Open AccessReducing sphingolipid synthesis orchestrates global changes to extend yeast lifespan
Author(s) -
Liu Jun,
Huang Xinhe,
Withers Bradley R.,
Blalock Eric,
Liu Ke,
Dickson Robert C.
Publication year - 2013
Publication title -
aging cell
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.103
H-Index - 140
eISSN - 1474-9726
pISSN - 1474-9718
DOI - 10.1111/acel.12107
Subject(s) - biology , sphingolipid , ampk , signal transduction , calorie restriction , autophagy , longevity , saccharomyces cerevisiae , metabolic pathway , microbiology and biotechnology , mtorc1 , protein kinase a , tor signaling , kinase , yeast , enzyme , pi3k/akt/mtor pathway , genetics , biochemistry , apoptosis , endocrinology
Summary 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 ( TORC 1) 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.