Researchers here outline recent discoveries relating to changes in the endoplasmic reticulum inside cells that occur over the course of aging. All cellular machinery falters with age due to accumulating damage, and the primary goal of the research community remains to catalog and fully understand these changes, with doing something about coming it a distant second where it is a focus at all. The endoplasmic reticulum is the site of protein synthesis, and since all cellular machinery is built out of proteins, it is not unreasonable to look for links between changes in the endoplasmic reticulum - and its many component parts - and the disruption of proteostasis in aging. In older tissues there are many more broken and misfolded proteins, and this may turn out to have as much to do with issues in production as with issues in quality control and damage repair.
Each cell consists of different compartments. One of them is the endoplasmic reticulum (ER). Here, proteins which are then secreted e.g. into the bloodstream, such as insulin or antibodies of the immune system, mature in an oxidative environment. A type of quality control, so-called redox homoeostasis, ensures that the oxidative milieu is maintained and disulphide bridges can form. Disulphide bridges form and stabilise the three-dimensional protein structure and are thus essential for a correct function of the secretory proteins, e.g. those migrating into the blood. Researchers have now shown that the ER loses its oxidative power in advanced age, which shifts the reducing/oxidising equilibrium - redox for short - in this compartment. This leads to a decline in the capacity to form the disulphide bridges that are so important for correct protein folding. As a consequence, many proteins can no longer mature properly and become unstable.Although, it was already known that increased protein misfolding occurs with the progression of ageing, it was not known whether the redox equilibrium is affected. Likewise, it was not known that the loss of oxidative power in the ER also affects the equilibrium in another compartment of the cell: in reverse, namely, the otherwise protein-reducing cytosol becomes more oxidising during ageing, which leads to the known oxidative protein damage such those caused by the release of free radicals. "Up to now, it has been completely unclear what happens in the endoplasmic reticulum during the ageing process. We have now succeeded in answering this question." At the same time, the scientists were able to show that there is a strong correlation between protein homoeostasis and redox equilibrium. "This is absolutely new and helps us to understand why secretory proteins become unstable and lose their function in advanced age and after stress. This may explain why the immune response declines as we get older. We gained a lot of insight, but have also learned that ageing is much more complex than previously assumed." Thus, for example, the mechanism of the signal transduction of protein folding stress to the redox equilibrium - both within the cell from one compartment to another and also between two different tissues - remains completely unclear.
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