Abstract
Recent evidence demonstrates that serum levels of specific miRNAs significantly change with age. The ability of circulating sncRNAs to act as signaling molecules and regulate a broad spectrum of cellular functions implicates them as key players in the aging process. To discover circulating sncRNAs that impact aging in the long-lived Ames dwarf mice, we conducted deep sequencing of small RNAs extracted from serum of young and old mice. Our analysis showed genotype-specific changes in the circulating levels of 21 miRNAs during aging [genotype-by-age interaction (GbA)]. Genotype-by-age miRNAs showed four distinct expression patterns and significant overtargeting of transcripts involved in age-related processes. Functional enrichment analysis of putative and validated miRNA targets highlighted cellular processes such as tumor suppression, anti-inflammatory response, and modulation of Wnt, insulin, mTOR, and MAPK signaling pathways, among others. The comparative analysis of circulating GbA miRNAs in Ames mice with circulating miRNAs modulated by calorie restriction (CR) in another long-lived mouse suggests CR-like and CR-independent mechanisms contributing to longevity in the Ames mouse. In conclusion, we showed for the first time a signature of circulating miRNAs modulated by age in the long-lived Ames mouse.
Highlights
MicroRNAs are small noncoding RNAs known to mediate different cellular functions through post-transcriptional regulation (Djuranovic et al, 2011)
To investigate potential relationships among circulating small RNAs and aging-related processes modulated in the long-lived Ames dwarf mice, we conducted deep sequencing of small RNAs extracted from serum of young and old mice
The second peak occurred at 30–33 nt and consisted of reads mapping to tRNA genes. This peak represents a class of tRNA-derived fragments previously described (Dhahbi et al, 2013b; Fig. 1a)
Summary
MicroRNAs (miRNAs) are small noncoding RNAs (sncRNAs) known to mediate different cellular functions through post-transcriptional regulation (Djuranovic et al, 2011). The tRNA halves class includes 50- and 30-tRNA halves that were first observed in stressed cultured cells where they are produced by cleavage of tRNAs near or at the anticodon loop with the ribonuclease Rny in Saccharomyces cerevisiae (Thompson & Parker, 2009b) and Angiogenin in higher eukaryotes (Fu et al, 2009; Yamasaki et al, 2009) They were later observed in unstressed human cells (Kawaji et al, 2008; Fu et al, 2009). The shorter tRFs were not detected at the sequencing depths we used in our studies of circulating sncRNAs
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