Date Published: July 05, 2017
Publisher: John Wiley and Sons Inc.
Author(s): Augusto Schneider, Joseph M. Dhahbi, Hani Atamna, Josef P. Clark, Ricki J. Colman, Rozalyn M. Anderson.
Caloric restriction (CR) is one of the most robust interventions shown to delay aging in diverse species, including rhesus monkeys (Macaca mulatta). Identification of factors involved in CR brings a promise of translatability to human health and aging. Here, we show that CR induced a profound change in abundance of circulating microRNAs (miRNAs) linked to growth and insulin signaling pathway, suggesting that miRNAs are involved in CR’s mechanisms of action in primates. Deep sequencing of plasma RNA extracts enriched for short species revealed a total of 243 unique species of miRNAs including 47 novel species. Approximately 70% of the plasma miRNAs detected were conserved between rhesus monkeys and humans. CR induced or repressed 24 known and 10 novel miRNA species. Regression analysis revealed correlations between bodyweight, adiposity, and insulin sensitivity for 10 of the CR‐regulated known miRNAs. Sequence alignment and target identification for these 10 miRNAs identify a role in signaling downstream of the insulin receptor. The highly abundant miR‐125a‐5p correlated positively with adiposity and negatively with insulin sensitivity and was negatively regulated by CR. Putative target pathways of CR‐associated miRNAs were highly enriched for growth and insulin signaling that have previously been implicated in delayed aging. Clustering analysis further pointed to CR‐induced miRNA regulation of ribosomal, mitochondrial, and spliceosomal pathways. These data are consistent with a model where CR recruits miRNA‐based homeostatic mechanisms to coordinate a program of delayed aging.
This study was conducted using fasted plasma from 10 male rhesus monkeys of ~25 years of age on control or CR diets for 17 years. Bodyweight and adiposity were lower in CR monkeys compared to controls, and insulin sensitivity was increased (P < 0.05; Table S1, Supporting information). Bodyweight and percent body fat were positively correlated with each other (r = 0.92, P = 0.0001), and both tended to be negatively correlated to insulin sensitivity (P = 0.06; P = 0.07, respectively). Total RNA was extracted from plasma, enriched for RNAs of <200 nucleotides, and sequenced at 1x50 base pair reads. On average, 11 676,740 ± 658 741 reads per sample were obtained. miRNAs represented ~15% of the aligned reads. Known and novel miRNAs were identified using miRDeep2. Genomic coordinates were assigned, and novel miRNAs were assigned by direct alignment to MacaM/rhemac8 (Zimin et al., 2014). This work was supported by NIH/NIA AG040178, AG047358, and the Glenn Foundation for Medical Research. JPC is a T32 Fellow NIH/NIA AG000213. The study was conducted with the use of resources and facilities at the William S. Middleton Memorial Veterans Hospital, Madison, WI. The authors report no conflict of interest financial or otherwise. Source: http://doi.org/10.1111/acel.12636