Advertisement

Springer Nature is making SARS-CoV-2 and COVID-19 research free. View research | View latest news | Sign up for updates

Folic acid supplementation at lower doses increases oxidative stress resistance and longevity in Caenorhabditis elegans

Abstract

Folic acid (FA) is an essential nutrient that the human body needs but cannot be synthesized on its own. Fortified foods and plant food sources such as green leafy vegetables, beans, fruits, and juices are good sources of FA to meet the daily requirements of the body. The aim was to evaluate the effect of dietary FA levels on the longevity of well-known experimental aging model Caenorhabditis elegans. Here, we show for first time that FA extends organism life span and causes a delay in aging. We observed that FA inhibits mechanistic target of rapamycin (mTOR) and insulin/insulin growth factor 1 (IGF-1) signaling pathways to control both oxidative stress levels and life span. The expression levels of stress- and life span-relevant gerontogenes, viz. daf-16, skn-1, and sir. 2.1, and oxidative enzymes, such as glutathione S-transferase 4 (GST-4) and superoxide dismutase 3 (SOD-3), were also found to be highly enhanced to attenuate the intracellular reactive oxygen species (ROS) damage and to delay the aging process. Our study promotes the use of FA to mitigate abiotic stresses and other aging-related ailments.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10

References

  1. Alavez S, Lithgow GJ (2012) Pharmacological maintenance of protein homeostasis could postpone age‐related disease. Aging Cell 11:187–191

  2. Alavez S, Vantipalli MC, Zucker DJ, Klang IM, Lithgow GJ (2011) Amyloid-binding compounds maintain protein homeostasis during ageing and extend lifespan. Nature 472:226–229

  3. Alcedo J, Maier W, Ch’ng Q (2010) Sensory influence on homeostasis and lifespan: molecules and circuits. Adv Exp Med Biol 694:197–210

  4. An JH, Blackwell TK (2003) SKN-1 links C. elegans mesendodermal specification to a conserved oxidative stress response. Genes Dev 17:1882–1893

  5. Arum O, Bonkowski MS, Rocha JS, Bartke A (2009) The growth hormone receptor gene‐disrupted mouse fails to respond to an intermittent fasting diet. Aging Cell 8:756–760

  6. Bacalini MG, Friso S, Olivieri F, Pirazzini C, Giuliani C, Capri M, Santoro A, Franceschi C, Garagnani P (2014) Present and future of anti-ageing epigenetic diets. Mech Ageing Dev 136:101–105

  7. Balamurugan K, Ashokkumar B, Moussaif M, Sze JY, Said HM (2007) Cloning and functional characterization of a folate transporter from the nematode Caenorhabditis elegans. Am J Physiol Cell Physiol 293:C670–C681

  8. Barry I (2008) Vitamin C: friend or foe? Nat Rev Cancer 8:830

  9. Bayés B, Pastor MC, Bonal J, Juncà J, Romero R (2001) Homocysteine and lipid peroxidation in haemodialysis: role of folinic acid and vitamin E. Nephrol Dial Transplant 16:2172–2175

  10. Berdichevsky A, Viswanathan M, Horvitz HR, Guarente L (2006) C. elegans SIR-2.1 interacts with 14-3-3 proteins to activate DAF-16 and extend life span. Cell 125:1165–1177

  11. Bishop NA, Guarente L (2007) Two neurons mediate diet-restriction-induced longevity in C. elegans. Nature 447:545–549

  12. Blencowe H, Cousens S, Modell B, Lawn J (2010) Folic acid to reduce neonatal mortality from neural tube disorders. Int J Epidemiol 39:i110–i121

  13. Bolanowski MA, Russell RL, Jacobson LA (1981) Quantitative measures of aging in the nematode Caenorhabditis elegans. I. Population and longitudinal studies of two behavioral parameters. Mech Ageing Dev 15:279–295

  14. Brunk UT, Terman A (2002) Lipofuscin: mechanisms of age-related accumulation and influence on cell function. Free Radic Biol Med 33:611–619

