RNA Interference in Ageing Research – A Mini-Review

Abstract

Background: The search for genetic mechanisms affecting life-span and ageing represents an important part of ageing research, especially since the discovery of single-gene mutations with dramatic effects on these traits. Due to its relative ease of use and its power to specifically target arbitrary genes, RNA interference (RNAi) has rapidly been adopted as a technique for silencing gene expression. The feasibility of genome-wide RNAi screens potentially much simplifies the identification of novel ageing-related genes. Objective: In a review of applications of RNAi in ageing research with a focus on the model organisms Caenorhabditis elegans and Drosophila melanogaster and discussing recent technical developments, we aim to highlight the current and future impact of this technology in the field. Method: We show how RNAi has successfully been used to complement classic mutant studies. Moreover, we discuss the novel opportunities and challenges of an application of RNAi in genome-wide screens in D. melanogaster, which has become possible with the recent availability of a comprehensive transgenic RNAi library for the fly. We highlight, in particular, how the flexible control of RNAi induction can support the study of dynamic processes like ageing through specific experiments and the development of matching computational methods. In an overview of complementary approaches we discuss the challenge of extracting insight from the high-dimensional measurement datasets that are required for the study of dynamic effects and interaction dependencies. Conclusion: RNAi has emerged as a powerful tool for the study of ageing, allowing the further characterization of the roles of specific genes in the ageing process as well as the efficient identification of new genes implicated. RNAi has contributed to our understanding of age-related diseases especially by making genes amenable to manipulation for which mutants were not easily available. Recent developments enable genome-wide screens with unprecedented temporal and spatial control of RNAi induction. Specific RNAi time-course experiments provide an opportunity for the analysis of high-resolution gene expression profiles capturing the dynamics of ageing-relevant processes and gene interactions. Research exploiting new avenues opened by the growing RNAi toolbox will considerably contribute to the next steps in researching the genetics of ageing and age-related diseases.

Modeling human neurodegenerative diseases in transgenic systems

“…Aging as a comorbid process is believed to be the result of the gradual loss of metabolic and genetic assets necessary to preserve the integrity and functionality of all cellular components. It has been assumed (Minois et al 2010) that senescence is under the control of many genes (Ljubuncic and Reznick 2009), and is aVected by accumulation of deleterious somatic mutations (Best 2009). The factor of pleiotrophic antagonism has also been invoked whereby certain gene functions that may be beneWcial in early life may be deleterious as the organism ages (Williams 1957).…”

Down-regulation of HSP60 expression by RNAi increases lipopolysaccharide- and cerulein-induced damages on isolated rat pancreatic tissues

“…In particular, we use the siRNA (Chu and Rana 2008;Minois et al 2010;Wu et al 2005) against HSP60 in isolated and cultured rat pancreatic tissues to reduce the expression of HSP60, stimulate these tissues with cerulein and lipopolysaccharide (LPS), and observe what ensues and how. Our purpose is to determine if the HSP60 protective function is essential to pancreatic tissue in pathological conditions.…”

RNAi screening: new approaches, understandings, and organisms

“…Large‐scale in vivo RNAi in model systems has led to new insights into topics like obesity and aging, and, making the most of what can be done in vivo but not in cells, studies of complex behaviors such as nociception 3,98,99,101,112. RNAi requires little more than transcript annotations, a reagent library, and a method of delivery of reagents and consequently, genome‐scale in vivo RNAi screens are becoming possible in an increasing number of health‐relevant species 3.…”

“…In C. elegans , RNAi is systemic and heritable. Notable recent examples of genome‐wide C. elegans RNAi screens include studies of aging and obesity 13,98–101. Although methods for RNAi screening in C. elegans are well established, screening in this system is not without caveats.…”