title: Gain of survival signaling by down-regulation of three key miRNAs in brain of calorie-restricted mice.
abstract: The decline in cognitive robustness with aging can be attributed to complex genetic pathways involving many cellular dysfunctions, cumulative over time, precipitating in frailty and loss of wellness in the elderly brain. The size and health of the neuronal cell population determines cognitive robustness in mammals. A transgenic mouse model over-expressing Bcl-2 has been shown to rescue neurons from naturally occurring cell death (NOCD). Here we show that in the brain of calorie-restricted (CR) mice, there is an age-dependent decreased expression of microRNAs mmu-miR-181a-1*, mmu-miR-30e and mmu-miR-34a, with a corresponding gain in Bcl-2 expression, and decreases in pro-apoptosis genes such as Bax and cleavage of Caspases. Functional characterization shows that these miRNAs repress Bcl-2 expression by the 3'UTR reporter assays, accompanied by loss of this gene's endogenous expression, and a gain in pro-apoptosome-specific proteins. Over-expression of these miRNAs increases the rate of apoptosis, accompanied by a decline in Bcl-2 expression in miRNA-transfected mouse and human cell lines. We report here that down-regulation of miR-34a, -30e, and -181a permits their shared target gene expression (Bcl-2) to remain at a high level without post-transcriptional repression, accompanied by concomitant low levels of Bax expression and Caspase cleaving; this chain event may be a part of the underlying mechanism contributing to the gain in neuronal survival in long-lived CR-fed mice.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Louisville School of Medicine, Louisville, KY 40202, USA.
authors.forename: Amit
authors.initials: A
authors.lastname: Khanna
authors.forename: Senthilkumar
authors.initials: S
authors.lastname: Muthusamy
authors.forename: Ruqiang
authors.initials: R
authors.lastname: Liang
authors.forename: Harshini
authors.initials: H
authors.lastname: Sarojini
authors.forename: Eugenia
authors.initials: E
authors.lastname: Wang
mesh_terms: D020413:3' Untranslated Regions; D000375:Aging / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D031204:Caloric Restriction; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival; D015536:Down-Regulation; D015870:Gene Expression; D019254:Genes, bcl-2; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics*; D008954:Models, Biological; D015398:Signal Transduction; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D020413:3' Untranslated Regions; C551848:MIRN34a microRNA, mouse; D035683:MicroRNAs; D051028:bcl-2-Associated X Protein; C529100:mirn181 microRNA, mouse; D053148:Caspase 3; D053453:Caspase 9