A gain-of-function screen identifies wdb and lkb1 as lifespan-extending genes in Drosophila

• Published in: Biochemical and biophysical research communications 2011-02, Vol.405 (4), p.667-672
• Main Authors: Funakoshi, Masabumi, Tsuda, Manabu, Muramatsu, Keigo, Hatsuda, Hiroshi, Morishita, Shinichi, Aigaki, Toshiro
• Format: Article
• Language: English
• Subjects: AMP-Activated Protein Kinases - metabolism; Animals; Drosophila; Drosophila melanogaster - anatomy & histology; Drosophila melanogaster - genetics; Drosophila melanogaster - physiology; Drosophila Proteins - genetics; Drosophila Proteins - metabolism; Drosophila Proteins - physiology; Gain-of-function screen; Lifespan extension; Longevity - genetics; Organ size; Organ Size - genetics; Protein Kinases - genetics; Protein Kinases - physiology; Proto-Oncogene Proteins c-akt - antagonists & inhibitors; Proto-Oncogene Proteins c-akt - metabolism; Wings, Animal - anatomy & histology
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2011.01.090

► We identified two lifespan-extending genes, wdb and lkb1, in Drosophila. ► Overexpression of wdb inactivates Akt and extends lifespan. ► Overexpression of lkb1 activates AMPK, inactivates S6K, and extends lifespan. The insulin/insulin-like growth factor (IGF) and the target of rapamycin (TOR) signaling pathways are known to regulate lifespan in diverse organisms. However, only a limited number of genes involved in these pathways have been examined regarding their effects on lifespan. Through a gain-of-function screen in Drosophila, we found that overexpression of the wdb gene encoding a regulatory subunit of PP2A, and overexpression of the lkb1 gene encoding a serine/threonine kinase, reduced organ size and extended lifespan. Overexpression of wdb also reduced the level of phosphorylated AKT, while overexpression of lkb1 increased the level of phosphorylated AMPK and decreased the level of phosphorylated S6K. Taken together, our results suggest that wdb- and lkb1-dependent lifespan extension is mediated by downregulation of S6K, a downstream component of the insulin/IGF and TOR signaling pathways.