aging signatures might be constantly erased rather than temporarily concealed in iPSCs (Frobel et al., 2014). However, the question of whether the cell-rejuvenating aspect and the dedifferentiation aspect of iPSC reprogramming can be uncoupled remains relevant. Interestingly, some rejuvenating aspects of the four Yamanaka factors appear to impact early during reprogramming, and aspects of rejuvenation might be possible without full dedifferentiation, as senescence-associated nucleocytoplasmic mobility of the epigenetic modifier HP1β could be restored in old cells within days (Manukyan and Singh, 2014). Taking all this into account, it can be expected that neurons differentiated from, for example, Alzheimer’s or Parkinson’s patient-specific iPSCs are phenotypically young. Consistently, attempts to model age-related neurodegenerative states in iPSC-derived neurons have made use of additional stressors such as excitotoxicity (Koch et al., 2011), reactive oxygen species (Mertens et al., 2013a; Nguyen et al., 2011; Reinhardt et al., 2013), or overexpression of disease- or aging-related mutant proteins to accelerate pathological processes in these otherwise rejuvenated neuronal cells (Koch et al., 2012; Miller et al., 2013). An issue with such approaches is that selected stressors, unlike intrinsic cell aging, usually act exogenously on the cells and mimic only limited, if any, aspects of cellular aging. In contrast,
