Mechanism Study Of SIRT6 In Organ Aging And Cell Senescence Regulation

Calorie restriction(CR)extends lifespan from yeast to mammals.SIRT6 is a member of the sirtuin family of NAD+-dependent histone deacetylases,which is responsible for mediating the effects of CR.The transcription factor NF-κB,which is involved in inflammation,immune responses,aging and apoptosis,has been shown to be regulated by SIRT6.In this study,we describe the crucial role of SIRT6 in aging,inflammation and apoptosis regulation.We show that CR improved renal insufficiency and enhanced SIRT6 expression after 6-month treatment in aged mice.Culture cells in low glucose(LG)condition also showed resistance to cell senescence and enhanced SIRT6 expression compared to normal glucose(NG)group,showing beneficial effects of the CR-mimic cultural conditions.Moreover,SIRT6 overexpression was sufficient to delay the replicative senescence of WI38 by attenuating NF-κB signaling,while SIRT6 knockdown resulted in accelerated cell senescence and overactive NF-κB signaling.These findings confirm the key status of CR and disclose the critical role of SIRT6 on aging and inflammation.Further more,recent studies indicate the potential of SIRT6 as a tumor suppressor,however it is still lack of evidence.It has been reported that the activation of NF-κB contributes to apoptosis resistance,which may protect cancer cells from killing.In this study,we provide the evidence that SIRT6 interacts with NF-κB to regulate cancer cell apoptosis.SIRT6 overexpression raised the sensitivity of cancer cells to apoptosis inducer,which may contributed to eliminate cancer cells.Meanwhile SIRT6 knockdown caused severe apoptosis resistance,which may help the cancer cells to survive.Our researches suggest the potential targets for cancer treatment.In addition,obesity-related renal diseases have been a worldwide issue.Effective strategy that prevents high fat-diet induced renal damage is of great significance.Resveratrol,a natural plant polyphenol,is famous for its antioxidant activity,cardioprotective effects and anticancer properties.However whether resveratrol can play a role in the treatment of age-relateddiseases is unknown.In this study,we provide evidences that resveratrol protected against high-glucose triggered oxidative stress and cell senescence.Moreover,resveratrol treatment prevented high-fat diet induced renal pathological damage by activating SIRT1,another member of the mammalian sirtuin family that response to calorie restriction life-extension method.These results confirm the potential role of resveratrol in the treatment of renal diseases and may provide an effective and convenient method to mimic the beneficial effects of calorie restriction.In conclusion,we provide evidence towards the beneficail effects of CR-induced SIRT6 activtion and demonstrate that level of SIRT6 can affect NF-κB signaling via its translocation into nuclei and deacetylation,then influence inflammation,cell senescencen,and apoptosis.This study may provide a new therapeutic target to resist cellular dysfunction and retard aging associated diseases.