Abstract
How lifespan and the rate of aging are set is a key problem in biology. Small RNAs are conserved molecules that impact diverse biological processes through the control of gene expression. However, in contrast to miRNAs, the role of endo-siRNAs in aging remains unexplored. Here, by combining deep sequencing and genomic and genetic approaches in Caenorhabditis elegans, we reveal an unprecedented role for endo-siRNA molecules in the maintenance of proteostasis and lifespan extension in germline-less animals. Furthermore, we identify an endo-siRNA-regulated tyrosine phosphatase, which limits the longevity of germline-less animals by restricting the activity of the heat shock transcription factor HSF-1. Altogether, our findings point to endo-siRNAs as a link between germline removal and the HSF-1 proteostasis and longevity-promoting somatic pathway. This establishes a role for endo siRNAs in the aging process and identifies downstream genes and physiological processes that are regulated by the endo siRNAs to affect longevity.
Highlights
Aging is a major risk factor for chronic age-related diseases, which have become a major cause of death in the elderly (Matus et al, 2011)
Dicer is a member of the RNase III family of nucleases that degrade double-stranded RNA
We made use of glp-1(e2144) mutants, which carry a temperature-sensitive notch receptor required for germline stem cells (GSC) proliferation (Priess et al, 1987)
Summary
Aging is a major risk factor for chronic age-related diseases, which have become a major cause of death in the elderly (Matus et al, 2011). Studies of the last decade identified about a dozen genes that function in the C. elegans reproductive-longevity pathway Many of these genes encode or regulate transcription factors, which are activated in the intestine upon germline removal. Along with transcription factors and transcription regulators, the small RNA silencing pathways impose a layer of gene regulation, which affects diverse biological processes This is achieved by the generation of short antisense RNAs that act in the cytoplasm, where they interfere with gene expression by inhibiting translation, by degrading cytoplasmic mRNA, or by altering mRNA storage (Grishok, 2013). By combining deep sequencing and genomic and genetic approaches in C. elegans, we have established a role of endo-siRNAs in lifespan extension and the regulation of the proteostasis-promoting transcription factor HSF-1 in germline-less animals and have identified direct and indirect aging-related targets of this silencing pathway
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