The molecular mechanisms underlying the aging process have garnered much attention in recent decades because aging is the most significant risk factor for many chronic diseases such as type 2 diabetes and cancer. Until recently, the aging process was not considered to be an actively regulated process; therefore, discovering that the insulin/insulin-like growth factor-1 signaling pathway is a lifespan-regulating genetic pathway in Caenorhabditis elegans was a major breakthrough that changed our understanding of the aging process. Currently, it is thought that animal lifespans are influenced by genetic and environmental factors. The genes involved in lifespan regulation are often associated with major signaling pathways that link the rate of aging to environmental factors. Although many of the major mechanisms governing the aging process have been identified from studies in short-lived model organisms such as yeasts, worms and flies, the same mechanisms are frequently observed in mammals, indicating that the genes and signaling pathways that regulate lifespan are highly conserved among different species. This review summarizes the lifespan-regulating genes, with a specific focus on studies in C. elegans.
{"title":"Lifespan-regulating genes in C. elegans","authors":"Masaharu Uno, Eisuke Nishida","doi":"10.1038/npjamd.2016.10","DOIUrl":"10.1038/npjamd.2016.10","url":null,"abstract":"The molecular mechanisms underlying the aging process have garnered much attention in recent decades because aging is the most significant risk factor for many chronic diseases such as type 2 diabetes and cancer. Until recently, the aging process was not considered to be an actively regulated process; therefore, discovering that the insulin/insulin-like growth factor-1 signaling pathway is a lifespan-regulating genetic pathway in Caenorhabditis elegans was a major breakthrough that changed our understanding of the aging process. Currently, it is thought that animal lifespans are influenced by genetic and environmental factors. The genes involved in lifespan regulation are often associated with major signaling pathways that link the rate of aging to environmental factors. Although many of the major mechanisms governing the aging process have been identified from studies in short-lived model organisms such as yeasts, worms and flies, the same mechanisms are frequently observed in mammals, indicating that the genes and signaling pathways that regulate lifespan are highly conserved among different species. This review summarizes the lifespan-regulating genes, with a specific focus on studies in C. elegans.","PeriodicalId":94160,"journal":{"name":"npj aging","volume":"2 1","pages":"1-8"},"PeriodicalIF":0.0,"publicationDate":"2016-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1038/npjamd.2016.10","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35179869","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Alejandro Martin-Montalvo, Yaning Sun, Alberto Diaz-Ruiz, Ahmed Ali, Vincent Gutierrez, Hector H Palacios, Jessica Curtis, Emilio Siendones, Julia Ariza, Gelareh A Abulwerdi, Xiaoping Sun, Annie X Wang, Kevin J Pearson, Kenneth W Fishbein, Richard G Spencer, Miao Wang, Xianlin Han, Morten Scheibye-Knudsen, Joe A Baur, Howard G Shertzer, Placido Navas, Jose Manuel Villalba, Sige Zou, Michel Bernier, Rafael de Cabo
Cytochrome b5 reductases (CYB5R) are required for the elongation and desaturation of fatty acids, cholesterol synthesis and mono-oxygenation of cytochrome P450 enzymes, all of which are associated with protection against metabolic disorders. However, the physiological role of CYB5R in the context of metabolism, healthspan and aging remains ill-defined. We generated CYB5R-overexpressing flies (CYB5R-OE) and created a transgenic mouse line overexpressing CYB5R3 (CYB5R3-Tg) in the C57BL/6J background to investigate the function of this class of enzymes as regulators of metabolism and age-associated pathologies. Gender- and/or stage-specific induction of CYB5R, and pharmacological activation of CYB5R with tetrahydroindenoindole extended fly lifespan. Increased expression of CYB5R3 was associated with significant improvements in several metabolic parameters that resulted in modest lifespan extension in mice. Diethylnitrosamine-induced liver carcinogenesis was reduced in CYB5R3-Tg mice. Accumulation of high levels of long-chain polyunsaturated fatty acids, improvement in mitochondrial function, decrease in oxidative damage and inhibition of chronic pro-inflammatory pathways occurred in the transgenic animals. These results indicate that CYB5R represents a new target in the study of genes that regulate lipid metabolism and healthspan. Increased activity of a single gene improves healthy lifespan of mice and flies, highlighting a new cellular pathway involved in aging. An international team of researchers led by Rafael de Cabo at the National Institutes of Health in Baltimore studied aging and disease progression in flies and mice genetically modified to overexpress antioxidant protein called cytochrome b5 reductase (CYB5R). These animals had modest improvements in lifespan, and mice had delayed tumor growth compared to controls in a model of liver cancer. Interestingly, the data suggest that this lifespan improvement was mediated by different biochemical pathways activated by calorie restriction, a well-studied longevity technique. Treatments or techniques that increase activity of the CYB5R pathway could thus be a viable alternative approach to lengthening healthy lifespan.