  15. Burnett C, Valentini S, Cabreiro F (2011) Absence of effects of Sir2 overexpression on lifespan in C. elegans and Drosophila. Nature 477:482–485

  16. Choe KP, Przybysz AJ, Strange K (2009) The WD40 repeat protein WDR-23 functions with the CUL4/DDB1 ubiquitin ligase to regulate nuclear abundance and activity of SKN-1 in Caenorhabditis elegans. Mol Cell Biol 29:2704–2715

  17. Clokey GV, Jacobson LA (1986) The autofluorescent “lipofuscin granules” in the intestinal cells of Caenorhabditis elegans are secondary lysosomes. Mech Ageing Dev 35:79–94

  18. Collins JJ, Evason K, Kornfeld K (2006) Pharmacology of delayed aging and extended lifespan of Caenorhabditis elegans. Exp Gerontol 41:1032–1039

  19. Colman RJ, Anderson RM, Johnson SC, Kastman EK, Kosmatka KJ, Beasley TM, Allison DB, Cruzen C, Simmons HA, Kemnitz JW, Weindruch R (2009) Caloric restriction delays disease onset and mortality in rhesus monkeys. Science 325:201–204

  20. Czeizel AE (2009) Periconceptional folic acid and multivitamin supplementation for the prevention of neural tube defects and other congenital abnormalities. Birth Defects Res A Clin Mol Teratol 85:260–268

  21. de Castro E, Hegi de Castro S, Johnson TE (2004) Isolation of long-lived mutants in Caenorhabditis elegans using selection for resistance to juglone. Free Radic Biol Med 37:139–145

  22. de la Lastra CA, Villegas I (2007) Resveratrol as an antioxidant and pro-oxidant agent: mechanisms and clinical implications. Biochem Soc Trans 35:1156–1160

  23. de Magalhães JP (2013) How ageing processes influence cancer. Nat Rev Cancer 13:357–365

  24. De Wals P, Tairou F, Van Allen MI, Uh SH, Lowry RB, Sibbald B, Evans JA, Van den Hof MC, Zimmer P, Crowley M, Fernandez B, Lee NS, Niyonsenga T (2007) Reduction in neural-tube defects after folic acid fortification in Canada. N Engl J Med 357:135–142

  25. Dolara P, Bigagli E, Collins A (2012) Antioxidant vitamins and mineral supplementation, life span expansion and cancer incidence: a critical commentary. Eur J Nutr 51:769–781

  26. Dror Y, Stern F, Gomori MJ (2014) Vitamins in the prevention or delay of cognitive disability of aging. Curr Aging Sci 7:187–213

  27. Eichholzer M, Tönz O, Zimmermann R (2006) Folic acid: a public-health challenge. Lancet 367:1352–1361

  28. Ernst IM, Pallauf K, Bendall JK, Paulsen L, Nikolai S, Huebbe P, Roeder T, Rimbach G (2013) Vitamin E supplementation and lifespan in model organisms. Ageing Res Rev 12:365–375

  29. Everitt AV, Rattan SI, Le Couteur DG, de Cabo R (eds) (2010) Calorie restriction, aging and longevity. Springer Press, New York

  30. Finkel T, Holbrook NJ (2000) Oxidants, oxidative stress and the biology of ageing. Nature 408:239–247

  31. Gami MS, Wolkow CA (2006) Studies of Caenorhabditis elegans DAF‐2/insulin signaling reveal targets for pharmacological manipulation of lifespan. Aging Cell 5:31–37

  32. Glenn CF, Chow DK, David L, Cooke CA, Gami MS, Iser WB, Hanselman KB, Goldberg IG, Wolkow CA (2004) Behavioral deficits during early stages of aging in Caenorhabditis elegans result from locomotory deficits possibly linked to muscle frailty. J Gerontol A Biol Sci Med Sci 59:1251–1260

  33. Gülçin I (2010) Antioxidant properties of resveratrol: a structure–activity insight. Innov Food Sci Emerg 11:210–218

  34. Hansen M, Taubert S, Crawford D, Libina N, Lee SJ, Kenyon C (2007) Lifespan extension by conditions that inhibit translation in Caenorhabditis elegans. Aging Cell 6:95–110

