LAUSR

The budding yeast, Saccharomyces cerevisiae , is a popular single-cell eukaryotic model for studying mechanisms of aging, having played key roles in the identi fi cation and characterization of several conserved longevity factors, including the canonical NAD + -dependent histone deacetylase Sir2 that silences transcription and maintains stability of the ribosomal DNA (rDNA) tandem array on chromosome XII (reviewed in ref. 1). Other Sir2 protein family members, the sirtuins, regulate numerous cellular functions linked with the aging of invertebrate models and mammals, thus making them central players in current aging research (2). The rDNA tandem arrays are among the most unstable loci in eukaryotic genomes, comprising up to hundreds of rRNA genes transcribed by RNA polymerase I in the nucleolus to drive ribosome biogenesis. In S. cerevisiae , the single rDNA array is especially unstable, as mother cells replicatively age due to DNA double-strand breaks (DSBs) within the intergenic spacers. Repair of these breaks can result in the excision and accumulation of extrachromosomal rDNA circles (ERCs) in mother cells that ultimately contribute to their senescence (3). Silencing by Sir2 normally suppresses improper excision in young cells, but natural depletion of Sir2 in older cells causes instability (4). In PNAS, Hotz et al. (5) now demonstrate that a major determinant of ERC and Sir2 levels, and therefore replicative aging in most strains, is the actual length (copy number) of the rDNA tandem array (Fig. 1). This has impor-tant implications for the interpretation of yeast replicative lifespan (RLS) studies and signals that rDNA copy number should be addressed in metazoan aging studies. RLS