Advertisement

European Journal of Nutrition

, Volume 54, Issue 2, pp 235–241 | Cite as

High plasma folate is negatively associated with leukocyte telomere length in Framingham Offspring cohort

  • Ligi PaulEmail author
  • Paul F. Jacques
  • Abraham Aviv
  • Ramachandran S. Vasan
  • Ralph B. D’Agostino
  • Daniel Levy
  • Jacob Selhub
Original Contribution

Abstract

Purpose

Shortening of telomeres, the protective structures at the ends of eukaryotic chromosomes, is associated with age-related pathologies. Telomere length is influenced by DNA integrity and DNA and histone methylation. Folate plays a role in providing precursors for nucleotides and methyl groups for methylation reactions and has the potential to influence telomere length.

Method

We determined the association between leukocyte telomere length and long-term plasma folate status (mean of 4 years) in Framingham Offspring Study (n = 1,044, females = 52.1 %, mean age 59 years) using data from samples collected before and after folic acid fortification. Leukocyte telomere length was determined by Southern analysis and fasting plasma folate concentration using microbiological assay.

Results

There was no significant positive association between long-term plasma folate and leukocyte telomere length among the Framingham Offspring Study participants perhaps due to their adequate folate status. While the leukocyte telomere length in the second quintile of plasma folate was longer than that in the first quintile, the difference was not statistically significant. The leukocyte telomere length of the individuals in the fifth quintile of plasma folate was shorter than that of those in the second quintile by 180 bp (P < 0.01). There was a linear decrease in leukocyte telomere length with higher plasma folate concentrations in the upper four quintiles of plasma folate (P for trend = 0.001). Multivitamin use was associated with shorter telomeres in this cohort (P = 0.015).

Conclusions

High plasma folate status possibly resulting from high folic acid intake may interfere with the role of folate in maintaining telomere integrity.

Keywords

Telomere length Folate Multivitamins Folic acid fortification 

Notes

Acknowledgments

Support from United States Department of Agriculture Cooperative Agreement 51520-008-04S, National Heart Lung and Blood Institute, Framingham Heart Study (NHLBI/NIH Contract #N01-HC-25195) and Boston University School of Medicine. Any opinions, findings, conclusion or recommendations expressed in this publication are those of the authors and do not necessarily reflect the view of the United States Department of Agriculture.

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

394_2014_704_MOESM1_ESM.docx (21 kb)
Supplementary material 1 (DOCX 20 kb)