  35. Heidler T, Hartwig K, Daniel H, Wenzel U (2010) Caenorhabditis elegans lifespan extension caused by treatment with an orally active ROS-generator is dependent on DAF-16 and SIR-2.1. Biogerontology 11:183–195

  36. Herranz D, Muñoz-Martin M, Cañamero M (2010) Sirt1 improves healthy ageing and protects from metabolic syndrome-associated cancer. Nat Commun 1:3

  37. Honda Y, Honda S (1999) The daf-2 gene network for longevity regulates oxidative stress resistance and Mn-superoxide dismutase gene expression in Caenorhabditis elegans. FASEB 13:1385–1393

  38. Honjoh S, Yamamoto T, Uno M, Nishida E (2009) Signalling through RHEB-1 mediates intermittent fasting-induced longevity in C. elegans. Nature 457:726–730

  39. Houthoofd K, Johnson TE, Vanfleteren JR (2005) Dietary restriction in the nematode Caenorhabditis elegans. J Gerontol A Biol Sci Med Sci 60:1125–1131

  40. Huang C, Xiong C, Kornfeld K (2004) Measurements of age-related changes of physiological processes that predict lifespan of Caenorhabditis elegans. Proc Natl Acad Sci U S A 101:8084–8089

  41. Hughes SE, Evason K, Xiong C, Kornfeld K (2007) Genetic and pharmacological factors that influence reproductive aging in nematodes. PLoS Genet 3, e25

  42. Ingram DK, Zhu M, Mamczarz J, Zou S, Lane MA (2006) Calorie restriction mimetics: an emerging research field. Aging Cell 5:97–108

  43. Ishii N, Fujii M, Hartman PS, Tsuda M, Yasuda K (1998) A mutation in succinate dehydrogenase cytochrome b causes oxidative stress and ageing in nematodes. Nature 394:694–697

  44. Jensen MB (2014) Vitamin D and male reproduction. Nat Rev Endocrinol 10:175–186

  45. Joshi R, Adhikari S, Patro BS, Chattopadhyay S, Mukherjee T (2001) Free radical scavenging behavior of folic acid: evidence for possible antioxidant activity. Free Radic Biol Med 30:1390–1399

  46. Kaeberlein M, Powers RW 3rd, Steffen KK, Westman EA, Hu D, Dang N, Kerr EO, Kirkland KT, Fields S, Kennedy BK (2005) Regulation of yeast replicative life span by TOR and Sch9 in response to nutrients. Science 310:1193–1196

  47. Kanfi Y, Naiman S, Amir G (2012) The sirtuin SIRT6 regulates lifespan in male mice. Nature 483:218–221

  48. Kapahi P, Zid BM, Harper T, Koslover D, Sapin V, Benzer S (2004) Regulation of lifespan in Drosophila by modulation of genes in the TOR signaling pathway. Curr Biol 14:885–890

  49. Kell A, Ventura N, Kahn N, Johnson TE (2007) Activation of SKN-1 by novel kinases in Caenorhabditis elegans. Free Radic Biol Med 43:1560–1566

  50. Kennedy BK (2008) The genetics of ageing: insight from genome‐wide approaches in invertebrate model organisms. J Intern Med 263:142–152

  51. Kenyon C (2005) The plasticity of aging: insights from long-lived mutants. Cell 120:449–460

  52. Kenyon CJ (2010) The genetics of ageing. Nature 464:504–512

  53. Kim CK, Park SK (2013) Effect of Acanthopanax sessiliflorus extracts on stress response and aging in Caenorhabditis elegans. Food Sci Technol Res 19:439–444

  54. Kirkwood TB (1977) Evolution of ageing. Nature 270:301–304

  55. Koenig H (1963) Neuronal lipofuscin in disease. Its relation to lysosomes. Trans Am Neurol Assoc 89:212–213

  56. Lakowski B, Hekimi S (1998) The genetics of caloric restriction in Caenorhabditis elegans. Proc Natl Acad Sci U S A 95:13091–13096

