S -adenosyl-L-homocysteine triggers an adaptive response that extends lifespan through the YBT1 ABC transporter
Year: 2026
Type: article
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.
Language: English
Subfield: Aging
Domain: Life Sciences
Open Access status: hybrid
Funders: Institute for Fermentation, Osaka, Japan Agency for Medical Research and Development, Noda Institute for Scientific Research, Takeda Medical Research Foundation, Astellas Foundation for Research on Metabolic Disorders, Nagase Science Technology Foundation, Asahi Group Foundation, Japan Society for the Promotion of Science, Core Research for Evolutional Science and Technology
OpenAlex ID: W7222651658