A prospective epigenetic paradigm between cellular senescence and epithelial-mesenchymal transition in organismal development and aging

Epigenetic states can govern the plasticity of a genome to be adaptive to environments where many stress stimuli and insults compromise the homeostatic system with age. Although certain elastic power may autonomously reset, reprogram, rejuvenate, 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 a noninvasive manner, particularly in a whole complex aging organism. Given inevitable increase of cancer with age, presumably any failure of resetting, reprogramming, 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 regulation. Thus, the epithelial-mesenchymal transition (EMT) and its reversal (mesenchymal-epithelial transition [MET]) function as a key of cellular transdifferentiation programs. On the one hand, the EMT-MET process was initially appreciated in developmental biology, but is now attracting increasing attention in oncogenesis and senescence, because the process is involved in the malignant progression vs regression 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 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.