REVIEW ARTICLE A prospective epigenetic paradigm between cellular senescence and epithelial-mesenchymal transition in organismal development and aging Q29 SHUJI KISHI, PETER E. BAYLISS, and JUN-ICHI HANAI FLORIDA; TORONTO, ONTARIO, CANADA; AND BOSTON, MASSACHUSETTS Epigenetic states can govern the plasticity of a genome to be adaptive to environ- ments where many stress stimuli and insults compromise the homeostatic system with age. Although certain elastic power may autonomously reset, reprogram, reju- venate, or reverse the organismal aging process, enforced genetic manipulations could at least reset and reprogram epigenetic states beyond phenotypic plasticity and elasticity in cells, which can be further manipulated into organisms. The question, however, remains how we can rejuvenate intrinsic resources and infrastructures in an intact/noninvasive Q11 manner, particularly in a whole complex aging organism. Given inevitable increase of cancer with age, presumably any failure of resetting, reprog- ramming, or even rejuvenation could be a prominent causative factor of malignancy. Accompanied by progressive deteriorations of physiological functions in organisms with advancing age, aging-associated cancer risk may essentially arise from unforeseen complications in cellular senescence. At the cellular level, epithelial- mesenchymal plasticity (dynamic and reversible transitions between epithelial and mesenchymal phenotypic states) is enabled by underlying shifts in epigenetic regu- lation. Thus, the epithelial-mesenchymal transition (EMT) and its reversal (mesen- chymal-epithelial transition [MET]) function as a key of cellular transdifferentiation programs. On the one hand, the EMT-MET process was initially appreciated in devel- opmental biology, but is now attracting increasing attention in oncogenesis and senescence, because the process is involved in the malignant progression vs regres- sion of cancer. On the other hand, senescence is often considered the antithesis of early development, but yet between these 2 phenomena, there may be common factors and/or Q12 governing mechanisms such as the EMT-MET program, to steer toward rejuvenation of the biological aging system, thereby precisely controlling or avoiding cancer through epigenetic interventions. (Translational Research 2014;-:1–9) Abbreviations: --- ¼ --- Q13 From the Department of Metabolism and Aging, The Scripps Research Institute, Florida; Campbell Family Cancer Research Institute, Ontario Cancer Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada; Division of Interdisciplinary Medicine and Biotechnology; Division of Nephrology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts. Submitted for publication March 6, 2014; revision submitted May 9, 2014; accepted for publication May 14, 2014. Reprint requests: Shuji Kishi, Department of Metabolism and Aging, The Scripps Research Institute, Scripps Florida, 130 Scripps Way, #3B3, Jupiter, FL 33458; e-mail: s.kishi@mac.com. 1931-5244/$ - see front matter Ó 2014 Mosby, Inc. All rights reserved. http://dx.doi.org/10.1016/j.trsl.2014.05.007 1 REV 5.2.0 DTD  TRSL788_proof  7 June 2014  6:38 pm  ce 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106