Rifampicin reduces advanced glycation end products and activates DAF-16 to increase lifespan in Caenorhabditis elegans.
Rifampicin reduces advanced glycation end products and activates DAF-16 to increase lifespan in Caenorhabditis elegans.
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DOI：
10.1111/acel.12327
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发表时间：
2015-06
期刊：
影响因子：
7.8
通讯作者：
Mukhopadhyay A
中科院分区：
文献类型：
--
作者：
Golegaonkar S;Tabrez SS;Pandit A;Sethurathinam S;Jagadeeshaprasad MG;Bansode S;Sampathkumar SG;Kulkarni MJ;Mukhopadhyay A
晚期糖基化终产物(AGEs)是当葡萄糖与蛋白质发生非酶反应时形成的；这些修饰与衰老和许多与年龄相关的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，能够降低年龄的药物干预措施可能会推迟老年性疾病并延长寿命。利用LC-MSE，我们发现利福平(RIF)减少了体内重要细胞蛋白的糖基化，从而使秀丽线虫的寿命延长了高达60%。RIF类似物利福霉素SV(RSV)具有类似的性质，而利福昔明(RMN)缺乏抗糖基化活性，因此不能对寿命产生积极影响。RIF和RSV作为有效的降血糖药物的有效性可能归因于对二羟基的存在，该部分可能发生自发氧化以产生高活性的对苯二酚结构，这是RMN所缺乏的特征。我们还表明，在成年后期补充利福平足以延长寿命。为了延长寿命，利福平需要DAF-18(线虫PTEN)和JNK-1，并激活FOXO同系物DAF-16。有趣的是，药物治疗调节了DAF-16靶基因的另一个子集的转录，这些基因不受保守的胰岛素-IGF-1信号通路控制。RIF尽管减少了糖基化，但未能延长daf-16缺失突变体的寿命，从而表明DAF-16可能不直接影响AGE的形成。总之，我们的数据表明，通过DAF-16减少体内糖基化和激活延长过程的双重能力使RIF和RSV有效地延长寿命。
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-MSE, 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.
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影响因子：
7.8
作者：
McGee MD;Weber D;Day N;Vitelli C;Crippen D;Herndon LA;Hall DH;Melov S
通讯作者：
Melov S
影响因子：
9.8
作者：
David DC;Ollikainen N;Trinidad JC;Cary MP;Burlingame AL;Kenyon C
通讯作者：
Kenyon C
影响因子：
64.8
作者：
Ogg, S;Paradis, S;Ruvkun, G
通讯作者：
Ruvkun, G
影响因子：
1.8
作者：
BOLT, HM;REMMER, H
通讯作者：
REMMER, H
影响因子：
5.9
作者：
Luevano-Contreras C;Chapman-Novakofski K
通讯作者：
Chapman-Novakofski K