Ssd1 and Gcn2 suppress global translation efficiency in replicatively aged yeast while their activation extends lifespan
Zheng Hu,
Bo Xia,
Spike DL Postnikoff,
Zih-Jie Shen,
Alin S Tomoiaga,
Troy A Harkness,
Ja Hwan Seol,
Wei Li,
Kaifu Chen,
Jessica K Tyler
Affiliations
Zheng Hu
Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, United States
Bo Xia
Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, United States; Department of Cardiothoracic Surgery, Weill Cornell Medicine, New York, United States
Spike DL Postnikoff
Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, United States
Zih-Jie Shen
Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, United States
Alin S Tomoiaga
Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, United States; Department of Cardiothoracic Surgery, Weill Cornell Medicine, New York, United States; Manhattan College, Bronx, United States
Troy A Harkness
Department of Anatomy and Cell Biology, University of Saskatchewan, Saskatoon, Canada
Ja Hwan Seol
Department of Epigenetics and Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Houston, United States
Wei Li
Dan L. Duncan Cancer Center and Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, United States
Kaifu Chen
Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, United States; Department of Cardiothoracic Surgery, Weill Cornell Medicine, New York, United States
Translational efficiency correlates with longevity, yet its role in lifespan determination remains unclear. Using ribosome profiling, translation efficiency is globally reduced during replicative aging in budding yeast by at least two mechanisms: Firstly, Ssd1 is induced during aging, sequestering mRNAs to P-bodies. Furthermore, Ssd1 overexpression in young cells reduced translation and extended lifespan, while loss of Ssd1 reduced the translational deficit of old cells and shortened lifespan. Secondly, phosphorylation of eIF2α, mediated by the stress kinase Gcn2, was elevated in old cells, contributing to the global reduction in translation without detectable induction of the downstream Gcn4 transcriptional activator. tRNA overexpression activated Gcn2 in young cells and extended lifespan in a manner dependent on Gcn4. Moreover, overexpression of Gcn4 sufficed to extend lifespan in an autophagy-dependent manner in the absence of changes in global translation, indicating that Gcn4-mediated autophagy induction is the ultimate downstream target of activated Gcn2, to extend lifespan.