References

  1. 1.
    Minamino T, Miyauchi H, Yoshida T, Ishida Y, Yoshida H, Komuro I (2002) Endothelial cell senescence in human atherosclerosis: role of telomere in endothelial dysfunction. Circulation 105:1541–1544CrossRefGoogle Scholar
  2. 2.
    Panossian LA, Porter VR, Valenzuela HF, Zhu X, Reback E, Masterman D, Cummings JL, Effros RB (2003) Telomere shortening in T cells correlates with Alzheimer’s disease status. Neurobiol Aging 24:77–84CrossRefGoogle Scholar
  3. 3.
    Guan JZ, Maeda T, Sugano M, Oyama J-I, Higuchi Y, Suzuki T, Makino N (2008) A percentage analysis of the telomere length in parkinson’s disease patients. J Gerontol A Biol Sci Med Sci 63:467–473CrossRefGoogle Scholar
  4. 4.
    Wu X, Amos CI, Zhu Y, Zhao H, Grossman BH, Shay JW, Luo S, Hong WK, Spitz MR (2003) Telomere dysfunction: a potential cancer predisposition factor. J Natl Cancer I 95:1211–1218CrossRefGoogle Scholar
  5. 5.
    Harley CB, Futcher AB, Greider CW (1990) Telomeres shorten during ageing of human fibroblasts. Nature 345:458–460CrossRefGoogle Scholar
  6. 6.
    von Zglinicki T, Pilger R, Sitte N (2000) Accumulation of single-strand breaks is the major cause of telomere shortening in human fibroblasts. Free Radic Biol Med 28:64–74CrossRefGoogle Scholar
  7. 7.
    Benetti R, Gonzalo S, Jaco I, Schotta G, Klatt P, Jenuwein T, Blasco MA (2007) Suv4-20 h deficiency results in telomere elongation and derepression of telomere recombination. J Cell Biol 178:925–936CrossRefGoogle Scholar
  8. 8.
    Garcia-Cao M, O’Sullivan R, Peters AH, Jenuwein T, Blasco MA (2004) Epigenetic regulation of telomere length in mammalian cells by the Suv39h1 and Suv39h2 histone methyltransferases. Nat Genet 36:94–99CrossRefGoogle Scholar
  9. 9.
    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
  10. 10.
    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
  11. 11.
    Latre L, Tusell L, Martin M, Miro R, Egozcue J, Blasco MA, Genesca A (2003) Shortened telomeres join to DNA breaks interfering with their correct repair. Exp Cell Res 287:282–288CrossRefGoogle Scholar
  12. 12.
    Woods DD (1964) The function of folic acid in cellular metabolism. Proc R Soc Med 57:388–390Google Scholar
  13. 13.
    James SJ, Yin L, Swendseid ME (1989) DNA strand break accumulation, thymidylate synthesis and NAD levels in lymphocytes from methyl donor-deficient rats. J Nutr 119:661–664Google Scholar
  14. 14.
    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
  15. 15.
    Friso S, Choi SW, Girelli D, Mason JB, Dolnikowski GG, Bagley PJ, Olivieri O, Jacques PF, Rosenberg IH, Corrocher R, Selhub J (2002) A common mutation in the 5,10-methylenetetrahydrofolate reductase gene affects genomic DNA methylation through an interaction with folate status. Proc Natl Acad Sci USA 99:5606–5611CrossRefGoogle Scholar
  16. 16.
    Bull CF, O’Callaghan NJ, Mayrhofer G, Fenech MF (2009) Telomere length in lymphocytes of older South Australian men may be inversely associated with plasma homocysteine. Rejuvenation Res 12:341–349CrossRefGoogle Scholar
  17. 17.
    Richards JB, Valdes AM, Gardner JP, Kato BS, Siva A, Kimura M, Lu X, Brown MJ, Aviv A, Spector TD (2008) Homocysteine levels and leukocyte telomere length. Atherosclerosis 200:271–277CrossRefGoogle Scholar
  18. 18.
    Jacques PF, Selhub J, Bostom AG, Wilson PW, Rosenberg IH (1999) The effect of folic acid fortification on plasma folate and total homocysteine concentrations. N Engl J Med 340:1449–1454CrossRefGoogle Scholar
  19. 19.
    Feinleib M, Kannel WB, Garrison RJ, McNamara PM, Castelli WP (1975) The Framingham offspring study. Design and preliminary data. Prev Med 4:518–525CrossRefGoogle Scholar
  20. 20.
    O’Donnell CJ, Demissie S, Kimura M, Levy D, Gardner JP, White C, D’Agostino RB, Wolf PA, Polak J, Cupples LA, Aviv A (2008) Leukocyte telomere length and carotid artery intimal medial thickness: the Framingham heart study. Arterioscler Thromb Vasc Biol 28:1165–1171CrossRefGoogle Scholar
