This open access review paper looks at stress granules in the context of aging. These are transient structures that form within cells, made up of a wide variety of biomolecules. There is a lot of information about stress granules in the literature, but a great deal of it is speculative. This is one of the less well explored areas of cellular biochemistry. Cells form these assemblies of under stressful conditions, and their function may be protective - perhaps a way to stash useful molecules and protect them from an aggressive upregulation of cellular maintenance activities, or perhaps a way to make those useful molecules more available to needed locations in the cell by putting a stockpile in close proximity.
There is evidence for stress granules to become abnormal in the cells of aged tissues, and this may be due to raised levels of misfolded or otherwise broken proteins and other forms of molecular waste. Whether the consequences are significant in comparison to other, better explored mechanisms of aging remains to be determined.
Stress granules (SGs) are membraneless assemblies. They form when cells experience stress conditions, and are thought to influence cellular signaling pathways, and mRNA function, localization, and turn over SGs are dynamic, complex, and variable assemblies, with composition and structure that can vary dramatically under different types of stresses, such as heat shock, oxidative stress, osmotic stress, nutrient starvation, and UV irradiation. SGs have two distinct layers with different components, functions, and dynamics: a stable inner core structure surrounded by a less dense shell layer. The components in the core structure are believed to be less dynamic, while the components in the shell layer are more dynamic.
Severe stress- and aging-related misfolded proteins could specifically accumulate and aggregate within SGs, which could alter SG composition, impair SG dynamics, and, finally, lead to aberrant conversion from a liquid-like to a solid-like state. Under mild stress conditions or normal growth conditions, the cellular chaperone machinery and degradation systems are sufficient to manage the surveillance of such aberrant interactions between RNA-binding proteins (RBPs) and other aggregation-prone proteins. In young cells, multiple cellular defense systems can protect the cells from being affected by damaging changes such as imbalanced cellular proteostasis and proteolysis, inappropriate covalent modifications, and lowered pH levels. In aged cells, however, age-dependent breakdown of such systems may lead to defects in maintaining normal SG assembly, dynamics, disassembly, and clearance. This in turn could lead to the subsequent onset of a barrage of diseases.
Further in-depth investigations will help to reveal the mechanisms underlying the interactions between SGs and aging. First of all, what are the components of SGs formed under chronic stress caused by aging-induced intracellular environmental changes? Dynamic analysis of changes in the properties of SGs and SG components during the aging process could provide vital clues on how aging influences SG formation. Whether these changes exert a synergistic effect that could accelerate aging will be an important question to be answered.
Moreover, it is known that aggregation-prone proteins can be recruited to SGs and that this could result in aberrant or persistent SGs during cellular stress and after the stress subsides. These aberrant SGs might induce a series of effects that can be attributed to reduced stress resistance with age. Such aberrant SGs may also act as seeds to facilitate the formation of irreversible mature protein aggregates in aged cells, further accelerating the decline of the cellular functions of these proteins. Thus, it seems that maintaining a proper SG dynamic might be a potential strategy to delay aging and increase lifespan. Two key questions that remain to be answered are as follows: (a) What kind of proteins are prone to form aggregates during aging? And (b) is aggregation triggered by interactions between aggregation-prone proteins and SG components?