PROTECTIVE MECHANISM OF SIRT1 ON SUBVENTRICULAR ZONE DERIVED NEURAL STEM CELLS DURING AGING IN MICE

Adult neurogenesis is important for the maintenance of nervous system function during ageing. As the source of adult neurogenesis, the adult neural stem cells (NSC) pool declines with age. As a result, DNA double-strand break (DSB) accumulates in adult stem cells leading to their dysfunction in various tissues from the aged organism, but less is known for NSCs. SIRT1 is an essential anti-ageing protein, protecting multiple kinds of tissue from ageing-related insults, including DSBs. We thus proposed that SIRT1 plays the protection role in NSCs confronting DSBs during ageing in mice. We obtained some findings in the study with in vivo and in vitro investigations. First, the activated NSCs from the SVZ of aged mice displayed decreased cell number, cell proliferation and DSBs but enhanced NHEJ repair capacity. Second, Sirt1 loss in SVZ NSCs of young mice increased cell proliferation, impaired DSB repair and ultimately led to premature ageing of SVZ. Third, Sirt1 loss in SVZ NSCs of aged mice increased the proliferative cells that could be apoptotic induced by DSB accumulation. Last, SIRT1 deacetylated NICD to suppress cell proliferation and KU70 to promote NHEJ repair of DSBs in adult SVZ NSCs; the reduced ubiquitination mediated proteasome degradation of SIRT1 protein may account for the low proliferation and few DSBs in SVZ NSCs of aged mice. In conclusion, the study demonstrates the critical role of SIRT1 in protecting SVZ NSCs during ageing in mice.