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Although numerous long noncoding RNAs (lncRNAs) have been identified, our understanding of their roles in mammalian physiology remains limited. Here, we investigated the physiologic function of the conserved lncRNA  Norad  in vivo. Deletion of  Norad  in mice results in genomic instability and mitochondrial dysfunction, leading to a dramatic multi-system degenerative phenotype resembling premature aging. Loss of tissue homeostasis in  Norad -deficient animals is attributable to augmented activity of PUMILIO proteins, which act as post-transcriptional repressors of target mRNAs to which they bind.  Norad  is the preferred RNA target of PUMILIO2 (PUM2) in mouse tissues and, upon loss of  Norad , PUM2 hyperactively represses key genes required for mitosis and mitochondrial function. Accordingly, enforced  Pum2  expression fully phenocopies  Norad  deletion, resulting in rapid-onset aging-associated phenotypes. These findings provide new insights and open new lines of investigation into the roles of noncoding RNAs and RNA binding proteins in normal physiology and aging.

PUMILIO hyperactivity drives premature aging of Norad -deficient mice