  21. 21.
    Horne DW, Patterson D (1988) Lactobacillus casei microbiological assay of folic acid derivatives in 96-well microtiter plates. Clin Chem 34:2357–2359Google Scholar
  22. 22.
    Choumenkovitch SF, Selhub J, Wilson PW, Rader JI, Rosenberg IH, Jacques PF (2002) Folic acid intake from fortification in United States exceeds predictions. J Nutr 132:2792–2798Google Scholar
  23. 23.
    Husdan H, Rapoport A (1968) Estimation of creatinine by the Jaffe reaction. A comparison of three methods. Clin Chem 14:222–238Google Scholar
  24. 24.
    Shin YS, Rasshofer R, Friedrich B, Endres W (1983) Pyridoxal-5′-phosphate determination by a sensitive micromethod in human blood, urine and tissues; its relation to cystathioninuria in neuroblastoma and biliary atresia. Clin Chim Acta 127:77–85CrossRefGoogle Scholar
  25. 25.
    Xu Q, Parks CG, DeRoo LA, Cawthon RM, Sandler DP, Chen H (2009) Multivitamin use and telomere length in women. Am J Clin Nutr 89:1857–1863CrossRefGoogle Scholar
  26. 26.
    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
  27. 27.
    Codd V, Mangino M, van der Harst P, Braund PS, Kaiser M, Beveridge AJ, Rafelt S, Moore J, Nelson C, Soranzo N, Zhai G, Valdes AM, Blackburn H, Leach IM, de Boer RA, Kimura M, Aviv A, Consortium WTCC, Goodall AH, Ouwehand W, van Veldhuisen DJ, van Gilst WH, Navis G, Burton PR, Tobin MD, Hall AS, Thompson JR, Spector T, Samani NJ (2010) Common variants near TERC are associated with mean telomere length. Nat Genet 42:197–199Google Scholar
  28. 28.
    Bleys J, Navas-Acien A, Guallar E (2008) Serum selenium levels and all-cause, cancer, and cardiovascular mortality among us adults. Arch Intern Med 168:404–410CrossRefGoogle Scholar
  29. 29.
    Gibson T, Weinstein S, Mayne S, Pfeiffer R, Selhub J, Taylor P, Virtamo J, Albanes D, Stolzenberg-Solomon R (2010) A prospective study of one-carbon metabolism biomarkers and risk of renal cell carcinoma. Cancer Cause Control 21:1061–1069CrossRefGoogle Scholar
  30. 30.
    Zhang SM, Willett WC, Selhub J, Hunter DJ, Giovannucci EL, Holmes MD, Colditz GA, Hankinson SE (2003) Plasma folate, vitamin B6, vitamin B12, homocysteine, and risk of breast cancer. J Natl Cancer I 95:373–380CrossRefGoogle Scholar
  31. 31.
    Morrison HI, Schaubel D, Desmeules M, Wigle DT (1996) Serum folate and risk of fatal coronary heart disease. JAMA 275:1893–1896CrossRefGoogle Scholar
  32. 32.
    Wang H, Odegaard A, Thyagarajan B, Hayes J, Cruz KS, Derosiers MF, Tyas SL, Gross MD (2012) Blood folate is associated with asymptomatic or partially symptomatic Alzheimer’s disease in the Nun study. J Alzheimer dis 28:637–645Google Scholar
  33. 33.
    Smithells RW, Sheppard S, Schorah CJ, Seller MJ, Nevin NC, Harris R, Read AP, Fielding DW (1980) Possible prevention of neural-tube defects by periconceptional vitamin supplementation. Lancet 1:339–340CrossRefGoogle Scholar
  34. 34.
    Bailey RL, Dodd KW, Gahche JJ, Dwyer JT, McDowell MA, Yetley EA, Sempos CA, Burt VL, Radimer KL, Picciano MF (2010) Total folate and folic acid intake from foods and dietary supplements in the United States: 2003–2006. Am J Clin Nutr 91:231–237CrossRefGoogle Scholar
  35. 35.
    Hara A, Sasazuki S, Inoue M, Shimazu T, Iwasaki M, Sawada N, Yamaji T, Ishihara J, Iso H, Tsugane S (2011) Use of vitamin supplements and risk of total cancer and cardiovascular disease among the Japanese general population: a population-based survey. BMC Public Health 11:540CrossRefGoogle Scholar
  36. 36.
    Larsson SC, Akesson A, Bergkvist L, Wolk A (2010) Multivitamin use and breast cancer incidence in a prospective cohort of Swedish women. Am J Clin Nutr 91:1268–1272CrossRefGoogle Scholar
  37. 37.
