Impaired iron status in aging research

International Journal of Molecular Sciences

Volumn 13, Issue 2, 2012, Pages 2368-2386

  Xu, Jinze ^a   Jia, Zhenhua ^b   Knutson, Mitchell D ^c   Leeuwenburgh, Christiaan ^a  

^a UNIVERSITY OF FLORIDA COLLEGE OF MEDICINE   (United States)

^b INSTITUTE OF ENERGY RESOURCES   (China)

^c UNIVERSITY OF FLORIDA   (United States)

Author keywords

Aging; Iron accumulation; Labile iron; Mitochondrial dysfunction; Oxidative damage

Indexed keywords

FERRITIN; FERROPORTIN; HEME; IRON; NATURAL RESISTANCE ASSOCIATED MACROPHAGE PROTEIN 2;

AGING; ATOMIC ABSORPTION SPECTROMETRY; BINDING AFFINITY; BINDING SITE; DISEASE ASSOCIATION; DISORDERS OF MITOCHONDRIAL FUNCTIONS; FERRITIN BLOOD LEVEL; HUMAN; INTERMETHOD COMPARISON; IRON ABSORPTION; IRON BALANCE; IRON BINDING CAPACITY; IRON METABOLISM; IRON TRANSPORT; LIFESPAN; MASS SPECTROMETRY; MOLECULAR DYNAMICS; MOLECULAR INTERACTION; NONHUMAN; OXIDATIVE STRESS; PROTEIN EXPRESSION; REGULATORY MECHANISM; REVIEW; STRAIN DIFFERENCE; ANIMALS; DISEASE MODELS, ANIMAL; HEALTH STATUS; HUMANS; IRON METABOLISM DISORDERS; METABOLISM; MITOCHONDRIA; PHYSIOLOGY; RODENTIA;

ANIMALIA; RODENTIA;

AGING; ANIMALS; DISEASE MODELS, ANIMAL; HEALTH STATUS; HUMANS; IRON; IRON METABOLISM DISORDERS; MITOCHONDRIA; RODENTIA;

EID: 84863296679     PISSN: None     EISSN: 14220067     Source Type: Journal    
DOI: 10.3390/ijms13022368     Document Type: Review

References (125)

