Further Investigation of the Endoplasmic Reticulum in Aging

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.

Link: http://www.alphagalileo.org/ViewItem.aspx?ItemId=155133&CultureCode=en


The authors seem to note that they don't know how misfolded protein amyloids lead to a loss of redox homestasis in the ER. I suppose that if you can clean up these intra-cellular amyloids, then this knowledge isn't really necessary.

Do these intra-cellular amyloids fall under the LysoSENS category? My understanding was that liposfuscin was proteins and other cellular junk that the lysosomes could not break down. This seems to be a slightly different case involving positive feedback where misfolded proteins lead to higher rates of protein misfolding.

Surely it is going to be very tough to develop drugs that break down misfolded intra cellular proteins while leaving the properly folded proteins alone?

Posted by: ji at August 3rd, 2015 9:30 AM

Since they don't know their cause, can this be a new type of SENS damage? If not, which damage could cause it?

Posted by: Antonio at August 3rd, 2015 9:37 AM

Reason, you've spent a lot of time talking about finding the "root cause". This is apparently it- or close to it. This could probably be categorized under the SENS model as #7, but it's the reason why all this intracellular crap keeps piling up.

Posted by: Slicer at August 3rd, 2015 11:05 AM

@Slicer: I'd be more inclined to believe it's a reaction to other forms of damage until such time as proven otherwise, mediated by redox status as the proximate cause, which changes because of gene expression, which in turn is reacting to the SENS damage list. If a linkage between this and other forms of damage can't be identified, then it is something that needs to be dealt with as fundamental.

Posted by: Reason at August 3rd, 2015 11:27 AM

Where do chaperones, which promote correct protein folding, fit into this? What of the unfolded protein response process? Most importantly, what is causing the loss of redox homeostasis: why is the normal oxidative environment of the ER not maintained as the cell ages?

Posted by: Dr Richard Wilson at September 22nd, 2015 4:07 AM
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