Increasing life span linked

to microRNA machinery

Published October 01 2017

Arrows indicate the edge of the intestine in C. elegans. The intestines shrink with age and are less wide in the older worm than the younger worm. courtesy of kyoto university

The Greek writer Plutarch advised, “Instead of using medicine, rather, fast a day.” Since his time, various scientific studies have provided evidence that fasting can promote well-being and increase lifespan in various organisms, such as yeast and mice. Still, the mechanisms underpinning this biological process remain elusive. Akiko Kogure and researchers at Kyoto University recently reported in the Journal of Biological Chemistry on the involvement of the microRNA machinery complex in extending lifespan through intermittent fasting. The study shows that fasting enhances microRNA machinery components as well as the expression levels of microRNAs in the roundworm Caenorhabditis elegans.

Health benefits derived from fasting include reduced rates of diabetes and cardiovascular disease, which are thought to play a role in slowing the rate of aging. Masaharu Uno, the corresponding author of the study, said, “Diet is closely related to aging. Eating too much shortens life expectancy, and restricting diet extends life expectancy.” Intermittent fasting is one example of diet restriction; others include caloric and protein restriction. “We Japanese have a slogan, ‘pin pin korori,’” Uno said, “‘Pin pin’ means a spry and energetic life, and ‘korori’ means sudden and painless death … Just restricting diet makes us live longer. This simplicity surprises us and brought us to study the mechanisms underlying dietary restriction-induced longevity.”

This study of intermittent fasting in C. elegans evaluated microRNAs, small noncoding RNAs that regulate gene expression post-transcriptionally as their main function. C. elegans provides a nice model to study aging because the lifespan, typically two to three weeks, allows for a short time frame to conduct many experiments and test a multitude of variables. In this study, the researchers tested a variety of knockdown and knockout conditions to probe the role of various miRNA machinery components. The miRNA pathway starts with a primary miRNA transcript that is cleaved and exported from the nucleus. In the cytoplasm, the pre-miRNA is processed by the enzyme Dicer to generate mature miRNAs that can form a complex with proteins, such as argonaute, to generate a miRNA-induced silencing complex, or miRISC, that functions to repress target genes.

In this work, the researchers observed considerable changes in components of miRISC under fasting conditions. For example, C. elegans mutants lacking miRISC components (e.g., alg-1, ain-1 and ain-2) showed a significant reduction in lifespan under intermittent fasting conditions. This suggests a role for miRISC in intermittent fasting-induced longevity. Also, a key player found to be upregulated upon intermittent fasting was Drosha/DRSH-1, a nuclease of the RNAse III family and an important miRNA-processing enzyme. The researchers’ studies involving null DRSH-1 mutants showed that intermittent fasting-induced longevity is completely inhibited.

“The mechanism of aging is one of the biggest outstanding questions in biology,” Uno said. Collectively, this study demonstrates for the first time that the miRNA machinery is activated upon intermittent fasting. This work provides a link between fasting and longevity at the miRNA level. Future work in mammals will help researchers to better understand this process and could lead to ways whereby we can extend lifespan and prevent age-related diseases.

Hailey Gahlon Hailey Gahlon is a senior scientist at ETH Zürich.