. J Gerontol A Biol Sci Med Sci glab201. https://doi.org/10.1093/gerona/glab201
Andrieu S, Guyonnet S, Coley N, et al (2017) Effect of long-term omega 3 polyunsaturated fatty acid supplementation with or without multidomain intervention on cognitive function in elderly adults with memory complaints (MAPT): a randomised, placebo-controlled trial. Lancet Neurol 16:377–389. https://doi.org/10.1016/S1474-4422(17)30040-6
Cruz-Jentoft AJ, Bahat G, Bauer J, et al (2019) Sarcopenia: revised European consensus on definition and diagnosis. Age Ageing 48:601. https://doi.org/10.1093/ageing/afy169
Kawamata Y, Habata Y, Fukusumi S, et al (2001) Molecular properties of apelin: tissue distribution and receptor binding. Biochim Biophys Acta 1538:162–171. https://doi.org/10.1016/s0167-4889(00)00143-9
Shin K, Chapman NA, Sarker M, Kenward C, Huang SK, Weatherbee-Martin N, Pandey A, Dupré DJ, Rainey JK (2017) Bioactivity of the putative apelin proprotein expands the repertoire of apelin receptor ligands. Biochim Biophys Acta Gen Subj 1861:1901–1912. https://doi.org/10.1016/j.bbagen.2017.05.017
Qiu J, Wang X, Wu F, Wan L, Cheng B, Wu Y, Bai B (2017) Low Dose of Apelin-36 Attenuates ER Stress-Associated Apoptosis in Rats with Ischemic Stroke. Front Neurol 8:556. https://doi.org/10.3389/fneur.2017.00556
Oba K, Ishikawa J, Tamura Y, et al (2020) Serum growth differentiation factor 15 level is associated with muscle strength and lower extremity function in older patients with cardiometabolic disease. Geriatr Gerontol Int 20:980–987. https://doi.org/10.1111/ggi.14021
Osawa Y, Semba RD, Fantoni G, Candia J, Biancotto A, Tanaka T, Bandinelli S, Ferrucci L (2020) Plasma proteomic signature of the risk of developing mobility disability: A 9-year follow-up. Aging Cell 19:e13132. https://doi.org/10.1111/acel.13132
Herpich C, Franz K, Ost M, Otten L, Coleman V, Klaus S, Müller-Werdan U, Norman K (2021) Associations Between Serum GDF15 Concentrations, Muscle Mass, and Strength Show Sex-Specific Differences in Older Hospital Patients. Rejuvenation Res 24:14–19. https://doi.org/10.1089/rej.2020.2308
Lerner L, Hayes TG, Tao N, Krieger B, Feng B, Wu Z, Nicoletti R, Chiu MI, Gyuris J, Garcia JM (2015) Plasma growth differentiation factor 15 is associated with weight loss and mortality in cancer patients. J Cachexia Sarcopenia Muscle 6:317–324. https://doi.org/10.1002/jcsm.12033
Nakajima T, Shibasaki I, Sawaguchi T, et al (2019) Growth Differentiation Factor-15 (GDF-15) is a Biomarker of Muscle Wasting and Renal Dysfunction in Preoperative Cardiovascular Surgery Patients. J Clin Med 8:E1576. https://doi.org/10.3390/jcm8101576
Bowen TS, Schuler G, Adams V (2015) Skeletal muscle wasting in cachexia and sarcopenia: molecular pathophysiology and impact of exercise training. J Cachexia Sarcopenia Muscle 6:197–207. https://doi.org/10.1002/jcsm.12043
Maden-Wilkinson TM, McPhee JS, Jones DA, Degens H (2015) Age-Related Loss of Muscle Mass, Strength, and Power and Their Association With Mobility in Recreationally-Active Older Adults in the United Kingdom. J Aging Phys Act 23:352–360. https://doi.org/10.1123/japa.2013-0219
Lauretani F, Russo CR, Bandinelli S, Bartali B, Cavazzini C, Di Iorio A, Corsi AM, Rantanen T, Guralnik JM, Ferrucci L (2003) Age-associated changes in skeletal muscles and their effect on mobility: an operational diagnosis of sarcopenia. J Appl Physiol 95:1851–1860. https://doi.org/10.1152/japplphysiol.00246.2003
Rodriguez-Mañas L, Rodríguez-Artalejo F, Sinclair AJ (2017) The Third Transition: The Clinical Evolution Oriented to the Contemporary Older Patient. J Am Med Dir Assoc 18:8–9. https://doi.org/10.1016/j.jamda.2016.10.005
Kim J, Wang Z, Heymsfield SB, Baumgartner RN, Gallagher D (2002) Total-body skeletal muscle mass: estimation by a new dual-energy X-ray absorptiometry method. Am J Clin Nutr 76:378–383. https://doi.org/10.1093/ajcn/76.2.378
Acknowledgements
