PDF(Pubmed)
Abstract：
Biguanides, including the world\'s most prescribed drug for type 2 diabetes, metformin, not only lower blood sugar, but also promote longevity in preclinical models. Epidemiologic studies in humans parallel these findings, indicating favorable effects of metformin on longevity and on reducing the incidence and morbidity associated with aging-related diseases. Despite this promise, the full spectrum of molecular effectors responsible for these health benefits remains elusive. Through unbiased screening in Caenorhabditis elegans, we uncovered a role for genes necessary for ether lipid biosynthesis in the favorable effects of biguanides. We demonstrate that biguanides prompt lifespan extension by stimulating ether lipid biogenesis. Loss of the ether lipid biosynthetic machinery also mitigates lifespan extension attributable to dietary restriction, target of rapamycin (TOR) inhibition, and mitochondrial electron transport chain inhibition. A possible mechanistic explanation for this finding is that ether lipids are required for activation of longevity-promoting, metabolic stress defenses downstream of the conserved transcription factor skn-1/Nrf. In alignment with these findings, overexpression of a single, key, ether lipid biosynthetic enzyme, fard-1/FAR1, is sufficient to promote lifespan extension. These findings illuminate the ether lipid biosynthetic machinery as a novel therapeutic target to promote healthy aging.
Metformin is the drug most prescribed to treat type 2 diabetes around the world and has been in clinical use since 1950. The drug belongs to a family of compounds known as biguanides which reduce blood sugar, making them an effective treatment against type 2 diabetes. More recently, biguanides have been found to have other health benefits, including limiting the growth of various cancer cells and improving the lifespan and long-term health of several model organisms. Epidemiologic studies also suggest that metformin may increase the lifespan of humans and reduce the incidence of age-related illnesses such as cardiovascular disease, cancer and dementia. Given the safety and effectiveness of metformin, understanding how it exerts these desirable effects may allow scientists to discover new mechanisms to promote healthy aging. The roundworm Caenorhabditis elegans is an ideal organism for studying the lifespan-extending effects of metformin. It has an average lifespan of two weeks, a genome that is relatively easy to manipulate, and a transparent body that enables scientists to observe cellular and molecular events in living worms. To discover the genes that enable metformin’s lifespan-extending properties, Cedillo, Ahsan et al. systematically switched off the expression of about 1,000 genes involved in C. elegans metabolism. They then screened for genes which impaired the action of biguanides when inactivated. This ultimately led to the identification of a set of genes involved in promoting a longer lifespan. Cedillo, Ahsan et al. then evaluated how these genes impacted other well-described pathways involved in longevity and stress responses. The analysis indicated that a biguanide drug called phenformin (which is similar to metformin) increases the synthesis of ether lipids, a class of fats that are critical components of cellular membranes. Indeed, genetically mutating the three major enzymes required for ether lipid production stopped the biguanide from extending the worms’ lifespans. Critically, inactivating these genes also prevented lifespan extension through other known strategies, such as dietary restriction and inhibiting the cellular organelle responsible for producing energy. Cedillo, Ahsan et al. also showed that increasing ether lipid production alters the activity of a well-known longevity and stress response factor called SKN-1, and this change alone is enough to extend the lifespan of worms. These findings suggest that promoting the production of ether lipids could lead to healthier aging. However, further studies, including clinical trials, will be required to determine whether this is a viable approach to promote longevity and health in humans.
Metformin is the drug most prescribed to treat type 2 diabetes around the world and has been in clinical use since 1950. The drug belongs to a family of compounds known as biguanides which reduce blood sugar, making them an effective treatment against type 2 diabetes. More recently, biguanides have been found to have other health benefits, including limiting the growth of various cancer cells and improving the lifespan and long-term health of several model organisms. Epidemiologic studies also suggest that metformin may increase the lifespan of humans and reduce the incidence of age-related illnesses such as cardiovascular disease, cancer and dementia. Given the safety and effectiveness of metformin, understanding how it exerts these desirable effects may allow scientists to discover new mechanisms to promote healthy aging. The roundworm Caenorhabditis elegans is an ideal organism for studying the lifespan-extending effects of metformin. It has an average lifespan of two weeks, a genome that is relatively easy to manipulate, and a transparent body that enables scientists to observe cellular and molecular events in living worms. To discover the genes that enable metformin’s lifespan-extending properties, Cedillo, Ahsan et al. systematically switched off the expression of about 1,000 genes involved in C. elegans metabolism. They then screened for genes which impaired the action of biguanides when inactivated. This ultimately led to the identification of a set of genes involved in promoting a longer lifespan. Cedillo, Ahsan et al. then evaluated how these genes impacted other well-described pathways involved in longevity and stress responses. The analysis indicated that a biguanide drug called phenformin (which is similar to metformin) increases the synthesis of ether lipids, a class of fats that are critical components of cellular membranes. Indeed, genetically mutating the three major enzymes required for ether lipid production stopped the biguanide from extending the worms’ lifespans. Critically, inactivating these genes also prevented lifespan extension through other known strategies, such as dietary restriction and inhibiting the cellular organelle responsible for producing energy. Cedillo, Ahsan et al. also showed that increasing ether lipid production alters the activity of a well-known longevity and stress response factor called SKN-1, and this change alone is enough to extend the lifespan of worms. These findings suggest that promoting the production of ether lipids could lead to healthier aging. However, further studies, including clinical trials, will be required to determine whether this is a viable approach to promote longevity and health in humans.
