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Regulation of gene expression by small non-coding RNAs, such as miRNAs and siRNAs, is an inherent part of complex biological processes that allow function and survival of eukaryotic cells. The type III ribonuclease DICER is widely recognized as a key step in the production of miRNAs and siRNAs, although it also has non-canonical functions such as DNA repair and induction of apoptosis. DICER is at the cornerstone of most biological processes; hence, its mRNA and protein levels are subject to multiple layers of regulation. Accordingly, DICER derangement is related to disease and leads to accelerated aging. Interventions that boost DICER function hold great potential as strategies to promote health and longevity. In this review, we will summarize the structural features of DICER, describe its canonical and non-canonical roles, and discuss the most common regulatory mechanisms having an impact on DICER abundance and function. We will also touch upon the current literature demonstrating that DICER deregulation can lead to diseases, thus highlighting the importance of DICER in warranting the beneficial effects of health-promoting interventions.

Intertissue RNA transport has emerged as a novel signaling mechanism. InC. elegans, this is conferred by the systemic RNAi pathway, in which the limiting step is the cellular import of extracellular RNAs via SID-1. To better understand the physiological role of systemic RNAiin vivo, we modified the function of SID-1 through loss-of-function mutation and tissue-specific overexpression ofsid-1inC. elegans. We observed thatsid-1loss-of-function mutants are as healthy as wild-type worms. Conversely, overexpression ofsid-1in intestine, muscle, or neurons rendered worms short-lived. The effects of intestinalsid-1overexpression were reversed by silencing the components of the systemic RNAi pathwaysid-1, sid-2andsid-5, thus implicating RNA transport. Moreover, silencing the miRNA biogenesis proteinspash-1anddcr-1rendered the lifespan of worms with intestinalsid-1overexpression similar to controls. Lastly, we observed that the lifespan decrease produced by tissue-specificsid-1overexpression was dependent on the bacterial food source. Collectively, our data support the notion that systemic RNA signaling is tightly regulated, and unbalancing that process provokes a reduction in lifespan.

Resumo O conceito de terapia angiogênica surgiu no início da década de 90, o que pode ser feito com genes que codificam fatores de crescimento para promover a formação de novos vasos e o remodelamento de vasos colaterais. Como o procedimento dessa terapia geralmente consiste em apenas injeções locais de vetores, esse processo é pouco invasivo, rápido e de simples realização. Entretanto, desde as primeiras evidências clínicas do efeito de terapia gênica com o fator de crescimento de endotélio vascular (vascular endothelial growth factor, VEGF) vistos nos pacientes com doença arterial obstrutiva periférica até hoje, apenas dois fármacos de terapia angiogênica foram aprovados, um na Rússia e outro no Japão, o que parece um número muito pequeno diante do grande número de investimentos feitos por meio de estudos pré-clínicos e clínicos. Afinal, podemos considerar que a terapia angiogênica já é uma realidade? Abstract The concept of angiogenic therapy emerged in the early 1990s. The method employs genes that encode growth factors to promote formation of new vessels and remodeling of collateral vessels. Since the procedure involved in this therapy usually only consists of local injections of vectors, the process is minimally invasive, quick, and simple to perform. However, since the first clinical evidence of the effects of gene therapy with vascular endothelial growth factor (VEGF) was observed in patients with peripheral artery disease, to date only two angiogenic therapy drugs have been approved, one in Russia and another in Japan, which seem a very small number, in view of the large volume of investment made in pre-clinical and clinical studies. After all, can we conclude that angiogenic therapy is a reality?