MAPT Study Group: Principal investigator: Bruno Vellas (Toulouse); Coordination: Sophie Guyonnet; Project leader: Isabelle Carrié; CRA: Lauréane Brigitte; Investigators: Catherine Faisant, Françoise Lala, Julien Delrieu, Hélène Villars; Psychologists: Emeline Combrouze, Carole Badufle, Audrey Zueras; Methodology, statistical analysis and data management: Sandrine Andrieu, Christelle Cantet, Christophe Morin; Multidomain group: Gabor Abellan Van Kan, Charlotte Dupuy, Yves Rolland (physical and nutritional components), Céline Caillaud, Pierre-Jean Ousset (cognitive component), Françoise Lala (preventive consultation). The cognitive component was designed in collaboration with Sherry Willis from the University of Seattle, and Sylvie Belleville, Brigitte Gilbert and Francine Fontaine from the University of Montreal. Co-Investigators in associated centres: Jean-François Dartigues, Isabelle Marcet, Fleur Delva, Alexandra Foubert, Sandrine Cerda (Bordeaux); Marie-Noëlle-Cuffi. Corinne Costes (Castres); Olivier Rouaud, Patrick Manckoundia, Valérie Quipourt, Sophie Marilier, Evelyne Franon (Dijon); Lawrence Bories, Marie-Laure Pader, Marie-France Basset, Bruno Lapoujade, Valérie Faure, Michael Li Yung Tong, Christine Malick-Loiseau, Evelyne Cazaban-Campistron (Foix); Françoise Desclaux, Colette Blatge (Lavaur); Thierry Dantoine, Cécile Laubarie-Mouret, Isabelle Saulnier, Jean-Pierre Clément, Marie-Agnès Picat, Laurence Bernard-Bourzeix, Stéphanie Willebois, Iléana Désormais, Noëlle Cardinaud (Limoges); Marc Bonnefoy, Pierre Livet, Pascale Rebaudet, Claire Gédéon, Catherine Burdet, Flavien Terracol (Lyon), Alain Pesce, Stéphanie Roth, Sylvie Chaillou, Sandrine Louchart (Monaco); Kristel Sudres, Nicolas Lebrun, Nadège Barro-Belaygues (Montauban); Jacques Touchon, Karim Bennys, Audrey Gabelle, Aurélia Romano, Lynda Touati, Cécilia Marelli, Cécile Pays (Montpellier); Philippe Robert, Franck Le Duff, Claire Gervais, Sébastien Gonfrier (Nice); Yannick Gasnier and Serge Bordes, Danièle Begorre, Christian Carpuat, Khaled Khales, Jean-François Lefebvre, Samira Misbah El Idrissi, Pierre Skolil, Jean-Pierre Salles (Tarbes). MRI group: Carole Dufouil (Bordeaux), Stéphane Lehéricy, Marie Chupin, Jean-François Mangin, Ali Bouhayia (Paris); Michèle Allard (Bordeaux); Frédéric Ricolfi (Dijon); Dominique Dubois (Foix); Marie Paule Bonceour Martel (Limoges); François Cotton (Lyon); Alain Bonafé (Montpellier); Stéphane Chanalet (Nice); Françoise Hugon (Tarbes); Fabrice Bonneville, Christophe Cognard, François Chollet (Toulouse). PET scans group: Pierre Payoux, Thierry Voisin, Julien Delrieu, Sophie Peiffer, Anne Hitzel, (Toulouse); Michèle Allard (Bordeaux); Michel Zanca (Montpellier); Jacques Monteil (Limoges); Jacques Darcourt (Nice). Medico-economics group: Laurent Molinier, Hélène Derumeaux, Nadège Costa (Toulouse). Biological sample collection: Bertrand Perret, Claire Vinel, Sylvie Caspar-Bauguil (Toulouse). Safety management: Pascale Olivier-Abbal. DSA Group: Sandrine Andrieu, Christelle Cantet, Nicola Coley
Funding
Funding: The present work was performed in the context of the Inspire Program, a research platform supported by grants from the Region Occitanie/Pyrénées-Méditerranée (Reference number: 1901175) and the European Regional Development Fund (ERDF) (Project number: MP0022856), and received additional funds from Alzheimer Prevention in Occitania and Catalonia (APOC Chair of Excellence — Inspire Program). The MAPT study was supported by grants from the Gérontopôle of Toulouse, the French Ministry of Health (PHRC 2008, 2009), Pierre Fabre Research Institute (manufacturer of the omega-3 supplement), ExonHit Therapeutics SA, and Avid Radiopharmaceuticals Inc. The promotion of this study was supported by the University Hospital Center of Toulouse. The data sharing activity was supported by the Association Monegasque pour la Recherche sur la maladie d’Alzheimer (AMPA) and the INSERM-University of Toulouse III UMR 1295 Unit.
Author information
Authors and Affiliations
Consortia
Corresponding author
Ethics declarations
Conflict of interests: All authors declare the absence of conflicts of interest.
Ethical standards: Our study complies with the ethical standard laid in the 1964 Declaration of Helsinki and its later amendments.
Electronic supplementary material
Rights and permissions
About this article
Cite this article
Sanchez-Sánchez, J.L., He, L., Virecoulon Giudici, K. et al. Circulating Levels of Apelin, GDF-15 and Sarcopenia: Lack of Association in the MAPT Study. J Nutr Health Aging 26, 564–570 (2022). https://doi.org/10.1007/s12603-022-1800-1
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12603-022-1800-1