Abstract
BackgroundA widespread modulation of gene expression occurs in the aging brain, but little is known as to the upstream drivers of these changes. MicroRNAs emerged as fine regulators of gene expression in many biological contexts and they are modulated by age. MicroRNAs may therefore be part of the upstream drivers of the global gene expression modulation correlated with aging and aging-related phenotypes.ResultsHere, we show that microRNA-29 (miR-29) is induced during aging in short-lived turquoise killifish brain and genetic antagonism of its function induces a gene-expression signature typical of aging. Mechanicistically, we identified Ireb2 (a master gene for intracellular iron delivery that encodes for IRP2 protein), as a novel miR-29 target. MiR-29 is induced by iron loading and, in turn, it reduces IRP2 expression in vivo, therefore limiting intracellular iron delivery in neurons. Genetically modified fish with neuro-specific miR-29 deficiency exhibit increased levels of IRP2 and transferrin receptor, increased iron content, and oxidative stress.ConclusionsOur results demonstrate that age-dependent miR-29 upregulation is an adaptive mechanism that counteracts the expression of some aging-related phenotypes and its anti-aging activity is primarily exerted by regulating intracellular iron homeostasis limiting excessive iron-exposure in neurons.
Highlights
A widespread modulation of gene expression occurs in the aging brain, but little is known as to the upstream drivers of these changes
The miR-29 family is present as two distinct genomic clusters that are both ubiquitously expressed and are enriched in the central nervous system (CNS) [13], in mature neurons [16]
We tested whether all three clusters exhibit an age-dependent transcriptional regulation by room temperature (RT)-qPCR
Summary
A widespread modulation of gene expression occurs in the aging brain, but little is known as to the upstream drivers of these changes. The miR-29 family is present as two distinct genomic clusters that are both ubiquitously expressed and are enriched in the CNS [13], in mature neurons [16]. Mutant mice lacking both clusters do not present evident abnormalities at birth, but they rapidly accumulate defects during post-. The miR-29 family was found to target Beta-Site APP-Cleaving Enzyme (BACE1) mRNA and to be downregulated in sporadic Alzheimer’s disease [23] All these data indicate that miR-29 plays a protective role in neurons and reduced miR-29 activity in adult life has detrimental effects
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