Pivotal role of SIRT6 in calorie restriction, aging and inflammation

Background The aggravating trend of aging population has brought us with great medical challenges. Calorie restriction （CR） has various beneficial effects on health, including lifespan prolongation and functional im- provement of multiple organisms. SIRT6, a member of the Sirtuin family of NAD^＋-dependent histone deacetylases, has been shown to play a key role in mediating the effects of CR. Aim Here we show how CR-triggered SIRT6-de- pendent pathways affect aging and the critical role of SIRT6 on inflammation. Methods 24-month-old mice were fed under ad libitum （AL） or CR condition for 6 months to determine the effects of CR. In addition, we took low glucose （LG） cultured WI38 human fibroblasts as a model to mimic CR in vitro. Further more, we stably overex- pressed or knockdown SIRT6 in WI38 to identify the role of SIRT6 in cell senescence and inflammation. Results Aged mice with CR had improved renal pathology and enhanced SIRT6 expression compared with AL group. In ad- dition, compared with normal glucose （NG） group, LG group had prolonged lifespan and increased expression of SIRT6. Furthermore, increased SA-β-gal positive cells were observed in SIRT6-deficient cells while the overexpres- sion of SIRT6 could delay the replicative senescence effectively. NF-KB was involved in the SIRT6 mediated lon- gevity control. SIRT6 overexpressed WI38 had low translocate rate of NF-KB into the nucleus and SIRT6 could at- tenuate the NF-KB signaling by deacetylating the RelA subunit of NF-KB complex. Conclusion In this study, we show that CR prevents age-dependent renal insufficiency by up-regulation of SIRT6. CR-triggered SIRT6 activation suppresses NF-KB signaling via preventing nuclear translocation of NF-KB. Here we identified the beneficial effects of CR on renal aging and determined the crucial role of SIRT6 on CR-mediated lifespan extension.