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Rifampicin reduces advanced glycation end products and activates DAF-16 to increase lifespan in Caenorhabditis elegans.
Aging Cell. 2015 Jun; 14(3):463-73.AC

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+Show Affiliations

Division of Biochemical Sciences, CSIR-National Chemical Laboratory, Pune, 411008, India.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25720500

Citation

Golegaonkar, Sandeep, et al. "Rifampicin Reduces Advanced Glycation End Products and Activates DAF-16 to Increase Lifespan in Caenorhabditis Elegans." Aging Cell, vol. 14, no. 3, 2015, pp. 463-73.
Golegaonkar S, Tabrez SS, Pandit A, et al. Rifampicin reduces advanced glycation end products and activates DAF-16 to increase lifespan in Caenorhabditis elegans. Aging Cell. 2015;14(3):463-73.
Golegaonkar, S., Tabrez, S. S., Pandit, A., Sethurathinam, S., Jagadeeshaprasad, M. G., Bansode, S., Sampathkumar, S. G., Kulkarni, M. J., & Mukhopadhyay, A. (2015). Rifampicin reduces advanced glycation end products and activates DAF-16 to increase lifespan in Caenorhabditis elegans. Aging Cell, 14(3), 463-73. https://doi.org/10.1111/acel.12327
Golegaonkar S, et al. Rifampicin Reduces Advanced Glycation End Products and Activates DAF-16 to Increase Lifespan in Caenorhabditis Elegans. Aging Cell. 2015;14(3):463-73. PubMed PMID: 25720500.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Rifampicin reduces advanced glycation end products and activates DAF-16 to increase lifespan in Caenorhabditis elegans. AU - Golegaonkar,Sandeep, AU - Tabrez,Syed S, AU - Pandit,Awadhesh, AU - Sethurathinam,Shalini, AU - Jagadeeshaprasad,Mashanipalya G, AU - Bansode,Sneha, AU - Sampathkumar,Srinivasa-Gopalan, AU - Kulkarni,Mahesh J, AU - Mukhopadhyay,Arnab, Y1 - 2015/02/26/ PY - 2015/01/15/accepted PY - 2015/2/28/entrez PY - 2015/2/28/pubmed PY - 2016/2/11/medline KW - Caenorhabditis elegans KW - DAF-16 KW - advanced glycation end products KW - aging KW - glycation KW - lifespan KW - rifampicin SP - 463 EP - 73 JF - Aging cell JO - Aging Cell VL - 14 IS - 3 N2 - 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. SN - 1474-9726 UR - https://www.unboundmedicine.com/medline/citation/25720500/Rifampicin_reduces_advanced_glycation_end_products_and_activates_DAF_16_to_increase_lifespan_in_Caenorhabditis_elegans_ L2 - https://doi.org/10.1111/acel.12327 DB - PRIME DP - Unbound Medicine ER -