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-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.

Sugar-derived AGEs accelerate pharyngeal pumping rate and increase the lifespan of Caenorhabditis elegans

“…Additionally, the link between DAF-16 and AGEs has been shown before. For example, reduced generation of endogenous AGEs following treatment with rifampicin has been shown to lead to lifespan extension in a DAF-16-dependent manner [51]. Analogous reduction of endogenous AGEs production was also shown upon GLOD-4 overexpression [52] that was also suggested to rely on DAF-16 [53].…”

Quantification of Information Encoded by Gene Expression Levels During Lifespan Modulation Under Broad-range Dietary Restriction in <em>C. elegans</em>

“…Thus, the use of bacteriostatic antibiotics, such as carbenicillin, in NGM agar prevents bacterial proliferation and increases lifespan of worms compared to non-antibiotic controls 16 . Certain types of antibiotics, such as rifampicin 36 and members of the tetracycline family 37 38 , have been shown to extend lifespan in C. elegans independently of their effect on bacterial proliferation. However, there is no evidence in the literature that either carbenicillin or streptomycin can increase longevity independently of their effect on bacterial proliferation.…”

Phenotypic Screening in C. elegans as a Tool for the Discovery of New Geroprotective Drugs

“…Notably, glp-1 has a longer lifespan compared to wild type N2 worms, and this increased longevity is dependent on DAF-16 [234,235]. Since various geroprotective drugs depend, in part, on DAF-16 for their effect on lifespan [236][237][238], these drugs would have been missed in glp-1 screens as they would not be able to induce a greater level of DAF-16 nuclear translocation than what is already achieved by the glp-1 mutation. As a consequence, few studies have used temperature-sensitive sterile mutants for geroprotective drug screening [131].…”