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Aging is a prominent risk factor for neurodegenerative disease. Defining gene expression mechanisms affecting healthy brain aging should lead to insight into genes that modulate susceptibility to disease. To define such mechanisms, we have pursued analysis of  miR-34  mutants in  Drosophila . The  miR-34  mutant brain displays a gene expression profile of accelerated aging, and  miR-34  upregulation is a potent suppressor of polyglutamine-induced neurodegeneration. We demonstrate that  Pcl  and  Su(z)12 , two components of polycomb repressive complex 2, (PRC2), are targets of  miR-34 , with implications for age-associated processes. Because PRC2 confers the repressive H3K27me3 mark, we hypothesize that  miR-34  modulates PRC2 activity to relieve silencing of genes promoting healthful aging. Gene expression profiling of the brains of hypomorphic mutants in  Enhancer of zeste  ( E(z) ), the enzymatic methyltransferase component of PRC2, revealed a younger brain transcriptome profile and identified the small heat shock proteins as key genes reduced in expression with age.

MiR-34 inhibits polycomb repressive complex 2 to modulate chaperone expression and promote healthy brain aging