European Journal of Nutrition

, Volume 56, Issue 5, pp 1887–1898 | Cite as

One-carbon metabolites and telomere length in a prospective and randomized study of B- and/or D-vitamin supplementation

  • Irene Pusceddu
  • Markus Herrmann
  • Susanne H. Kirsch
  • Christian Werner
  • Ulrich Hübner
  • Marion Bodis
  • Ulrich Laufs
  • Thomas Widmann
  • Stefan Wagenpfeil
  • Jürgen Geisel
  • Wolfgang HerrmannEmail author
Original Contribution



Vitamin B deficiency is common in elderly people and has been associated with an increased risk of developing age-related diseases. B-vitamins are essential for the synthesis and stability of DNA. Telomers are the end caps of chromosomes that shorten progressively with age, and short telomers are associated with DNA instability.


In the present randomized intervention study, we investigated whether the one-carbon metabolism is related to telomere length, a surrogate marker for cellular aging.


Sixty-five subjects (>54 years) were randomly assigned to receive either a daily combination of vitamin D3 (1200 IU), folic acid (0.5 mg), vitamin B12 (0.5 mg), vitamin B6 (50 mg) and calcium carbonate (456 mg) (group A) or vitamin D3 and calcium carbonate alone (group B). Blood testing was performed at baseline and after 1 year of supplementation. The concentrations of several metabolites of the one-carbon pathway, as well as relative telomere length (RTL) and 5,10-methylenetetrahydrofolate reductase C677T genotype, were analyzed.


At baseline, age- and gender-adjusted RTL correlated with total folate and 5-methyltetrahydrofolate (5-methylTHF). Subjects with RTL above the median had higher concentrations of total folate and 5-methylTHF compared to subjects below the median. At study end, gender- and age-adjusted RTL correlated in group A with methylmalonic acid (MMA; r = −0.460, p = 0.0012) and choline (r = 0.434, p = 0.0021) and in group B with 5,10-methenyltetrahydrofolate (r = 0.455, p = 0.026) and dimethylglycine (DMG; r = −0.386, p = 0.047). Subjects in the group A with RTL above the median had lower MMA and higher choline compared to subjects below the median.


The present pilot study suggests a functional relationship between one-carbon metabolism and telomere length. This conclusion is supported by several correlations that were modified by B-vitamin supplementation. In agreement with our hypothesis, the availability of nucleotides and methylation groups seems to impact telomere length. Due to the small sample size and the limitations of the study, further studies should confirm the present results in a larger cohort.


Telomere length Vitamin B supplementation One-carbon metabolites 



Relative telomere length


5,10-Methylenetetrahydrofolate reductase




Methylmalonic acid












Human telomerase reverse transcriptase




Body mass index


Compliance with ethical standards

Conflict of interest

On behalf of all authors, the corresponding author states that there is no conflict of interest.

Supplementary material

394_2016_1231_MOESM1_ESM.doc (218 kb)
Supplementary material 1 (DOC 217 kb)
394_2016_1231_MOESM2_ESM.ppt (104 kb)
Supplementary material 2 (PPT 103 kb)


