Ribosomes and aging
Protein cause found for aging
Kirill Stasevich, Science and Life (nkj.ru )
Aging is described in different ways, depending on whether we consider the body as a whole, individual organs, cells, or descend to the level of molecules. Accordingly, we get a whole set of causes of aging; if we look from the point of view of molecular biology and biochemistry, then this is the accumulation of mutations in DNA that the cell can no longer correct, and epigenetic modifications that change the activity of genes, and background oxidative stress, which increases due to the fact that antioxidant systems begin to work is getting worse, and the appearance of a large number of improperly folded proteins.
Of course, all these reasons are closely related to each other, in addition, the question always arises why this is happening, that is, what deeper reasons are there. For example, we said about incorrectly folded proteins. It is known that any protein works only in the desired spatial form: amino acids in the polypeptide chain interact with each other, tighten and twist different parts of the protein molecule, and as a result, the protein folds into a complex lump, or a complex thread, or a flat long sheet. But it happens that folding goes wrong, and the protein not only cannot perform its direct duties, it sometimes begins to harm: toxic complexes of incorrectly folded molecules form in the cell, because of which it begins to get sick and eventually dies. The most famous examples here are neurodegenerative diseases such as Alzheimer's disease. But in general, the accumulation of incorrectly folded proteins in the cell (not necessarily related to Alzheimer's disease, etc.) — one of the common signs of aging. Why are they accumulating?
The reason is not necessarily mutations that cause proteins to fold incorrectly. The cell has special garbage collection systems that timely rid it of such proteins — with age, such systems increasingly fail. Another explanation is changes in the redox potential where proteins fold, that is, in the endoplasmic network of the cell. Staff Stanford University offers another option — in an article in Nature (Stein et al., Aging exacerbates ribosome pausing to disrupt cotranslational proteostasis), they write that age-related defects in the folding (or folding) of protein molecules begin even during their synthesis on ribosomes.
As we know, ribosomes are large and complex molecular complexes that travel along the matrix RNA (mRNA) and assemble a polypeptide chain from amino acids. Ribosomes read the protein code copied from DNA into mRNA, and according to what they read, they take one or another amino acid and combine it with the previous one (there are many features and subtleties that we will now omit). A lot of ribosomes travel along one mRNA at the same time, and they travel quite fast. A growing polypeptide chain hangs from each ribosome, which begins to collapse as it grows: the synthesized protein tries to enter the correct, functional 3D conformation.
The researchers observed what happens to protein synthesis in aging yeast and nematode worms Caenorhabditis elegans. It turned out that with age, ribosomes begin to slow down periodically and often collide with each other (that is, the back catches up with the front). The appearance of a larger number of improperly folded protein molecules is precisely due to ribosomal inhibitions and collisions: amino acids in the growing polypeptide chain establish incorrect contacts with each other. And even if the proportion of improperly folded proteins is small — only about 10% of all synthesized polypeptide chains, this will already be enough for the garbage collection system to stop coping with them and non-working and dangerous protein molecules begin to accumulate in the cell. (Protein synthesis occurs on the membranes of the endoplasmic reticulum, so an explanation with redox imbalance can complement the overall picture.)
Since protein synthesis on ribosomes (or translation) — one of the most fundamental processes of life, and in all eukaryotes, which include worms, yeast, and humans, the translation is more or less similar, then most likely the same thing happens in aging human cells. However, another question arises here: why, in fact, do ribosomes begin to slow down with age? Each ribosome is a huge complex of several special RNAs and eight dozen proteins sitting on these RNAs; in addition, other service RNAs and proteins also participate in translation. Which of them is to blame for slowing down the ribosome and why? So far, there is no answer here. However, it is known that if yeast acquires mutations that prolong life — and some of these mutations are well studied — then yeast ribosomes return to normal. Probably, it is with these mutations that we can begin to decipher the mechanism of ribosome aging.
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