Human Genetics

, Volume 133, Issue 9, pp 1149–1159 | Cite as

Mitochondrial DNA copy number in peripheral blood cells declines with age and is associated with general health among elderly

  • Jonas Mengel-FromEmail author
  • Mikael Thinggaard
  • Christine Dalgård
  • Kirsten Ohm Kyvik
  • Kaare Christensen
  • Lene Christiansen
Original Investigation


The role of the mitochondria in disease, general health and aging has drawn much attention over the years. Several attempts have been made to describe how the numbers of mitochondria correlate with age, although with inconclusive results. In this study, the relative quantity of mitochondrial DNA compared to nuclear DNA, i.e. the mitochondrial DNA copy number, was measured by PCR technology and used as a proxy for the content of mitochondria copies. In 1,067 Danish twins and singletons (18–93 years of age), with the majority being elderly individuals, the estimated mean mitochondrial DNA copy number in peripheral blood cells was similar for those 18–48 years of age [mean relative mtDNA content: 61.0; 95 % CI (52.1; 69.9)], but declined by −0.54 mtDNA 95 % CI (−0.63; −0.45) every year for those older than approximately 50 years of age. However, the longitudinal, yearly decline within an individual was more than twice as steep as observed in the cross-sectional analysis [decline of mtDNA content: −1.27; 95 % CI (−1.71; −0.82)]. Subjects with low mitochondrial DNA copy number had poorer outcomes in terms of cognitive performance, physical strength, self-rated health, and higher all-cause mortality than subjects with high mitochondrial DNA copy number, also when age was controlled for. The copy number mortality association can contribute to the smaller decline in a cross-sectional sample of the population compared to the individual, longitudinal decline. This study suggests that high mitochondrial DNA copy number in blood is associated with better health and survival among elderly.


Birth Cohort Twin Pair Danish Twin POLG Gene Cognitive Composite Score 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



We would like to thank Tinna Stevnsner for commenting on and discussing the paper and Steen Gregersen, Ulla Munk and Susanne Knudsen for technical assistance, colleagues at the epidemiology unit for collecting materials and participants for their contributions. The study was supported by a grant from the US National Institutes of Health/National Institute on Aging, Grant No. P01 AG08761; by a grant from The Danish Agency for Science, Technology and Innovation, Grant No. 09–070081, the European Union’s Seventh Framework Programme (FP7/2007-2011) under grant agreement n° 259679 and by grants from the Oda and Hans Svenningsens Foundation and Dagmar Marshalls Foundation. The Danish Aging Research Center is supported by a grant from the VELUX Foundation. The GEMINAKAR project was supported by grants from the Danish Medical Research Council, the Danish Diabetes Association, the NOVO Foundation and the Danish Heart Foundation. JMF initiated this study. MT contributed with statistical analysis. All co-authors contributed to the work by supplying materials or planning and writing this paper. All authors approved the final version. The authors declare no conflicts of interest.