{"title":"Cytochrome b5 reductase and the control of lipid metabolism and healthspan","authors":"Alejandro Martin-Montalvo, Yaning Sun, Alberto Diaz-Ruiz, Ahmed Ali, Vincent Gutierrez, Hector H Palacios, Jessica Curtis, Emilio Siendones, Julia Ariza, Gelareh A Abulwerdi, Xiaoping Sun, Annie X Wang, Kevin J Pearson, Kenneth W Fishbein, Richard G Spencer, Miao Wang, Xianlin Han, Morten Scheibye-Knudsen, Joe A Baur, Howard G Shertzer, Placido Navas, Jose Manuel Villalba, Sige Zou, Michel Bernier, Rafael de Cabo","doi":"10.1038/npjamd.2016.6","DOIUrl":"10.1038/npjamd.2016.6","url":null,"abstract":"Cytochrome b5 reductases (CYB5R) are required for the elongation and desaturation of fatty acids, cholesterol synthesis and mono-oxygenation of cytochrome P450 enzymes, all of which are associated with protection against metabolic disorders. However, the physiological role of CYB5R in the context of metabolism, healthspan and aging remains ill-defined. We generated CYB5R-overexpressing flies (CYB5R-OE) and created a transgenic mouse line overexpressing CYB5R3 (CYB5R3-Tg) in the C57BL/6J background to investigate the function of this class of enzymes as regulators of metabolism and age-associated pathologies. Gender- and/or stage-specific induction of CYB5R, and pharmacological activation of CYB5R with tetrahydroindenoindole extended fly lifespan. Increased expression of CYB5R3 was associated with significant improvements in several metabolic parameters that resulted in modest lifespan extension in mice. Diethylnitrosamine-induced liver carcinogenesis was reduced in CYB5R3-Tg mice. Accumulation of high levels of long-chain polyunsaturated fatty acids, improvement in mitochondrial function, decrease in oxidative damage and inhibition of chronic pro-inflammatory pathways occurred in the transgenic animals. These results indicate that CYB5R represents a new target in the study of genes that regulate lipid metabolism and healthspan. Increased activity of a single gene improves healthy lifespan of mice and flies, highlighting a new cellular pathway involved in aging. An international team of researchers led by Rafael de Cabo at the National Institutes of Health in Baltimore studied aging and disease progression in flies and mice genetically modified to overexpress antioxidant protein called cytochrome b5 reductase (CYB5R). These animals had modest improvements in lifespan, and mice had delayed tumor growth compared to controls in a model of liver cancer. Interestingly, the data suggest that this lifespan improvement was mediated by different biochemical pathways activated by calorie restriction, a well-studied longevity technique. Treatments or techniques that increase activity of the CYB5R pathway could thus be a viable alternative approach to lengthening healthy lifespan.","PeriodicalId":94160,"journal":{"name":"npj aging","volume":"2 1","pages":"1-12"},"PeriodicalIF":0.0,"publicationDate":"2016-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1038/npjamd.2016.6","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35179867","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
We previously reported that molecular hydrogen (H2) acts as a novel antioxidant to exhibit multiple functions. Moreover, long-term drinking of H2-water (water infused with H2) enhanced energy expenditure to improve obesity and diabetes in db/db mice accompanied by the increased expression of fibroblast growth factor 21 (FGF21) by an unknown mechanism. H2 was ingested by drinking of H2-water or by oral administration of an H2-producing material, MgH2. The comprehensive gene expression profile in the liver of db/db mice was analyzed by DNA microarray. The molecular mechanisms underlying the gene expression profile was investigated using cultured HepG2 cells. Moreover, the effects on lifespan of drinking H2-water were examined using wild-type mice that were fed a fatty diet. Pathway analyses based on comprehensive gene expression revealed the increased expression of various genes involved in fatty acid and steroid metabolism. As a transcription pathway, the PPARα signaling pathway was identified to upregulate their genes by ingesting H2. As an early event, the gene expression of PGC-1α was transiently increased, followed by increased expression of FGF21. The expression of PGC-1α might be regulated indirectly through sequential regulation by H2, 4-hydroxy-2-nonenal, and Akt/FoxO1 signaling, as suggested in cultured cell experiments. In wild-type mice fed the fatty diet, H2-water improved the level of plasma triglycerides and extended their average of lifespan. H2 induces expression of the PGC-1α gene, followed by stimulation of the PPARα pathway that regulates FGF21, and the fatty acid and steroid metabolism. Oral consumption of molecular hydrogen (H2) activates genes with a critical role in fatty acid metabolism. H2 can prevent the cellular damage caused by oxidizing chemical compounds, and a previous study suggested that water infused with H2 can improve metabolic health in genetically obese rodents. In order to identify a potential mechanism of action, researchers led by Shigeo Ohta at Nippon Medical School dosed obese mice with H2-infused water for two weeks. Before the animals'' health did not notably change, the researchers observed clear changes in the expression of several genes in a pathway that regulate the metabolism of steroids and fatty acids in the liver. This treatment was also associated with lower blood triglycerides in genetically normal mice fed a high-fat diet, suggesting that such treatments could induce a clinically useful metabolic response.
