MicroRNAs (miRNAs) are short, non-coding RNA molecules that negatively regulate gene expression post-transcriptionally. When bound with Argonautes (AGOs) and other companion proteins, miRNAs can target mRNAs for degradation or translational repression. The miRNA pathway is conserved through many organisms and is involved in development, longevity, and stress responses. Two integral Caenorhabditis elegans AGOs (ALG-1 and ALG-2) are 81% identical at the amino acid level and have similar spatiotemporal expression patterns in developing C. elegans, but recent work shows that these developmentally redundant AGOs take on opposing roles in adults. There is a global reduction of ALG-1 expression in adults, while ALG-2 levels remain constant. Loss of function (LOF)
alg-1 mutants have shortened lifespans, whereas LOF
alg-2 mutants live longer than wildtype organisms. Through transcriptional profiling of these mutants, we've identified unique sets of misregulated miRNAs and protein-coding genes. Interestingly, there is an enrichment of up-regulated neuronal-specific genes in the
alg-1 adult mutant, and previous work has shown that individual tissues play pivotal roles in regulating longevity. We have begun to test well-characterized aging phenotypes at the tissue level, which reveal that ALG-1 is important in the maintenance of pharyngeal, muscular, and intestinal integrity in adulthood. Additionally, we have generated tissue-specific ALG-1- or ALG-2-depleted strains to begin testing the hypothesis that ALG-1 and ALG-2 regulate miRNA targets in a tissue-specific manner, leading to opposing roles in the lifespan of C. elegans.