Skip to main content
Log in

The role of melatonin, sirtuin2 and FoXO1 transcription factor in the aging process of colon in male rats

  • Research Article
  • Published:
Biogerontology Aims and scope Submit manuscript

Abstract

The protein family of sirtuins and FoXO1 transcription factor have been shown to play significant roles in the aging process. In this study we aimed to investigate the changes in the levels of SIRT2, NFκB and FoXO1 and oxidative parameters of colonic mucosa during aging, and the effects of exogenous melatonin (MLT). A total of twenty-four young (3-months-old) and aged (24 months old) male Wistar rats, divided into control [1 % ethanol—phosphate-buffered saline (PBS), s.c. for 21 days] and melatonin (10 mg kg−1 MLT 1 % ethanol in PBS, s.c. for 21 days) were used in the study. The levels of malondialdehyde (MDA) as a parameter of lipid peroxidation, glutathione, NFkB pathway activation, SIRT2 expression, and FoXO1 transcription factor of colonic mucosa were assayed. The MDA levels and SIRT2 expression in the colonic mucosa were significantly increased in the aged group when compared to the younger group. However, the levels of FoXO1 transcription factor were significantly decreased in the aged group. Melatonin significantly decreased the MDA and SIRT2 expression levels of the colonic mucosa in the aged rats. In conclusion, our findings suggest a suppressive role of melatonin in the aging process of colonic tissue via decreasing SIRT2 expression.

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

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2

Similar content being viewed by others

References

  • Afanas’ev I (2011) Reactive oxygen species signaling in cancer: comparison with aging. Aging Dis 2:219–230

    PubMed Central  PubMed  Google Scholar 

  • Akbulut KG, Gonul B, Akbulut H (2009) The role of melatonin on gastric mucosal cell proliferation and telomerase activity in ageing. J Pineal Res 47:308–312

    Article  CAS  PubMed  Google Scholar 

  • Akbulut KG, Akbulut H, Akgun N, Gonul B (2012) Melatonin decreases apoptosis in gastric mucosa during aging. Aging Clin Exp Res 24:15–20

    CAS  PubMed  Google Scholar 

  • Aykac G, Uysal M, Yalcin AS, Koçak-Toker N, Sivas A, Oz H (1985) The effects of chronic ethanol ingestion on hepatic lipid peroxide, glutathione, glutathione peroxidase and glutathione transferase in rats. Toxicology 36:71–76

    Article  CAS  PubMed  Google Scholar 

  • Brunet A, Sweeney LB, Sturgill JF, Chua KF, Greer PL, Lin Y, Tran H, Ross SE, Mostoslavsky R, Cohen HY, Hu LS, Cheng HL, Jedrychowski MP, Gygi SP, Sinclair DA, Alt FW, Greenberg ME (2004) Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Science 303:2011–2015

    Article  CAS  PubMed  Google Scholar 

  • Calnan DR, Brunet A (2008) The FoxO code. Oncogene 27:2276–2288

    Article  CAS  PubMed  Google Scholar 

  • Casini A, Ferrali M, Pompella A, Maellaro E, Comporti M (1986) Lipid peroxidation and cellular damage in extrahepatic tissue of bromobenzene intoxicated mice. Am J Pathol 123:520–531

    CAS  PubMed Central  PubMed  Google Scholar 

  • Chobotova K (2009) Aging and cancer: converging routes to disease prevention. Integr Cancer Ther 8:115–122

    CAS  PubMed  Google Scholar 

  • Chung HY, Lee EK, Choi YJ, Kim JM, Kim DH, Zou Y, Kim CH, Lee J, Kim HS, Kim ND, Jung JH, Yu BP (2011) Molecular inflammation as an underlying mechanism of the aging process and age-related diseases. J Dent Res 90:830–840

    Article  CAS  PubMed  Google Scholar 

  • Donmez G (2012) The neurobiology of sirtuins and their role in neurodegeneration. Trends Pharmacol Sci 33:494–501

    Article  CAS  PubMed  Google Scholar 

  • Ferrara N, Rinaldi B, Corbi G, Conti V, Stiuso P, Boccuti S, Rengo G, Rossi F, Filippelli A (2008) Exercise training promotes SIRT1 activity in aged rats. Rejuvenation Res 11:139–150

    Article  CAS  PubMed  Google Scholar 

  • Finkel T, Deng CX, Mostoslavsky R (2009) Recent progress in the biology and physiology of sirtuins. Nature 460:587–591

