S-adenosyl-L-homocysteine triggers an adaptive response that extends lifespan through the YBT1 ABC transporter.
9 affiliations
- 1Laboratory of Healthy Aging, Unit of Biotechnology, Graduate School of Integrated Sciences for Life, Hiroshima University, Higashi-Hiroshima 739-8530, Japan.
- 2Brewing Microbiology Division, National Research Institute of Brewing, Higashi-Hiroshima 739-0046, Japan.
- 3Laboratory of Molecular Physiology and Genetics, Faculty of Agriculture, Graduate School of Agriculture, Ehime University, Matsuyama 790-8566, Japan.
- 4Research and Development Bureau, Saitama University, Saitama 338-8570, Japan.
- 5Division of Cell-Free Sciences, Proteo-Science Center, Ehime University, Matsuyama 790-8577, Japan.
- 6Division of Genetic Research Support, the Advanced Research Support Center, Ehime University, Matsuyama 790-8566, Japan.
- 7Institute for Advanced Biosciences, Keio University, Tsuruoka 997-0052, Japan.
- 8Human Biology-Microbiome-Quantum Research Center, Keio University, Tokyo 160-8582, Japan.
- 9Hiroshima Research Center for Healthy Aging, Hiroshima University, Higashi-Hiroshima 739-8530, Japan.
Abstract
S-adenosyl-L-methionine (SAM) is a fundamental methyl donor; however, the physiological role of its byproduct and competitive inhibitor, S-adenosyl-L-homocysteine (SAH), remains unclear. Here, we show that transient reactive oxygen species (ROS) production triggered by SAH during the early logarithmic phase mimics partial SAH hydrolase inhibition, extending the yeast chronological lifespan (CLS) through a hormetic mechanism. This study reveals that the dual nature of ROS in aging is determined by the specific degree of SAH hydrolase activity. We identified the adenosine 5'-triphosphate-binding cassette (ABC) transporter Ybt1 as a key downstream effector of SAH. Ybt1 localizes to the vacuolar membrane and facilitates the sequestration of SAM from the cytosol into the vacuole. Notably, YBT1 overexpression extends CLS, mimicking SAH effects through an integrated pathway involving target of rapamycin complex 1 downregulation, autophagy, and adenosine 5'-monophosphate-activated protein kinase activation. Our findings establish that SAH acts as a metabolic signal coupling nutrient and energy availability to longevity via Ybt1, defining an adaptive/hormetic response for lifespan regulation in yeast.
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BibTeX
@article{masumura2026sadenosyllhomocysteine,
title = {{S-adenosyl-L-homocysteine triggers an adaptive response that extends lifespan through the YBT1 ABC transporter.}},
author = {Koji Masumura and Sayaka Kawasaki and Mayu Tsutsumi and Hiiro Yamashita and Muneyoshi Kanai and Haruto Nakajo and Wakaba Yagi and Shoma Katsunoi and Kaori Yoneyama and Miyuki Kawano-Kawada and Takayuki Sekito and Takafumi Ogawa and Tomoyoshi Soga and Masaki Mizunuma},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
year = {2026},
month = oct,
doi = {10.1073/pnas.2621286123},
url = {https://europepmc.org/article/MED/42886693},
note = {CC BY},
}
RIS
TY - JOUR
TI - S-adenosyl-L-homocysteine triggers an adaptive response that extends lifespan through the YBT1 ABC transporter.
AU - Koji Masumura
AU - Sayaka Kawasaki
AU - Mayu Tsutsumi
AU - Hiiro Yamashita
AU - Muneyoshi Kanai
AU - Haruto Nakajo
AU - Wakaba Yagi
AU - Shoma Katsunoi
AU - Kaori Yoneyama
AU - Miyuki Kawano-Kawada
AU - Takayuki Sekito
AU - Takafumi Ogawa
AU - Tomoyoshi Soga
AU - Masaki Mizunuma
PY - 2026
DA - 2026/10/16
JO - Proceedings of the National Academy of Sciences of the United States of America
DO - 10.1073/pnas.2621286123
UR - https://europepmc.org/article/MED/42886693
AB - S-adenosyl-L-methionine (SAM) is a fundamental methyl donor; however, the physiological role of its byproduct and competitive inhibitor, S-adenosyl-L-homocysteine (SAH), remains unclear. Here, we show that transient reactive oxygen species (ROS) production triggered by SAH during the early logarithmic phase mimics partial SAH hydrolase inhibition, extending the yeast chronological lifespan (CLS) through a hormetic mechanism. This study reveals that the dual nature of ROS in aging is determined by the specific degree of SAH hydrolase activity. We identified the adenosine 5'-triphosphate-binding cassette (ABC) transporter Ybt1 as a key downstream effector of SAH. Ybt1 localizes to the vacuolar membrane and facilitates the sequestration of SAM from the cytosol into the vacuole. Notably, YBT1 overexpression extends CLS, mimicking SAH effects through an integrated pathway involving target of rapamycin complex 1 downregulation, autophagy, and adenosine 5'-monophosphate-activated protein kinase activation. Our findings establish that SAH acts as a metabolic signal coupling nutrient and energy availability to longevity via Ybt1, defining an adaptive/hormetic response for lifespan regulation in yeast.
SN - 0027-8424
SN - 1091-6490
ER -