41. Janig E, Haslbeck M, Aigelsreiter A, Braun N, Unterthor D, et al. (2007) Clusterin associates with altered elastic fibers in human photoaged skin and prevents elastin from ultraviolet-induced aggregation in vitro. Am J Pathol 171: 1474–82. 42. Ressler S, Bartkova J, Niederegger H, Bartek J, Scharffetter-Kochanek K, et al. (2006) p16INK4A is a robust in vivo biomarker of cellular aging in human skin. Aging Cell 5: 379–89. 43. Flurkey K, Papaconstantinou J, Miller RA, Harrison DE (2001) Lifespan extension and delayed immune and collagen aging in mutant mice with defects in growth hormone production. Proc Natl Acad Sci U S A 98: 6736–41. 44. Brink TC, Regenbrecht C, Demetrius L, Lehrach H, Adjaye J (2009) Activation of the immune response is a key feature of aging in mice. Biogerontology 10: 721–34. 45. Park SK, Kim K, Page GP, Allison DB, Weindruch R, et al. (2009) Gene expression profiling of aging in multiple mouse strains: identification of aging biomarkers and impact of dietary antioxidants. Aging Cell 8: 484–95. 46. Lustig A, Weeraratna AT, Wood WW, 3rd, Teichberg D, Bertak D, et al. (2007) Transcriptome analysis of age-, gender- and diet-associated changes in murine thymus. Cell Immunol 245: 42–61. 47. Lustig A, Carter A, Bertak D, Enika D, Vandanmagsar B, et al. (2009) Transcriptome analysis of murine thymocytes reveals age-associated changes in thymic gene expression. Int J Med Sci 6: 51–64. 48. Karim R, Stanczyk FZ, Hodis HN, Cushman M, Lobo RA, et al. (2010) Associations between markers of inflammation and physiological and pharma- cological levels of circulating sex hormones in postmenopausal women. Menopause 17: 785–90. 49. Le´lu K, Delpy L, Robert V, Foulon E, Laffont S, et al. (2010) Endogenous estrogens, through estrogen receptor a, constrain autoimmune inflammation in female mice by limiting CD4+ T-cell homing into the CNS. Eur J Immunol 40: 3489–98. 50. Stice JP, Lee JS, Pechenino AS, Knowlton AA (2009) Estrogen, aging and the cardiovascular system. Future Cardiol 5: 93–103. 51. Contoreggi CS, Blackman MR, Andres R, Muller DC, Lakatta EG, et al. (1990) Plasma levels of estradiol, testosterone, and DHEAS do not predict risk of coronary artery disease in men. J Androl 11: 460–70. 52. Hurt EM, Saykally JN, Anose BM, Kalli KR, Sanders MM (2008) Expression of the ZEB1 (deltaEF1) transcription factor in human: additional insights. Mol Cell Biochem 318: 89–99. 53. Dillner NB, Sanders MM (2004) Transcriptional activation by the zinc-finger homeodomain protein delta EF1 in estrogen signaling cascades. DNA Cell Biol 23: 25–34. 54. Richer JK, Jacobsen BM, Manning NG, Abel MG, Wolf DM, et al. (2002) Differential gene regulation by the two progesterone receptor isoforms in human breast cancer cells. J Biol Chem 277: 5209–18. 55. Liu Y, El-Naggar S, Darling DS, Higashi Y, Dean DC (2008) Zeb1 links epithelial-mesenchymal transition and cellular senescence. Development 135: 579–88. 56. Terraz C, Toman D, Delauche M, Ronco P, Rossert J (2001) delta Ef1 binds to a far upstream sequence of the mouse pro-alpha 1(I) collagen gene and represses its expression in osteoblasts. J Biol Chem 276: 37011–9. 57. Ponticos M, Partridge T, Black CM, Abraham DJ, Bou-Gharios G (2004) Regulation of collagen type I in vascular smooth muscle cells by competition between Nkx2.5 and deltaEF1/ZEB1. Mol Cell Biol 24: 6151–61. 58. Murray D, Precht P, Balakir R, Horton WE, Jr. (2000) The transcription factor deltaEF1 is inversely expressed with type II collagen mRNA and can repress Col2a1 promoter activity in transfected chondrocytes. J Biol Chem 275: 3610–8. 59. Tanaka K, Tsumaki N, Kozak CA, Matsumoto Y, Nakatani F, et al. (2002) A Kr u¨ppel-associated box-zinc finger protein, NT2, represses cell-type-specific promoter activity of the alpha 2(XI) collagen gene. Mol Cell Biol 22: 4256–67. Mechanisms of Transcriptome Aging 60. Harper JM, Durkee SJ, Dysko RC, Austad SN, Miller RA (2006) Genetic modulation of hormone levels and life span in hybrids between laboratory and wild-derived mice. J Gerontol A Biol Sci Med Sci 61: 1019–29. 