Fight Aging!

Stress granules are a comparatively poorly understood portion of the processes that a cell uses to maintain its protein machinery and component structures. When cells are subject to mild stress or damage, whether it is due to radiation, heat, lack of nutrients, or other challenges, they upregulate the activity of both autophagy and the ubuiquitin-proteasome system. Autophagy involves flagging proteins and structures for disassembly, followed by transport to a lysosome packed with enzymes to break down molecules into component parts that can be reused. The ubuiquitin-proteasome system tags proteins with ubiquitin, allowing them to be drawn into a proteasome for disassembly into raw materials. In addition, cells also form stress granules, carefully packed assemblies of RNA that are presently thought to act as stockpiles that prevent vital molecules from being recycled too aggressively.

Upregulation of autophagy and proteasomal activity are both known to improve health and extend life in short-lived laboratory species. Functional autophagy in particularly is necessary for the life extension produced by calorie restriction. Recently, it was established that the existence of stress granules is also necessary in order for the mild nutrient stress of calorie restriction to extend healthy life span. Further, abnormal stress granule formation is observed in older individuals. This makes stress granules a target of interest in the development of therapies for a range of conditions. That said, as is the case for calorie restriction mimetic drugs, it seems unlikely that very large benefits for patients can be engineered atop this foundation. We know the outcome of calorie restriction in humans: health benefits, but no great extension of life span. Better and more direct strategies to address the cell and tissue damage of aging are needed.

Targeting stress granules: A novel therapeutic strategy for human diseases

A large portion of mRNA in mammalian eukaryotic cells completes transcription in the nucleus and is then transported to the cytoplasm for translation and expression. When eukaryotic cells are stimulated or disturbed, the mature mRNA in cells cannot be translated into proteins immediately. These temporarily untranslated mRNA or translation-stalled mRNA then polymerize with RNA-binding proteins (RBPs) to form messenger ribonucleoprotein (mRNP) granules without a membrane structure, known as Cajal bodies, stress granules (SGs), processing bodies (P-bodies), RNA transport granules, or germ granules.

While mRNP granule types are complex and diverse, there are three commonalities between mRNP granules: first, mRNP granules usually contain non-translated or poorly translated mRNA, and these mRNA can re-enter polysome for translation after cellular adaption or environmental recovery. Second, different mRNP granules may contain the same mRNA or RBP and these components can be relocated from one mRNP granule to another granule. Third, different mRNP granules can interact dynamically, involving docking, fusion, and becoming another mRNP granule after maturation.

mRNP granules have a very important effect on mRNA function and cell signalling, and are also closely related to diseases. One of the most studied mRNP granules is SGs. SGs are a type of dynamic granular substance formed of mRNA of stagnant translation and RBPs in the cytoplasm of eukaryotic cells, the formation of which is stimulated by various stresses including oxidative stress, heat shock, hypoxia, or viral infection. It is an adaptive regulatory mechanism that protects cells from apoptosis under adverse conditions.

SGs have been identified in many biological processes and diseases. The assembly and disassembly of SGs determine further storage, translation remodelling, or degradation of untranslated mRNA, which affect cell death or survival under specific conditions. In cancer treatment, on the one hand, the formation of SGs can lead to cell survival and increase cell resistance to chemotherapeutic drugs. The combined use of drugs that inhibit SG formation or promote SG disassembly with chemotherapeutic drugs may alleviate drug resistance. On the other hand, some drugs may enhance the effects of chemotherapy by inducing SG-mediated cell apoptosis. Furthermore, the persistence of stress particles leads to chronic SG formation and irreversible pathogenesis, for example in neurodegeneration and aging.

It is therefore possible that targeting chronic SGs that inhibit the abnormal aggregation of related SGs or promote SG clearance may be a novel therapeutic strategy in neurodegenerative diseases and other chronic diseases. The formation and the biological functions of SGs are complex. Many questions need to be answered by research and the development of SG-targeting drugs. (1) Studies on SGs are largely confined to cell culture and C. elegans because of the absence of a suitable in vivo mammalian model. Ideally, a mouse model will be developed that can directly assess stress particles in living animals and more intuitively present direct associations between SGs, drugs, and diseases. (2) The side effects of the long-term administration of SG-interfering agents remain unclear. (3) Most SG contents are not the direct target of small molecules. So, the identification of druggable targets in SGs will reveal new biological functions and mechanisms of SG biology. Thus, SGs deserve more in-depth research.