title: Rifampicin reduces advanced glycation end products and activates DAF-16 to increase lifespan in Caenorhabditis elegans.
abstract: 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.
authors.affiliation: Division of Biochemical Sciences, CSIR-National Chemical Laboratory, Pune, 411008, India.
authors.forename: Sandeep
authors.initials: S
authors.lastname: Golegaonkar
authors.forename: Syed S
authors.initials: SS
authors.lastname: Tabrez
authors.forename: Awadhesh
authors.initials: A
authors.lastname: Pandit
authors.forename: Shalini
authors.initials: S
authors.lastname: Sethurathinam
authors.forename: Mashanipalya G
authors.initials: MG
authors.lastname: Jagadeeshaprasad
authors.forename: Sneha
authors.initials: S
authors.lastname: Bansode
authors.forename: Srinivasa-Gopalan
authors.initials: SG
authors.lastname: Sampathkumar
authors.forename: Mahesh J
authors.initials: MJ
authors.lastname: Kulkarni
authors.forename: Arnab
authors.initials: A
authors.lastname: Mukhopadhyay
mesh_terms: D000375:Aging; D000818:Animals; D000904:Antibiotics, Antitubercular / Q000494:pharmacology*; D017173:Caenorhabditis elegans / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism*; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism; D008136:Longevity / Q000187:drug effects*; D009154:Mutation / Q000235:genetics; D012293:Rifampin / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics
chemical_list: D000904:Antibiotics, Antitubercular; D029742:Caenorhabditis elegans Proteins; D051858:Forkhead Transcription Factors; D017127:Glycation End Products, Advanced; D007328:Insulin; C108831:daf-16 protein, C elegans; D012293:Rifampin
keywords: Caenorhabditis elegans; DAF-16; advanced glycation end products; aging; glycation; lifespan; rifampicin