  57. Landis JN, Murphy CT (2010) Integration of diverse inputs in the regulation of Caenorhabditis elegans DAF‐16/FOXO. Dev Dyn 239:1405–1412

  58. Lapierre LR, Hansen M (2012) Lessons from C. elegans: signaling pathways for longevity. Trends Endocrinol Metab 23:637–644

  59. Lee SJ, Kenyon C (2009) Regulation of the longevity response to temperature by thermosensory neurons in Caenorhabditis elegans. Curr Biol 19:715–722

  60. Lee CK, Pugh TD, Klopp RG, Edwards J, Allison DB, Weindruch R, Prolla TA (2004) The impact of alpha-lipoic acid, coenzyme Q10 and caloric restriction on life span and gene expression patterns in mice. Free Radic Biol Med 36:1043–1057

  61. Lee D, Hwang W, Artan M, Jeong DE, Lee SJ (2014) Effects of nutritional components on aging. Aging Cell 14:8–16

  62. Leiers B, Kampkötter A, Grevelding CG, Link CD, Johnson TE, Henkle-Dührsen K (2003) A stress-responsive glutathione S-transferase confers resistance to oxidative stress in Caenorhabditis elegans. Free Radic Biol Med 34:1405–1415

  63. Li Y, Xu W, McBurney MW, Longo VD (2008) SirT1 inhibition reduces IGF-I/IRS-2/Ras/ERK1/2 signaling and protects neurons. Cell Metab 8:38–48

  64. Li L, Gao F, Jiang W, Wu X, Cai Y, Tang J, Gao X, Gao F (2015) Folic acid-conjugated superparamagnetic iron oxide nanoparticles for tumor-targeting MR imaging. Drug Deliv 1–8

  65. Lithgow GJ, Walker GA (2002) Stress resistance as a determinate of C. elegans lifespan. Mech Ageing Dev 123:765–771

  66. Lithgow GJ, White TM, Melov S, Johnson TE (1995) Thermotolerance and extended life-span conferred by single-gene mutations and induced by thermal stress. Proc Natl Acad Sci U S A 92:7540–7544

  67. Lucanic M, Lithgow GJ, Alavez S (2013) Pharmacological lifespan extension of invertebrates. Ageing Res Rev 12:445–458

  68. Mahmood L (2014) The metabolic processes of folic acid and vitamin B12 deficiency. J Health Res Rev 1:5

  69. Manayi A, Saeidnia S, Gohari AR, Abdollahi M (2014) Methods for the discovery of new anti-aging products-targeted approaches. Expert Opin Drug Discov 9:383–405

  70. Messing JA, Heuberger R, Schisa JA (2013) Effect of vitamin D3 on lifespan in Caenorhabditis elegans. Curr Aging Sci 6:220–224

  71. Moens AL, Vrints CJ, Claeys MJ, Timmermans JP, Champion HC, Kass DA (2008) Mechanisms and potential therapeutic targets for folic acid in cardiovascular disease. Am J Physiol Heart Circ Physiol 294:H1971–H1977

  72. Mora JR, Iwata M, von Andrian UH (2008) Vitamin effects on the immune system: vitamins A and D take centre stage. Nat Rev Immunol 8:685–698

  73. Muller FL, Lustgarten MS, Jang Y, Richardson A, Van Remmen H (2007) Trends in oxidative aging theories. Free Radic Biol Med 43:477–503

  74. Murakami S, Murakami H (2005) The effects of aging and oxidative stress on learning behavior in C. elegans. Neurobiol Aging 26:899–905

  75. Murphy CT, McCarroll SA, Bargmann CI, Fraser A, Kamath RS, Ahringer J, Li H, Kenyon C (2003) Genes that act downstream of DAF-16 to influence the lifespan of Caenorhabditis elegans. Nature 424:277–283

  76. Narasimhan SD, Yen K, Tissenbaum HA (2009) Converging pathways in lifespan regulation. Curr Biol 19:R657–R666

  77. Olsen A, Vantipalli MC, Lithgow GJ (2006) Using Caenorhabditis elegans as a model for aging and age‐related diseases. Ann N Y Acad Sci 1067:120–128

