Abstract
Organ-specific changes of iron- and redox-related proteins occur with age in the rat. Ferritin, the major iron storage and detoxifying protein, as well as the proteins of the methionine-centered redox cycle (MCRC) were examined in old and young animals, and showed organ-dependent changes. In spleens and livers of aged rats, ferritin (protein) levels were greater than in young ones, and their iron saturation increased, rendering higher ferritin-bound iron (FtBI). Iron saturation of the ferritin molecule in the tongues and sternohyoids of old rats was lower but ferritin level was higher than in young rats, resulting in increased FtBI with age. Ferritin level in the esophagus of older rats was lower than in young rats but its molecular iron content higher thus the total FtBI remained the same. In the larynx, both ferritin and its iron content were the same in young and old animals. MCRC proteins were measured in livers and spleens only. With aging, methionine sulfoxide reductase A and B (MsrA and MsrB) levels in livers and spleens decreased. Thioredoxin1 (Trx) and Trx-reductase1 were elevated in old spleens, but reduced in livers. Aged spleens showed reduced Msr isozyme activity; but in the liver, its activity increased. mRNA changes with age were monitored and found to be organ specific. These organ-specific changes could reflect the different challenges and the selective pathways of each organ and its resultant capacity to cope with aging.
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Abbreviations
- Ft:
-
Ferritin
- Ft-H and Ft:
-
L—the H and L subunits of Ft
- FtBI:
-
Ft-bound iron
- MCRC:
-
Methionine-centered redox cycle
- Met:
-
Methionine
- MetO:
-
Methionine sulfoxide
- MetO2 :
-
Methionine sulfone
- Msr:
-
Methionine sulfoxide reductase
- ROS:
-
Reactive oxygen-derived species
- Trx:
-
Thioredoxin 1
- TrxR:
-
Thioredoxin reductase 1
References
Altun M, Edstrom E, Spooner E, Flores-Moralez A, Bergman E, Tollet-Egnell P, Norstedt G, Kessler BM, Ulfhake B (2007) Iron load and redox stress in skeletal muscle of aged rats. Muscle Nerve 36(2):223–233
Bandyopadhyay U, Dipak Das D, Banerjee RK (1999) Reactive oxygen species: oxidative damage and pathogenesis. Curr Science 77:658–666
Berenshtein E, Vaisman B, Goldberg-Langerman C, Kitrossky N, Konijn AM, Chevion M (2002) Roles of ferritin and iron in ischemic preconditioning of the heart. Mol Cell Biochem 234–235(1–2):283–292
Brot N, Weissbach H (1991) Biochemistry of methionine sulfoxide residues in proteins. Biofactors 3(2):91–96
Bulvik B, Grinberg L, Eliashar R, Berenshtein E, Chevion MM (2009) Iron, ferritin and proteins of the methionine-centered redox cycle in young and old rat hearts. Mech Ageing Dev 130(3):139–144
Cairo G, Tacchini L, Pogliaghi G, Anzon E, Tomasi A, Bernelli-Zazzera A (1995) Induction of ferritin synthesis by oxidative stress. Transcriptional and post-transcriptional regulation by expansion of the “free” iron pool. J Biol Chem 270(2):700–703
Chen Y, Cai J, Murphy TJ, Jones DP (2002) Overexpressed human mitochondrial thioredoxin confers resistance to oxidant-induced apoptosis in human osteosarcoma cells. J Biol Chem 277(36):33242–33248
Cheung HT, Nadakavukaren MJ (1983) Age-dependent changes in the cellularity and ultrastructure of the spleen of Fischer F344 rats. Mech Ageing Dev 22(1):23–33
Ercal N, Gurer-Orhan H, Aykin-Burns N (2001) Toxic metals and oxidative stress part I: mechanisms involved in metal-induced oxidative damage. Curr Top Med Chem 1(6):529–539
Frasca D, Van der Put E, Landin AM, Gong D, Riley RL, Blomberg BB (2005) RNA stability of the E2A-encoded transcription factor E47 is lower in splenic activated B cells from aged mice. J Immunol 175(10):6633–6644