  1. Bai RK, Perng CL, Hsu CH, Wong LJ (2004) Quantitative PCR analysis of mitochondrial DNA content in patients with mitochondrial disease. Ann N Y Acad Sci 1011:304–309PubMedCrossRefGoogle Scholar
  2. Barazzoni R, Short KR, Nair KS (2000) Effects of aging on mitochondrial DNA copy number and cytochrome c oxidase gene expression in rat skeletal muscle, liver, and heart. J Biol Chem 275(5):3343–3347PubMedCrossRefGoogle Scholar
  3. Bonner MR, Shen M, Liu CS, Divita M, He X, Lan Q (2009) Mitochondrial DNA content and lung cancer risk in Xuan Wei, China. Lung Cancer 63(3):331–334PubMedCentralPubMedCrossRefGoogle Scholar
  4. Christensen K, McGue M (2012) Commentary: twins, worms and life course epidemiology. Int J Epidemiol 41(4):1010–1011PubMedCrossRefGoogle Scholar
  5. Christensen K, McGue M, Yashin A, Iachine I, Holm NV, Vaupel JW (2000) Genetic and environmental influences on functional abilities in Danish twins aged 75 years and older. J Gerontol A Biol Sci Med Sci 55(8):M446–M452PubMedGoogle Scholar
  6. Christensen K, Gaist D, Vaupel JW, McGue M (2002) Genetic contribution to rate of change in functional abilities among Danish twins aged 75 years or more. Am J Epidemiol 155(2):132–139PubMedCrossRefGoogle Scholar
  7. Christensen K, Frederiksen H, Vaupel JW, McGue M (2003) Age trajectories of genetic variance in physical functioning: a longitudinal study of Danish twins aged 70 years and older. Behav Genet 33(2):125–136PubMedCrossRefGoogle Scholar
  8. Christensen K, McGue M, Petersen I, Jeune B, Vaupel JW (2008) Exceptional longevity does not result in excessive levels of disability. Proc Natl Acad Sci USA 105(36):13274–13279PubMedCentralPubMedCrossRefGoogle Scholar
  9. Christensen K, Thinggaard M, McGue M, Rexbye H, Hjelmborg JV, Aviv A, Gunn D, van der Ouderaa F, Vaupel JW (2009) Perceived age as clinically useful biomarker of ageing: cohort study. BMJ 339:b5262PubMedCentralPubMedCrossRefGoogle Scholar
  10. Chu HT, Hsiao WW, Tsao TT, Chang CM, Liu YW, Fan CC, Lin H, Chang HH, Yeh TJ, Chen JC, Huang DM, Chen CC, Kao CY (2012) Quantitative assessment of mitochondrial DNA copies from whole genome sequencing. BMC Genom 13(Suppl 7):S5Google Scholar
  11. Cree LM, Patel SK, Pyle A, Lynn S, Turnbull DM, Chinnery PF, Walker M (2008) Age-related decline in mitochondrial DNA copy number in isolated human pancreatic islets. Diabetologia 51(8):1440–1443PubMedCrossRefGoogle Scholar
  12. Curran JE, Johnson MP, Dyer TD, Goring HH, Kent JW, Charlesworth JC, Borg AJ, Jowett JB, Cole SA, MacCluer JW, Kissebah AH, Moses EK, Blangero J (2007) Genetic determinants of mitochondrial content. Hum Mol Genet 16(12):1504–1514PubMedCrossRefGoogle Scholar
  13. Das G, Hickey DR, Principio L, Conklin KT, Short J, Miller JR, McLendon G, Sherman F (1988) Replacements of lysine 32 in yeast cytochrome c. Effects on the binding and reactivity with physiological partners. J Biol Chem 263(34):18290–18297PubMedGoogle Scholar
  14. Frahm T, Mohamed SA, Bruse P, Gemund C, Oehmichen M, Meissner C (2005) Lack of age-related increase of mitochondrial DNA amount in brain, skeletal muscle and human heart. Mech Ageing Dev 126(11):1192–1200PubMedCrossRefGoogle Scholar
  15. Frederiksen H, Gaist D, Petersen HC, Hjelmborg J, McGue M, Vaupel JW, Christensen K (2002) Hand grip strength: a phenotype suitable for identifying genetic variants affecting mid- and late-life physical functioning. Genet Epidemiol 23(2):110–122PubMedCrossRefGoogle Scholar
  16. Gaist D, Bathum L, Skytthe A, Jensen TK, McGue M, Vaupel JW, Christensen K (2000) Strength and anthropometric measures in identical and fraternal twins: no evidence of masculinization of females with male co-twins. Epidemiology 11(3):340–343PubMedCrossRefGoogle Scholar
