European Journal of Epidemiology

, Volume 33, Issue 5, pp 485–495 | Cite as

Longitudinal associations of lifetime adiposity with leukocyte telomere length and mitochondrial DNA copy number

  • Dong Hang
  • Hongmei Nan
  • Ane Sørlie Kværner
  • Immaculata De Vivo
  • Andrew Tan Chan
  • Zhibin Hu
  • Hongbing Shen
  • Edward Giovannucci
  • Mingyang Song


Adiposity may cause adverse health outcomes by increasing oxidative stress and systemic inflammation, which can be reflected by altered telomere length (TL) and mitochondrial DNA copy number (mtCN) in peripheral blood leukocytes. However, little is known about the influence of lifetime adiposity on TL and mtCN in later life. This study was performed to investigate the associations of lifetime adiposity with leukocyte TL and mtCN in 9613 participants from the Nurses’ Health Study. A group-based trajectory modelling approach was used to create trajectories of body shape from age 5 through 60 years, and a genetic risk score (GRS) was created based on 97 known adiposity susceptibility variants. Associations of body shape trajectories and GRS with dichotomized TL and mtCN were assessed by logistic regression models. After adjustment for lifestyle and dietary factors, compared with the lean-stable group, the lean-marked increase group had higher odds of having below-median TL (OR = 1.18, 95% CI 1.04, 1.35; P = 0.01), and the medium-marked increase group had higher odds of having below-median mtCN (OR = 1.28, 95% CI 1.00, 1.64; P = 0.047). There was a suggestive trend toward lower mtCN across the GRS quartiles (P for trend = 0.07). In conclusion, telomere attrition may be accelerated by marked weight gain in middle life, whereas mtCN is likely to be reduced persistently by adiposity over the life course. The findings indicate the importance of lifetime weight management to preserve functional telomeres and mitochondria.


Adiposity Telomere Mitochondrion Trajectory analysis Genetic variants 



We would like to thank the participants and staff of the Nurses’ Health Study for their valuable contributions as well as the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, WY. The authors assume full responsibility for analyses and interpretation of these data.

Authors’ contributions

MS and EG were responsible for study design. DH performed statistical analyses and drafted the manuscript. HN, IV, and AC contributed to acquisition of data. AK, ZH, and HS helped to interpret the results and revised the manuscript critically. All authors read and approved the final manuscript.


This work was supported by the National Institutes of Health (UM1 CA186107, P01 CA87969, R01 CA49449, R01 HL034594, and R01 HL088521) and by the American Cancer Society Mentored Research Scholar Grant (MRSG-17-220-01 - NEC to M.S.). The funders had no role in design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript; and the decision to submit the manuscript for publication.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Supplementary material

10654_2018_382_MOESM1_ESM.docx (539 kb)
Supplementary material 1 (DOCX 539 kb)


