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, iN conversion represents a technology that circumvents the early embryonic and pre-germline state of iPSCs, and we demonstrated that direct conversion yields authentic human neurons that reflect important aspects of cellular age. In addition, the fact that iN goes directly from one fibroblast to one neuron and does not involve or require cell divisions that might dilute or induce repair of macromolecular damage might contribute to the fact that aging phenotypes present in cultured primary fibroblasts become translated to a neuronal context during iN (Hennekam, 2006; Liu et al., 2013; Toyama and Hetzer, 2013). Consistent with earlier transcriptome studies on the aging brain, we found gene categories differentially expressed in aging iNs that point to age-dependent differential regulation of synaptic function, projection development, and Ca2+ homeostasis, which in turn impacts functions such as synaptic plasticity and projection (Burke and Barnes, 2006; Fraser et al., 2005; Lu et al., 2004). Interestingly, while only less than 4% of the iN aging genes
