A role for SIR-2.1 regulation of ER stress response genes in determining C. elegans life span.
C. elegans SIR-2.1, a member of the Sir-2 family of NAD(+)-dependent protein deacetylases, has been shown to regulate nematode aging via the insulin/IGF pathway transcription factor daf-16. Treatment of C. elegans with the small molecule resveratrol, however, extends life span in a manner fully dependent upon sir-2.1, but independent of daf-16. Microarray analysis of worms treated with resveratrol demonstrates the transcriptional induction of a family of genes encoding prion-like glutamine/asparagine-rich proteins involved in endoplasmic reticulum (ER) stress response to unfolded proteins. RNA interference of abu-11, a member of this ER stress gene family, abolishes resveratrol-mediated life span extension, and overexpression of abu-11 extends the life span of transgenic animals. Furthermore, SIR-2.1 normally represses transcription of abu-11 and other ER stress gene family members, indicating that resveratrol extends life span by inhibiting sir-2.1-mediated repression of ER stress genes. Our findings demonstrate that abu-11 and other members of its ER stress gene family are positive determinants of C. elegans life span.
Viswanathan
Mohan
M
Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
Kim
Stuart K
SK
Berdichevsky
Ala
A
Guarente
Leonard
L
D000818:Animals; D001216:Asparagine / Q000737:chemistry; D017173:Caenorhabditis elegans / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism*; D005656:Fungal Proteins / Q000378:metabolism*; D020869:Gene Expression Profiling; D005973:Glutamine / Q000737:chemistry; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D008136:Longevity / Q000187:drug effects / Q000235:genetics; D034622:RNA Interference / Q000187:drug effects / Q000502:physiology; D000077185:Resveratrol; D037761:Sirtuins / Q000378:metabolism*; D013267:Stilbenes / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics
C507015:Abu-11 protein, C elegans; D029742:Caenorhabditis elegans Proteins; D005656:Fungal Proteins; D006360:Heat-Shock Proteins; D013267:Stilbenes; D005973:Glutamine; D001216:Asparagine; C507014:SIR-2.1 protein, C elegans; D037761:Sirtuins; D000077185:Resveratrol