The identification of NCC impairment in aging holds serious implications for nuclear integrity related to cell aging. For example, genetic polymorphisms within the FOXO3 gene have been associated with human longevity (Flachsbart et al., 2009; Willcox et al., 2008). Interestingly, FOXO3a protein mediates oxidative defense and cell survival, and its activity is regulated by nucleocytoplasmic shuttling through its NLS and NES sequences; thus it might represent a potential downstream effector of impaired NCC in old cells (Lehtinen et al., 2006). Similarly, the anti-neurogenic repressor element 1-silencing transcription factor (REST) is an important neuroprotective factor in the old brain that, when lost from the nucleus, might permit neurodegeneration (Lu et al., 2014). Furthermore, injury-induced and Ca2+-mediated HDAC5 export from the nucleus is important for the regeneration of peripheral nerves (Cho et al., 2013), and impor-tin-β itself has been shown to play a role in transducing NLS-containing damage signals back from the injured axon to the nucleus (Hanz et al., 2003). Together with our data, all these findings point to NCC as potentially a key process in the age-related loss of neuronal
