UC Berkeley

Until the last few decades, aging was thought to be the stochastic accumulation of errors not subject to any active regulation. However, recent evidence suggests that aging is under regulatory control and is subject to modulation by classical signaling pathways. These pathways include the insulin/IGF-1 pathway, the mTOR pathway, and sirtuins, whose up- or downregulation can trigger diverse cell-protective mechanisms against environmental and physiological stress and lead to extension of lifespan.

Sirtuins have been shown to play a significant role in tissue maintenance by regulating cellular response to stresses such as genome instability, oxidative stress, and nutritional stress. However, since their role in maintaining proteostasis has not been studied yet, we set out to investigate if SIRT7, a nuclear member of the sirtuin family, functions in regulating protein homeostasis, particularly in the context of protein folding stress. Using a murine model, we focused on studying the function of SIRT7 in the liver and the hematopoietic system, two tissues that SIRT7 is most highly expressed in. We found that in the liver, SIRT7 relieves ER stress through suppressing translation by inhibiting the transcription of ribosomal proteins via Myc. In hematopoietic stem cells, SIRT7 regulates mitochondrial stress by repressing the activity of NRF-1 and inhibiting the transcription of mitochondrial ribosomal subunits. In a physiological context, loss of SIRT7 leads to a steatohepatitis phenotype in the liver and an aging phenotype in the hematopoietic stem cells. Thus, our study suggests the maintenance of stress by SIRT7 as an important mechanism for hepatic lipid metabolism and hematopoietic stem cell function.