  1. 1.
    Stabler SP (2013) Clinical practice. Vitamin B12 deficiency. N Engl J Med 368:149–160CrossRefGoogle Scholar
  2. 2.
    Herrmann W, Knapp JP (2002) Hyperhomocysteinemia: a new risk factor for degenerative diseases. Clin Lab 48:471–481Google Scholar
  3. 3.
    Herrmann W, Herrmann M, Joseph J, Tyagi SC (2007) Homocysteine, brain natriuretic peptide and chronic heart failure, a critical review. Clin Chem Lab Med 45:1633–1644Google Scholar
  4. 4.
    Blasco MA (2007) Telomere length, stem cells and aging. Nat Chem Biol 3:640–649CrossRefGoogle Scholar
  5. 5.
    Blasco MA (2005) Telomeres and human disease: ageing, cancer and beyond. Nat Rev Genet 6:611–622CrossRefGoogle Scholar
  6. 6.
    Blasco MA (2005) Mice with bad ends: mouse models for the study of telomeres and telomerase in cancer and aging. EMBO J 24:1095–1103CrossRefGoogle Scholar
  7. 7.
    Blasco MA (2007) The epigenetic regulation of mammalian telomeres. Nat Rev Genet 8:299–309CrossRefGoogle Scholar
  8. 8.
    Gonzalo S, Jaco I, Fraga MF, Chen T, Li E, Esteller M, Blasco MA (2006) DNA methyltransferases control telomere length and telomere recombination in mammalian cells. Nat Cell Biol 8:416–424CrossRefGoogle Scholar
  9. 9.
    Hayflick L (1965) The limited in vitro lifetime of human diploid cell strains. Exp Cell Res 37:614–636CrossRefGoogle Scholar
  10. 10.
    Paul L, Cattaneo M, D’Angelo A, Sampietro F, Fermo I, Razzari C, Fontana G, Eugene N, Jacques PF, Selhub J (2009) Telomere length in peripheral blood mononuclear cells is associated with folate status in men. J Nutr 139:1273–1278CrossRefGoogle Scholar
  11. 11.
    Liu JJ, Prescott J, Giovannucci E, Hankinson SE, Rosner B, De Vivo I (2013) One-carbon metabolism factors and leukocyte telomere length. Am J Clin Nutr 97:794–799CrossRefGoogle Scholar
  12. 12.
    Richards JB, Valdes AM, Gardner JP, Kato BS, Siva A, Kimura M, Lu X, Brown MJ, Aviv A, Spector TD (2008) Homocyteine levels and leukocyte telomere length. Atherosclerosis 200:271–277CrossRefGoogle Scholar
  13. 13.
    Paul L, Jacques PF, Aviv A, Vasan RS, D’Agostino RB, Levy D, Selhub J (2015) High plasma folate is negatively associated with leukocyte telomere length in the Framingham Offspring cohort. Eur J Nutr 54:235–241CrossRefGoogle Scholar
  14. 14.
    Herrmann W, Kirsch SH, Kruse V, Eckert R, Graber S, Geisel J, Obeid R (2013) One year B and D vitamins supplementation improves metabolic bone markers. Clin Chem Lab Med 51:639–647Google Scholar
  15. 15.
    Kirsch SH, Knapp JP, Herrmann W, Obeid R (2010) Quantification of key folate forms in serum using stable-isotope dilution ultra performance liquid chromatography–tandem mass spectrometry. J Chromatogr B Anal Technol Biomed Life Sci 878:68–75CrossRefGoogle Scholar
  16. 16.
    Kirsch SH, Herrmann W, Kruse V, Eckert R, Gräber S, Geisel J, Obeid R (2015) One year B-vitamins increases serum and whole blood forms and lowers plasma homocysteine in older Germans. Clin Chem Lab Med 53:445–452CrossRefGoogle Scholar
  17. 17.
    Allen RH, Stabler SP, Savage DG, Lindenbaum J (1993) Elevation of 2-methylcitric acid I and II levels in serum, urine, and cerebrospinal fluid of patients with cobalamin deficiency. Metabolism 42:978–988CrossRefGoogle Scholar
  18. 18.
    Stabler SP, Lindenbaum J, Savage DG, Allen RH (1993) Elevation of serum cystathionine levels in patients with cobalamin and folate deficiency. Blood 81:3404–3413Google Scholar
  19. 19.
    Herrmann W, Schorr H, Bodis M, Knapp JP, Müller A, Stein G, Geisel J (2000) Role of homocysteine, cystathionine and methylmalonic acid measurement for diagnosis of vitamin deficiency in high-aged subjects. Eur J Clin Invest 30:1083–1089CrossRefGoogle Scholar
  20. 20.
    Kirsch SH, Knapp JP, Geisel J, Herrmann W, Obeid R (2009) Simultaneous quantification of S-adenosyl methionine and S-adenosyl homocysteine in human plasma by stable-isotope dilution ultra performance liquid chromatography tandem mass spectrometry. J Chromatogr B Anal Technol Biomed Life Sci 877:3865–3870CrossRefGoogle Scholar
  21. 21.
    Hübner U, Geisel J, Kirsch SH, Kruse V, Bodis M, Klein C, Herrmann W, Obeid R (2013) Effect of 1 year B and D vitamin supplementation on LINE-1 repetitive element methylation in older subjects. Clin Chem Lab Med 51:649–655CrossRefGoogle Scholar
  22. 22.