{"title":"Molecular hydrogen stimulates the gene expression of transcriptional coactivator PGC-1α to enhance fatty acid metabolism","authors":"Naomi Kamimura, Harumi Ichimiya, Katsuya Iuchi, Shigeo Ohta","doi":"10.1038/npjamd.2016.8","DOIUrl":"10.1038/npjamd.2016.8","url":null,"abstract":"We previously reported that molecular hydrogen (H2) acts as a novel antioxidant to exhibit multiple functions. Moreover, long-term drinking of H2-water (water infused with H2) enhanced energy expenditure to improve obesity and diabetes in db/db mice accompanied by the increased expression of fibroblast growth factor 21 (FGF21) by an unknown mechanism. H2 was ingested by drinking of H2-water or by oral administration of an H2-producing material, MgH2. The comprehensive gene expression profile in the liver of db/db mice was analyzed by DNA microarray. The molecular mechanisms underlying the gene expression profile was investigated using cultured HepG2 cells. Moreover, the effects on lifespan of drinking H2-water were examined using wild-type mice that were fed a fatty diet. Pathway analyses based on comprehensive gene expression revealed the increased expression of various genes involved in fatty acid and steroid metabolism. As a transcription pathway, the PPARα signaling pathway was identified to upregulate their genes by ingesting H2. As an early event, the gene expression of PGC-1α was transiently increased, followed by increased expression of FGF21. The expression of PGC-1α might be regulated indirectly through sequential regulation by H2, 4-hydroxy-2-nonenal, and Akt/FoxO1 signaling, as suggested in cultured cell experiments. In wild-type mice fed the fatty diet, H2-water improved the level of plasma triglycerides and extended their average of lifespan. H2 induces expression of the PGC-1α gene, followed by stimulation of the PPARα pathway that regulates FGF21, and the fatty acid and steroid metabolism. Oral consumption of molecular hydrogen (H2) activates genes with a critical role in fatty acid metabolism. H2 can prevent the cellular damage caused by oxidizing chemical compounds, and a previous study suggested that water infused with H2 can improve metabolic health in genetically obese rodents. In order to identify a potential mechanism of action, researchers led by Shigeo Ohta at Nippon Medical School dosed obese mice with H2-infused water for two weeks. Before the animals'' health did not notably change, the researchers observed clear changes in the expression of several genes in a pathway that regulate the metabolism of steroids and fatty acids in the liver. This treatment was also associated with lower blood triglycerides in genetically normal mice fed a high-fat diet, suggesting that such treatments could induce a clinically useful metabolic response.","PeriodicalId":94160,"journal":{"name":"npj aging","volume":"2 1","pages":"1-8"},"PeriodicalIF":0.0,"publicationDate":"2016-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1038/npjamd.2016.8","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35179868","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Elena M Vayndorf, Courtney Scerbak, Skyler Hunter, Jason R Neuswanger, Marton Toth, J Alex Parker, Christian Neri, Monica Driscoll, Barbara E Taylor
Understanding cellular outcomes, such as neuronal remodeling, that are common to both healthy and diseased aging brains is essential to the development of successful brain aging strategies. Here, we used Caenorhabdits elegans to investigate how the expression of proteotoxic triggers, such as polyglutamine (polyQ)-expanded huntingtin and silencing of proteostasis regulators, such as the ubiquitin–proteasome system (UPS) and protein clearance components, may impact the morphological remodeling of individual neurons as animals age. We examined the effects of disrupted proteostasis on the integrity of neuronal cytoarchitecture by imaging a transgenic C. elegans strain in which touch receptor neurons express the first 57 amino acids of the human huntingtin (Htt) gene with expanded polyQs (128Q) and by using neuron-targeted RNA interference in adult wild-type neurons to knockdown genes encoding proteins involved in proteostasis. We found that proteostatic challenges conferred by polyQ-expanded Htt and knockdown of specific genes involved in protein homeostasis can lead to morphological changes that are restricted to specific domains of specific neurons. The age-associated branching of PLM neurons is suppressed by N-ter polyQ-expanded Htt expression, whereas ALM neurons with polyQ-expanded Htt accumulate extended outgrowths and other soma abnormalities. Furthermore, knockdown of genes important for ubiquitin-mediated degradation, lysosomal function, and autophagy modulated these age-related morphological changes in otherwise normal neurons. Our results show that the expression of misfolded proteins in neurodegenerative disease such as Huntington’s disease modifies the morphological remodeling that is normally associated with neuronal aging. Our results also show that morphological remodeling of healthy neurons during aging can be regulated by the UPS and other proteostasis pathways. Collectively, our data highlight a model in which morphological remodeling during neuronal aging is strongly affected by disrupted proteostasis and expression of disease-associated, misfolded proteins such as human polyQ-Htt species. Misfolded proteins and disrupted protein maintenance can lead to aging-related changes in neuron shape. Elena Vayndorf from the University of Alaska Fairbanks and colleagues in the US, Canada and France studied a strain of nematode Caenorhabditis elegans in which selected neurons express part of the human gene responsible for Huntington’s disease, which is an aging-related, neurodegenerative disorder. The researchers also blocked expression of genes involved in protein manufacture, folding, trafficking and degradation in healthy neurons. With both experimental manipulations, they observed changes in the morphology of the animal’s neurons that normally occur during aging. Given the similarities between C. elegans and human neurons, the authors propose that drugs targeting the cellular pathways that guide protein maintenance could help retain brai