  1. 1.
    Swinburn BA, Sacks G, Hall KD, McPherson K, Finegood DT, Moodie ML, et al. The global obesity pandemic: shaped by global drivers and local environments. Lancet. 2011;378(9793):804–14. Scholar
  2. 2.
    Ng M, Fleming T, Robinson M, Thomson B, Graetz N, Margono C, et al. Global, regional, and national prevalence of overweight and obesity in children and adults during 1980–2013: a systematic analysis for the global burden of disease study 2013. Lancet. 2014;384(9945):766–81. Scholar
  3. 3.
    Heymsfield SB, Wadden TA. Mechanisms, pathophysiology, and management of obesity. N Engl J Med. 2017;376(3):254–66. Scholar
  4. 4.
    Rani V, Deep G, Singh RK, Palle K, Yadav UC. Oxidative stress and metabolic disorders: pathogenesis and therapeutic strategies. Life Sci. 2016;148:183–93. Scholar
  5. 5.
    Houben JM, Moonen HJ, van Schooten FJ, Hageman GJ. Telomere length assessment: biomarker of chronic oxidative stress? Free Radic Biol Med. 2008;44(3):235–46. Scholar
  6. 6.
    Liu CS, Tsai CS, Kuo CL, Chen HW, Lii CK, Ma YS, et al. Oxidative stress-related alteration of the copy number of mitochondrial DNA in human leukocytes. Free Radic Res. 2003;37(12):1307–17.CrossRefPubMedGoogle Scholar
  7. 7.
    Blackburn EH. Structure and function of telomeres. Nature. 1991;350(6319):569–73. Scholar
  8. 8.
    von Zglinicki T. Oxidative stress shortens telomeres. Trends Biochem Sci. 2002;27(7):339–44.CrossRefGoogle Scholar
  9. 9.
    Armanios M, Blackburn EH. The telomere syndromes. Nat Rev Genet. 2012;13(10):693–704. Scholar
  10. 10.
    Gustafsson CM, Falkenberg M, Larsson NG. Maintenance and expression of mammalian mitochondrial DNA. Annu Rev Biochem. 2016;85:133–60. Scholar
  11. 11.
    Yakes FM, Van Houten B. Mitochondrial DNA damage is more extensive and persists longer than nuclear DNA damage in human cells following oxidative stress. Proc Natl Acad Sci USA. 1997;94(2):514–9.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Haycock PC, Heydon EE, Kaptoge S, Butterworth AS, Thompson A, Willeit P. Leucocyte telomere length and risk of cardiovascular disease: systematic review and meta-analysis. BMJ. 2014;349:g4227. Scholar
  13. 13.
    Kong CM, Lee XW, Wang X. Telomere shortening in human diseases. FEBS J. 2013;280(14):3180–93. Scholar
  14. 14.
    Blake R, Trounce IA. Mitochondrial dysfunction and complications associated with diabetes. Biochim Biophys Acta. 2014;1840(4):1404–12. Scholar
  15. 15.
    Yu M. Generation, function and diagnostic value of mitochondrial DNA copy number alterations in human cancers. Life Sci. 2011;89(3–4):65–71. Scholar
  16. 16.
    Mundstock E, Sarria EE, Zatti H, Mattos Louzada F, Kich Grun L, Herbert Jones M, et al. Effect of obesity on telomere length: systematic review and meta-analysis. Obesity (Silver Spring). 2015;23(11):2165–74. Scholar
  17. 17.
    Strandberg TE, Saijonmaa O, Tilvis RS, Pitkala KH, Strandberg AY, Miettinen TA, et al. Association of telomere length in older men with mortality and midlife body mass index and smoking. J Gerontol A Biol Sci Med Sci. 2011;66(7):815–20. Scholar
  18. 18.
    Wulaningsih W, Watkins J, Matsuguchi T, Hardy R. Investigating the associations between adiposity, life course overweight trajectories, and telomere length. Aging (Albany NY). 2016;8(11):2689–701. Scholar
  19. 19.
    Weischer M, Bojesen SE, Nordestgaard BG. Telomere shortening unrelated to smoking, body weight, physical activity, and alcohol intake: 4576 general population individuals with repeat measurements 10 years apart. PLoS Genet. 2014;10(3):e1004191. Scholar
  20. 20.
    Muezzinler A, Mons U, Dieffenbach AK, Butterbach K, Saum KU, Schick M, et al. Body mass index and leukocyte telomere length dynamics among older adults: results from the ESTHER cohort. Exp Gerontol. 2016;74:1–8. Scholar
  21. 21.
    Lee JY, Lee DC, Im JA, Lee JW. Mitochondrial DNA copy number in peripheral blood is independently associated with visceral fat accumulation in healthy young adults. Int J Endocrinol. 2014;2014:586017. Scholar
  22. 22.
    Ding J, Sidore C, Butler TJ, Wing MK, Qian Y, Meirelles O, et al. Assessing mitochondrial DNA variation and copy number in lymphocytes of ~ 2000 sardinians using tailored sequencing analysis tools. PLoS Genet. 2015;11(7):e1005306. Scholar
  23. 23.
    Meng S, Wu S, Liang L, Liang G, Giovannucci E, De Vivo I, et al. Leukocyte mitochondrial DNA copy number, anthropometric indices, and weight change in US women. Oncotarget. 2016;7(37):60676–86. Scholar
  24. 24.
    Singh AS, Mulder C, Twisk JW, van Mechelen W, Chinapaw MJ. Tracking of childhood overweight into adulthood: a systematic review of the literature. Obes Rev. 2008;9(5):474–88. Scholar
  25. 25.
    Song M, Hu FB, Wu K, Must A, Chan AT, Willett WC, et al. Trajectory of body shape in early and middle life and all cause and cause specific mortality: results from two prospective US cohort studies. BMJ. 2016;353:i2195. Scholar
  26. 26.
    Locke AE, Kahali B, Berndt SI, Justice AE, Pers TH, Day FR, et al. Genetic studies of body mass index yield new insights for obesity biology. Nature. 2015;518(7538):197–206. Scholar
  27. 27.
    Colditz GA, Manson JE, Hankinson SE. The Nurses’ Health Study: 20-year contribution to the understanding of health among women. J Womens Health. 1997;6(1):49–62.CrossRefPubMedGoogle Scholar
  28. 28.
    De Vivo I, Prescott J, Wong JY, Kraft P, Hankinson SE, Hunter DJ. A prospective study of relative telomere length and postmenopausal breast cancer risk. Cancer Epidemiol Biomark Prev. 2009;18(4):1152–6. Scholar
  29. 29.
    Han J, Qureshi AA, Prescott J, Guo Q, Ye L, Hunter DJ, et al. A prospective study of telomere length and the risk of skin cancer. J Investig Dermatol. 2009;129(2):415–21. Scholar
  30. 30.
    Prescott J, McGrath M, Lee IM, Buring JE, De Vivo I. Telomere length and genetic analyses in population-based studies of endometrial cancer risk. Cancer. 2010;116(18):4275–82. Scholar
  31. 31.