1. Roijers, R.B.; Debernardi, N.; Cleutjens, J.P.; Schurgers, L.J.; Mutsaers, P.H.; van der Vusse, G.J. Microcalcifications in early intimal lesions of atherosclerotic human coronary arteries. Am. J. Pathol. 2011, 178, 2879-2887.
2. Sullivan, J.L. Iron in arterial plaque: Modifiable risk factor for atherosclerosis. Biochim. Biophys. Acta 2009, 1790, 718-723.
3. Carpenter, J.P.; He, T.; Kirk, P.; Roughton, M.; Anderson, L.J.; de Noronha, S.V.; Sheppard, M.N.; Porter, J.B.; Walker, J.M.; Wood, J.C. et al. On t2* magnetic resonance and cardiac iron. Circulation 2011, 123, 1519-1528.
4. Tajima, S.; Ikeda, Y.; Sawada, K.; Yamano, N.; Horinouchi, Y.; Kihira, Y.; Ishizawa, K.; Izawa-Ishizawa, Y.; Kawazoe, K.; Tomita, S. et al. Iron reduction by deferoxamine leads to amelioration of adiposity via the regulation of oxidative stress and inflammation in obese and type 2 diabetes kkay mice. Am. J. Physiol. Endocrinol. Metab. 2011, doi:10.1152/ajpendo.00033.2011.
5. Toyokuni, S. Role of iron in carcinogenesis: Cancer as a ferrotoxic disease. Cancer Sci. 2009, 100, 9-16.
6. Toyokuni, S. Iron as a target of chemoprevention for longevity in humans. Free Radic Res. 2011, 45, 906-917.
7. Torti, S.V.; Torti, F.M. Ironing out cancer. Cancer Res. 2011, 71, 1511-1514.
8. Morgan, N.V.; Westaway, S.K.; Morton, J.E.; Gregory, A.; Gissen, P.; Sonek, S.; Cangul, H.; Coryell, J.; Canham, N.; Nardocci, N.; et al. Pla2g6, encoding a phospholipase a2, is mutated in neurodegenerative disorders with high brain iron. Nat.Genet. 2006, 38, 752-754.
9. Pandolfo, M.; Pastore, A. The pathogenesis of friedreich ataxia and the structure and function of frataxin. J. Neurol. 2009, 256, 9-17.
10. Oshiro, S.; Morioka, M.S.; Kikuchi, M. Dysregulation of iron metabolism in alzheimer's disease, parkinson's disease, and amyotrophic lateral sclerosis. Adv. Pharmacol. Sci. 2011, 2011, 378278.
11. He, Q.; Du, T.; Yu, X.; Xie, A.; Song, N.; Kang, Q.; Yu, J.; Tan, L.; Xie, J.; Jiang, H. Dmt1 polymorphism and risk of parkinson's disease. Neurosci. Lett. 2011, 501, 128-131.
12. Lei, P.; Ayton, S.; Finkelstein, D.I.; Spoerri, L.; Ciccotosto, G.D.; Wright, D.K.; Wong, B.X.; Adlard, P.A.; Cherny, R.A.; Lam, L.Q. et al. Tau deficiency induces parkinsonism with dementia by impairing app-mediated iron export. Nat. Med. 2012, 18, 291-295.
13. Ahluwalia, N.; Gordon, M.A.; Handte, G.; Mahlon, M.; Li, N.Q.; Beard, J.L.; Weinstock, D.; Ross, A.C. Iron status and stores decline with age in lewis rats. J. Nutr. 2000, 130, 2378-2383.
14. Altun, M.; Edstrom, E.; Spooner, E.; Flores-Moralez, A.; Bergman, E.; Tollet-Egnell, P.; Norstedt, G.; Kessler, B.M.; Ulfhake, B. Iron load and redox stress in skeletal muscle of aged rats. Muscle Nerve 2007, 36, 223-233.
15. Xu, J.; Hwang, J.C.; Lees, H.A.; Wohlgemuth, S.E.; Knutson, M.D.; Judge, A.R.; Dupont-Versteegden, E.E.; Marzetti, E.; Leeuwenburgh, C. Long-term perturbation of muscle iron homeostasis following hindlimb suspension in old rats is associated with high levels of oxidative stress and impaired recovery from atrophy. Exp. Gerontol. 2012, 47, 100-108.
16. Hofer, T.; Marzetti, E.; Xu, J.; Seo, A.Y.; Gulec, S.; Knutson, M.D.; Leeuwenburgh, C.; Dupont-Versteegden, E.E. Increased iron content and rna oxidative damage in skeletal muscle with aging and disuse atrophy. Exp.Gerontol. 2008, 43, 563-570.
17. Xu, J.; Knutson, M.D.; Carter, C.S.; Leeuwenburgh, C. Iron accumulation with age, oxidative stress and functional decline. PLoS One 2008, 3, e2865.