了解健康和患病的衰老大脑所共有的细胞结果（如神经元重塑）对于制定成功的大脑衰老策略至关重要。在这里，我们利用草履虫研究了多聚谷氨酰胺（polyQ）扩增的亨廷蛋白等蛋白毒性触发因子的表达以及泛素蛋白酶体系统（UPS）和蛋白质清除元件等蛋白稳态调节因子的沉默如何随着动物的衰老而影响单个神经元的形态重塑。我们研究了蛋白稳态紊乱对神经元细胞结构完整性的影响，方法是对一株转基因线虫进行成像，在这株线虫中，触觉受体神经元表达带有扩展多聚酶（128Q）的人类亨廷汀（Htt）基因的前57个氨基酸，并在成年野生型神经元中使用神经元靶向RNA干扰来敲除编码参与蛋白稳态的蛋白质的基因。我们发现，polyQ-expanded Htt 和敲除参与蛋白稳态的特定基因所带来的蛋白稳态挑战可导致形态学变化，而这种变化仅限于特定神经元的特定区域。PLM神经元与年龄相关的分枝受到N-端多Q扩展Htt表达的抑制，而多Q扩展Htt的ALM神经元会积累扩展的外生长和其他体节异常。此外，敲除泛素介导的降解、溶酶体功能和自噬的重要基因可以调节这些与年龄相关的形态学变化，而这些变化在其他方面是正常的。我们的研究结果表明，在亨廷顿氏病等神经退行性疾病中，错误折叠蛋白的表达改变了正常情况下与神经元衰老相关的形态重塑。我们的研究结果还表明，健康神经元在衰老过程中的形态重塑可由 UPS 和其他蛋白稳态通路调控。总之，我们的数据强调了一个模型，在该模型中，神经元衰老过程中的形态重塑受到蛋白稳态紊乱和与疾病相关的错误折叠蛋白（如人类 polyQ-Htt 蛋白）表达的强烈影响。折叠错误的蛋白质和蛋白质维持紊乱会导致神经元形状发生与衰老相关的变化。阿拉斯加费尔班克斯大学的 Elena Vayndorf 及其在美国、加拿大和法国的同事研究了一株线虫秀丽隐杆线虫，在这株线虫中，选定的神经元表达了部分人类亨廷顿氏病基因，亨廷顿氏病是一种与衰老相关的神经退行性疾病。研究人员还阻止了健康神经元中参与蛋白质制造、折叠、贩运和降解的基因的表达。通过这两种实验操作，他们观察到动物神经元的形态发生了变化，这些变化通常发生在衰老过程中。鉴于优雅蛛和人类神经元之间的相似性，作者提出，针对指导蛋白质维持的细胞途径的药物可以帮助亨廷顿氏症等与年龄相关的神经系统疾病患者保持大脑功能。
{"title":"Morphological remodeling of C. elegans neurons during aging is modified by compromised protein homeostasis","authors":"Elena M Vayndorf, Courtney Scerbak, Skyler Hunter, Jason R Neuswanger, Marton Toth, J Alex Parker, Christian Neri, Monica Driscoll, Barbara E Taylor","doi":"10.1038/npjamd.2016.1","DOIUrl":"10.1038/npjamd.2016.1","url":null,"abstract":"Understanding cellular outcomes, such as neuronal remodeling, that are common to both healthy and diseased aging brains is essential to the development of successful brain aging strategies. Here, we used Caenorhabdits elegans to investigate how the expression of proteotoxic triggers, such as polyglutamine (polyQ)-expanded huntingtin and silencing of proteostasis regulators, such as the ubiquitin–proteasome system (UPS) and protein clearance components, may impact the morphological remodeling of individual neurons as animals age. We examined the effects of disrupted proteostasis on the integrity of neuronal cytoarchitecture by imaging a transgenic C. elegans strain in which touch receptor neurons express the first 57 amino acids of the human huntingtin (Htt) gene with expanded polyQs (128Q) and by using neuron-targeted RNA interference in adult wild-type neurons to knockdown genes encoding proteins involved in proteostasis. We found that proteostatic challenges conferred by polyQ-expanded Htt and knockdown of specific genes involved in protein homeostasis can lead to morphological changes that are restricted to specific domains of specific neurons. The age-associated branching of PLM neurons is suppressed by N-ter polyQ-expanded Htt expression, whereas ALM neurons with polyQ-expanded Htt accumulate extended outgrowths and other soma abnormalities. Furthermore, knockdown of genes important for ubiquitin-mediated degradation, lysosomal function, and autophagy modulated these age-related morphological changes in otherwise normal neurons. Our results show that the expression of misfolded proteins in neurodegenerative disease such as Huntington’s disease modifies the morphological remodeling that is normally associated with neuronal aging. Our results also show that morphological remodeling of healthy neurons during aging can be regulated by the UPS and other proteostasis pathways. Collectively, our data highlight a model in which morphological remodeling during neuronal aging is strongly affected by disrupted proteostasis and expression of disease-associated, misfolded proteins such as human polyQ-Htt species. Misfolded proteins and disrupted protein maintenance can lead to aging-related changes in neuron shape. Elena Vayndorf from the University of Alaska Fairbanks and colleagues in the US, Canada and France studied a strain of nematode Caenorhabditis elegans in which selected neurons express part of the human gene responsible for Huntington’s disease, which is an aging-related, neurodegenerative disorder. The researchers also blocked expression of genes involved in protein manufacture, folding, trafficking and degradation in healthy neurons. With both experimental manipulations, they observed changes in the morphology of the animal’s neurons that normally occur during aging. Given the similarities between C. elegans and human neurons, the authors propose that drugs targeting the cellular pathways that guide protein maintenance could help retain brai","PeriodicalId":94160,"journal":{"name":"npj aging","volume":"2 1","pages":"1-10"},"PeriodicalIF":0.0,"publicationDate":"2016-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1038/npjamd.2016.1","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34613394","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Extensive investigations have demonstrated that organismal aging is associated with tissue dysfunction in many organs. The eye is no exception to this rule. Under healthy conditions, the eye is designed like an advanced camera with the central role of translating light from the external world into a coherent neural signal that can be transmitted to the brain for processing into a precise visual image. This complex process requires precisely maintained machinery. At the front of the eye, the transparency of both the cornea and the lens are crucial to allow passage of photons to the light-sensitive portion of the eye. Similarly, the highly organized structure of the retina located at the back of the eye is indispensable to allow for effective signal transduction and efficient signal transmission. Aging affects ocular structures in various ways, and these sequelae have been well defined as distinct clinical entities. In many instances, aging leads to ocular tissue dysfunction and disease. Nonetheless, despite clear evidence that age-associated visual impairment has significant psychosocial consequences, current treatment paradigms for many of these conditions are inadequate. In addition, strategies to decelerate or reverse age-associated deterioration in ocular function are still in their infancy. This review focuses on the cellular and molecular pathophysiology of the aging eye. Ultimately, we hope that a refined understanding of the aging eye can guide targeted therapies against cellular aging and disease.
