Rejuvenation by Partial Reprogramming of the Epigenome.

Epigenetic variation with age is one of the most important hallmarks of aging. Resetting or repairing the epigenome of aging cells in intact animals may rejuvenate the cells and perhaps the entire organism. In fact, differentiated adult cells, which by definition have undergone some epigenetic changes, are capable of being rejuvenated and reprogrammed to create pluripotent stem cells and viable cloned animals. Apparently, such reprogramming is capable of completely resetting the epigenome. However, attempts to fully reprogram differentiated cells in adult animals have failed in part because reprogramming leads to the formation of teratomas. A preliminary method to partially reprogram adult cells in mature Hutchinson-Gilford Progeria Syndrome (HGPS) mice by transient induction of the Yamanaka factors OSKM (Oct4/Sox2/Klf4/c-Myc) appears to ameliorate aging-like phenotypes in HGPS mice, and promote youthful regenerative capability in middle-aged wild-type individuals exposed to beta cell and muscle cell-specific toxins. However, whatever epigenetic repair is induced by transient reprogramming does not endure and may be due to the induction of key homeostatic regulators instead. Some of the effect of transient reprogramming may result from increased proliferation and enhanced function of adult stem cells. Partial reprogramming may point the way to new antiaging and proregenerative therapeutics. Redifferentiation of cells into their preexisting phenotype with simultaneous epigenomic rejuvenation is an interesting variation that also should be pursued. However, discovery of methods to more precisely repair the epigenome is the most likely avenue to the development of powerful new antiaging agents.

Epigenetic/Genetic Mismatch: Using Transdifferentiation as a Potential Cancer Therapy to Exploit the Cell Type Specificity of Cancer.

Every cell type capable of proliferation can be malignantly transformed. However, there appears to be no naturally occurring universal set of genetic mutations capable of converting every cell type to a malignant state. Any specific cell type is generally resistant to transformation by the cancer mutations accumulated by cells of different lineages, presumably due to epigenetic differences. Evidence for this idea derives from experiments in which the developmental fates of cancer cells are altered to reduce malignancy. Reprogramming cancer cells to more primitive developmental states using pluripotency factors (IPS) or somatic nuclear transfer suppresses the malignant phenotype, as does subsequent directed differentiation to mature cells of lineages distinct from the originating cell. Direct transdifferentiation to an alternative cell fate also reduces tumorigenicity. In contrast, after reprogramming, cells induced to redifferentiate toward the original tumor cell type are tumorigenic. In these types of experiments an epigenetic/genetic mismatch often results in suppression of malignancy or cell death. Elucidating the specific transcription and cell signaling network incompatibilities will identify new targets for cancer therapy. Moreover, novel strategies to induce an incompatible transdifferentiated state, in which expression of thousands of genes are altered, will prove useful in controlling malignancies that otherwise easily evolve resistance to single target-based therapeutics. Engineering small molecules, genetic vectors, cytokines, growth factors, targeted extracellular vesicles, and cell fusion will help realize transdifferentiation-based therapeutics for cancer.