18. Seo, A.Y.; Xu, J.; Servais, S.; Hofer, T.; Marzetti, E.; Wohlgemuth, S.E.; Knutson, M.D.; Chung, H.Y.; Leeuwenburgh, C. Mitochondrial iron accumulation with age and functional consequences. Aging Cell 2008, 7, 706-716.
19. Cook, C.I.; Yu, B.P. Iron accumulation in aging: Modulation by dietary restriction. Mech. Ageing Dev. 1998, 102, 1-13.
20. Massie, H.R.; Aiello, V.R.; Banziger, V. Iron accumulation and lipid peroxidation in aging c57bl/6j mice. Exp. Gerontol. 1983, 18, 277-285.
21. Arvapalli, R.K.; Paturi, S.; Laurino, J.P.; Katta, A.; Kakarla, S.K.; Gadde, M.K.; Wu, M.; Rice, K.M.; Walker, E.M.; Wehner, P. et al. Deferasirox decreases age-associated iron accumulation in the aging f344xbn rat heart and liver. Cardiovasc. Toxicol. 2010, 10, 108-116.
22. Jung, S.H.; DeRuisseau, L.R.; Kavazis, A.N.; Deruisseau, K.C. Plantaris muscle of aged rats demonstrates iron accumulation and altered expression of iron regulation proteins. Exp. Physiol. 2008, 93, 407-414.
23. Sohn, Y.S.; Breuer, W.; Munnich, A.; Cabantchik, Z.I. Redistribution of accumulated cell iron: A modality of chelation with therapeutic implications. Blood 2008, 111, 1690-1699.
24. Sohal, R.S.; Wennberg-Kirch, E.; Jaiswal, K.; Kwong, L.K.; Forster, M.J. Effect of age and caloric restriction on bleomycin-chelatable and nonheme iron in different tissues of c57bl/6 mice. Free Radic. Biol. Med. 1999, 27, 287-293.
25. Bulvik, B.E.; Berenshtein, E.; Konijn, A.M.; Grinberg, L.; Vinokur, V.; Eliashar, R.; Chevion, M.M. Aging is an organ-specific process: Changes in homeostasis of iron and redox proteins in the rat. Age (Dordr.) 2011, doi:10.1007/s11357-011-9268-7.
26. Aquino, D.; Bizzi, A.; Grisoli, M.; Garavaglia, B.; Bruzzone, M.G.; Nardocci, N.; Savoiardo, M.; Chiapparini, L. Age-related iron deposition in the basal ganglia: Quantitative analysis in healthy subjects. Radiology 2009, 252, 165-172.
27. Gregory, A.; Polster, B.J.; Hayflick, S.J. Clinical and genetic delineation of neurodegeneration with brain iron accumulation. J. Med. Genet. 2009, 46, 73-80.
28. Gaskell, H.; Derry, S.; Andrew Moore, R.; McQuay, H.J. Prevalence of anaemia in older persons: Systematic review. BMC Geriatr. 2008, 8, 1.
29. Peran, P.; Cherubini, A.; Luccichenti, G.; Hagberg, G.; Demonet, J.F.; Rascol, O.; Celsis, P.; Caltagirone, C.; Spalletta, G.; Sabatini, U. Volume and iron content in basal ganglia and thalamus. Hum. Brain Mapp. 2009, 30, 2667-2675.
30. Cherubini, A.; Peran, P.; Caltagirone, C.; Sabatini, U.; Spalletta, G. Aging of subcortical nuclei: Microstructural, mineralization and atrophy modifications measured in vivo using mri. Neuroimage 2009, 48, 29-36.
31. Zecca, L.; Gallorini, M.; Schunemann, V.; Trautwein, A.X.; Gerlach, M.; Riederer, P.; Vezzoni, P.; Tampellini, D. Iron, neuromelanin and ferritin content in the substantia nigra of normal subjects at different ages: Consequences for iron storage and neurodegenerative processes. J. Neurochem. 2001, 76, 1766-1773.
32. Inelmen, E.M.; D'Alessio, M.; Gatto, M.R.; Baggio, M.B.; Jimenez, G.; Bizzotto, M.G.; Enzi, G. Descriptive analysis of the prevalence of anemia in a randomly selected sample of elderly people living at home: Some results of an italian multicentric study. Aging (Milano) 1994, 6, 81-89.
33. Thomson, C.A.; Stanaway, J.D.; Neuhouser, M.L.; Snetselaar, L.G.; Stefanick, M.L.; Arendell, L.; Chen, Z. Nutrient intake and anemia risk in the women's health initiative observational study. J. Am. Diet Assoc. 2011, 111, 532-541.
34. Tussing-Humphreys, L.; Braunschweig, C. Anemia in postmenopausal women: Dietary inadequacy or nondietary factors? J. Am. Diet Assoc. 2011, 111, 528-531.