  78. Onken B, Driscoll M (2010) Metformin induces a dietary restriction-like state and the oxidative stress response to extend C. elegans healthspan via AMPK, LKB1, and SKN-1. PLoS One 5:e8758

  79. Pandey R, Gupta S, Shukla V, Tandon S, Shukla V (2013) Antiageing, antistress and ROS scavenging activity of crude extract of Ocimum sanctum (L.) in Caenorhabditis elegans (Maupas, 1900). Indian J Exp Biol 51:515–521

  80. Panowski SH, Wolff S, Aguilaniu H, Durieux J, Dillin A (2007) PHA-4/Foxa mediates diet restriction induced longevity of C. elegans. Nature 447:550–555

  81. Pant A, Saikia SK, Shukla V, Asthana J, Akhoon BA, Pandey R (2014) Beta-caryophyllene modulates expression of stress response genes and mediates longevity in Caenorhabditis elegans. Exp Gerontol 57:81–95

  82. Park SK, Tedesco PM, Johnson TE (2009) Oxidative stress and longevity in Caenorhabditis elegans as mediated by SKN‐1. Aging Cell 8:258–269

  83. Partridge L, Piper MD, Mair W (2005) Dietary restriction in Drosophila. Mech Ageing Dev 126:938–950

  84. Powolny AA, Singh SV, Melov S, Hubbard A, Fisher AL (2011) The garlic constituent diallyl trisulfide increases the lifespan of C. elegans via skn-1 activation. Exp Gerontol 46:441–452

  85. Racek J, Rusnakova H, Trefil L, Siala KK (2005) The influence of folate and antioxidants on homocysteine levels and oxidative stress in patients with hyperlipidemia and hyperhomocysteinemia. Expert Opin Drug Discov 54:87–95

  86. Rizki G, Iwata TN, Li J, Riedel CG, Picard CL, Jan M, Murphy CT, Lee SS (2011) The evolutionarily conserved longevity determinants HCF-1 and SIR-2.1/SIRT1 collaborate to regulate DAF-16/FOXO. PLoS Genet 7, e1002235

  87. Rogina B, Helfand SL (2004) Sir2 mediates longevity in the fly through a pathway related to calorie restriction. Proc Natl Acad Sci U S A 101:15998–16003

  88. Said HM, Chatterjee N, Haq RU, Subramanian VS, Ortiz A, Matherly LH, Sirotnak FM, Halsted C, Rubin SA (2000) Adaptive regulation of intestinal folate uptake: effect of dietary folate deficiency. Am J Physiol Cell Physiol 279:C1889–C1995

  89. Schlernitzauer A, Oiry C, Hamad R (2013) Chicoric acid is an antioxidant molecule that stimulates AMP kinase pathway in L6 myotubes and extends lifespan in Caenorhabditis elegans. PLoS One 8:e78788

  90. Shelke N, Keith L (2011) Folic acid supplementation for women of childbearing age versus supplementation for the general population: a review of the known advantages and risks. Int J Family Med

  91. Shukla V, Phulara SC, Yadav D, Tiwari S, Kaur S, Gupta MM, Nazir A, Pandey R (2012) Iridoid compound 10-O-trans-p-coumaroylcatalpol extends longevity and reduces alpha synuclein aggregation in Caenorhabditis elegans. CNS Neurol Disord Drug Targets 11:984–992

  92. Sie KK, Medline A, van Weel J, Sohn KJ, Choi SW, Croxford R, Kim YI (2011) Effect of maternal and postweaning folic acid supplementation on colorectal cancer risk in the offspring. Gut 60:1687–1694

  93. Smith ED, Kennedy BK, Kaeberlein M (2007) Genome-wide identification of conserved longevity genes in yeast and worms. Mech Ageing Dev 128:106–111

  94. Song BM, Avery L (2012) Serotonin activates overall feeding by activating two separate neural pathways in Caenorhabditis elegans. J Neurosci 32:1920–1931

  95. Stiernagle T (2006) Maintenance of C. elegans. WormBook, 1–11

  96. Subramanian VS, Chatterjee N, Said HM (2003) Folate uptake in the human intestine: promoter activity and effect of folate deficiency. J Cell Physiol 196:403–408