    Page JH, Ma J, Rexrode KM, Rifai N, Manson JE, Hankinson SE. Plasma dehydroepiandrosterone and risk of myocardial infarction in women. Clin Chem. 2008;54(7):1190–6. Scholar
  32. 32.
    Schurks M, Prescott J, Dushkes R, De Vivo I, Rexrode KM. Telomere length and ischaemic stroke in women: a nested case-control study. Eur J Neurol. 2013;20(7):1068–74. Scholar
  33. 33.
    Prescott J, Karlson EW, Orr EH, Zee RY, De Vivo I, Costenbader KH. A prospective study investigating prediagnostic leukocyte telomere length and risk of developing rheumatoid arthritis in women. J Rheumatol. 2016;43(2):282–8. Scholar
  34. 34.
    Devore EE, Prescott J, De Vivo I, Grodstein F. Relative telomere length and cognitive decline in the Nurses’ Health Study. Neurosci Lett. 2011;492(1):15–8. Scholar
  35. 35.
    Meng S, De Vivo I, Liang L, Hu Z, Christiani DC, Giovannucci E, et al. Pre-diagnostic leukocyte mitochondrial DNA copy number and risk of lung cancer. Oncotarget. 2016;7(19):27307–12. Scholar
  36. 36.
    Meng S, De Vivo I, Liang L, Giovannucci E, Tang JY, Han J. Pre-diagnostic leukocyte mitochondrial DNA copy number and skin cancer risk. Carcinogenesis. 2016;37(9):897–903. Scholar
  37. 37.
    Stunkard AJ, Sorensen T, Schulsinger F. Use of the Danish adoption register for the study of obesity and thinness. Res Publ Assoc Res Nerv Ment Dis. 1983;60:115–20.PubMedGoogle Scholar
  38. 38.
    Must A, Willett WC, Dietz WH. Remote recall of childhood height, weight, and body build by elderly subjects. Am J Epidemiol. 1993;138(1):56–64.CrossRefPubMedGoogle Scholar
  39. 39.
    Nagin DS. Group-based trajectory modeling: an overview. Ann Nutr Metab. 2014;65(2–3):205–10. Scholar
  40. 40.
    Jones BL, Nagin DS. Advances in group-based trajectory modeling and an SAS procedure for estimating them. Sociol Methods Res. 2007;35:542–71.CrossRefGoogle Scholar
  41. 41.
    Song M, Willett WC, Hu FB, Spiegelman D, Must A, Wu K, et al. Trajectory of body shape across the lifespan and cancer risk. Int J Cancer. 2016;138(10):2383–95. Scholar
  42. 42.
    Nagin DS. Group-based modeling of development. Cambridge: Harvard University Press; 2005.CrossRefGoogle Scholar
  43. 43.
    Willett WC, Reynolds RD, Cottrell-Hoehner S, Sampson L, Browne ML. Validation of a semi-quantitative food frequency questionnaire: comparison with a 1-year diet record. J Am Diet Assoc. 1987;87(1):43–7.PubMedGoogle Scholar
  44. 44.
    Cawthon RM. Telomere measurement by quantitative PCR. Nucleic Acids Res. 2002;30(10):e47.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Hunter DJ, Kraft P, Jacobs KB, Cox DG, Yeager M, Hankinson SE, et al. A genome-wide association study identifies alleles in FGFR2 associated with risk of sporadic postmenopausal breast cancer. Nat Genet. 2007;39(7):870–4. Scholar
  46. 46.
    Song M, Giovannucci E. Estimating the influence of obesity on cancer risk: stratification by smoking is critical. J Clin Oncol. 2016;34(27):3237–9. Scholar
  47. 47.
    Fernandez-Sanchez A, Madrigal-Santillan E, Bautista M, Esquivel-Soto J, Morales-Gonzalez A, Esquivel-Chirino C, et al. Inflammation, oxidative stress, and obesity. Int J Mol Sci. 2011;12(5):3117–32. Scholar
  48. 48.
    Lee HC, Wei YH. Mitochondrial biogenesis and mitochondrial DNA maintenance of mammalian cells under oxidative stress. Int J Biochem Cell Biol. 2005;37(4):822–34. Scholar
  49. 49.
    Vincent HK, Innes KE, Vincent KR. Oxidative stress and potential interventions to reduce oxidative stress in overweight and obesity. Diabetes Obes Metab. 2007;9(6):813–39. Scholar
  50. 50.
    Marseglia L, Manti S, D’Angelo G, Nicotera A, Parisi E, Di Rosa G, et al. Oxidative stress in obesity: a critical component in human diseases. Int J Mol Sci. 2014;16(1):378–400. Scholar
  51. 51.
    Akhmedov AT, Marin-Garcia J. Mitochondrial DNA maintenance: an appraisal. Mol Cell Biochem. 2015;409(1–2):283–305. Scholar
  52. 52.
    An R, Yan H. Body weight status and telomere length in U.S. middle-aged and older adults. Obes Res Clin Pract. 2017;11(1):51–62. Scholar
  53. 53.
    Oeseburg H, de Boer RA, van Gilst WH, van der Harst P. Telomere biology in healthy aging and disease. Pflug Arch. 2010;459(2):259–68. Scholar
  54. 54.
    Janssen-Heininger YM, Mossman BT, Heintz NH, Forman HJ, Kalyanaraman B, Finkel T, et al. Redox-based regulation of signal transduction: principles, pitfalls, and promises. Free Radic Biol Med. 2008;45(1):1–17. Scholar
  55. 55.
    Mishra S, Kumar R, Malhotra N, Singh N, Dada R. Mild oxidative stress is beneficial for sperm telomere length maintenance. World J Methodol. 2016;6(2):163–70. Scholar
  56. 56.
    Jokinen R, Rinnankoski-Tuikka R, Kaye S, Saarinen L, Heinonen S, Myohanen M, et al. Adipose tissue mitochondrial capacity associates with long-term weight loss success. Int J Obes (Lond). 2017. Scholar
  57. 57.
    Larsen NB, Rasmussen M, Rasmussen LJ. Nuclear and mitochondrial DNA repair: Similar pathways? Mitochondrion. 2005;5(2):89–108. Scholar
  58. 58.
    Shokolenko I, Venediktova N, Bochkareva A, Wilson GL, Alexeyev MF. Oxidative stress induces degradation of mitochondrial DNA. Nucleic Acids Res. 2009;37(8):2539–48. Scholar
  59. 59.
    Sandholt CH, Allin KH, Toft U, Borglykke A, Ribel-Madsen R, Sparso T, et al. The effect of GWAS identified BMI loci on changes in body weight among middle-aged Danes during a five-year period. Obesity (Silver Spring). 2014;22(3):901–8. Scholar
  60. 60.
    Hertel JK, Johansson S, Sonestedt E, Jonsson A, Lie RT, Platou CG, et al. FTO, type 2 diabetes, and weight gain throughout adult life: a meta-analysis of 41,504 subjects from the scandinavian HUNT, MDC, and MPP studies. Diabetes. 2011;60(5):1637–44. Scholar
  61. 61.
    Belsky DW, Moffitt TE, Houts R, Bennett GG, Biddle AK, Blumenthal JA, et al. Polygenic risk, rapid childhood growth, and the development of obesity: evidence from a 4-decade longitudinal study. Arch Pediatr Adolesc Med. 2012;166(6):515–21. Scholar