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Helenius M, Ha¨nninen M, Lehtinen SK, Salminen A (1996) Aging-induced up-regulation of nuclear binding activities of oxidative stress responsive NF-kB transcription factor in mouse cardiac muscle. J Mol Cell Cardiol 28:487–498

    Article  CAS  PubMed  Google Scholar 

  • Hill SM, Frasch T, Xiang S, Yuan L, Duplessis T, Mao L (2009) Molecular mechanisms of melatonin anticancer effects. Integr Cancer Ther 8:337–346

    Article  CAS  PubMed  Google Scholar 

  • Huang H, Tindall DJ (2007) Dynamic FoxO transcription factors. J Cell Sci 120(15):2479–2487

  • Jung-Hynes B, Nihal M, Zhong W, Ahmad N (2009) Role of sirtuin histone deacetylase SIRT1 in prostate cancer. A target for prostate cancer management via its inhibition? J Biol Chem 284:3823–3832

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Jung-Hynes B, Reiter RJ, Ahmad N (2010) Sirtuins, melatonin and circadian rhythms: building a bridge between aging and cancer. J Pineal Res 48:9–19

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Jung-Hynes B, Schmit TL, Reagan-Shaw SR, Siddiqui IA, Mukhtar H, Ahmad N (2011) Melatonin, a novel SIRT1 inhibitor, imparts antiproliferative effects against prostate cancer in vitro in culture and in vivo in TRAMP model. J Pineal Res 50:140–149

    CAS  PubMed Central  PubMed  Google Scholar 

  • Kara H, Cevik A, Konar V, Dayangac A, Servi K (2008) Effects of selenium with vitamin E and melatonin on cadm, ium-induced oxidative damage in rat liver and kidneys. Biol Trace Elem Res 125:236–244

    Article  CAS  PubMed  Google Scholar 

  • Karasek M (2007) Does melatonin play a role in aging processes? J Physiol Pharmacol 58:105–113

    PubMed  Google Scholar 

  • Kim HS, Vassilopoulos A, Wang RH, Lahusen T, Xiao Z, Xu X, Li C, Veenstra TD, Li B, Yu H, Ji J, Wang XW, Park SH, Cha YI, Gius D, Deng CX (2011) SIRT2 maintains genome integrity and suppresses tumorigenesis through regulating APC/C activity. Cancer Cell 20:487–499

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Kireev RA, Vara E, Tresguerres JAF (2013) Growth hormone and melatonin prevent age-related alteration in apoptosis processes in the dentate gyrus of male rats. Biogerontology 14:431–442

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Korhonen P, Helenius M, Salminen A (1997) Age-related changes in the regulation of transcription factor NF-kB in rat brain. Neurosci Lett 225:61–64

    Article  CAS  PubMed  Google Scholar 

  • Li W, Zhang B, Tang I, Cao Q, Wu Y, Wu C, Guo J, Ling EA, Liang F (2007) Sirtuin 2 a mammalian homolog of yeast silent information regulator-2 longevity regulator is an oligidendrigliai protein that decerelates cell differentiation through deacetylating alpha-tubulin. J Neurosci 27:2606–2616

    Article  PubMed  Google Scholar 

  • Li Y, Matsumori H, Nakayama Y, Osaki M, Kojima H, Kurimasa A, Ito H, Mori S, Katoh M, Oshimura M, Inoue T (2011) SIRT2 down-regulation in HeLa can induce p53 accumulation via p38 MAPK activation dependent p300 decrease, eventually leading to apoptosis. Genes Cells 16:34–45

    Article  CAS  PubMed  Google Scholar 

  • Lim HD, Kim YS, Ko SH, Yoon IJ, Cho SG, Chun YH, Choi BJ, Kim EC (2012) Cytoprotective and anti-inflammatory effects of melatonin in hydrogen peroxide-stimulated CHON-001 human chondrocyte cell line and rabbit model of osteoarthritis via the SIRT1 pathway. J Pineal Res 53:225–237

    Article  CAS  PubMed  Google Scholar 

  • Mandir N, FitzGerald AJ, Goodlad RA (2005) Differences I the effects of age on intestinal proliferation, crypt fission and apoptosis on the small intestine and the colon of the rat. Int J Exp Pathol 86:125–130

    Article  PubMed Central  PubMed  Google Scholar 

  • Maxwell MM, Tomkinson EM, Nobles J, Wizeman JW, Amore AM, Quinti L, Chopra V, Hersch SM, Kazantsev AG (2011) The Sirtuin 2 microtubule deacetylase is an abundant neuronal protein that accumulates in the aging CNS. Hum Mol Genet 20:3986–3996