{"title":"A glimpse at the aging eye","authors":"Jonathan B Lin, Kazuo Tsubota, Rajendra S Apte","doi":"10.1038/npjamd.2016.3","DOIUrl":"10.1038/npjamd.2016.3","url":null,"abstract":"Extensive investigations have demonstrated that organismal aging is associated with tissue dysfunction in many organs. The eye is no exception to this rule. Under healthy conditions, the eye is designed like an advanced camera with the central role of translating light from the external world into a coherent neural signal that can be transmitted to the brain for processing into a precise visual image. This complex process requires precisely maintained machinery. At the front of the eye, the transparency of both the cornea and the lens are crucial to allow passage of photons to the light-sensitive portion of the eye. Similarly, the highly organized structure of the retina located at the back of the eye is indispensable to allow for effective signal transduction and efficient signal transmission. Aging affects ocular structures in various ways, and these sequelae have been well defined as distinct clinical entities. In many instances, aging leads to ocular tissue dysfunction and disease. Nonetheless, despite clear evidence that age-associated visual impairment has significant psychosocial consequences, current treatment paradigms for many of these conditions are inadequate. In addition, strategies to decelerate or reverse age-associated deterioration in ocular function are still in their infancy. This review focuses on the cellular and molecular pathophysiology of the aging eye. Ultimately, we hope that a refined understanding of the aging eye can guide targeted therapies against cellular aging and disease.","PeriodicalId":94160,"journal":{"name":"npj aging","volume":"2 1","pages":"1-7"},"PeriodicalIF":0.0,"publicationDate":"2016-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1038/npjamd.2016.3","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35179865","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Dysregulation of metabolism develops with organismal aging. Both genetic and environmental manipulations promote longevity by effectively diverting various metabolic processes against aging. How these processes converge on the metabolome is not clear. Here we report that the heavy isotopic forms of common elements, a universal feature of metabolites, decline in yeast cells undergoing chronological aging. Supplementation of deuterium, a heavy hydrogen isotope, through heavy water (D2O) uptake extends yeast chronological lifespan (CLS) by up to 85% with minimal effects on growth. The CLS extension by D2O bypasses several known genetic regulators, but is abrogated by calorie restriction and mitochondrial deficiency. Heavy water substantially suppresses endogenous generation of reactive oxygen species (ROS) and slows the pace of metabolic consumption and disposal. Protection from aging by heavy isotopes might result from kinetic modulation of biochemical reactions. Altogether, our findings reveal a novel perspective of aging and new means for promoting longevity. The lifespan of yeast cells can be extended by supplying them with heavy isotopes of common elements, according to US researchers. Heavy isotopes such as deuterium–a type of hydrogen containing a neutron–exist in small quantities in natural environments, but their effects on living organisms are unclear. Michael Snyder and Xiyan Li at Stanford University showed for the first time that amino acids in yeast cells tend to contain lower levels of heavy isotopes as the cells age. They then incubated yeast cells with increased doses of ‘heavy water’ (which contains deuterium instead of hydrogen) and found that, remarkably, the yeast’s lifespan was extended by up to 85%. The researchers suggest that heavy isotopes affect biochemical reactions by strengthening molecular bonds, and suppress reactive oxygen species, thereby slowing the metabolism and prolonging life.