35. Przybyszewska, J.; Zekanowska, E.; Kedziora-Kornatowska, K.; Boinska, J.; Cichon, R.; Porzych, K. Prohepcidin and iron metabolism parameters in the obese elderly patients with anemia. J. Nutr. Health Aging 2011, 15, 259-264.
36. Price, E.A.; Mehra, R.; Holmes, T.H.; Schrier, S.L. Anemia in older persons: Etiology and evaluation. Blood Cells Mol. Dis. 2011, 46, 159-165.
37. House, M.J.; St Pierre, T.G.; Milward, E.A.; Bruce, D.G.; Olynyk, J.K. Relationship between brain r(2) and liver and serum iron concentrations in elderly men. Magn. Reson. Med. 2010, 63, 275-281.
38. Penninx, B.W.; Pahor, M.; Cesari, M.; Corsi, A.M.; Woodman, R.C.; Bandinelli, S.; Guralnik, J.M.; Ferrucci, L. Anemia is associated with disability and decreased physical performance and muscle strength in the elderly. J. Am. Geriatr. Soc. 2004, 52, 719-724.
39. Roy, C.N. Anemia in frailty. Clin. Geriatr. Med. 2011, 27, 67-78.
40. Chaves, P.H.; Carlson, M.C.; Ferrucci, L.; Guralnik, J.M.; Semba, R.; Fried, L.P. Association between mild anemia and executive function impairment in community-dwelling older women: The women's health and aging study ii. J. Am. Geriatr. Soc. 2006, 54, 1429-1435.
41. Denny, S.D.; Kuchibhatla, M.N.; Cohen, H.J. Impact of anemia on mortality, cognition, and function in community-dwelling elderly. Am. J. Med. 2006, 119, 327-334.
42. Blasiak, J.; Szaflik, J.; Szaflik, J.P. Implications of altered iron homeostasis for age-related macular degeneration. Front Biosci. 2011, 16, 1551-1559.
43. Franzini, C.; Berlusconi, A.; Favarelli, C.; Brambilla, S. Low frequency of elevated serum transferrin saturation in elderly subjects. Clin. Chim. Acta 2000, 298, 181-186.
44. Richer, S.; Rudy, D.; Statkute, L.; Karofty, K.; Frankowski, J. Serum iron, transferrin saturation, ferritin, and dietary data in age-related macular degeneration. Am. J. Ther. 2002, 9, 25-28.
45. Zekanowska, E.; Boinska, J.; Kwapisz, J.; Kedziora-Kornatowska, K.; Porzych, K.; Ratajczak, M. Serum Prohepcidin and Other Iron Metabolism Parameters in Healthy Adults. Przegl. Lek. 2011, 68, 82-86.
46. Schrag, M.; Mueller, C.; Oyoyo, U.; Smith, M.A.; Kirsch, W.M. Iron, zinc and copper in the alzheimer's disease brain: A quantitative meta-analysis. Some insight on the influence of citation bias on scientific opinion. Prog. Neurobiol. 2011, 94, 296-306.
47. Sullivan, J.L. Is stored iron safe? J. Lab. Clin. Med. 2004, 144, 280-284.
48. Anderson, L.J.; Wonke, B.; Prescott, E.; Holden, S.; Walker, J.M.; Pennell, D.J. Comparison of effects of oral deferiprone and subcutaneous desferrioxamine on myocardial iron concentrations and ventricular function in beta-thalassaemia. Lancet 2002, 360, 516-520.
49. Pennell, D.J.; Berdoukas, V.; Karagiorga, M.; Ladis, V.; Piga, A.; Aessopos, A.; Gotsis, E.D.; Tanner, M.A.; Smith, G.C.; Westwood, M.A. et al. Randomized controlled trial of deferiprone or deferoxamine in beta-thalassemia major patients with asymptomatic myocardial siderosis. Blood 2006, 107, 3738-3744.
50. Turturro, A.; Witt, W.W.; Lewis, S.; Hass, B.S.; Lipman, R.D.; Hart, R.W. Growth curves and survival characteristics of the animals used in the biomarkers of aging program. J. Gerontol. A Biol. Sci. Med. Sci. 1999, 54, B492-B501.
51. Takeda, T.; Kimura, M.; Yokoi, K.; Itokawa, Y. Effect of age and dietary protein level on tissue mineral levels in female rats. Biol. Trace Elem. Res. 1996, 54, 55-74.
