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Enhancing S-adenosyl-methionine catabolism extends Drosophila lifespan

Author

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  • Fumiaki Obata

    (Graduate School of Pharmaceutical Sciences, The University of Tokyo)

  • Masayuki Miura

    (Graduate School of Pharmaceutical Sciences, The University of Tokyo
    CREST, Japan Agency for Medical Research and Development)

Abstract

Methionine restriction extends the lifespan of various model organisms. Limiting S-adenosyl-methionine (SAM) synthesis, the first metabolic reaction of dietary methionine, extends longevity in Caenorhabditis elegans but accelerates pathology in mammals. Here, we show that, as an alternative to inhibiting SAM synthesis, enhancement of SAM catabolism by glycine N-methyltransferase (Gnmt) extends the lifespan in Drosophila. Gnmt strongly buffers systemic SAM levels by producing sarcosine in either high-methionine or low-sams conditions. During ageing, systemic SAM levels in flies are increased. Gnmt is transcriptionally induced in a dFoxO-dependent manner; however, this is insufficient to suppress SAM elevation completely in old flies. Overexpression of gnmt suppresses this age-dependent SAM increase and extends longevity. Pro-longevity regimens, such as dietary restriction or reduced insulin signalling, attenuate the age-dependent SAM increase, and rely at least partially on Gnmt function to exert their lifespan-extending effect in Drosophila. Our study suggests that regulation of SAM levels by Gnmt is a key component of lifespan extension.

Suggested Citation

  • Fumiaki Obata & Masayuki Miura, 2015. "Enhancing S-adenosyl-methionine catabolism extends Drosophila lifespan," Nature Communications, Nature, vol. 6(1), pages 1-9, November.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms9332
    DOI: 10.1038/ncomms9332
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    Cited by:

    1. Hyo Sub Choi & Ajay Bhat & Marshall B. Howington & Megan L. Schaller & Rebecca L. Cox & Shijiao Huang & Safa Beydoun & Hillary A. Miller & Angela M. Tuckowski & Joy Mecano & Elizabeth S. Dean & Lindy , 2023. "FMO rewires metabolism to promote longevity through tryptophan and one carbon metabolism in C. elegans," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    2. Juewon Kim & Yunju Jo & Donghyun Cho & Dongryeol Ryu, 2022. "L-threonine promotes healthspan by expediting ferritin-dependent ferroptosis inhibition in C. elegans," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    3. Christopher Livelo & Yiming Guo & Farah Abou Daya & Vasanthi Rajasekaran & Shweta Varshney & Hiep D. Le & Stephen Barnes & Satchidananda Panda & Girish C. Melkani, 2023. "Time-restricted feeding promotes muscle function through purine cycle and AMPK signaling in Drosophila obesity models," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    4. Hina Kosakamoto & Fumiaki Obata & Junpei Kuraishi & Hide Aikawa & Rina Okada & Joshua N. Johnstone & Taro Onuma & Matthew D. W. Piper & Masayuki Miura, 2023. "Early-adult methionine restriction reduces methionine sulfoxide and extends lifespan in Drosophila," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    5. Ruohong Wang & Yandong Yin & Jingshu Li & Hongmiao Wang & Wanting Lv & Yang Gao & Tangci Wang & Yedan Zhong & Zhiwei Zhou & Yuping Cai & Xiaoyang Su & Nan Liu & Zheng-Jiang Zhu, 2022. "Global stable-isotope tracing metabolomics reveals system-wide metabolic alternations in aging Drosophila," Nature Communications, Nature, vol. 13(1), pages 1-14, December.

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