Down regulation of miR-124 in both Werner syndrome DNA helicase mutant mice and mutant Caenorhabditis elegans wrn-1 reveals the importance of this microRNA in accelerated aging.
Small non-coding microRNAs are believed to be involved in the mechanism of aging but nothing is known on the impact of microRNAs in the progeroid disorder Werner syndrome (WS). WS is a premature aging disorder caused by mutations in a RecQ-like DNA helicase. Mice lacking the helicase domain of the WRN ortholog exhibit many phenotypic features of WS, including a pro-oxidant status and a shorter mean life span.Caenorhabditis elegans (C. elegans) with a nonfunctional wrn-1 DNA helicase also exhibit a shorter life span. Thus, both models are relevant to study the expression of microRNAs involved in WS. In this study, we show that miR-124 expression is lost in the liver of Wrn helicase mutant mice. Interestingly, the expression of this conserved miR-124 in whole wrn-1 mutant worms is also significantly reduced. The loss of mir-124 in C. elegans increases reactive oxygen species formation and accumulation of the aging marker lipofuscin, reduces whole body ATP levels and results in a reduction in life span. Finally, supplementation of vitamin C normalizes the median life span of wrn-1 and mir-124 mutant worms. These results suggest that biological pathways involving WRN and miR-124 are conserved in the aging process across different species.
Centre de Recherche en Cancérologie de l'Université Laval, Hôpital Hôtel-Dieu de Québec, Québec City, Québec, Canada.
Alexandra
A
Dallaire
Chantal
C
Garand
Eric R
ER
Paquel
Sarah J
SJ
Mitchell
Rafael
R
de Cabo
Martin J
MJ
Simard
Michel
M
Lebel
D000375:Aging / Q000235:genetics*; D000818:Animals; D017173:Caenorhabditis elegans; D029742:Caenorhabditis elegans Proteins / Q000235:genetics*; D004265:DNA Helicases / Q000235:genetics*; D015536:Down-Regulation; D051379:Mice; D008817:Mice, Mutant Strains; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D017382:Reactive Oxygen Species; D053484:RecQ Helicases / Q000235:genetics* / Q000378:metabolism; D000071657:Werner Syndrome Helicase
D029742:Caenorhabditis elegans Proteins; D035683:MicroRNAs; C540079:Mirn124 microRNA, mouse; D017382:Reactive Oxygen Species; D004265:DNA Helicases; D053484:RecQ Helicases; D000071657:Werner Syndrome Helicase; C499253:Wrn protein, mouse; C488009:WRN-1 protein, C elegans