To experimentally assess how progressive human age can cause persistent cellular alterations that eventually emerge as decreased functionality, vital human cells, particularly neurons from donors of a broad range of ages, would be highly desirable. However, due to the inaccessibility of live human brain tissue, most studies have been limited to animal models that, while yielding important insights, have also revealed limitations regarding transferability to human physiology and lifespan. Human patient-specific induced pluripotent stem cell (iPSC)-based disease models have provided fascinating insights into disease-relevant mechanisms and pre-clinical drug evaluation directly in functional human neurons (Israel et al., 2012; Mertens et al., 2013b). However, preservation of human age as a major pathogenic risk factor would seem unlikely, given that cells must transit the embryo-like iPSC state, which likely rejuvenates old somatic cells back into an embryonic state (Lapasset et al., 2011; Maherali et al., 2007; Meissner et al., 2008). Furthermore, the numerous cell divisions required for the reprogramming process and differentiation may dilute any accumulated macromolecular damage. The direct transcription factor-based conversion of fibroblasts into induced neurons (iNs) represents an alternative