  97. Tian R, Ingwall JS (2008) How does folic acid cure heart attacks? Circulation 117:1772–1774

  98. Tissenbaum HA, Guarente L (2001) Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegans. Nature 410:227–230

  99. Tissenbaum HA, Ruvkun G (1998) An insulin-like signaling pathway affects both longevity and reproduction in Caenorhabditis elegans. Genetics 148:703–717

  100. Tullet JM, Hertweck M, An JH, Baker J, Hwang JY, Liu S, Oliveira RP, Baumeister R, Blackwell TK (2008) Direct inhibition of the longevity-promoting factor SKN-1 by insulin-like signaling in C. elegans. Cell 132:1025–1038

  101. Upadhyay A, Chompoo J, Taira N, Fukuta M et al (2013) Significant longevity-extending effects of Alpinia zerumbet leaf extract on the life span of Caenorhabditis elegans. Biosci Biotechnol Biochem 77:217–223

  102. Valera-Gran D, García de la Hera M, Navarrete-Muñoz EM, Fernandez-Somoano A, Tardón A, Julvez J, Forns J, Lertxundi N, Ibarluzea JM, Murcia M, Rebagliato M, Vioque J, Infancia y Medio Ambiente (INMA) Project (2014) Folic acid supplements during pregnancy and child psychomotor development after the first year of life. JAMA Pediatr 168:e142611

  103. Virk B, Correia G, Dixon DP, Feyst I, Jia J, Oberleitner N, Briggs Z, Hodge E, Edwards R, Ward J, Gems D, Weinkove D (2012) Excessive folate synthesis limits lifespan in the C. elegans: E. coli aging model. BMC Biol 10:67

  104. Viswanathan M, Guarente L (2011) Regulation of Caenorhabditis elegans lifespan by sir-2.1 transgenes. Nature 477:E1–E2

  105. Watson E, Walhout AJ (2014) Caenorhabditis elegans metabolic gene regulatory networks govern the cellular economy. Trends Endocrinol Metabol 25:502–508

  106. Watson E, MacNeil LT, Ritter AD, Yilmaz LS, Rosebrock AP, Caudy AA, Walhout AJ (2014) Interspecies systems biology uncovers metabolites affecting C. elegans gene expression and life history traits. Cell 156:759–770

  107. Wolff S, Dillin A (2006) The trifecta of aging in Caenorhabditis elegans. Exp Gerontol 41:894–903

  108. Yin D (1996) Biochemical basis of lipofuscin, ceroid, and age pigment-like fluorophores. Free Radic Biol Med 21:871–888

  109. Zhang Y, Lu H, Bargmann CI (2005) Pathogenic bacteria induce aversive olfactory learning in Caenorhabditis elegans. Nature 438:179–184

  110. Zhang Y, Chen H, Zhang N, Ma L (2013) Antioxidant and functional properties of tea protein as affected by the different tea processing methods. J Food Sci Technol 52:742–752

Download references

Acknowledgments

We are grateful to the Director, CSIR–CIMAP, Lucknow, India, for his kind support. The C. elegans strains used in this study were provided by the Caenorhabditis Genetics Center, which is funded by the National Center for Research Resources of NIH. BAA was supported by the CSIR, India (31/029(0251)/2013-EMR-I).

Author information

Correspondence to Rakesh Pandey.

Ethics declarations

Conflict of interest

The authors declare that they have no competing interests.

Additional information

Laxmi Rathor and Bashir Akhlaq Akhoon contributed equally to this work.

About this article

Verify currency and authenticity via CrossMark

Cite this article

Rathor, L., Akhoon, B.A., Pandey, S. et al. Folic acid supplementation at lower doses increases oxidative stress resistance and longevity in Caenorhabditis elegans . AGE 37, 113 (2015). https://doi.org/10.1007/s11357-015-9850-5

Download citation

Keywords

  • Folic acid
  • Oxidative stress
  • Dietary restriction
  • Caenorhabditis elegans
  • Aging