Golegaonkar Sandeep, Tabrez Syed S, Pandit Awadhesh, Sethurathinam Shalini, Jagadeeshaprasad Mashanipalya G, Bansode Sneha, Sampathkumar Srinivasa-Gopalan, Kulkarni Mahesh J, Mukhopadhyay Arnab
Division of Biochemical Sciences, CSIR-National Chemical Laboratory, Pune, 411008, India.
Aging Cell. 2015 Jun;14(3):463-73. doi: 10.1111/acel.12327. Epub 2015 Feb 26.
Advanced glycation end products (AGEs) are formed when glucose reacts nonenzymatically with proteins; these modifications are implicated in aging and pathogenesis of many age-related diseases including type II diabetes, atherosclerosis, and neurodegenerative disorders. Thus, pharmaceutical interventions that can reduce AGEs may delay age-onset diseases and extend lifespan. Using LC-MS(E), we show that rifampicin (RIF) reduces glycation of important cellular proteins in vivo and consequently increases lifespan in Caenorhabditis elegans by up to 60%. RIF analog rifamycin SV (RSV) possesses similar properties, while rifaximin (RMN) lacks antiglycation activity and therefore fails to affect lifespan positively. The efficacy of RIF and RSV as potent antiglycating agents may be attributed to the presence of a p-dihydroxyl moiety that can potentially undergo spontaneous oxidation to yield highly reactive p-quinone structures, a feature absent in RMN. We also show that supplementing rifampicin late in adulthood is sufficient to increase lifespan. For its effect on longevity, rifampicin requires DAF-18 (nematode PTEN) as well as JNK-1 and activates DAF-16, the FOXO homolog. Interestingly, the drug treatment modulates transcription of a different subset of DAF-16 target genes, those not controlled by the conserved Insulin-IGF-1-like signaling pathway. RIF failed to increase the lifespan of daf-16 null mutant despite reducing glycation, showing thereby that DAF-16 may not directly affect AGE formation. Together, our data suggest that the dual ability to reduce glycation in vivo and activate prolongevity processes through DAF-16 makes RIF and RSV effective lifespan-extending interventions.
当葡萄糖与蛋白质发生非酶促反应时，会形成晚期糖基化终末产物（AGEs）；这些修饰与衰老以及许多与年龄相关疾病的发病机制有关，包括II型糖尿病、动脉粥样硬化和神经退行性疾病。因此，能够减少AGEs的药物干预可能会延缓与年龄相关疾病的发生并延长寿命。通过液相色谱-质谱联用仪（LC-MS(E)），我们发现利福平（RIF）在体内可减少重要细胞蛋白质的糖基化，从而使秀丽隐杆线虫的寿命延长高达60%。RIF类似物利福霉素SV（RSV）具有相似的特性，而利福昔明（RMN）缺乏抗糖基化活性，因此无法对寿命产生积极影响。RIF和RSV作为有效的抗糖基化剂的功效可能归因于存在对二羟基部分，该部分可能会自发氧化生成高反应性的对醌结构，而RMN中不存在这一特征。我们还表明，在成年后期补充利福平足以延长寿命。就其对寿命的影响而言，利福平需要DAF-18（线虫PTEN）以及JNK-1，并激活FOXO同源物DAF-16。有趣的是，药物治疗可调节DAF-16靶基因不同子集的转录，这些基因不受保守的胰岛素-IGF-1样信号通路控制。尽管RIF可减少糖基化，但未能延长daf-16基因敲除突变体的寿命，这表明DAF-16可能不会直接影响AGE的形成。总之，我们的数据表明，RIF和RSV具有在体内减少糖基化以及通过DAF-16激活延长寿命过程的双重能力，从而成为有效的延长寿命干预措施。
