Aging is closely related to redox regulation.In our previous work,we proposed a new concept,“redox-stress response capacity(RRC),”and found that the decline in RRC was a dynamic characteristic of aging.However,the m...Aging is closely related to redox regulation.In our previous work,we proposed a new concept,“redox-stress response capacity(RRC),”and found that the decline in RRC was a dynamic characteristic of aging.However,the mechanism of RRC decline during aging remains unknown.In this study,using the senescent human fibroblast cell model and Caenorhabditis elegans model,we identified that peroxiredoxin 2(PRDX2),as a hydrogen peroxide(H_(2)O_(2))sensor,was involved in mediating RRC.PRDX2 knockdown led to a decline of RRC and accelerated senescence in fibroblasts and prdx-2 mutant C.elegans also showed decreased RRC.The mechanism study showed that the decreased sensor activity of PRDX2 was related to the increase in hyperoxidation of PRDX2 in senescent cells.Moreover,the level of PRDX2 hyperoxidation also increased in old C.elegans.Simultaneous overexpression of both PRDX2 and sulfiredoxin(SRX)rescued the reduced RRC and delayed senescence.The increase in PRDX2 hyperoxidation in senescent cells led to a decrease in its sensor activity,resulting in the decreased cellular response to H_(2)O_(2),which is similar to the mechanism of insulin resistance due to the lower insulin receptor sensitivity.Treatment of young cells with a high level of H_(2)O_(2)to induce a higher level of PRDX2-SO_(3) resulted in mimicking the RRC decline in senescent cells,which is also similar to a model of insulin resistance induced by high levels of insulin.All these results thrillingly indicate that there is an insulin-resistance-like phenomenon in senescent cells,we named it redox-stress response resistance,RRR.RRR in senescent cells is an important new discovery that explains RRC decline during aging and reveals the internal relationship between redox regulation and aging from a new perspective.展开更多
Fasting is a popular dietary strategy because it grants numerous advantages,and redox regulation is one mecha-nism involved.However,the precise redox changes with respect to the redox species,organelles and tissues re...Fasting is a popular dietary strategy because it grants numerous advantages,and redox regulation is one mecha-nism involved.However,the precise redox changes with respect to the redox species,organelles and tissues remain unclear,which hinders the understanding of the metabolic mechanism,and exploring the precision redox map under various dietary statuses is of great significance.Twelve redox-sensitive C.elegans strains stably expressing genetically encoded redox fluorescent probes(Hyperion sensing H_(2)O_(2) and Grx1-roGFP2 sensing GSH/GSSG)in three organelles(cytoplasm,mitochondria and endoplasmic reticulum(ER))were constructed in two tissues(body wall muscle and neurons)and were confirmed to respond to redox challenge.The H_(2)O_(2) and GSSG/GSH redox changes in two tissues and three organelles were obtained by confocal microscopy during fasting,refeeding,and satiation.We found that under fasting condition,H_(2)O_(2) decreased in most compartments,except for an increase in mitochondria,while GSSG/GSH increased in the cytoplasm of body muscle and the ER of neurons.After refeeding,the redox changes in H_(2)O_(2) and GSSG/GSH caused by fasting were reversed in most organelles of the body wall muscle and neurons.In the sati-ated state,H_(2)O_(2) increased markedly in the cytoplasm,mitochondria and ER of muscle and the ER of neurons,while GSSG/GSH exhibited no change in most organelles of the two tissues except for an increase in the ER of muscle.Our study systematically and precisely presents the redox characteristics under different dietary states in living animals and provides a basis for further investigating the redox mechanism in metabolism and optimizing dietary guidance.展开更多
基金the Strategic Priority Research Program of the Chinese Academy of Sciences(XDB39000000)the National Key Research and Development Program of China(2022YFA1303000,2022YFA1305100,2017YFA0504000)the National Natural Science Foundation of China(91849203)。
文摘Aging is closely related to redox regulation.In our previous work,we proposed a new concept,“redox-stress response capacity(RRC),”and found that the decline in RRC was a dynamic characteristic of aging.However,the mechanism of RRC decline during aging remains unknown.In this study,using the senescent human fibroblast cell model and Caenorhabditis elegans model,we identified that peroxiredoxin 2(PRDX2),as a hydrogen peroxide(H_(2)O_(2))sensor,was involved in mediating RRC.PRDX2 knockdown led to a decline of RRC and accelerated senescence in fibroblasts and prdx-2 mutant C.elegans also showed decreased RRC.The mechanism study showed that the decreased sensor activity of PRDX2 was related to the increase in hyperoxidation of PRDX2 in senescent cells.Moreover,the level of PRDX2 hyperoxidation also increased in old C.elegans.Simultaneous overexpression of both PRDX2 and sulfiredoxin(SRX)rescued the reduced RRC and delayed senescence.The increase in PRDX2 hyperoxidation in senescent cells led to a decrease in its sensor activity,resulting in the decreased cellular response to H_(2)O_(2),which is similar to the mechanism of insulin resistance due to the lower insulin receptor sensitivity.Treatment of young cells with a high level of H_(2)O_(2)to induce a higher level of PRDX2-SO_(3) resulted in mimicking the RRC decline in senescent cells,which is also similar to a model of insulin resistance induced by high levels of insulin.All these results thrillingly indicate that there is an insulin-resistance-like phenomenon in senescent cells,we named it redox-stress response resistance,RRR.RRR in senescent cells is an important new discovery that explains RRC decline during aging and reveals the internal relationship between redox regulation and aging from a new perspective.
基金supported by the National Key R&D Program(2022YFA1303000 and 2017YFA0504000)the National Natural Science Foundation of China(91849203,31900893)the Strategic Priority Research Program of the Chinese Academy of Sciences(XDB39000000).
文摘Fasting is a popular dietary strategy because it grants numerous advantages,and redox regulation is one mecha-nism involved.However,the precise redox changes with respect to the redox species,organelles and tissues remain unclear,which hinders the understanding of the metabolic mechanism,and exploring the precision redox map under various dietary statuses is of great significance.Twelve redox-sensitive C.elegans strains stably expressing genetically encoded redox fluorescent probes(Hyperion sensing H_(2)O_(2) and Grx1-roGFP2 sensing GSH/GSSG)in three organelles(cytoplasm,mitochondria and endoplasmic reticulum(ER))were constructed in two tissues(body wall muscle and neurons)and were confirmed to respond to redox challenge.The H_(2)O_(2) and GSSG/GSH redox changes in two tissues and three organelles were obtained by confocal microscopy during fasting,refeeding,and satiation.We found that under fasting condition,H_(2)O_(2) decreased in most compartments,except for an increase in mitochondria,while GSSG/GSH increased in the cytoplasm of body muscle and the ER of neurons.After refeeding,the redox changes in H_(2)O_(2) and GSSG/GSH caused by fasting were reversed in most organelles of the body wall muscle and neurons.In the sati-ated state,H_(2)O_(2) increased markedly in the cytoplasm,mitochondria and ER of muscle and the ER of neurons,while GSSG/GSH exhibited no change in most organelles of the two tissues except for an increase in the ER of muscle.Our study systematically and precisely presents the redox characteristics under different dietary states in living animals and provides a basis for further investigating the redox mechanism in metabolism and optimizing dietary guidance.
