Regulation of gene expression by microRNAs (miRNAs) is essential for normal development, but the roles of miRNAs in the physiology of adult animals are poorly understood. We have isolated a conditional allele of DGCR8/pash-1, which allows reversible and rapid inactivation of miRNA synthesis in vivo in Caenorhabditis elegans. This is a powerful new tool that allows dissection of post-developmental miRNA functions. We demonstrate that continuous synthesis of miRNAs is dispensable for cellular viability but critical for the physiology of adult animals. Loss of miRNA synthesis in the adult reduces lifespan and results in rapid aging. The insulin/IGF-1 signaling pathway is a critical determinant of lifespan, and is modulated by miRNAs. We find that although miRNA expression is required for some mechanisms of lifespan extension, it is not essential for the longevity of animals lacking insulin/IGF-1 signaling. Further, misregulated insulin/IGF-1 signaling cannot account for the reduced lifespan caused by disruption of miRNA synthesis. We show that miRNAs act in parallel with insulin/IGF-1 signaling to regulate a shared set of downstream genes important for physiological processes that determine lifespan. We conclude that coordinated transcriptional and post-transcriptional regulation of gene expression promotes longevity.
Created on Nov. 17, 2012, 9:47 p.m.
and lastly updated on Nov. 18, 2012, 9:48 p.m.
Half of animal mRNAs are directly subject to miRNA regulation (Friedman et al. 2008).
Inactivation of lin-14 does not increase the lifespan of pash-1 mutants.
JNK-1 overexpression extends the lifespan in a daf-16-dependent manner. JNK-1 directly phosphorylates DAF-16. JNK-1 overexpression does not extend the lifespan of animals unable to synthesize miRNAs.
Simultaneous inactivation of pash-1 and daf-12(e1370) results in an extended lifespan.
Inactivation of DAF-2 increases mean lifespan by 146%. In pash-1 mutants inactivation extends the mean lifespan by 121%.
daf-16(mj283) mutants shortens the lifespan of pash-1 mutants by 12%.
Lifespan extension by chronic caloric restriction (eat-2 mutants) and removal of the germline are largely dependent on miRNAs. The degree of lifespan extension by reduction of mitochondrial function and inactivation of insulin receptor DAF-2 is not dependent on miRNA synthesis.
genotype max temperature
pash-1(mj100) 10
wt 15
pash-1(mj100) 27 25
control 51 25
pash-1(mj100) 36 15
control 47 15
genotype mean max temperature
control 10 15
lin-15(n719) 12 25
control 15
jnk-1(OE)
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