Retrodifferentiation and reversibility of aging: forever young?

Maturation of stem cells or precursor cells is associated with the acquisition of certain properties finally resulting in specifically functional cell types within the diverse tissues. This maturation process requires distinct steps of differentiation and is accompanied by a constantly increasing process of aging paralleled by a progressively reduced proliferative capacity. The eventually growth arrested and terminally differentiated cells perform their appropriate specific functions associated with developing senescence by STASIS (stress or aberrant signaling-inducing senescence) and/or by replicative senescence. Finally, elimination via apoptosis concludes their life span. However, nature also provides a surprise within this concept of life: Sometimes, differentiation and aging steps are reversible. A biological phenomenon of completely reversible differentiation events has been characterized as retrodifferentiation rather than dedifferentiation. Thus, all morphological and functional properties of retrodifferentiated and previously more undifferentiated cells are indistinguishable. Consequently, reversible differentiation may simultaneously be associated with a reversibility of the aging process and therefore, contributes to longevity and rejuvenation. Tissue renewals or regenerative potential for tissue-specific requirements, if not sufficiently compensated by the appropriate stem cells, may necessitate the generation of undifferentiated precursors by retrodifferentiation followed by a subsequent transdifferentiation process with the consequence of cell type conversion which also includes the risk for tumor development. This interference with the normal biological clock mediated by threshold effects in certain individual cells, raises important questions: What signals trigger retrodifferentiation and what would be the finite life span of cells with a retrodifferentiation capacity?