52. Koolhaas, J.M. The Ufaw Handbook on the Care and Management of Laboratory Animals; The Universities Federation for Animal Welfare: Hertfordshire, UK, 2010; pp. 311-322.
53. Feldman, J.D.; Woda, B.A. Pathology and tumor incidence in aged lewis and bn rats. Clin. Immunol. Immunopathol. 1980, 15, 331-343.
54. Keenan, K.P.; Smith, P.F.; Hertzog, P.; Soper, K.; Ballam, G.C.; Clark, R.L. The effects of overfeeding and dietary restriction on sprague-dawley rat survival and early pathology biomarkers of aging. Toxicol. Pathol. 1994, 22, 300-315.
55. Rice, K.M.; Linderman, J.K.; Kinnard, R.S.; Blough, E.R. The fischer 344/nniahsd x brown norway/binia is a better model of sarcopenia than the fischer 344/nniahsd: A comparative analysis of muscle mass and contractile properties in aging male rat models. Biogerontology 2005, 6, 335-343.
56. Rice, K.M.; Wu, M.; Blough, E.R. Aortic aging in the fischer 344/nniahsd x brown norway/binia rat. J. Pharmacol. Sci. 2008, 108, 393-398.
57. Hahn, P.; Song, Y.; Ying, G.S.; He, X.; Beard, J.; Dunaief, J.L. Age-dependent and gender-specific changes in mouse tissue iron by strain. Exp.Gerontol. 2009, 44, 594-600.
58. Bitar, M.; Weiner, M. Modification of age-induced changes in heme and hemoproteins by testosterone in male rats. Mech. Ageing Dev. 1983, 23, 285-296.
59. Atamna, H. Heme, iron, and the mitochondrial decay of ageing. Ageing Res. Rev. 2004, 3, 303-318.
60. Atamna, H.; Killilea, D.W.; Killilea, A.N.; Ames, B.N. Heme deficiency may be a factor in the mitochondrial and neuronal decay of aging. Proc. Natl. Acad. Sci. USA 2002, 99, 14807-14812.
61. Atamna, H.; Liu, J.; Ames, B.N. Heme deficiency selectively interrupts assembly of mitochondrial complex iv in human fibroblasts: Revelance to aging. J. Biol. Chem. 2001, 276, 48410-48416.
62. Atamna, H.; Walter, P.B.; Ames, B.N. The role of heme and iron-sulfur clusters in mitochondrial biogenesis, maintenance, and decay with age. Arch. Biochem. Biophys. 2002, 397, 345-353.
63. Chua, A.C.; Graham, R.M.; Trinder, D.; Olynyk, J.K. The regulation of cellular iron metabolism. Crit. Rev. Clin. Lab. Sci. 2007, 44, 413-459.
64. Kohgo, Y.; Ikuta, K.; Ohtake, T.; Torimoto, Y.; Kato, J. Body iron metabolism and pathophysiology of iron overload. Int. J. Hematol. 2008, 88, 7-15.
65. Dunn, L.L.; Rahmanto, Y.S.; Richardson, D.R. Iron uptake and metabolism in the new millennium. Trends Cell Biol. 2007, 17, 93-100.
66. Leverence, R.; Mason, A.B.; Kaltashov, I.A. Noncanonical interactions between serum transferrin and transferrin receptor evaluated with electrospray ionization mass spectrometry. Proc. Natl. Acad. Sci. USA 2010, 107, 8123-8128.
67. Hofer, T.; Marzetti, E.; Seo, A.Y.; Xu, J.; Knutson, M.D.; Leeuwenburgh, C. Mechanisms of iron regulation and oxidative stress in sarcopenia and neurodegenerative diseases. In Free Radicals in Biology and Medicine; Gutierrez-Merino, C., Leeuwenburgh, C., Eds.; Research Signpost: Kerala, India, 2008; pp. 1-22.
68. Liuzzi, J.P.; Aydemir, F.; Nam, H.; Knutson, M.D.; Cousins, R.J. Zip14 (slc39a14) mediates non-transferrin-bound iron uptake into cells. Proc. Natl. Acad. Sci. USA 2006, 103, 13612-13617.
69. Zhao, N.; Gao, J.; Enns, C.A.; Knutson, M.D. Zrt/irt-like protein 14 (zip14) promotes the cellular assimilation of iron from transferrin. J. Biol. Chem. 2010, 285, 32141-32150.
70. Donovan, A.; Lima, C.A.; Pinkus, J.L.; Pinkus, G.S.; Zon, L.I.; Robine, S.; Andrews, N.C. The iron exporter ferroportin/slc40a1 is essential for iron homeostasis. Cell Metab. 2005, 1, 191-200.
