Hoffmann Julia, Romey Renja, Fink Christine, Yong Li, Roeder Thomas
University of Kiel, Dept. of Zoophysiology II, 24098 Kiel, Germany.
Aging (Albany NY). 2013 Apr;5(4):315-27. doi: 10.18632/aging.100553.
Sir2 is the most intensively discussed longevity gene in current aging research. Although, the gene encoding a NAD(+)-dependent histone deacetylase initially was found to extend lifespan of various organisms ranging from yeast to mammals, serious doubts regarding its role in longevity have been expressed recently. In this study, we tested whether tissue-specific overexpression of Sir2 in the adult fat body can extend lifespan when compared to genetically identical controls. We also wanted to elucidate the mechanisms by which fat body Sir2 promotes longevity by studying the phenotypic and transcriptional changes in the fat body. We found that moderate (3-fold) Sir2 overexpression in the fat body during adulthood only can promote longevity in both sexes by roughly 13 %. In addition, we obtained transcriptional profiles elicited by this overexpression and propose a role for Sir2 in lipid droplet biology especially under conditions of starvation. Furthermore, our data do not support the idea of Sir2 mediating the response to dietary restriction (DR) because transcriptional profiles of fat bodies after DR or Sir2 overexpression do not match. This study provides additional independent evidence for the concept of Sir2 as a longevity gene and as a promising pharmacological target to cure age-related diseases.
Sir2是当前衰老研究中讨论最为深入的长寿基因。尽管最初发现编码一种依赖烟酰胺腺嘌呤二核苷酸（NAD⁺）的组蛋白脱乙酰酶的该基因可延长从酵母到哺乳动物等多种生物的寿命，但最近人们对其在长寿中的作用表达了严重怀疑。在本研究中，我们测试了与基因相同的对照相比，成年脂肪体中Sir2的组织特异性过表达是否能延长寿命。我们还想通过研究脂肪体中的表型和转录变化来阐明脂肪体Sir2促进长寿的机制。我们发现，成年期脂肪体中适度（3倍）的Sir2过表达仅能使两性的寿命延长约13%。此外，我们获得了这种过表达引发的转录谱，并提出Sir2在脂滴生物学中发挥作用，尤其是在饥饿条件下。此外，我们的数据不支持Sir2介导对饮食限制（DR）反应的观点，因为DR或Sir2过表达后脂肪体的转录谱不匹配。本研究为Sir2作为长寿基因以及作为治疗与年龄相关疾病的有前景的药理学靶点这一概念提供了额外的独立证据。
