Stress Granules are Required for Calorie Restriction Induced Longevity

The formation of stress granules in cells is an interesting topic. As the name might suggest, this behavior emerges in cells undergoing stress, such as lack of nutrients, heat, cold, and so forth. Stress granules are transient structures that form within cells, made up of a wide variety of biomolecules that are packed away in a complex manner. These structures may act as a repository for useful molecules, protecting them from aggressive recycling processes triggered by cellular stress, but their function is much debated and comparatively poorly understood.

Mild cellular stress exerts a beneficial hormetic effect, improving health and longevity by triggering greater activity of cellular maintenance processes such as autophagy. Autophagy acts to recycle damaged and unwanted cellular machinery, breaking down proteins, structures, and molecular waste. Calorie restriction is one of the better studied ways to induce mild stress, stress responses, and consequent extension of life in short-lived species. Researchers have demonstrated that upregulation of autophagy is key to that outcome.

In today's open access paper, the authors report that the formation of stress granules is also essential to extension of life via calorie restriction, at least in nematode worms. It reinforces the concept of stress granules as a necessary part of the overall response to stress, a protective mechanism that prevents vital molecular machinery from being broken down by increased recycling.

AMPK-mediated formation of stress granules is required for dietary restriction-induced longevity in Caenorhabditis elegans

Regulation of cellular homeostasis is pivotal for the survival of a cell. Highly conserved mechanisms have evolved which enable cells to cope with various environmental stresses that often disrupt cellular homeostasis. Sequestration of nontranslating mRNAs into stress granules (SGs) is one such mechanism that attenuates protein synthesis during stress. Stress granules are cytosolic assemblies consisting of nontranslating mRNAs, small 40S ribosomes, mRNA-associated translation initiation complexes, and RNA-binding proteins.

It has been suggested that the SGs function as triage sites redirecting mRNAs to either translation, sequestration, or degradation. Therefore, SG assembly represents a key role in protein and RNA homeostasis under adverse conditions and is a tightly regulated process. Not surprisingly, dysregulation of SG dynamic has recently been linked to various diseases, such as cancer, inflammatory, neurodegenerative, and neuromuscular diseases.

It has been previously demonstrated that SG formation enhances cell survival and stress resistance. However, the physiological role of SGs in organismal aging and longevity regulation remains unclear. In this study, we used markers to monitor the formation of SGs in Caenorhabditis elegans. We found that, in addition to acute heat stress, SG formation could also be triggered by dietary changes, such as starvation and dietary restriction (DR). We found that HSF-1 is required for the SG formation in response to acute heat shock and starvation but not DR, whereas the AMPK-eEF2K signaling is required for starvation and DR-induced SG formation but not heat shock. Moreover, our data suggest that this AMPK-eEF2K pathway-mediated SG formation is required for lifespan extension by DR, but dispensable for the longevity by reduced insulin/IGF-1 signaling.

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