71. McKie, A.T.; Marciani, P.; Rolfs, A.; Brennan, K.; Wehr, K.; Barrow, D.; Miret, S.; Bomford, A.; Peters, T.J.; Farzaneh, F. et al. A novel duodenal iron-regulated transporter, ireg1, implicated in the basolateral transfer of iron to the circulation. Mol. Cell 2000, 5, 299-309.
72. Galy, B.; Ferring, D.; Minana, B.; Bell, O.; Janser, H.G.; Muckenthaler, M.; Schumann, K.; Hentze, M.W. Altered body iron distribution and microcytosis in mice deficient in iron regulatory protein 2 (irp2). Blood 2005, 106, 2580-2589.
73. Reeves, P.G.; Nielsen, F.H.; Fahey, G.C., Jr. Ain-93 purified diets for laboratory rodents: Final report of the american institute of nutrition ad hoc writing committee on the reformulation of the ain-76a rodent diet. J. Nutr. 1993, 123, 1939-1951.
74. Nutrient requirements of the mouse. In Nutrient Requirements of Laboratory Animals, 4th ed.; Subcommittee on Laboratory Animal Nutrition; Commitee on Animal Nutrition, Board on Agriculture, National Research Council, Eds.; National Academy Press: Washington, DC, USA, 1995; p. 90.
75. Knapka, J.J.; Smith, K.P.; Judge, F.J. Effect of open and closed formula rations on the performance of three strains of laboratory mice. Lab. Anim. Sci. 1974, 24, 480-487.
76. Sorbie, J.; Valberg, L.S. Iron balance in the mouse. Lab. Anim. Sci. 1974, 24, 900-904.
77. Cooksey, R.C.; Jones, D.; Gabrielsen, S.; Huang, J.; Simcox, J.A.; Luo, B.; Soesanto, Y.; Rienhoff, H.; Abel, E.D.; McClain, D.A. Dietary iron restriction or iron chelation protects from diabetes and loss of beta-cell function in the obese (ob/ob lep-/-) mouse. Am. J. Physiol. Endocrinol. Metab. 2010, 298, E1236-E1243.
78. Breuer, W.; Shvartsman, M.; Cabantchik, Z.I. Intracellular labile iron. Int. J. Biochem. Cell Biol. 2007, 40, 350-354.
79. Rauen, U.; Springer, A.; Weisheit, D.; Petrat, F.; Korth, H.G.; de, G.H.; Sustmann, R. Assessment of chelatable mitochondrial iron by using mitochondrion-selective fluorescent iron indicators with different iron-binding affinities. ChemBioChem 2007, 8, 341-352.
80. Wang, J.; Pantopoulos, K. Regulation of cellular iron metabolism. Biochem. J. 2011, 434, 365-381.
81. Cantu, D.; Schaack, J.; Patel, M. Oxidative inactivation of mitochondrial aconitase results in iron and h2o2-mediated neurotoxicity in rat primary mesencephalic cultures. PLoS One 2009, 4, e7095.
82. Cabantchik, Z.I.; Kakhlon, O.; Epsztejn, S.; Zanninelli, G.; Breuer, W. Intracellular and extracellular labile iron pools. Adv. Exp. Med. Biol. 2002, 509, 55-75.
83. Kruszewski, M. Labile iron pool: The main determinant of cellular response to oxidative stress. Mutat. Res. 2003, 531, 81-92.
84. Simunek, T.; Boer, C.; Bouwman, R.A.; Vlasblom, R.; Versteilen, A.M.; Sterba, M.; Gersl, V.; Hrdina, R.; Ponka, P.; de Lange, J.J.; et al. Sih-a novel lipophilic iron chelator-protects h9c2 cardiomyoblasts from oxidative stress-induced mitochondrial injury and cell death. J. Mol. Cell Cardiol. 2005, 39, 345-354.
85. Kondo, H.; Miura, M.; Kodama, J.; Ahmed, S.M.; Itokawa, Y. Role of iron in oxidative stress in skeletal muscle atrophied by immobilization. Pflugers Arch. 1992, 421, 295-297.
86. Cherayil, B.J.; Ellenbogen, S.; Shanmugam, N.N. Iron and intestinal immunity. Curr. Opin. Gastroenterol. 2011, 27, 523-528.
87. Weijl, N.I.; Elsendoorn, T.J.; Moison, R.M.; Lentjes, E.G.; Brand, R.; Berger, H.M.; Osanto, S. Non-protein bound iron release during chemotherapy in cancer patients. Clin. Sci. (Lond.) 2004, 106, 475-484.
88. Salonen, J.T.; Nyyssonen, K.; Korpela, H.; Tuomilehto, J.; Seppanen, R.; Salonen, R. High stored iron levels are associated with excess risk of myocardial infarction in eastern finnish men. Circulation 1992, 86, 803-811.
