Eating less suppresses microRNA assassins in the brain

most fragile of tissues, with a population of structurally elaborate and metabolically demanding neurons that are seldom replenished during adulthood. Neurodegenerative disorders such as Alzheimer's disease (AD) and acute insults such as an ischemic stroke lead to seemingly irreparable damage that impairs cognitive and/or motor function. Considerable evidence suggests that the vulnerability of neurons to aging and associated disorders can be modified by environmental factors including dietary energy intake and exercise [1,2,3]. Energy (caloric) restriction (CR) and exercise induce the expression of neurotrophic factors, including brain-derived neurotrophic factor (BDNF), cytoprotective protein chaperones, and proteins that can prevent apoptosis. The mechanisms responsible for the neuro-protective effects of CR and exercise are mediated, in part, by changes in gene transcription [3]. However, new findings reported in this issue of Aging suggest a role for down-regulation of microRNAs (miRNAs) that target mRNAs encoding cell survival proteins in the beneficial effects of CR on the aging brain [4]. miRNAs are short non-coding RNAs that typically bind to scores of transcripts an inhibit translation of the targeted mRNA [5]. Khanna et al found that levels of three miRNAs (miR-34a, miR30e and miR181-a-1*) are significantly lower in brain tissue samples from old mice (24-28 months-old) that had been maintained on a CR diet (40% CR beginning at 4 months of age) compared to mice on the usual ad libitum diet. Interestingly, all three of these miRNAs were predicted to have at least one target site for Bcl2, an anti-apoptotic protein previously been shown to increase with CR. The authors confirmed the repressive action of Commentary these miRNAs on Bcl2. These changes in miRNA expression were validated in both cortical and hippocampal tissues, suggesting a more global repression of these miRNAs in the CNS due to CR. Although the authors chose to solely investigate Bcl2 as a target of these three miRNAs in mediating the beneficial effects of CR, eight additional shared mRNA targets were found using multiple target-prediction algorithms. One of these targets, cAMP response element binding protein 1 (CREB1), is an important activator of several immediate response genes that are critical to synaptic plasticity [6]. Repression of CREB1 by these three age-dependent miRNAs could play a role in the cognitive decline observed with aging. Additionally, huntingtin (Htt) is a predicted target of these miRNAs, and this possible interaction may play a role in the beneficial effects of dietary energy restriction in Htt mutant mice, a …