  17. Hartmann N, Reichwald K, Wittig I, Drose S, Schmeisser S, Luck C, Hahn C, Graf M, Gausmann U, Terzibasi E, Cellerino A, Ristow M, Brandt U, Platzer M, Englert C (2011) Mitochondrial DNA copy number and function decrease with age in the short-lived fish Nothobranchius furzeri. Aging Cell 10(5):824–831PubMedCrossRefGoogle Scholar
  18. Herskind AM, McGue M, Iachine IA, Holm N, Sorensen TI, Harvald B, Vaupel JW (1996) Untangling genetic influences on smoking, body mass index and longevity: a multivariate study of 2464 Danish twins followed for 28 years. Hum Genet 98(4):467–475PubMedCrossRefGoogle Scholar
  19. Hosgood HD 3rd, Liu CS, Rothman N, Weinstein SJ, Bonner MR, Shen M, Lim U, Virtamo J, Cheng WL, Albanes D, Lan Q (2010) Mitochondrial DNA copy number and lung cancer risk in a prospective cohort study. Carcinogenesis 31(5):847–849PubMedCentralPubMedCrossRefGoogle Scholar
  20. Kim MY, Lee JW, Kang HC, Kim E, Lee DC (2011) Leukocyte mitochondrial DNA (mtDNA) content is associated with depression in old women. Arch Gerontol Geriatr 53(2):e218–e221PubMedCrossRefGoogle Scholar
  21. Lee HK, Song JH, Shin CS, Park DJ, Park KS, Lee KU, Koh CS (1998) Decreased mitochondrial DNA content in peripheral blood precedes the development of non-insulin-dependent diabetes mellitus. Diabetes Res Clin Pract 42(3):161–167PubMedCrossRefGoogle Scholar
  22. Lee JW, Park KD, Im JA, Kim MY, Lee DC (2010) Mitochondrial DNA copy number in peripheral blood is associated with cognitive function in apparently healthy elderly women. Clin Chim Acta 411(7–8):592–596PubMedCrossRefGoogle Scholar
  23. Liu CS, Tsai CS, Kuo CL, Chen HW, Lii CK, Ma YS, Wei YH (2003) Oxidative stress-related alteration of the copy number of mitochondrial DNA in human leukocytes. Free Radic Res 37(12):1307–1317PubMedCrossRefGoogle Scholar
  24. McGue M, Christensen K (2001) The heritability of cognitive functioning in very old adults: evidence from Danish twins aged 75 years and older. Psychol Aging 16(2):272–280PubMedCrossRefGoogle Scholar
  25. McGue M, Christensen K (2002) The heritability of level and rate-of-change in cognitive functioning in Danish twins aged 70 years and older. Exp Aging Res 28(4):435–451PubMedCrossRefGoogle Scholar
  26. Mengel-From J, Christensen K, McGue M, Christiansen L (2011) Genetic variations in the CLU and PICALM genes are associated with cognitive function in the oldest old. Neurobiol Aging 32(3):554 e557–511 e557CrossRefGoogle Scholar
  27. Miller FJ, Rosenfeldt FL, Zhang C, Linnane AW, Nagley P (2003) Precise determination of mitochondrial DNA copy number in human skeletal and cardiac muscle by a PCR-based assay: lack of change of copy number with age. Nucleic Acids Res 31(11):e61PubMedCentralPubMedCrossRefGoogle Scholar
  28. Navarro-Sastre A, Tort F, Garcia-Villoria J, Pons MR, Nascimento A, Colomer J, Campistol J, Yoldi ME, Lopez-Gallardo E, Montoya J, Unceta M, Martinez MJ, Briones P, Ribes A (2012) Mitochondrial DNA depletion syndrome: new descriptions and the use of citrate synthase as a helpful tool to better characterise the patients. Mol Genet Metab 107(3):409–415PubMedCrossRefGoogle Scholar
  29. Nybo H, Petersen HC, Gaist D, Jeune B, Andersen K, McGue M, Vaupel JW, Christensen K (2003) Predictors of mortality in 2,249 nonagenarians—the Danish 1905-Cohort Survey. J Am Geriatr Soc 51(10):1365–1373PubMedCrossRefGoogle Scholar
  30. Pedersen CB, Gotzsche H, Moller JO, Mortensen PB (2006) The Danish civil registration system. A cohort of eight million persons. Dan Med Bull 53(4):441–449PubMedGoogle Scholar
  31. Pohjoismaki JL, Goffart S, Taylor RW, Turnbull DM, Suomalainen A, Jacobs HT, Karhunen PJ (2010) Developmental and pathological changes in the human cardiac muscle mitochondrial DNA organization, replication and copy number. PLoS One 5(5):e10426PubMedCentralPubMedCrossRefGoogle Scholar