    Kirsch SH, Herrmann W, Rabagny Y, Obeid R (2010) Quantification of acetylcholine, choline, betaine, and dimethylglycine in human plasma and urine using stable-isotope dilution ultra performance liquid chromatography-tandem mass spectrometry. J Chromatogr B Anal Technol Biomed Life Sci 878:3338–3344CrossRefGoogle Scholar
  23. 23.
    Ulleland M, Eilertsen I, Quadros EV, Rothenberg SP, Fedosov SN, Sundrehagen E, Orning L (2002) Direct assay for cobalamin bound to transcobalamin (holo-transcobalamin) in serum. Clin Chem 48:526–532Google Scholar
  24. 24.
    Cawthon RM (2002) Telomere measurement by quantitative PCR. Nucleic Acids Res 30:2–6CrossRefGoogle Scholar
  25. 25.
    Werner C, Fürster T, Widmann T, Pöss J, Roggia C, Hanhoun M, Scharhag T, Büchner N, Meyer T, Kindermann W et al (2009) Physical exercise prevents cellular senescence in circulating leukocytes and in the vessel wall. Circulation 120:2438–2447CrossRefGoogle Scholar
  26. 26.
    Pusceddu I, Herrmann M, Kirsch SH, Werner C, Hübner U, Bodis M, Laufs U, Wagenpfeil S, Geisel J, Herrmann W (2015) Prospective study of telomere length and LINE-1 methylation in peripheral blood cells: the role of B and/or D vitamins supplementation. Eur J Nutr. doi: 10.1007/500394-015-1003-1 Google Scholar
  27. 27.
    Verri A, Focher F, Tettamanti G, Grazioli V (2005) Two-step genetic screening of thrombophilia by pyrosequencing. Clin Chem 51:1282–1284CrossRefGoogle Scholar
  28. 28.
    Moores CJ, Fenech M, O’Callaghan NJ (2011) Telomere dynamics: the influence of folate and DNA methylation. Ann NY Acad Sci 1229:76–88CrossRefGoogle Scholar
  29. 29.
    Blount BC, Mack MM, Wher CM, MacGregor JT, Hiatt RA, Wang G, Wickramasinghe SN, Everson RB, Ames BN (1997) Folate deficiency causes uracil misincorporation into human DNA and chromosome breakage: implications for cancer and neuronal damage. Proc Natl Acad Sci USA 94:3290–3295CrossRefGoogle Scholar
  30. 30.
    Kruk PA, Rampino NJ, Bohr VA (1995) DNA damage and repair in telomeres: relation to aging. Proc Natl Acad Sci USA 92:258–262CrossRefGoogle Scholar
  31. 31.
    Fenech M (2012) Folate (vitamin B9) and vitamin B12 and their function in the maintenance of nuclear and mitochondrial genome integrity. Mutat Res 733:21–33CrossRefGoogle Scholar
  32. 32.
    Bull CF, Mayrhofer G, O’Callaghan NJ, Au AY, Pickett HA, Low GKM, Zeegers D, Hande MP, Fenech MF (2013) Folate deficiency induces dysfunctional long and short telomeres; both states are associated with hypomethylation and DNA damage in human WIL2-NS cells. Cancer Prev Res 7:128–138CrossRefGoogle Scholar
  33. 33.
    Zhang D, Wen X, Wu W, Xu E, Zhang Y, Cui W (2013) Homocysteine-related hTERT DNA demethylation contributes to shortened leukocyte telomere length in atherosclerosis. Atherosclerosis 231:173–179CrossRefGoogle Scholar
  34. 34.
    Zhang D, Sun X, Liu J, Xie X, Cui W, Zhu Y (2015) Homocysteine accelerates senescence of endothelial cells via DNA hypomethylation of human telomerase reverse transcriptase. Arterioscler Thromb Vasc Biol 35:71–78CrossRefGoogle Scholar
  35. 35.
    Jiang WQ, Zhong ZH, Henson JD, Reddel RR (2007) Identification of candidate alternative lengthening of telomeres genes by methionine restriction and RNA interference. Oncogene 26:4635–4647CrossRefGoogle Scholar
  36. 36.
    Kim S, Parks CG, Xu Z, Carswell G, DeRoo LA, Sandler DP et al (2012) Association between genetic variants in DNA and histone methylation and telomere length. PLoS One 7:1–7CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Irene Pusceddu
    • 1
  • Markus Herrmann
    • 2
  • Susanne H. Kirsch
    • 1
  • Christian Werner
    • 3
  • Ulrich Hübner
    • 1
  • Marion Bodis
    • 1
  • Ulrich Laufs
    • 3
  • Thomas Widmann
    • 4
  • Stefan Wagenpfeil
    • 5
  • Jürgen Geisel
    • 1
  • Wolfgang Herrmann
    • 1
    Email author
  1. 1.Department of Clinical Chemistry and Laboratory MedicineSaarland University HospitalHomburg/SaarGermany
  2. 2.Department of Clinical PathologyDistrict Hospital BolzanoBolzanoItaly
  3. 3.Department of CardiologySaarland University HospitalHomburg/SaarGermany
  4. 4.Department of OncologyAsklepiosklinik TribergTribergGermany
  5. 5.Institute for Medical Biometry, Epidemiology and Medical InformaticsSaarland UniversityHomburg/SaarGermany

Personalised recommendations