{"title":"Yeast longevity promoted by reversing aging-associated decline in heavy isotope content","authors":"Xiyan Li, Michael P Snyder","doi":"10.1038/npjamd.2016.4","DOIUrl":"10.1038/npjamd.2016.4","url":null,"abstract":"Dysregulation of metabolism develops with organismal aging. Both genetic and environmental manipulations promote longevity by effectively diverting various metabolic processes against aging. How these processes converge on the metabolome is not clear. Here we report that the heavy isotopic forms of common elements, a universal feature of metabolites, decline in yeast cells undergoing chronological aging. Supplementation of deuterium, a heavy hydrogen isotope, through heavy water (D2O) uptake extends yeast chronological lifespan (CLS) by up to 85% with minimal effects on growth. The CLS extension by D2O bypasses several known genetic regulators, but is abrogated by calorie restriction and mitochondrial deficiency. Heavy water substantially suppresses endogenous generation of reactive oxygen species (ROS) and slows the pace of metabolic consumption and disposal. Protection from aging by heavy isotopes might result from kinetic modulation of biochemical reactions. Altogether, our findings reveal a novel perspective of aging and new means for promoting longevity. The lifespan of yeast cells can be extended by supplying them with heavy isotopes of common elements, according to US researchers. Heavy isotopes such as deuterium–a type of hydrogen containing a neutron–exist in small quantities in natural environments, but their effects on living organisms are unclear. Michael Snyder and Xiyan Li at Stanford University showed for the first time that amino acids in yeast cells tend to contain lower levels of heavy isotopes as the cells age. They then incubated yeast cells with increased doses of ‘heavy water’ (which contains deuterium instead of hydrogen) and found that, remarkably, the yeast’s lifespan was extended by up to 85%. The researchers suggest that heavy isotopes affect biochemical reactions by strengthening molecular bonds, and suppress reactive oxygen species, thereby slowing the metabolism and prolonging life.","PeriodicalId":94160,"journal":{"name":"npj aging","volume":"2 1","pages":"1-10"},"PeriodicalIF":0.0,"publicationDate":"2016-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1038/npjamd.2016.4","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35179866","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Plasticity is a critical factor enabling stem cells to contribute to the development and regeneration of tissues. In the mammalian central nervous system (CNS), neural stem cells (NSCs) that are defined by their capability for self-renewal and differentiation into neurons and glia, are present in the ventricular neuroaxis throughout life. However, the differentiation potential of NSCs changes in a spatiotemporally regulated manner and these cells progressively lose plasticity during development. One of the major alterations in this process is the switch from neurogenesis to gliogenesis. NSCs initiate neurogenesis immediately after neural tube closure and then turn to gliogenesis from midgestation, which requires an irreversible competence transition that enforces a progressive reduction of neuropotency. A growing body of evidence indicates that the neurogenesis-to-gliogenesis transition is governed by multiple layers of regulatory networks consisting of multiple factors, including epigenetic regulators, transcription factors, and non-coding RNA (ncRNA). In this review, we focus on critical roles of microRNAs (miRNAs), a class of small ncRNA that regulate gene expression at the post-transcriptional level, in the regulation of the switch from neurogenesis to gliogenesis in NSCs in the developing CNS. Unraveling the regulatory interactions of miRNAs and target genes will provide insights into the regulation of plasticity of NSCs, and the development of new strategies for the regeneration of damaged CNS.
{"title":"Heterochronic microRNAs in temporal specification of neural stem cells: application toward rejuvenation","authors":"Takuya Shimazaki, Hideyuki Okano","doi":"10.1038/npjamd.2015.14","DOIUrl":"10.1038/npjamd.2015.14","url":null,"abstract":"Plasticity is a critical factor enabling stem cells to contribute to the development and regeneration of tissues. In the mammalian central nervous system (CNS), neural stem cells (NSCs) that are defined by their capability for self-renewal and differentiation into neurons and glia, are present in the ventricular neuroaxis throughout life. However, the differentiation potential of NSCs changes in a spatiotemporally regulated manner and these cells progressively lose plasticity during development. One of the major alterations in this process is the switch from neurogenesis to gliogenesis. NSCs initiate neurogenesis immediately after neural tube closure and then turn to gliogenesis from midgestation, which requires an irreversible competence transition that enforces a progressive reduction of neuropotency. A growing body of evidence indicates that the neurogenesis-to-gliogenesis transition is governed by multiple layers of regulatory networks consisting of multiple factors, including epigenetic regulators, transcription factors, and non-coding RNA (ncRNA). In this review, we focus on critical roles of microRNAs (miRNAs), a class of small ncRNA that regulate gene expression at the post-transcriptional level, in the regulation of the switch from neurogenesis to gliogenesis in NSCs in the developing CNS. Unraveling the regulatory interactions of miRNAs and target genes will provide insights into the regulation of plasticity of NSCs, and the development of new strategies for the regeneration of damaged CNS.","PeriodicalId":94160,"journal":{"name":"npj aging","volume":"2 1","pages":"1-6"},"PeriodicalIF":0.0,"publicationDate":"2016-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1038/npjamd.2015.14","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35181853","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Adipocytes are not merely organs for energy conservation but endocrine organs secreting a wide array of physiologically active substances, i.e., adipokines. Of these adipokines, adiponectin is known to exert anti-diabetic and anti-atherosclerotic effects via adiponectin receptors (AdipoR)s, AdipoR1 and AdipoR2. Adiponectin has also recently been shown to regulate longevity signaling thus prolonging lifespan. Therefore, the strategy for activating adiponectin/AdipoR signaling pathways are expected to provide a solid basis for the prevention and treatment of obesity-related diseases such as the metabolic syndrome, type 2 diabetes and cardiovascular disease, as well as for ensuring healthy longevity in humans.
