A recent study employing a Perturb-seq-based CRISPR–dCas9–KRAB knockdown system has systematically analyzed 32 high-abundance long noncoding RNAs (lncRNAs) associated with aging and senescence. This research integrates single-nucleus multiomics profiling to provide a comprehensive view of the regulatory roles these lncRNAs play in cellular senescence. Notably, it identifies previously uncharacterized lncRNAs that modulate distinct transcriptomic and chromatin accessibility profiles, revealing their critical involvement in the aging process.

The findings underscore the significance of HOTAIRM1, an lncRNA linked to DNA repair, which interacts with BANF1 and p53 at double-strand break sites. The study demonstrates that HOTAIRM1 deficiency leads to impaired DNA repair and triggers p53-mediated senescence. Furthermore, in aged mouse lung models, AAV-mediated overexpression of HOTAIRM1 resulted in reduced fibrosis and tissue damage, highlighting its potential as a therapeutic target for age-related diseases.

This research shifts the paradigm in aging biology by emphasizing the therapeutic potential of lncRNAs, particularly in the context of cellular senescence and tissue regeneration. The identification of lncRNAs as modulators of DNA repair mechanisms opens avenues for drug development focused on enhancing tissue repair and combating age-related fibrosis. As such, this study could accelerate the timeline for developing novel therapies aimed at improving healthspan and mitigating the effects of aging.

Source: nature.com