SUMMARY Aging is an inevitable process that involves profound physiological changes. Long non-coding RNAs (lncRNAs) are emerging as important regulators in various biological processes but are not systemically studied in aging. To provide an organism-wide lncRNA landscape during aging, we conduct comprehensive RNA sequencing (RNA-seq) analyses across the mouse lifespan. Of the 1,675 aging-regulated lncRNAs (AR-lncRNAs) identified, the majority are connected to inflammation-related biological pathways. AR-lncRNAs exhibit high tissue specificity; conversely, those with higher tissue specificity are preferentially regulated during aging. White adipose tissue (WAT) displays the highest number of AR-lncRNAs and develops the most dynamic crosstalk between AR-lncRNA and AR-mRNA during aging. An adipose-enriched AR-lncRNA, lnc-adipoAR1, is negatively correlated with aging, and knocking it down inhibits adipogenesis, phenocopying the compromised adipogenic capacity of aged fat. Our works together reveal AR-lncRNAs as essential components in aging and suggest that although each tissue ages in a distinct manner, WAT is a leading contributor to aging-related health decline.

Although long noncoding RNAs (lncRNAs) experience weaker evolutionary constraints and exhibit lower sequence conservation than coding genes, they can still conserve their features in various aspects. Here, we used multiple approaches to systemically evaluate the conservation between human and mouse lncRNAs from various dimensions including sequences, promoter, global synteny, and local synteny, which led to the identification of 1,731 conserved lncRNAs with 427 high-confidence ones meeting multiple criteria. Conserved lncRNAs, compared with non-conserved ones, generally have longer gene bodies, more exons and transcripts, stronger connections with human diseases, and are more abundant and widespread across different tissues. Transcription factor (TF) profile analysis revealed a significant enrichment of TF types and numbers in the promoters of conserved lncRNAs. We further identified a set of TFs that preferentially bind to conserved lncRNAs and exert stronger regulation on conserved than non-conserved lncRNAs. Our study has reconciled some discrepant interpretations of lncRNA conservation and revealed a new set of transcriptional factors ruling the expression of conserved lncRNAs.