SIRT1 suppresses self-renewal of adult hippocampal neural stem cells

Abstract

The balance between self-renewal and differentiation of adult neural stem cells (aNSCs) is essential for the maintenance of the aNSC reservoir and the continuous supply of new neurons, but how this balance is fine-tuned in the adult brain is not fully understood. Here, we investigate the role of SIRT1, an important metabolic sensor and epigenetic repressor, in regulating adult hippocampal neurogenesis in mice. We found that there was an increase in SIRT1 expression during aNSC differentiation. In Sirt1 knockout (KO) mice, as well as in brain-specific and inducible stem cell-specific conditional KO mice, the proliferation and self-renewal rates of aNSCs in vivo were elevated. Proliferation and self-renewal rates of aNSCs and adult neural progenitor cells (aNPCs) were also elevated in neurospheres derived from Sirt1 KO mice and were suppressed by the SIRT1 agonist resveratrol in neurospheres from wild-type mice. In cultured neurospheres, 2-deoxy-D-glucose-induced metabolic stress suppressed aNSC/aNPC proliferation, and this effect was mediated in part by elevating SIRT1 activity. Microarray and biochemical analysis of neurospheres suggested an inhibitory effect of SIRT1 on Notch signaling in aNSCs/aNPCs. Inhibition of Notch signaling by a γ-secretase inhibitor also largely abolished the increased aNSC/aNPC proliferation caused by Sirt1 deletion. Together, these findings indicate that SIRT1 is an important regulator of aNSC/aNPC self-renewal and a potential mediator of the effect of metabolic changes.

Exogenous nicotinamide supplementation and moderate physical exercise can attenuate the aging process in skeletal muscle of rats

“…It has been noted that sirtuins, especially SIRT1, can directly influence brain function (Barhwal et al 2015;Fujitsuka et al 2016;Koltai et al 2011;Sarga et al 2013;Torma et al 2014;Tulino et al 2016). SIRT1 appears to be involved in neuronal stem cell differentiation (Ma et al 2014), synaptic plasticity (Michan et al 2010) and metabolism (Li et al 2008). …”

Resveratrol Activated Sonic Hedgehog Signaling to Enhance Viability of NIH3T3 Cells in Vitro via Regulation of Sirt1

“…For example, Sirt1 interacted directly with LSD1 and regulated Notch target gene expression [64] . In adult neural stem cells, Sirt1 is a key metabolic sensor for regulating adult hippocampal neurogenesis, partly through its suppression of Notch signaling [65]. In Ewing sarcoma, Sirt1 inhibitors restored abrogation of Notch signaling and caused tumor-growth arrest [66].…”

Modifiers of Neural Stem Cells and Aging: Pulling the Trigger of a Neurogenic Decline

“…Whichever is the mechanism responsible for DNA lesions accumulation in aNSCs during aging, this could impact on the reservoir of resident stem cells as well as on their differentiated progenies [24], though the extent of damage or the specific mutation in the genome will certainly influence the impact to aNSCs. Of interest, loss-of-function mutations have revealed aging-like phenotypes in aNSCs, highlighting the importance of a series of gene products in regulating aNSC homeostasis throughout life; including PRDM16 [25], BMI1 [26], ATM [27], SIRT1 [28], and members of the Forkhead transcription factor family O (FoxO) [29,30]. For example, the transcription factor FoxO3 has been associated with extreme longevity and the Brunet laboratory has highlighted the importance of this gene in the regulation of the aNSC pool in mice by showing that FoxO3 coordinates the expression of a specific program of genes that can control self-renewal, differentiation, and oxygen metabolism [30].…”