How Does Age Affect Induced Pluripotency for Regenerative Medicine?

One of the more intriguing discoveries relating to the cell reprogramming used to produce induced pluripotent stem cells is that this process appears to reverse some aspects of cell aging. It perhaps triggers some fraction of the mechanisms at work in early embryonic development, those that ensure that children are born young, with nowhere near the load of persistent damage present in the adult parents. This is not a well-explored topic, unfortunately - it is still too recent for much to be said in certainty, and a sizable fraction of the evidence is conflicting. Related to all of this is the question of how exactly the age of the donor affects the reprogramming of donated cells. Near all potential uses of regenerative medicine based on reprogrammed cells involve age-related disease and older individuals. It is important to understand whether it is safe to proceed, how effective approaches might be in practice, and where the problems lie, so that they can be addressed.

Induced pluripotent stem cells (iPSCs) avoid many of the restrictions that hamper the application of human embryonic stem cells, and the donor's clinical phenotype is often known when working with iPSCs. Therefore, iPSCs seem ideal to tackle the two biggest tasks of regenerative medicine: degenerative diseases with genetic cause (e.g., Duchenne's muscular dystrophy) and organ replacement in age-related diseases (e.g., end-stage heart or renal failure), especially in combination with recently developed gene-editing tools.

In the setting of autologous transplantation in elderly patients, donor age becomes a potentially relevant factor that needs to be assessed. Here, we review and critically discuss available data pertinent to the questions: How does donor age influence the reprogramming process and iPSC functionality? Would it even be possible to reprogram senescent somatic cells? How does donor age affect iPSC differentiation into specialised cells and their functionality? We also identify research needs, which might help resolve current unknowns.

Until recently, most hallmarks of ageing were attributed to an accumulation of DNA damage over time, and it was thus expected that DNA damage from a somatic cell would accumulate in iPSCs and the cells derived from them. In line with this, a decreased lifespan of cloned organisms compared with the donor was also observed in early cloning experiments. Therefore, it was questioned for a time whether iPSC derived from an old individual's somatic cells would suffer from early senescence and, thus, may not be a viable option either for disease modelling nor future clinical applications. Instead, typical signs of cellular ageing are reverted in the process of iPSC reprogramming, and iPSCs from older donors do not show diminished differentiation potential nor do iPSC-derived cells from older donors suffer early senescence or show functional impairments when compared with those from younger donors.

Thus, the data would suggest that donor age does not limit iPSC application for modelling genetic diseases nor regenerative therapies. However, open questions remain, e.g., regarding the potential tumourigenicity of iPSC-derived cells and the impact of epigenetic pattern retention.



Engineering Biology Center have opened for donations. I donated 10.000 NOK since it will be essential to make immune compatible organs.

Posted by: Norse at February 19th, 2018 10:46 AM

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