| Aging is an inevitable event and is a complex process resulting from a series of degenerative processes for all organisms.Although aging itself is irreversible,the aging process can be delayed by intervention.The use of drugs to interfere in aging is currently recognized as one of the effective means by the academic community,therefore,the screening of drugs or compounds with anti-aging effects and the study of the underlying mechanism of action are important topics in the field of anti-aging.The 2-(1-Benzofuran-2-yl)-N-(diphenylmethyl)quinoline-4-carboxamide(12q)is a newly synthesized SIRT6 activator,referred to as activator 6546.The activator 6546 has been shown to have antitumor effects in mice and to interfere with several molecular signaling pathways associated with aging.Therefore,the activator 6546 may be a potential anti-aging compound.In this study,we used Drosophila melanogaster as a model organism to investigate whether SIRT6 activator 6546 has anti-aging effects,and further explored its underlying molecular mechanism.The main findings were as follows.1.When different concentrations of SIRT6 activator 6546 were added to the fly food,we found that low concentrations of SIRT6 activator could prolong the lifespan of Drosophila.By the further screening for the concentration of activator 6546,we found that the optimal concentration of 1μM activator was able to significantly extend the lifespan of female and male flies,by 9% and 15 %,respectively,compared to control.2.SIRT6 activator 6546 significantly increased the expression of SIRT6 gene in both male and female Drosophila.It was also found that the acetylation level of the H3K9 locus was significantly reduced in flies after the use of activator 6546.It indicates that this activator can promote SIRT6 overexpression and exert the role of deacetylation in Drosophila.3.SIRT6 activator 6546 had no significant effect on fecundity of Drosophila.But positively,it significantly slowed down the decline of locomotor ability with age.4.SIRT6 activator 6546 has a benefit effect on the stress resistance in Drosophila.For example,it significantly improved the resistance to hunger as well as heating,although it did not have a significant effect on the antioxidant in Drosophila.5.SIRT6 activator 6546 significantly improved the fly glucolipid metabolism level,blood glucose and triglyceride level.The results showed that the blood glucose levels in the aged group of Drosophila were similar to those in the younger control group,indicating that SIRT6 activator maintained the blood glucose levels of the elder fly at a younger age.6.SIRT6 activator 6546 reduced body weight and protein synthesis in flies to some extent without significant changes in feed intake.Therefore,it may have overlapping effects with rapamycin inhibition for m TOR to reduce protein synthesis and prolong the lifespan of Drosophila.7.SIRT6 activator could extend lifespan by participating in the glycolipid metabolic pathway in Drosophila.The expression of genes related to the TCA cycle,aerobic respiration and electron transport chain was significantly increased.8.SIRT6 activator 6546 can regulate the mitochondrial function of flies and thus improve the healthy lifespan of Drosophila.In summary,this study found that SIRT6 activator 6546 has a benefit effect on extending the lifespan of Drosophila.On the one hand,activator 6546 acts by maintaining the rejuvenation of glucolipid metabolism level in aged flies.On the other hand,it regulates the aging process by modulating the mitochondrial functions,which in turn prolongs the lifespan of Drosophila.This drug also improves the fly’s resistance to harsh environments and improves the fly’s locomotion,thus exerting anti-aging effects.The results of this study can provide an experimental basis for other animal and human studies on this drug,and provide a reference for the selection of anti-aging drugs,which has important theoretical and practical significance for anti-aging research. |
PDF Full Text Request