Friguet B (2006) Oxidized protein degradation and repair in ageing and oxidative stress. FEBS Lett 580(12):2910–2916
Gallegos A, Gasdaska JR, Taylor CW, Paine-Murrieta GD, Goodman D, Gasdaska PY, Berggren M, Briehl MM, Powis G (1996) Transfection with human thioredoxin increases cell proliferation and a dominant-negative mutant thioredoxin reverses the transformed phenotype of human breast cancer cells. Cancer Res 56(24):5765–5770
Harman D (1956) Aging: a theory based on free radical and radiation chemistry. J Gerontol 11(3):298–300
Harman D (1981) The aging process. Proc Natl Acad Sci U S A 78(11):7124–7128
Harrison PM, Arosio P (1996) The ferritins: molecular properties, iron storage function and cellular regulation. Biochim Biophys Acta 1275(3):161–203
Hintze KJ, Theil EC (2006) Cellular regulation and molecular interactions of the ferritins. Cell Mol Life Sci 63(5):591–600
Hoy TG, Jacobs A (1981) Ferritin polymers and the formation of haemosiderin. Br J Haematol 49(4):593–602
Konijn AM, Hershko C (1977) Ferritin synthesis in inflammation I. Pathogenesis of impaired iron release. Br J Haematol 37(1):7–16
Konijn AM, Levy R, Link G, Hershko C (1982) A rapid and sensitive ELISA for serum ferritin employing a fluorogenic substrate. J Immunol Methods 54(3):297–307
Konijn AM, Tal R, Levy R, Matzner Y (1985) Isolation and fractionation of ferritin from human term placenta–a source for human isoferritins. Anal Biochem 144(2):423–428
Konijn AM, Glickstein H, Vaisman B, Meyron-Holtz EG, Slotki IN, Cabantchik ZI (1999) The cellular labile iron pool and intracellular ferritin in K562 cells. Blood 94(6):2128–2134
Koolhaas JM (2010) The Laboratory rat. In: Hubrecht R, Kirkwood J (eds) The UFAW Handbook on the Care and Management of Laboratory and Other Research Animals, 8th edn. Wiley-Blackwell, West Sussex
Kregel KC, Zhang HJ (2007) An integrated view of oxidative stress in aging: basic mechanisms, functional effects, and pathological considerations. Am J Physiol Regul Integr Comp Physiol 292(1):R18–R36
Leibovitz BE, Siegel BV (1980) Aspects of free radical reactions in biological systems: aging. J Gerontol 35(1):45–56
Levenson CW, Tassabehji NM (2004) Iron and ageing: an introduction to iron regulatory mechanisms. Ageing Res Rev 3(3):251–263
Liu X, Theil EC (2005) Ferritin as an iron concentrator and chelator target. Ann N Y Acad Sci 1054:136–140
Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) Method. Methods 25(4):402–408
Masuda T, Satodate R, Tsuruga K, Kasai T (1993) Quantitative assessment of a change of hemosiderin deposition with age in splenic compartments of rats. Tohoku J Exp Med 170(3):169–179
Mitsui A, Hamuro J, Nakamura H, Kondo N, Hirabayashi Y, Ishizaki-Koizumi S, Hirakawa T, Inoue T, Yodoi J (2002) Overexpression of human thioredoxin in transgenic mice controls oxidative stress and life span. Antioxid Redox Signal 4(4):693–696
Moskovitz J (2005) Methionine sulfoxide reductases: ubiquitous enzymes involved in antioxidant defense, protein regulation, and prevention of aging-associated diseases. Biochim Biophys Acta 1703(2):213–219
Moskovitz J, Berlett BS, Poston JM, Stadtman ER (1997) The yeast peptide-methionine sulfoxide reductase functions as an antioxidant in vivo. Proc Natl Acad Sci U S A 94(18):9585–9589
Moskovitz J, Bar-Noy S, Williams WM, Requena J, Berlett BS, Stadtman ER (2001) Methionine sulfoxide reductase (MsrA) is a regulator of antioxidant defense and lifespan in mammals. Proc Natl Acad Sci U S A 98(23):12920–12925
