How stem cells stay young

Much has been made of the therapeutic promise of embryonic stem cells (ESCs), especially in the treatment and prevention of aging-associated diseases and age-related decline in tissue function.

ESCs are pluripotent, and are thought to be capable of differentiating into any type (or at least most types) of somatic cell. Unlike differentiated cells, ESCs can divide indefinitely, and they maintain this replicative immortality for as long as they retain their pluripotency.

But how do ESCs escape replicative exhaustion and cellular senescence, the internal “clock” that prevents the unlimited division of differentiated cells? Telomerase expression certainly helps, but it’s not the whole story: Zeng and Rao review the evidence that differences in epigenetic modifations, damage-response and checkpoint pathways (as well as telomerase) influence the ability of ESCs to retain replicative potential indefinitely.

Unlike normal somatic cells, human embryonic stem cells (hESCs) can proliferate indefinitely in culture in an undifferentiated state where they do not appear to undergo senescence and yet remain nontransformed. Cells maintain their pluripotency both in vivo and in vitro, exhibit high telomerase activity, and maintain telomere length after prolonged in vitro culture. Thus, hESCs may provide an unlimited cell source for replacement in a number of aging-related neurodegenerative diseases such as Parkinson’s disease and Alzheimer’s disease as well as other neurological disorders including spinal cord injuries. The ability of hESCs to bypass senescence is lost as hESCs differentiate into fully differentiated somatic cells. Evidence has been accumulated that differences in telomere length, telomerase activity, cell cycle signaling, DNA repair ability, as well as the lack of genomic, mitochondrial and epigenetic changes, may contribute to the lack of senescence in hESC. In this manuscript, we will review recent advances in characterizing hESCs and monitoring changes in these aspects in prolonged cultures. We will focus on the potential roles of several cellular pathways including the telomerase, p53 and the Rb pathways in escaping senescence in hESCs. We will also discuss the genomic and epigenetic changes in long-term hESC culture and their potential roles in bypassing senescence.

On the subject of the value of stem cell research in combating neurodegeneration: A deep bow of respect to Michael J. Fox, currently working to support candidates who advocate federal support for stem cell research, and striking a blow against the ideologically motivated anti-science stance of the current administration.


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