Circular RNAs are Enigmatic, and Grow in Number with Age

Large swathes of cellular biochemistry remain comparatively unexplored and uncategorized. Any process or cellular component discovered in the past twenty to thirty years still has, at the very least, sizable gaps in the body of knowledge relating to it. Cells as a whole are by no means fully understood at the detail level - and this is exactly why, if we want to see significant progress towards human rejuvenation in the next few decades, the approach taken has to be to reverse the known root causes of aging, while tampering as little as possible with the way in which cells work, and let the cells take care of everything else. Other approaches are based on altering the way in which cells operate. These require far too much new work and new knowledge in order to safely implement, or even understand how to produce effective results.

Today's topic is circular RNA (circRNA), a form of RNA quite prevalent in cells, but that was only discovered in the 1990s. These molecules are highly varied in form and function, and what exactly those functions might be remains largely unknown. Interestingly, the open access paper I'll point out today reports that circRNAs increase in number inside cells with advancing age, particularly in long-lived cells. Does that mean they are significant in aging? Perhaps, perhaps not. It is a topic to watch in the years ahead, but the research community is presently some distance removed from being able to answer questions of this sort regarding circRNAs. Work is still focused on the foundation of a basic understanding. The sort of extensive investigation of relationships and mechanisms that takes place for other forms of RNA still lies ahead for circRNAs.

Global accumulation of circRNAs during aging in Caenorhabditis elegans

Circular RNAs (circRNAs) have recently been identified as a natural occurring family of widespread and diverse endogenous RNAs. They are highly stable molecules mostly generated by backsplicing events from protein-coding genes. The expression trends of circRNAs are only recently emerging. Most circRNAs are derived from protein-coding genes, and thus one challenge in mapping and quantifying circRNAs is to distinguish reads that can be uniquely ascribed to circular molecules versus linear RNAs emanating from the same gene. Elements located within introns flanking circularizing exons play a role in promoting circRNA biogenesis, and several RNA binding proteins and splicing factors have been shown to influence circRNA expression.

Despite the current interest in circRNAs, their functions are only beginning to emerge. Recent reports have identified roles for circRNAs in regulating transcription, protein binding, and sequestration of microRNAs. Some circRNAs can be translated via cap-independent mechanisms to generate proteins. Moreover, circRNAs have been implicated in antiviral immunity, and expression patterns of circRNAs in the brain suggest that they might serve important functions in the nervous system.

Several RNA-seq studies have found that circRNAs are differentially expressed during aging. Over 250 circRNAs increased in expression within Drosophila head tissue between 1 and 20 days of age. Trends for increased circRNA expression have also been identified during embryonic/postnatal mouse development, suggesting that circRNA accumulation might begin early in development. We recently reported that circRNAs were biased for age-accumulation in the mouse brain. In hippocampus and cortex, ~5% of expressed circRNAs were found to increase from 1 month to 22 months of age, whereas ~1% decreased. This accumulation trend was independent of linear RNA changes from cognate genes and thus was not attributed to transcriptional regulation. CircRNA accumulation during aging might be a result of the enhanced stability of circRNAs compared to linear RNAs. Age-related deregulation of alternative splicing leading to increased circRNA biogenesis might also play a role.

C. elegans is a powerful model organism for studying aging. Previously, thousands of circRNAs were annotated from RNA-seq data obtained from C. elegans sperm, oocytes, embryos, and unsynchronized young adults. Here, we annotated circRNAs from very deep total RNA-seq data obtained from C. elegans at different aging time points and uncovered 575 novel circRNAs. A massive trend for increased circRNA levels with age was identified. This age-accumulation was independent of linear RNA changes from shared host genes. Our findings suggest that circRNA resistance to degradation in post-mitotic cells is largely responsible for the age-upregulation trends identified both here in C. elegans, and possibly in neural tissues of other animals.

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