Nilsson UA, Bassen M, Savman K, Kjellmer I (2002) A simple and rapid method for the determination of “free” iron in biological fluids. Free Radic Res 36(6):677–684
Petropoulos I, Friguet B (2006) Maintenance of proteins and aging: the role of oxidized protein repair. Free Radic Res 40(12):1269–1276
Ponka P, Beaumont C, Richardson DR (1998) Function and regulation of transferrin and ferritin. Semin Hematol 35(1):35–54
Reno C, Marchuk L, Sciore P, Frank CB, Hart DA (1997) Rapid isolation of total RNA from small samples of hypocellular, dense connective tissues. Biotechniques 22(6):1082–1086
Rikans LE, Ardinska V, Hornbrook KR (1997) Age-associated increase in ferritin content of male rat liver: implication for diquat-mediated oxidative injury. Arch Biochem Biophys 344(1):85–93
Rohrbach S, Gruenler S, Teschner M, Holtz J (2006) The thioredoxin system in aging muscle: key role of mitochondrial thioredoxin reductase in the protective effects of caloric restriction? Am J Physiol Regul Integr Comp Physiol 291(4):R927–R935
Sen CK, Packer L (1996) Antioxidant and redox regulation of gene transcription. Faseb J 10(7):709–720
Sen CK, Packer L (2000) Thiol homeostasis and supplements in physical exercise. Am J Clin Nutr 72(2 Suppl):653S–669S
Shioji K, Kishimoto C, Nakamura H, Toyokuni S, Nakayama Y, Yodoi J, Sasayama S (2000) Upregulation of thioredoxin (TRX) expression in giant cell myocarditis in rats. FEBS Lett 472(1):109–113
Squier TC (2001) Oxidative stress and protein aggregation during biological aging. Exp Gerontol 36(9):1539–1550
Stadtman ER, Moskovitz J, Levine RL (2003) Oxidation of methionine residues of proteins: biological consequences. Antioxid Redox Signal 5(5):577–582
Takeda T, Kimura M, Yokoi K, Itokawa Y (1996) Effect of age and dietary protein level on tissue mineral levels in female rats. Biol Trace Elem Res 54(1):55–74
Tappia PS, Dent MR, Dhalla NS (2006) Oxidative stress and redox regulation of phospholipase D in myocardial disease. Free Radic Biol Med 41(3):349–361
Thomson AM, Rogers JT, Leedman PJ (1999) Iron-regulatory proteins, iron-responsive elements and ferritin mRNA translation. Int J Biochem Cell Biol 31(10):1139–1152
Vaisman B, Santambrogio P, Arosio P, Fibach E, Konijn AM (1999) An ELISA for the H-subunit of human ferritin which employs a combination of rabbit poly- and mice monoclonal antibodies and an enzyme labeled anti-mouse-IgG. Clin Chem Lab Med 37(2):121–125
Vaisman B, Meyron-Holtz EG, Fibach E, Krichevsky AM, Konijn AM (2000) Ferritin expression in maturing normal human erythroid precursors. Br J Haematol 110(2):394–401
Vinokur V, Grinberg L, Berenshtein E, Gross M, Moskovitz J, Reznick AZ, Chevion M, Eliashar R (2009) Methionine-centered redox cycle in organs of the aero-digestive tract of young and old rats. Biogerontology 10(1):43–52
Yoshida T, Oka S, Masutani H, Nakamura H, Yodoi J (2003) The role of thioredoxin in the aging process: involvement of oxidative stress. Antioxid Redox Signal 5(5):563–570
Acknowledgments
We are grateful to Dr. A. Reznick, of the Technion-Israel Institute of Technology, for the supply the old animals. We also thank Dr. Sue Goo Rhee (Ewha Womans University, Seoul, Korea) and Dr. Jackob Moskovitz (School of Pharmacy, University of Kansas) for generously providing antibodies.
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Bulvik, B.E., Berenshtein, E., Konijn, A.M. et al. Aging is an organ-specific process: changes in homeostasis of iron and redox proteins in the rat. AGE 34, 693–704 (2012). https://doi.org/10.1007/s11357-011-9268-7
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DOI: https://doi.org/10.1007/s11357-011-9268-7