ORIGINAL ARTICLE Depression, telomeres and mitochondrial DNA: between- and within-person associations from a 10-year longitudinal study JE Verhoeven 1,2 , D Révész 1,2 , M Picard 3,4,5 , EE Epel 2 , OM Wolkowitz 2 , KA Matthews 6,7,8 , BWJH Penninx 1 and E Puterman 2,9 Alterations in cellular aging, indexed by leukocyte telomere length (LTL) and mitochondrial DNA copy number (mtDNAcn), might partly account for the increased health risks in persons with depression. Although some studies indeed found cross-sectional associations of depression with LTL and mtDNAcn, the longitudinal associations remain unclear. This 10-year longitudinal study examined between- and within-person associations of depressive symptoms with LTL and mtDNAcn in a large community sample. Data are from years 15, 20 and 25 follow-up evaluations in 977 subjects from the Coronary Artery Risk Development in Young Adults study. Depressive symptoms (years 15, 20, 25) were assessed with the Center for Epidemiologic Studies Depression (CES-D) scale; LTL (years 15, 20, 25) and mtDNAcn (years 15, 25) were measured in whole blood by quantitative PCR. With mixed-model analyses, we explored between- and within-person associations between CES-D scores and cellular aging markers. Results showed that high levels of depressive symptomatology throughout the 10-year time span was associated with shorter average LTL over 10 years (B = - 4.2; P = 0.014) after covarying for age, sex, race and education. However, no within-person association was found between depressive symptoms and LTL at each year (B = - 0.8; P = 0.548). Further, we found no between-person (B = - 0.2; P = 0.744) or within-person (B = 0.4; P = 0.497) associations between depressive symptomatology and mtDNAcn. Our results provide evidence for a long-term, between-person relationship of depressive symptoms with LTL, rather than a dynamic and direct within-person relationship. In this study, we found no evidence for an association between depressive symptoms and mtDNAcn. Molecular Psychiatry advance online publication, 28 March 2017; doi:10.1038/mp.2017.48 INTRODUCTION Persons with depression have increased risks for developing aging-related somatic conditions. 1,2 This may partly be explained by processes of accelerated cellular aging, such as deterioration of telomere maintaining mechanisms and alterations in mitochon- drial functioning. 3 Hence, two increasingly studied markers of cellular aging are telomere length (TL) and mitochondrial DNA copy number (mtDNAcn). Telomeres are DNA–protein complexes that cap chromosomal ends and promote chromosomal stability. 4 TL naturally decreases over time unless counteracted upon by the ribonucleoprotein cellular enzyme telomerase that adds telomeric DNA. 5 When telomeres reach a critical short length, their function declines and cells progress into senescence or apoptosis. Average TL is therefore strongly associated with age 6,7 and with the incidence of various aging-related somatic diseases, such as cardiovascular disease or type II diabetes. 8,9 Mitochondrial function is proposed to be another marker of cellular aging. Mitochondria are cellular energy-generating orga- nelles that have an important role in adenosine triphosphate production and regulation of apoptosis. 10 Mitochondria have their own DNA (mtDNA) with genes that encode essential components for adenosine triphosphate synthesis. 11 Every cell has hundreds to thousands of mitochondria in their cytoplasm, each containing 2–10 copies of mtDNA. 12 A sufficient mtDNAcn is found to be essential for healthy cellular function. 13 Further, damage to mtDNA, as a consequence of reactive oxygen species, is postulated as one of the major causes of aging 14 and may ultimately lead to the development of aging-related diseases 15,16 and pathophysiology of the central nervous system. 17,18 Decre- ased leukocyte mtDNAcn per cell has been cross-sectionally associated with several somatic conditions, such as Parkinson’s disease, 19 hyperlipidemia 20 and metabolic syndrome. 21 However, associations between somatic diseases and (possibly compensa- tory) excess mtDNA proliferation have also been reported. 22 Recent research indicates co-regulation of telomere and mito- chondrial processes, 23,24 suggesting that both telomeres and mitochondria are functionally linked and associated with the aging process. 25 An increasing number of studies have examined leukocyte TL (LTL) and, to a lesser extent, mtDNAcn in relation to depression. Recent meta-analyses found a significant cross-sectional associa- tion between clinically diagnosed depression and short LTL, 26,27 while evidence of short LTL in studies using self-reported measures of depression (and no clinical diagnosis) remains more mixed. Few studies have examined whether depression is associated with mtDNAcn and results were inconsistent. Although some studies found a negative association between depressive symptomatology 28,29 and clinical depression 30 mtDNAcn, another 1 Department of Psychiatry, VU University Medical Center, Amsterdam Public Health Research Institute, Amsterdam, The Netherlands; 2 Department of Psychiatry, University of California, San Francisco, School of Medicine, San Francisco, CA, USA; 3 Division of Behavioral Medicine, Department of Psychiatry, Columbia University Medical Center, New York, NY, USA; 4 Department of Neurology, Columbia University Medical Center, New York, NY, USA; 5 Columbia Translational Neuroscience Initiative, Columbia University Medical Center, New York, NY, USA; 6 Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA; 7 Department of Epidemiology, University of Pittsburgh, Pittsburgh, PA, USA; 8 Department of Psychology, University of Pittsburgh, Pittsburgh, PA, USA and 9 School of Kinesiology, Faculty of Education, University of British Columbia, Vancouver, BC, Canada. Correspondence: Dr JE Verhoeven, Department of Psychiatry, VU University Medical Center, A.J. Ernststraat 1187, Room MB.14A, Amsterdam 1081 HL, The Netherlands. E-mail: j.verhoeven@ggzingeest.nl Received 29 August 2016; revised 21 December 2016; accepted 17 January 2017 Molecular Psychiatry (2017) 00, 1 – 8 © 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved 1359-4184/17 www.nature.com/mp