title: Reducing sphingolipid synthesis orchestrates global changes to extend yeast lifespan.
abstract: Studies of aging and longevity are revealing how diseases that shorten life can be controlled to improve the quality of life and lifespan itself. Two strategies under intense study to accomplish these goals are rapamycin treatment and calorie restriction. New strategies are being discovered including one that uses low-dose myriocin treatment. Myriocin inhibits the first enzyme in sphingolipid synthesis in all eukaryotes, and we showed recently that low-dose myriocin treatment increases yeast lifespan at least in part by down-regulating the sphingolipid-controlled Pkh1/2-Sch9 (ortholog of mammalian S6 kinase) signaling pathway. Here we show that myriocin treatment induces global effects and changes expression of approximately forty percent of the yeast genome with 1252 genes up-regulated and 1497 down-regulated (P < 0.05) compared with untreated cells. These changes are due to modulation of evolutionarily conserved signaling pathways including activation of the Snf1/AMPK pathway and down-regulation of the protein kinase A (PKA) and target of rapamycin complex 1 (TORC1) pathways. Many processes that enhance lifespan are regulated by these pathways in response to myriocin treatment including respiration, carbon metabolism, stress resistance, protein synthesis, and autophagy. These extensive effects of myriocin match those of rapamycin and calorie restriction. Our studies in yeast together with other studies in mammals reveal the potential of myriocin or related compounds to lower the incidence of age-related diseases in humans and improve health span.
authors.affiliation: Key Laboratory of Bio-Resources and Eco-Environment of Ministry of Education, College of Life Science, Sichuan University, Chengdu, 610064, China; Department of Molecular and Cellular Biochemistry and the Lucille Markey Cancer Center, University of Kentucky College of Medicine, Lexington, KY, 40536, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Liu
authors.forename: Xinhe
authors.initials: X
authors.lastname: Huang
authors.forename: Bradley R
authors.initials: BR
authors.lastname: Withers
authors.forename: Eric
authors.initials: E
authors.lastname: Blalock
authors.forename: Ke
authors.initials: K
authors.lastname: Liu
authors.forename: Robert C
authors.initials: RC
authors.lastname: Dickson
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology; D015966:Gene Expression Regulation, Fungal; D008136:Longevity / Q000502:physiology*; D015398:Signal Transduction; D013107:Sphingolipids / Q000096:biosynthesis*; D015003:Yeasts / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*
chemical_list: D000935:Antifungal Agents; D005229:Fatty Acids, Monounsaturated; D013107:Sphingolipids; C001996:thermozymocidin
keywords: AMPK; S6 kinase; TORC1; aging; myriocin; sphingolipids