61. Wennmalm K, Wahlestedt C, Larsson O (2005) The expression signature of in vitro senescence resembles mouse but not human aging. Genome Biol 6: R109. 62. Ku HH, Brunk UT, Sohal RS (1993) Relationship between mitochondrial superoxide and hydrogen peroxide production and longevity of mammalian species. Free Radic Biol Med 15: 621–7. 63. Miller RA, Nadon NL (2000) Principles of animal use for gerontological research. J Gerontol A Biol Sci Med Sci 55: B117–23. 64. Kavak E, Unlu¨ M, Niste´r M, Koman A (2010) Meta-analysis of cancer gene expression signatures reveals new cancer genes, SAGE tags and tumor associated regions of co-regulation. Nucleic Acids Res 38: 7008–21. 65. Arking R (2006) Biology of Aging: Observations & Principles, Third Edition. New York: Oxford University Press. 604 p. 66. Gudjonsson JE, Ding J, Li X, Nair RP, Tejasvi T, et al. (2009) Global gene expression analysis reveals evidence for decreased lipid biosynthesis and increased innate immunity in uninvolved psoriatic skin. J Invest Dermatol 129: 2795–804. 67. Liu G, Loraine AE, Shigeta R, Cline M, Cheng J, et al. (2003) NetAffx: Affymetrix probesets and annotations. Nucleic Acids Res 31: 82–6. 68. Hornberger TA, Mateja RD, Chin ER, Andrews JL, Esser KA (2005) Aging does not alter the mechanosensitivity of the p38, p70S6k, and JNK2 signaling pathways in skeletal muscle. J Appl Physiol 98: 1562–6. 69. Gudjonsson JE, Johnston A, Dyson M, Valdimarsson H, Elder JT (2007) Mouse models of psoriasis. J Invest Dermatol 127: 1292–308. 70. Bolstad BM, Collin F, Brettschneider J, Simpson K, Cope L, et al. (2005) Quality assessment of Affymetrix GeneChip Data. In: Gentleman R, Huber W, Carey VJ, Irizarry RA, Dudoit, eds. Bioinformatics and computational biology solutions using R and Bioconductor. New York: Springer. pp 33–47. 71. Johnson WE, Rabinovic A, Li C (2007) Adjusting batch effects in microarray expression data using Empirical Bayes methods. Biostatistics 8: 118–127. 72. Smyth GK (2004) Linear models and empirical bayes methods for assessing differential expression in microarray experiments. Stat Appl Genet Mol Biol 3: 3. 73. Benjamini Y, Hochberg Y (1995) Controlling the false discovery rate: a powerful and practical approach to multiple testing. J Roy Stat Soc B 57: 289–300. 74. Neter J, Kutner MH, Nachtsheim CJ, Wasserman W (1996) Applied Linear Regression Models, Fourth Edition. Burr Ridge: Irwin. 720 p. 75. Reimers M, Carey VJ (2006) Bioconductor: an open source framework for bioinformatics and computational biology. Methods Enzymol 411: 119–134. 76. Venables WN, Ripley BD (2002) Modern Applied Statistics with S, Fourth Edition. New York: Springer-Verlag. 495 p. 77. Falcon S, Gentleman R (2007) Using GOstats to test gene lists for GO term association. Bioinformatics 23: 257–258. 78. Liu WM, Mei R, Di X, Ryder TB, Hubbell E, et al. (2002) Analysis of high density expression microarrays with signed-rank call algorithms. Bioinformatics 18: 1593–9. 79. Woo Y, Affourtit J, Daigle S, Viale A, Johnson K, et al. (2004) A comparison of cDNA, oligonucleotide, and Affymetrix GeneChip gene expression microarray platforms. J Biomol Tech 15: 276–84. 80. Mah N, Thelin A, Lu T, Nikolaus S, Ku¨hbacher T, et al. (2004) A comparison of oligonucleotide and cDNA-based microarray systems. Physiol Genomics 16: 361–70. 81. Rogojina AT, Orr WE, Song BK, Geisert EE, Jr. (2003) Comparing the use of Affymetrix to spotted oligonucleotide microarrays using two retinal pigment epithelium cell lines. Mol Vis 9: 482–96. 82. Wasserman WW, Sandelin A (2004) Applied bioinformatics for the identification of regulatory elements. Nat Rev Genet 5: 276–87. PLoS ONE | www.plosone.org 21 March 2012 | Volume 7 | Issue 3 | e33204