    Ericson U, Borgquist S, Ivarsson MIL, Sonestedt E, Gullberg B, Carlson J, Olsson H, Jirstram K, Wirfolt E (2010) Plasma folate concentrations are positively associated with risk of estrogen receptor β negative breast cancer in a Swedish nested case control study. J Nutr 140:1661–1668CrossRefGoogle Scholar
  38. 38.
    Inoue-Choi M, Greenlee H, Oppeneer SJ, Robien K (2014) The association between postdiagnosis dietary supplement use and total mortality differs by diet quality among older female cancer survivors. Cancer Epidemiol Biomarkers Prev. doi: 10.1158/1055-9965.EPI-13-1303
  39. 39.
    Pickell L, Brown K, Li D, Wang XL, Deng L, Wu Q, Selhub J, Luo L, Jerome-Majewska L, Rozen R (2010) High intake of folic acid disrupts embryonic development in mice. Birth Defects Res A Clin Mol Teratol 91:8–19CrossRefGoogle Scholar
  40. 40.
    Marean A, Graf A, Zhang Y, Niswander L (2011) Folic acid supplementation can adversely affect murine neural tube closure and embryonic survival. Hum Mol Genet 20:3678–3683CrossRefGoogle Scholar
  41. 41.
    Mikael LG, Deng L, Paul L, Selhub J, Rozen R (2013) Moderately high intake of folic acid has a negative impact on mouse embryonic development. Birth Defects Res A Clin Mol Teratol 97:47–52CrossRefGoogle Scholar
  42. 42.
    Iskandar BJ, Nelson A, Resnick D, Skene JH, Gao P, Johnson C, Cook TD, Hariharan N (2004) Folic acid supplementation enhances repair of the adult central nervous system. Ann Neurol 56:221–227CrossRefGoogle Scholar
  43. 43.
    Wills L, Clutterbuck PW, Evans BD (1937) A new factor in the production and cure of macrocytic anaemias and its relation to other haemopoietic principles curative in pernicious anaemia. Biochem J 31:2136–2147Google Scholar
  44. 44.
    Thomas ED, Lochte HL Jr (1958) Studies on the biochemical defect of pernicious anemia. I. In vitro observations on oxygen consumption, heme synthesis and deoxyribonucleic acid synthesis by pernicious anemia bone marrow. J Clin Invest 37:166–171CrossRefGoogle Scholar
  45. 45.
    Morris MS, Jacques PF, Rosenberg IH, Selhub J (2010) Circulating unmetabolized folic acid and 5-methyltetrahydrofolate in relation to anemia, macrocytosis, and cognitive test performance in American seniors. Am J Clin Nutr 91:1733–1744CrossRefGoogle Scholar
  46. 46.
    Aviv A (2009) Leukocyte telomere length: the telomere tale continues. Am J Clin Nutr 89:1721–1722CrossRefGoogle Scholar
  47. 47.
    Mirabello L, Huang W-Y, Wong JYY, Chatterjee N, Reding D, David Crawford E, De Vivo I, Hayes RB, Savage SA (2009) The association between leukocyte telomere length and cigarette smoking, dietary and physical variables, and risk of prostate cancer. Aging Cell 8:405–413CrossRefGoogle Scholar
  48. 48.
    Paul L (2011) Diet, nutrition and telomere length. J Nutr Biochem 22:895–901CrossRefGoogle Scholar
  49. 49.
    Rowe PB, Lewis GP (1973) Mammalian folate metabolism. Regulation of folate interconversion enzymes. Biochemistry 12:1862–1869CrossRefGoogle Scholar
  50. 50.
    Matthews RG, Ghose C, Green JM, Matthews KD, Dunlap RB (1987) Folylpolyglutamates as substrates and inhibitors of folate-dependent enzymes. Adv Enzyme Regul 26:157–171CrossRefGoogle Scholar
  51. 51.
    Troen AM, Mitchell B, Sorensen B, Wener MH, Johnston A, Wood B, Selhub J, McTiernan A, Yasui Y, Oral E, Potter JD, Ulrich CM (2006) Unmetabolized folic acid in plasma is associated with reduced natural killer cell cytotoxicity among postmenopausal women. J Nutr 136:189–194Google Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Ligi Paul
    • 1
    Email author
  • Paul F. Jacques
    • 1
  • Abraham Aviv
    • 2
  • Ramachandran S. Vasan
    • 3
  • Ralph B. D’Agostino
    • 3
  • Daniel Levy
    • 3
  • Jacob Selhub
    • 1
  1. 1.JM USDA HNRCTufts UniversityBostonUSA
  2. 2.Center of Human Development and AgingNew Jersey Medical SchoolNewarkUSA
  3. 3.Framingham Heart StudyNational Heart Lung and Blood InstituteFraminghamUSA

Personalised recommendations