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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 improvement 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.Ain Here we show how CRtriggered SIRT6dependent pathways affect aging and the critical role of SIRT6 on inflammation.Methods 24monthold 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 overexpressed 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 addition, compared with normal glucose (NG) group, LG group had prolonged lifespan and increased expression of SIRT6.Furthermore, increased SAβgal positive cells were observed in SIRT6deficient cells while the overexpression of SIRT6 could delay the replicative senescence effectively.NFκB was involved in the SIRT6 mediated longevity control.SIRT6 overexpressed WI38 had low translocate rate of NFκB into the nucleus and SIRT6 could attenuate the NFκB signaling by deacetylating the RelA subunit of NFκB complex.Conclusion In this study, we show that CR prevents agedependent renal insufficiency by upregulation of SIRT6.CRtriggered SIRT6 activation suppresses NFκB signaling via preventing nuclear translocation of NFκB.Here we identified the beneficial effects of CR on renal aging and determined the crucial role of SIRT6 on CRmediated lifespan extension.