89. Tuomainen, T.P.; Punnonen, K.; Nyyssonen, K.; Salonen, J.T. Association between body iron stores and the risk of acute myocardial infarction in men. Circulation 1998, 97, 1461-1466.
90. Casale, G.; Bonora, C.; Migliavacca, A.; Zurita, I.E.; de Nicola, P. Serum ferritin and ageing. Age Ageing 1981, 10, 119-122.
91. Joosten, E.; Van Loon, R.; Billen, J.; Blanckaert, N.; Fabri, R.; Pelemans, W. Serum transferrin receptor in the evaluation of the iron status in elderly hospitalized patients with anemia. Am. J. Hematol. 2002, 69, 1-6.
92. Tull, K.I.; Hirani, V.; Ali, A.; Chua, E.; Mindell, J.S. Impact of different diagnostic thresholds and the anaemia-ferritin-transferrin receptor model on the prevalence of anaemia and impaired iron status in older people. Age Ageing 2009, 38, 609-613.
93. Boggs, D.R.; Patrene, K. Hematopoiesis and aging. V. A decline in hematocrit occurs in all aging female b6d2f1 mice. Exp. Aging Res. 1986, 12, 131-134.
94. Boggs, D.R.; Patrene, K.D. Hematopoiesis and aging iii: Anemia and a blunted erythropoietic response to hemorrhage in aged mice. Am. J. Hematol. 1985, 19, 327-338.
95. Finch, C.E.; Foster, J.R. Hematologic and serum electrolyte values of the c57bl-6j male mouse in maturity and senescence. Lab. Anim. Sci. 1973, 23, 339-349.
96. Seaverson, E.L.; Buell, J.S.; Fleming, D.J.; Bermudez, O.I.; Potischman, N.; Wood, R.J.; Chasan-Taber, L.; Tucker, K.L. Poor iron status is more prevalent in hispanic than in non-hispanic white older adults in massachusetts. J. Nutr. 2007, 137, 414-420.
97. Eisenstaedt, R.; Penninx, B.W.; Woodman, R.C. Anemia in the elderly: Current understanding and emerging concepts. Blood Rev. 2006, 20, 213-226.
98. Saitoh, T.; Morimoto, K.; Kumagai, T.; Tsuboi, I.; Aikawa, S.; Horie, T. Comparison of erythropoietic response to androgen in young and old senescence accelerated mice. Mech. Ageing Dev. 1999, 109, 125-139.
99. Lipschitz, D.A. Age-related declines in hematopoietic reserve capacity. Semin. Oncol. 1995, 22, 3-5.
100. Balducci, L.; Hardy, C.L.; Lyman, G.H. Hemopoiesis and aging. Cancer Treat Res. 2005, 124, 109-134.
101. Loeffler, M.; Pantel, K. A mathematical model of erythropoiesis suggests an altered plasma volume control as cause for anemia in aged mice. Exp. Gerontol. 1990, 25, 483-495.
102. Nemeth, E.; Valore, E.V.; Territo, M.; Schiller, G.; Lichtenstein, A.; Ganz, T. Hepcidin, a putative mediator of anemia of inflammation, is a type ii acute-phase protein. Blood 2003, 101, 2461-2463.
103. Pigeon, C.; Ilyin, G.; Courselaud, B.; Leroyer, P.; Turlin, B.; Brissot, P.; Loreal, O. A new mouse liver-specific gene, encoding a protein homologous to human antimicrobial peptide hepcidin, is overexpressed during iron overload. J. Biol. Chem. 2001, 276, 7811-7819.
104. Nemeth, E.; Ganz, T. The role of hepcidin in iron metabolism. Acta Haematol. 2009, 122, 78-86.
105. Nemeth, E.; Tuttle, M.S.; Powelson, J.; Vaughn, M.B.; Donovan, A.; Ward, D.M.; Ganz, T.; Kaplan, J. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science 2004, 306, 2090-2093.
106. Ganz, T.; Olbina, G.; Girelli, D.; Nemeth, E.; Westerman, M. Immunoassay for human serum hepcidin. Blood 2008, 112, 4292-4297.
107. Lee, P.; Gelbart, T.; Waalen, J.; Beutler, E. The anemia of ageing is not associated with increased plasma hepcidin levels. Blood Cells Mol. Dis. 2008, 41, 252-254.
108. Levi, S.; Rovida, E. The role of iron in mitochondrial function. Biochim. Biophys. Acta 2009, 1790, 629-636.