摘要：
Biguanides,包括世界上治疗2型糖尿病的处方药，二甲双胍,不仅降低血糖，而且还可以促进临床前模型的寿命。人类流行病学研究与这些发现平行，表明二甲双胍对长寿和降低与衰老相关疾病的发病率和发病率的有利作用。尽管有这个承诺,负责这些健康益处的全部分子效应物仍然难以捉摸。通过对秀丽隐杆线虫的无偏见筛查，我们发现了醚脂生物合成所必需的基因在双胍的有利作用中的作用。我们证明双胍通过刺激醚脂质生物合成来促进寿命延长。醚类脂生物合成机制的丧失也减轻了由于饮食限制而导致的寿命延长，雷帕霉素靶蛋白（TOR）抑制，和线粒体电子传递链抑制。对这一发现的一个可能的机制解释是，醚脂质是促进长寿的激活所必需的，保守转录因子skn-1/Nrf下游的代谢应激防御。与这些发现一致，单一的过表达，键,醚脂生物合成酶，fard-1/FAR1，足以促进寿命延长。这些发现阐明了醚脂质生物合成机制作为促进健康衰老的新型治疗靶标。
二甲双胍是世界上最常用于治疗2型糖尿病的药物，自1950年以来一直在临床使用。该药物属于双胍化合物家族，可降低血糖，使它们成为2型糖尿病的有效治疗方法。最近,已发现双胍具有其他健康益处，包括限制各种癌细胞的生长和改善几种模式生物的寿命和长期健康。流行病学研究还表明，二甲双胍可以延长人类的寿命，降低心血管疾病等与年龄相关的疾病的发病率。癌症和痴呆症。鉴于二甲双胍的安全性和有效性，了解它如何发挥这些理想的作用可能会使科学家发现促进健康衰老的新机制。线虫线虫是研究二甲双胍延长寿命的理想生物。平均寿命为两周,一个相对容易操纵的基因组，和一个透明的身体，使科学家能够观察活蠕虫的细胞和分子事件。为了发现能够延长二甲双胍寿命的基因，塞迪略,Ahsan等人。系统地关闭了约1,000个参与秀丽隐杆线虫代谢的基因的表达。然后，他们筛选了失活时损害双胍作用的基因。这最终导致了一组参与促进更长寿命的基因的鉴定。塞迪略,Ahsan等人。然后评估了这些基因如何影响其他描述良好的与长寿和应激反应有关的途径。分析表明，一种称为苯乙双胍（类似于二甲双胍）的双胍药物会增加醚脂质的合成，一类脂肪是细胞膜的关键成分。的确,通过遗传突变产生醚脂质所需的三种主要酶，可以阻止双胍延长蠕虫的寿命。严重的,这些基因的失活也通过其他已知的策略阻止了寿命的延长，例如限制饮食和抑制负责产生能量的细胞器。塞迪略,Ahsan等人。还表明，增加醚脂质的产量会改变一种众所周知的寿命和应激反应因子SKN-1的活性，这种变化本身就足以延长蠕虫的寿命。这些发现表明，促进醚脂质的产生可能会导致更健康的衰老。然而,进一步研究,包括临床试验,将需要确定这是否是促进人类长寿和健康的可行方法。
二甲双胍是世界上最常用于治疗2型糖尿病的药物，自1950年以来一直在临床使用。该药物属于双胍化合物家族，可降低血糖，使它们成为2型糖尿病的有效治疗方法。最近,已发现双胍具有其他健康益处，包括限制各种癌细胞的生长和改善几种模式生物的寿命和长期健康。流行病学研究还表明，二甲双胍可以延长人类的寿命，降低心血管疾病等与年龄相关的疾病的发病率。癌症和痴呆症。鉴于二甲双胍的安全性和有效性，了解它如何发挥这些理想的作用可能会使科学家发现促进健康衰老的新机制。线虫线虫是研究二甲双胍延长寿命的理想生物。平均寿命为两周,一个相对容易操纵的基因组，和一个透明的身体，使科学家能够观察活蠕虫的细胞和分子事件。为了发现能够延长二甲双胍寿命的基因，塞迪略,Ahsan等人。系统地关闭了约1,000个参与秀丽隐杆线虫代谢的基因的表达。然后，他们筛选了失活时损害双胍作用的基因。这最终导致了一组参与促进更长寿命的基因的鉴定。塞迪略,Ahsan等人。然后评估了这些基因如何影响其他描述良好的与长寿和应激反应有关的途径。分析表明，一种称为苯乙双胍（类似于二甲双胍）的双胍药物会增加醚脂质的合成，一类脂肪是细胞膜的关键成分。的确,通过遗传突变产生醚脂质所需的三种主要酶，可以阻止双胍延长蠕虫的寿命。严重的,这些基因的失活也通过其他已知的策略阻止了寿命的延长，例如限制饮食和抑制负责产生能量的细胞器。塞迪略,Ahsan等人。还表明，增加醚脂质的产量会改变一种众所周知的寿命和应激反应因子SKN-1的活性，这种变化本身就足以延长蠕虫的寿命。这些发现表明，促进醚脂质的产生可能会导致更健康的衰老。然而,进一步研究,包括临床试验,将需要确定这是否是促进人类长寿和健康的可行方法。
