Determining the role of ribosomal DNA in metazoan aging

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ABSTRACT Ribosomal RNA (rRNA) accounts for 80% of all cellular transcripts. rRNA is encoded by long tandem ribosomal DNA repeats (rDNA). Differences in rDNA copy number associate with changes in transcriptome and mitochondrial abundance, which suggests that rDNA copy number may have bearing on phenotype. Two aspects of rDNA copy number – the number of genomic repeats, and the number of extrachromosomal repeats – have been associated with aging. Specifically, a reduction of genomic rDNA repeats has been observed in some aging mammalian tissues. Additionally, an increase in extrachromosomal circular rDNA (ecc-rDNA) repeats occurs with yeast replicative age. Whether rDNA copy number itself influences aging phenotypes remains unresolved. While reductions in genomic rDNA copy number with age have been reported in specific post-mitotic mammalian tissues, it is unclear how prevalent this feature is, or by what mechanisms rDNA copies may be lost in a multicellular eukaryote. Furthermore, age-associated increases in ecc-rDNA have been extensively characterized in yeast but have been largely unexplored in metazoans. I propose to utilize Caenorhabditis elegans as an aging model to determine 1) If rDNA copy number influences aging and 2) How aging affects rDNA copy number. In Aim 1, I will assess lifespan, fertility, and length of development in two sets of recombinant inbred lines (RILs). The first set of RILs, which I developed from a cross of a C. elegans wild isolate and a derivative of the lab strain, were selected specifically for high (~420 copies) or low (~130 copies) rDNA copy number. The second set of RILs, part of the C. elegans Multiparental Experimental Evolution (CeMEE) panel, were developed from an advanced intercross of 16 wild isolates that underwent multiple rounds of experimental evolution prior to RIL development. For both sets of RILs, I will perform genome-wide association analyses to determine if rDNA copy number either additively or epistatically affects aging phenotypes. In Aim 2, I will assess both genomic rDNA copy number and ecc-rDNA levels during aging in C. elegans. Together these Aims will determine the relationship between rDNA and aging in a metazoan system, including if rDNA copy number changes are a universal hallmark of aging.