{"title":"Adiponectin/adiponectin receptor in disease and aging","authors":"Masato Iwabu, Miki Okada-Iwabu, Toshimasa Yamauchi, Takashi Kadowaki","doi":"10.1038/npjamd.2015.13","DOIUrl":"10.1038/npjamd.2015.13","url":null,"abstract":"Adipocytes are not merely organs for energy conservation but endocrine organs secreting a wide array of physiologically active substances, i.e., adipokines. Of these adipokines, adiponectin is known to exert anti-diabetic and anti-atherosclerotic effects via adiponectin receptors (AdipoR)s, AdipoR1 and AdipoR2. Adiponectin has also recently been shown to regulate longevity signaling thus prolonging lifespan. Therefore, the strategy for activating adiponectin/AdipoR signaling pathways are expected to provide a solid basis for the prevention and treatment of obesity-related diseases such as the metabolic syndrome, type 2 diabetes and cardiovascular disease, as well as for ensuring healthy longevity in humans.","PeriodicalId":94160,"journal":{"name":"npj aging","volume":"1 1","pages":"1-6"},"PeriodicalIF":0.0,"publicationDate":"2015-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1038/npjamd.2015.13","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35181851","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Elisabeth M van Leeuwen, Jennifer E Huffman, Joshua C Bis, Aaron Isaacs, Monique Mulder, Aniko Sabo, Albert V Smith, Serkalem Demissie, Ani Manichaikul, Jennifer A Brody, Mary F Feitosa, Qing Duan, Katharina E Schraut, Pau Navarro, Jana V van Vliet-Ostaptchouk, Gu Zhu, Hamdi Mbarek, Stella Trompet, Niek Verweij, Leo-Pekka Lyytikäinen, Joris Deelen, Ilja M Nolte, Sander W van der Laan, Gail Davies, Andrea JM Vermeij-Verdoold, Andy ALJ van Oosterhout, Jeannette M Vergeer-Drop, Dan E Arking, Holly Trochet, Generation Scotland, Carolina Medina-Gomez, Fernando Rivadeneira, Andre G Uitterlinden, Abbas Dehghan, Oscar H Franco, Eric J Sijbrands, Albert Hofman, Charles C White, Josyf C Mychaleckyj, Gina M Peloso, Morris A Swertz, LifeLines Cohort Study, Gonneke Willemsen, Eco J de Geus, Yuri Milaneschi, Brenda WJH Penninx, Ian Ford, Brendan M Buckley, Anton JM de Craen, John M Starr, Ian J Deary, Gerard Pasterkamp, Albertine J Oldehinkel, Harold Snieder, P Eline Slagboom, Kjell Nikus, Mika Kähönen, Terho Lehtimäki, Jorma S Viikari, Olli T Raitakari, Pim van der Harst, J Wouter Jukema, Jouke-Jan Hottenga, Dorret I Boomsma, John B Whitfield, Grant Montgomery, Nicholas G Martin, CHARGE Lipids Working Group, Ozren Polasek, Veronique Vitart, Caroline Hayward, Ivana Kolcic, Alan F Wright, Igor Rudan, Peter K Joshi, James F Wilson, Leslie A Lange, James G Wilson, Vilmundur Gudnason, Tamar B Harris, Alanna C Morrison, Ingrid B Borecki, Stephen S Rich, Sandosh Padmanabhan, Bruce M Psaty, Jerome I Rotter, Blair H Smith, Eric Boerwinkle, L Adrienne Cupples, Cornelia van Duijn
Individuals with exceptional longevity and their offspring have significantly larger high-density lipoprotein concentrations (HDL-C) particle sizes due to the increased homozygosity for the I405V variant in the cholesteryl ester transfer protein (CETP) gene. In this study, we investigate the association of CETP and HDL-C further to identify novel, independent CETP variants associated with HDL-C in humans. We performed a meta-analysis of HDL-C within the CETP region using 59,432 individuals imputed with 1000 Genomes data. We performed replication in an independent sample of 47,866 individuals and validation was done by Sanger sequencing. The meta-analysis of HDL-C within the CETP region identified five independent variants, including an exonic variant and a common intronic insertion. We replicated these 5 variants significantly in an independent sample of 47,866 individuals. Sanger sequencing of the insertion within a single family confirmed segregation of this variant. The strongest reported association between HDL-C and CETP variants, was rs3764261; however, after conditioning on the five novel variants we identified the support for rs3764261 was highly reduced (βunadjusted=3.179 mg/dl (P value=5.25×10−509), βadjusted=0.859 mg/dl (P value=9.51×10−25)), and this finding suggests that these five novel variants may partly explain the association of CETP with HDL-C. Indeed, three of the five novel variants (rs34065661, rs5817082, rs7499892) are independent of rs3764261. The causal variants in CETP that account for the association with HDL-C remain unknown. We used studies imputed to the 1000 Genomes reference panel for fine mapping of the CETP region. We identified and validated five variants within this region that may partly account for the association of the known variant (rs3764261), as well as other sources of genetic contribution to HDL-C. Newly discovered variants of the cholesteryl ester transfer protein (CETP) gene are associated with levels of “good” cholesterol. One version of the CETP gene is known to lead to higher concentrations of high-density lipoprotein (HDL) cholesterol, the type that helps protect against heart disease. However, other beneficial variants remain undiscovered. An international research team led by Cornelia van Duijn from Erasmus Medical Center in Rotterdam, The Netherlands, conducted a meta-analysis of previous studies that collectively compiled data from close to 60,000 people. They identified five novel variants linking CETP with HDL levels. Four of these were single letter differences and one was an insertion of a chunk of DNA. The researchers validated the findings in an independent cohort of around 48,000 people. People who carry these genetic variants may live longer and experience healthier aging.