  32. Reiling E, Ling C, Uitterlinden AG, Van’t Riet E, Welschen LM, Ladenvall C, Almgren P, Lyssenko V, Nijpels G, van Hove EC, Maassen JA, de Geus EJ, Boomsma DI, Dekker JM, Groop L, Willemsen G, 't Hart LM (2010) The association of mitochondrial content with prevalent and incident type 2 diabetes. J Clin Endocrinol Metab 95(4):1909–1915PubMedCrossRefGoogle Scholar
  33. Schousboe K, Visscher PM, Henriksen JE, Hopper JL, Sorensen TI, Kyvik KO (2003) Twin study of genetic and environmental influences on glucose tolerance and indices of insulin sensitivity and secretion. Diabetologia 46(9):1276–1283PubMedCrossRefGoogle Scholar
  34. Short KR, Bigelow ML, Kahl J, Singh R, Coenen-Schimke J, Raghavakaimal S, Nair KS (2005) Decline in skeletal muscle mitochondrial function with aging in humans. Proc Natl Acad Sci USA 102(15):5618–5623PubMedCentralPubMedCrossRefGoogle Scholar
  35. Skytthe A, Kyvik K, Holm NV, Vaupel JW, Christensen K (2002) The Danish twin registry: 127 birth cohorts of twins. Twin Res 5(5):352–357PubMedCrossRefGoogle Scholar
  36. Skytthe A, Christiansen L, Kyvik KO, Bodker FL, Hvidberg L, Petersen I, Nielsen MM, Bingley P, Hjelmborg J, Tan Q, Holm NV, Vaupel JW, McGue M, Christensen K (2013) The Danish twin registry: linking surveys, national registers, and biological information. Twin Res Hum Genet: Off J Int Soc Twin Stud 16(1):104–111CrossRefGoogle Scholar
  37. Stier A, Bize P, Schull Q, Zoll J, Singh F, Geny B, Gros F, Royer C, Massemin S, Criscuolo F (2013) Avian erythrocytes have functional mitochondria, opening novel perspectives for birds as animal models in the study of ageing. Front Zool 10(1):33PubMedCentralPubMedCrossRefGoogle Scholar
  38. Tan D, Goerlitz DS, Dumitrescu RG, Han D, Seillier-Moiseiwitsch F, Spernak SM, Orden RA, Chen J, Goldman R, Shields PG (2008) Associations between cigarette smoking and mitochondrial DNA abnormalities in buccal cells. Carcinogenesis 29(6):1170–1177PubMedCentralPubMedCrossRefGoogle Scholar
  39. Tiainen K, Thinggaard M, Jylha M, Bladbjerg E, Christensen K, Christiansen L (2012) Associations between inflammatory markers, candidate polymorphisms and physical performance in older Danish twins. Exp Gerontol 47(1):109–115PubMedCentralPubMedCrossRefGoogle Scholar
  40. Venegas V, Wang J, Dimmock D, Wong LJ (2011) Real-time quantitative PCR analysis of mitochondrial DNA content. Curr Protoc Hum Genet Chapter 19:Unit 19 17Google Scholar
  41. Welle S, Bhatt K, Shah B, Needler N, Delehanty JM, Thornton CA (2003) Reduced amount of mitochondrial DNA in aged human muscle. J Appl Physiol 94(4):1479–1484PubMedGoogle Scholar
  42. Xing J, Chen M, Wood CG, Lin J, Spitz MR, Ma J, Amos CI, Shields PG, Benowitz NL, Gu J, de Andrade M, Swan GE, Wu X (2008) Mitochondrial DNA content: its genetic heritability and association with renal cell carcinoma. J Natl Cancer Inst 100(15):1104–1112PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Jonas Mengel-From
    • 1
    • 2
    Email author
  • Mikael Thinggaard
    • 1
  • Christine Dalgård
    • 3
  • Kirsten Ohm Kyvik
    • 4
  • Kaare Christensen
    • 1
    • 2
    • 5
  • Lene Christiansen
    • 1
  1. 1.Epidemiology, Biostatistics and Biodemography Unit, The Danish Aging Research Center, The Danish Twin Registry, Institute of Public HealthUniversity of Southern DenmarkOdenseDenmark
  2. 2.Department of Clinical GeneticsOdense University HospitalOdenseDenmark
  3. 3.Department of Environmental Medicine, Institute of Public HealthUniversity of Southern DenmarkOdenseDenmark
  4. 4.Institute of Regional Health ResearchUniversity of Southern Denmark, Odense Patient Data Explorative Network (OPEN), Odense University HospitalOdenseDenmark
  5. 5.Department of Clinical Biochemistry and PharmacologyOdense University HospitalOdenseDenmark

Personalised recommendations