Copyright information

© Springer Science+Business Media B.V., part of Springer Nature 2018

Authors and Affiliations

  • Dong Hang
    • 1
    • 2
  • Hongmei Nan
    • 3
    • 4
  • Ane Sørlie Kværner
    • 1
    • 5
  • Immaculata De Vivo
    • 6
    • 7
  • Andrew Tan Chan
    • 7
    • 8
  • Zhibin Hu
    • 2
  • Hongbing Shen
    • 2
  • Edward Giovannucci
    • 1
    • 6
    • 7
  • Mingyang Song
    • 1
    • 8
  1. 1.Department of NutritionHarvard T.H. Chan School of Public HealthBostonUSA
  2. 2.Department of Epidemiology and Biostatistics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, School of Public HealthNanjing Medical UniversityNanjingChina
  3. 3.Department of Epidemiology, Richard M. Fairbanks School of Public HealthIndiana UniversityIndianapolisUSA
  4. 4.Indiana University Melvin and Bren Simon Cancer CenterIndianapolisUSA
  5. 5.Department of Nutrition, Institute of Basic Medical SciencesUniversity of OsloOsloNorway
  6. 6.Department of EpidemiologyHarvard T.H. Chan School of Public HealthBostonUSA
  7. 7.Channing Division of Network Medicine, Department of MedicineBrigham and Women’s Hospital and Harvard Medical SchoolBostonUSA
  8. 8.Clinical and Translational Epidemiology Unit and Division of GastroenterologyMassachusetts General Hospital and Harvard Medical SchoolBostonUSA

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