{"title":"Fine mapping the CETP region reveals a common intronic insertion associated to HDL-C","authors":"Elisabeth M van Leeuwen, Jennifer E Huffman, Joshua C Bis, Aaron Isaacs, Monique Mulder, Aniko Sabo, Albert V Smith, Serkalem Demissie, Ani Manichaikul, Jennifer A Brody, Mary F Feitosa, Qing Duan, Katharina E Schraut, Pau Navarro, Jana V van Vliet-Ostaptchouk, Gu Zhu, Hamdi Mbarek, Stella Trompet, Niek Verweij, Leo-Pekka Lyytikäinen, Joris Deelen, Ilja M Nolte, Sander W van der Laan, Gail Davies, Andrea JM Vermeij-Verdoold, Andy ALJ van Oosterhout, Jeannette M Vergeer-Drop, Dan E Arking, Holly Trochet, Generation Scotland, Carolina Medina-Gomez, Fernando Rivadeneira, Andre G Uitterlinden, Abbas Dehghan, Oscar H Franco, Eric J Sijbrands, Albert Hofman, Charles C White, Josyf C Mychaleckyj, Gina M Peloso, Morris A Swertz, LifeLines Cohort Study, Gonneke Willemsen, Eco J de Geus, Yuri Milaneschi, Brenda WJH Penninx, Ian Ford, Brendan M Buckley, Anton JM de Craen, John M Starr, Ian J Deary, Gerard Pasterkamp, Albertine J Oldehinkel, Harold Snieder, P Eline Slagboom, Kjell Nikus, Mika Kähönen, Terho Lehtimäki, Jorma S Viikari, Olli T Raitakari, Pim van der Harst, J Wouter Jukema, Jouke-Jan Hottenga, Dorret I Boomsma, John B Whitfield, Grant Montgomery, Nicholas G Martin, CHARGE Lipids Working Group, Ozren Polasek, Veronique Vitart, Caroline Hayward, Ivana Kolcic, Alan F Wright, Igor Rudan, Peter K Joshi, James F Wilson, Leslie A Lange, James G Wilson, Vilmundur Gudnason, Tamar B Harris, Alanna C Morrison, Ingrid B Borecki, Stephen S Rich, Sandosh Padmanabhan, Bruce M Psaty, Jerome I Rotter, Blair H Smith, Eric Boerwinkle, L Adrienne Cupples, Cornelia van Duijn","doi":"10.1038/npjamd.2015.11","DOIUrl":"10.1038/npjamd.2015.11","url":null,"abstract":"Individuals with exceptional longevity and their offspring have significantly larger high-density lipoprotein concentrations (HDL-C) particle sizes due to the increased homozygosity for the I405V variant in the cholesteryl ester transfer protein (CETP) gene. In this study, we investigate the association of CETP and HDL-C further to identify novel, independent CETP variants associated with HDL-C in humans. We performed a meta-analysis of HDL-C within the CETP region using 59,432 individuals imputed with 1000 Genomes data. We performed replication in an independent sample of 47,866 individuals and validation was done by Sanger sequencing. The meta-analysis of HDL-C within the CETP region identified five independent variants, including an exonic variant and a common intronic insertion. We replicated these 5 variants significantly in an independent sample of 47,866 individuals. Sanger sequencing of the insertion within a single family confirmed segregation of this variant. The strongest reported association between HDL-C and CETP variants, was rs3764261; however, after conditioning on the five novel variants we identified the support for rs3764261 was highly reduced (βunadjusted=3.179 mg/dl (P value=5.25×10−509), βadjusted=0.859 mg/dl (P value=9.51×10−25)), and this finding suggests that these five novel variants may partly explain the association of CETP with HDL-C. Indeed, three of the five novel variants (rs34065661, rs5817082, rs7499892) are independent of rs3764261. The causal variants in CETP that account for the association with HDL-C remain unknown. We used studies imputed to the 1000 Genomes reference panel for fine mapping of the CETP region. We identified and validated five variants within this region that may partly account for the association of the known variant (rs3764261), as well as other sources of genetic contribution to HDL-C. Newly discovered variants of the cholesteryl ester transfer protein (CETP) gene are associated with levels of “good” cholesterol. One version of the CETP gene is known to lead to higher concentrations of high-density lipoprotein (HDL) cholesterol, the type that helps protect against heart disease. However, other beneficial variants remain undiscovered. An international research team led by Cornelia van Duijn from Erasmus Medical Center in Rotterdam, The Netherlands, conducted a meta-analysis of previous studies that collectively compiled data from close to 60,000 people. They identified five novel variants linking CETP with HDL levels. Four of these were single letter differences and one was an insertion of a chunk of DNA. The researchers validated the findings in an independent cohort of around 48,000 people. People who carry these genetic variants may live longer and experience healthier aging.","PeriodicalId":94160,"journal":{"name":"npj aging","volume":"1 1","pages":"1-9"},"PeriodicalIF":0.0,"publicationDate":"2015-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1038/npjamd.2015.11","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35181852","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：