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.
Similar content being viewed by others
References
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 105:1541–1544
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 24:77–84
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 63:467–473
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 95:1211–1218
Harley CB, Futcher AB, Greider CW (1990) Telomeres shorten during ageing of human fibroblasts. Nature 345:458–460
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 28:64–74
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 178:925–936
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 36:94–99
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 8:416–424
Kruk PA, Rampino NJ, Bohr VA (1995) DNA damage and repair in telomeres: relation to aging. Proc Natl Acad Sci USA 92:258–262
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 287:282–288
Woods DD (1964) The function of folic acid in cellular metabolism. Proc R Soc Med 57:388–390
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 119:661–664
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 139:1273–1278
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 99:5606–5611
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 12:341–349
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 200:271–277
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 340:1449–1454
Feinleib M, Kannel WB, Garrison RJ, McNamara PM, Castelli WP (1975) The Framingham offspring study. Design and preliminary data. Prev Med 4:518–525
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 28:1165–1171
Horne DW, Patterson D (1988) Lactobacillus casei microbiological assay of folic acid derivatives in 96-well microtiter plates. Clin Chem 34:2357–2359
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 132:2792–2798
Husdan H, Rapoport A (1968) Estimation of creatinine by the Jaffe reaction. A comparison of three methods. Clin Chem 14:222–238
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 127:77–85
Xu Q, Parks CG, DeRoo LA, Cawthon RM, Sandler DP, Chen H (2009) Multivitamin use and telomere length in women. Am J Clin Nutr 89:1857–1863
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 97:794–799
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 42:197–199
Bleys J, Navas-Acien A, Guallar E (2008) Serum selenium levels and all-cause, cancer, and cardiovascular mortality among us adults. Arch Intern Med 168:404–410
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 21:1061–1069
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 95:373–380
Morrison HI, Schaubel D, Desmeules M, Wigle DT (1996) Serum folate and risk of fatal coronary heart disease. JAMA 275:1893–1896
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 28:637–645
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 1:339–340
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 91:231–237
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 11:540
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 91:1268–1272
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 140:1661–1668
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
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 91:8–19
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 20:3678–3683
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 97:47–52
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 56:221–227
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 31:2136–2147
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 37:166–171
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 91:1733–1744
Aviv A (2009) Leukocyte telomere length: the telomere tale continues. Am J Clin Nutr 89:1721–1722
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 8:405–413
Paul L (2011) Diet, nutrition and telomere length. J Nutr Biochem 22:895–901
Rowe PB, Lewis GP (1973) Mammalian folate metabolism. Regulation of folate interconversion enzymes. Biochemistry 12:1862–1869
Matthews RG, Ghose C, Green JM, Matthews KD, Dunlap RB (1987) Folylpolyglutamates as substrates and inhibitors of folate-dependent enzymes. Adv Enzyme Regul 26:157–171
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 136:189–194
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.
Author information
Authors and Affiliations
Corresponding author
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Paul, L., Jacques, P.F., Aviv, A. et al. High plasma folate is negatively associated with leukocyte telomere length in Framingham Offspring cohort. Eur J Nutr 54, 235–241 (2015). https://doi.org/10.1007/s00394-014-0704-1
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00394-014-0704-1