109. Veatch, J.R.; McMurray, M.A.; Nelson, Z.W.; Gottschling, D.E. Mitochondrial dysfunction leads to nuclear genome instability via an iron-sulfur cluster defect. Cell 2009, 137, 1247-1258.
110. Liang, L.P.; Jarrett, S.G.; Patel, M. Chelation of mitochondrial iron prevents seizure-induced mitochondrial dysfunction and neuronal injury. J. Neurosci. 2008, 28, 11550-11556.
111. Duvigneau, J.C.; Piskernik, C.; Haindl, S.; Kloesch, B.; Hartl, R.T.; Huttemann, M.; Lee, I.; Ebel, T.; Moldzio, R.; Gemeiner, M. et al. A novel endotoxin-induced pathway: Upregulation of heme oxygenase 1, accumulation of free iron, and free iron-mediated mitochondrial dysfunction. Lab. Invest. 2008, 88, 70-77.
112. Weinberg, E.D.; Miklossy, J. Iron withholding: A defense against disease. J. Alzheimers. Dis. 2008, 13, 451-463.
113. Liu, G.; Men, P.; Perry, G.; Smith, M.A. Nanoparticle and iron chelators as a potential novel alzheimer therapy. Methods Mol. Biol. 2010, 610, 123-144.
114. Kaur, D.; Andersen, J. Does cellular iron dysregulation play a causative role in parkinson's disease? Ageing Res. Rev. 2004, 3, 327-343.
115. Ghosh, B.; Antonio, T.; Reith, M.E.; Dutta, A.K. Discovery of 4-(4-(2-((5-hydroxy-1,2,3,4- tetrahydronaphthalen-2-yl)(propyl)amino)ethyl) piperazin-1-yl)quinolin-8-ol and its analogues as highly potent dopamine d2/d3 agonists and as iron chelator: In vivo activity indicates potential application in symptomatic and neuroprotective therapy for parkinson's disease. J. Med. Chem. 2010, 53, 2114-2125.
116. Whitnall, M.; Rahmanto, Y.S.; Sutak, R.; Xu, X.; Becker, E.M.; Mikhael, M.R.; Ponka, P.; Richardson, D.R. The mck mouse heart model of friedreich's ataxia: Alterations in iron-regulated proteins and cardiac hypertrophy are limited by iron chelation. Proc. Natl. Acad. Sci. USA 2008, 105, 9757-9762.
117. Goncalves, S.; Paupe, V.; Dassa, E.P.; Rustin, P. Deferiprone targets aconitase: Implication for friedreich's ataxia treatment. BMC Neurol. 2008, 8, 20.
118. Dunaief, J.L. Iron induced oxidative damage as a potential factor in age-related macular degeneration: The cogan lecture. Invest Ophthalmol. Vis. Sci. 2006, 47, 4660-4664.
119. Lukinova, N.; Iacovelli, J.; Dentchev, T.; Wolkow, N.; Hunter, A.; Amado, D.; Ying, G.S.; Sparrow, J.R.; Dunaief, J.L. Iron chelation protects the retinal pigment epithelial cell line arpe-19 against cell death triggered by diverse stimuli. Invest Ophthalmol. Vis. Sci. 2009, 50, 1440-1447.
120. Darnton-Hill, I.; Webb, P.; Harvey, P.W.; Hunt, J.M.; Dalmiya, N.; Chopra, M.; Ball, M.J.; Bloem, M.W.; De, B.B. Micronutrient deficiencies and gender: Social and economic costs. Am. J. Clin. Nutr. 2005, 81, 1198S-1205S.
121. Choi, J.H.; Kim, D.W.; Yu, B. Modulation of age-related alterations of iron, ferritin, and lipid peroxidation in rat brain synaptosomes. J. Nutr. Health Aging 1998, 2, 133-137.
122. Weindruch, R.; Walford, R.L. Dietary restriction in mice beginning at 1 year of age: Effect on life-span and spontaneous cancer incidence. Science 1982, 215, 1415-1418.
123. Olshansky, S.J.; Hayflick, L.; Carnes, B.A. Position statement on human aging. J. Gerontol. A Biol. Sci. Med. Sci. 2002, 57, B292-B297.
124. Brune, M.; Rossander, L.; Hallberg, L. Iron absorption and phenolic compounds: Importance of different phenolic structures. Eur. J. Clin. Nutr. 1989, 43, 547-557.
125. Hurrell, R.F.; Reddy, M.; Cook, J.D. Inhibition of non-haem iron absorption in man by polyphenolic-containing beverages. Br. J. Nutr. 1999, 81, 289-295.