Aging involves the progressive accumulation of deleterious molecular changes that leads to age-related physiological declines and diseases. A newly appreciated class of non-coding RNAs are circular RNAs (circRNAs) that are expressed from nematodes to humans. RNA-seq studies have found that circRNAs accumulate during aging in mice and Drosophila, suggesting that these age-associated changes in circRNA expression may influence lifespan. C. elegans is a premier model organism for aging research with a relatively short lifespan, and has many advantages for investigating the regulation and function of circRNAs in organismal aging. We found for the first time that hundreds of circRNAs accumulate during C. elegans aging. Interestingly, circRNAs that are highly accumulated include those derived from genes that play a conserved role in lifespan regulation in both mammals and in C. elegans. Preliminary data found that mutations in conserved components of the nonsense-mediated decay (NMD) RNA surveillance pathway (e.g. smg-1/kinase smg-6/endonuclease) increases the expression levels of age-accumulated circRNAs. Given that NMD is a key pathway for RNA quality control and lifespan regulation in C. elegans, this collaborative proposal will test the hypothesis that NMD-mediated circRNA abundance contributes to aging.
In Aim 1, we propose to profile circRNAs in animals with defective NMD activity (e.g. smg-1/kinase, smg-2/Upf1 mutants), which are known to play a role in lifespan regulation. We expect that this global analysis will uncover specific NMD-regulated circRNAs, with circRNA abundance being negatively correlated with lifespan. In addition, we will elucidate the molecular mechanisms underlying NMD-mediated regulation of circRNAs during aging by examining circRNA degradation rates in mutant animals of smg-6 with defective endonuclease activity.
In Aim 2, we will delete and overexpress individual circRNAs derived from identified host longevity genes, and assess their effects on lifespan. Because the effects of aging on circRNA accumulation occurs in C. elegans, Drosophila and mice, and they all share conserved NMD components, determining how circRNA abundance is regulated by NMD activity in the C. elegans aging system is expected to be of general interest, and might be relevant to human aging.
Circular RNAs (circRNAs) accumulate during normal aging in C. elegans, Drosophila, and mice, and thus it is likely a molecular feature of aging across metazoan life. This project investigates the impact of removing individual circRNAs on lifespan of C. elegans, and seeks to determine whether a molecular surveillance pathway called nonsense-mediated decay influences circRNA age-accumulation. This work might be relevant to understanding how nonsense-mediated decay and circRNAs influence lifespan and disease susceptibility in humans.
