PSIX-14 Circulating microRNAs associated with inflammation in aging canines

Abstract Aging is associated with ‘inflammaging’ which is characterized by systemic chronic low-grade inflammation. The increase in circulating pro-inflammatory cytokines and chemokines contributes to adverse health conditions including chronic kidney disease, cancer, and cognitive dysfunction in aging canines. MicroRNAs (miRNAs) are small non-coding RNAs which bind to the target mRNAs to reduce their function. Depending on the target mRNAs, the miRNAs act as post-transcriptional silencers of gene expression including pro-inflammatory genes. miRNAs can regulate inflammation at different times including the initiation and progression phases. We investigated the expression profiles of circulating miRNAs in blood, collected from healthy canines housed at Hill’s animal colony, in young (n = 6, 2 to 3 yr) and old (n = 6, 10 to 11 yr). Gene expression was assessed in blood collected in PAXgene RNA tubes using Qiagen’s miCURY LNA PCR array. Data were analyzed using the ΔΔCt method normalized to miR-191. There was a significant increase in the levels of miR182-5p in older dogs when compared with young (1.44-fold; P < 0.05). Increased level of miR-182 has been reported in models of osteoarthritis in rodents. In addition, miR-182 is hypothesized to regulate inflammation by affecting FOXO3 production. Down regulation of FOXO3, a transcription factor, is implicated in several aging-related vascular diseases. There was an increase in miR-204-5p in older dogs (3.64-fold; P < 0.05). miR-204 has been reported to downregulate TRPML1, a gene involved in mitochondrial autophagy which is important to preserve mitochondrial function in aging. Interestingly, miR-204-5p has also been reported to have anti-inflammatory effects. Thus, the role of miR-204 in the aging process in canines is unclear. Genes that were significantly downregulated in older dogs include miR-181b (-1.60-fold) and miR-192-5p (-1.67 fold). Both miRNA-181b and miR-192 have tumor suppressor effects and downregulation of these miRNA may contribute to certain types of cancer including gastric tumors, gliomas, and pancreatic cancer. There was also a reduction in miR-146b in aging dogs compared with young (-1.36 fold, ns). As COX-2 and IL-1b can be negatively regulated by miR-146, an increase in inflammation is conceivable due to reduced levels of miR-146. Other miRNAs that were decreased more than 1.25-fold in aging dogs include miR-7, miR-15a, miR-17, miR-23a, miR-31, miR-103a, miR-133, miR-133b, miR-146b, miR-148a, miR-181a, miR-200b, miR-203a, miR-205, miR-210, miR-223, and miR-499a (all ns). Our results highlight, at the molecular level, the importance of profiling the circulating miRNAs that can affect inflammation in aging canines and are potential targets for nutritional intervention.