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Michian S, Sinclair D (2007) Sirtuins in mammals: insights into their biological function. Biochem J 404:1–13

    Article  Google Scholar 

  • O’Mahony F, Alzamora R, Chung H-L, Thomas W, Harvey JB (2009) Genomic priming of the antisecretory response to estrogen in rat distal colon throughout the estrous cycle. Mol Endocrinol 23:1885–1899

  • Pascua P, Camello-Almaraz C, Camello PJ, Martin-Cano FE, Vara E, Fernandez-Tresguerres JA, Pozo MJ (2011) Melatonin, and to a lesser extent growth hormone, restores colonic smooth muscle physiology in old rats. J Pineal Res 51:405–415

    Article  CAS  PubMed  Google Scholar 

  • Peck B, Chen CY, Ho KK, Di Fruscia P, Myatt SS, Coombes RC, Fuchter MJ, Hsiao CD, Lam EW (2010) SIRT inhibitors induce cell death and p53 acetylation through targeting both SIRT1 and SIRT2. Mol Cancer Ther 9:844–855

    Article  CAS  PubMed  Google Scholar 

  • Roos CM, Hagler M, Zhang B, Oehler EA, Arghami A, Miller JD (2013) Transcriptional and phenotypic changes in aorta and aortic valve with aging and MnSOD deficiency in mice. Am J Physiol Heart Circ Physiol 305:H1428–H1439

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Salih DAM, Brunet A (2008) FoxO transcription factors in the maintenance of cellular homeostasis during aging. Curr Opin Cell Biol 20:126–136

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Salminen A, Kaarniranta K (2010) Insulin/IGF-1 paradox of aging: regulation via AKT/IKK/NF-kB signaling. Cell Signal 22:573–577

    Article  CAS  PubMed  Google Scholar 

  • Sasaki T, Maier B, Bartke A, Scrable H (2006) Progressive loss of SIRT1 with cell cycle withdrawal. Aging Cell 5:413–422

    Article  CAS  PubMed  Google Scholar 

  • Tilstra JS, Clauson CL, Niedernhofer LJ, Robbins PD (2011) NF-κB in aging and disease. Aging Dis 2:449–465

    PubMed Central  PubMed  Google Scholar 

  • Tomobe K, Shinozuka T, Kawashima T, Kawashima-Ohya Y, Nomura Y (2013) Age-related changes of forkhead transcription factor FOXO1 in the liver of senescence-accelerated mouse SAMP8. Arch Gerontol Geriatr 57:417–422

    Article  CAS  PubMed  Google Scholar 

  • Tresguerres JA, Kireev R, Forman K, Cuesta S, Tresguerres AF, Vara E (2012) Effect of chronic melatonin administration on several physiological parameters from old Wistar rats and SAMP8 mice. Curr Aging Sci 5:242–253

    Article  CAS  PubMed  Google Scholar 

  • van den Berg R, Haenen GRMM, van den Berg H, Bast A (2001) Transcription factor NF-kB as a potential biomarker for oxidative stress. Br J Nutr 86:S121–S127

    Article  PubMed  Google Scholar 

  • Wada-Hiraike O, Imamov O, Hiraike H, Hultenby K, Schwend T, Omoto Y, Warner M, Gustafsson JA (2006) Role of estrogen receptor beta in colonic epithelium. Proc Natl Acad Sci U S A 103:2959–2964

  • Xiong S, Salazar G, Patrushev N, Alexander RW (2011) FoxO1 Mediates an autofeedback loop regulating SIRT1 expression. J Biol Chem 286:5289–5299

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Yu J, Auwerx J (2009) The role of sirtuins in the control of metabolic homeostasis. Ann N Y Acad Sci 1173:E10–E19

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Zhao Y, Yang J, Liao W, Liu X, Zhang H, Wang S, Wang D, Feng J, Yu L, Zhu WG (2010) Cytosolic FoxO1 is essential for the induction of autophagy and tumour suppressor activity. Nat Cell Biol 12:665–675

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was partly supported by a grant from Turkish Academy of Sciences (TUBA) and Gazi University (2010-37).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Hakan Akbulut.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Akbulut, K.G., Aktas, S.H. & Akbulut, H. The role of melatonin, sirtuin2 and FoXO1 transcription factor in the aging process of colon in male rats. Biogerontology 16, 99–108 (2015). https://doi.org/10.1007/s10522-014-9540-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10522-014-9540-1

Keywords

Navigation