04 August 2015

A new reason has been added to aging


Doctors and biologists still do not know all the reasons, although many readers will surely remember the most famous theories of aging, which talk about telomeres and mitochondria. 

On the one hand, it is known that the telomeric regions protecting the ends of chromosomes shorten with each division, so that the cell can freely divide a limited number of times, after which important genes adjacent to the bare chromosomal ends will begin to be damaged. And the aging process is partly associated with the shortening of telomeres. On the other hand, cellular mitochondria, although they provide us with energy, as a side effect serve as an inexhaustible source of aggressive oxidizing molecules - oxygen radicals that damage proteins, DNA, membrane lipids and other biomolecules. Usually the cell has something to counteract oxidative stress, but over time the antioxidant mechanisms weaken (a separate question, of course, why they weaken), and oxidative stress becomes stronger, at the level of the body becoming the cause of age-related diseases. 

However, as we know, everything is interconnected in living matter, and it would be strange if the aging processes originated in separate parts of the cell, without affecting its other departments. As the experiments of Janine Kirstein from the Leibniz Institute of Molecular Pharmacology and her colleagues from Japan and the USA have shown, one of the most powerful "sources of aging", so to speak, is the endoplasmic reticulum, or endoplasmic network (ER, or ES). He (or she) is a complex branched network of membrane channels, cisterns and vesicles, and school biology textbooks say that on the membranes of the endoplasmic network, lined with ribosomes, protein molecules are synthesized and ready-made protein molecules are folded into the correct spatial conformation. 

The amino acids that make up the protein molecule interact with each other and with the surrounding solution, some attract, some repel, as a result, the polypeptide chain acquires a so–called tertiary structure - it collapses into an extremely complex tangle. It is in this form that a protein, whether it is an enzyme, a transporter protein, etc., can perform its function (for example, the active center of enzymes in which substrate molecules are cleaved or stitched together is formed as a result of spatial folding of the amino acid chain). 

One of the most well–known "staples" that helps the protein keep in a folded state is the covalent bond between sulfur atoms that are part of the amino acid cysteine. The resulting disulfide bridges can bring together rather distant sections of the polypeptide chain; and such connections are necessary for the functioning of a variety of proteins, including insulin and antibodies. 

Disulfide crosslinking is formed in the endoplasmic network, which has the necessary physical and chemical conditions. Redox potential (not to be confused with acidity!) in the system of membrane channels and cisterns, it is shifted to the oxidative side, so that sulfur atoms from cysteines can easily form a covalent bond between themselves. But, as the authors write in EMBO Journal (Kirstein et al., Proteotoxic stress and aging triggers the loss of redox homeostasis across cellular compartments), over time, the redox potential in the endoplasmic network loses oxidative abilities, which is why proteins stop folding and working as they should. 

This explains a lot: it is known, for example, that with age there are more and more incorrectly folded protein molecules, that many secretory proteins become unstable and cease to function at the slightest stress; even age-related weakening of immunity can be explained by a shift in the redox potential, since antibodies before leaving the cell cannot fix the desired spatial structure. (At the same time, the opposite happens in the surrounding cytoplasm: the oxidative potential of the medium increases and the notorious oxidative stress increases, due to which proteins deteriorate.) 

Irregularities in the work of the endoplasmic network can also occur under stress and lead to the same consequences – the accumulation of incorrectly folded protein molecules. It is worth remembering here that neurodegenerative diseases, such as Alzheimer's syndrome, Parkinson's syndrome, Huntington's syndrome, arise precisely because of proteins with an incorrect spatial structure. And here, too, according to the researchers, everything starts with problems in the redox potential of the endoplasmic network. Moreover, as it turned out, pathogenic protein molecules, appearing in some tissues, can cause changes in the redox potential of other tissues, thereby accelerating the aging process. 

In molecular and cellular biology, in fact, for quite a long time there has been the concept of ER stress (stress associated with the endoplasmic reticulum), when proteins with improper stacking suddenly begin to accumulate actively in the cell. New experiments have made it possible to link ER stress with aging processes and with physico-chemical malfunctions in the most important cellular organoid. Experiments were carried out on nematode worms, which were modified in such a way that it was possible to monitor changes in the redox potential in different parts of cells. However, given that protein synthesis and its folding occur in all organisms, there is every reason to believe that age-related changes in the endoplasmic network also occur in humans. 

Of course, all this only complicates the picture of aging, but, on the other hand, in biology there is almost never a "single main cause" of anything, you always have to consider a whole bunch of causes and effects. And the more we know here, the more accurately we will be able to determine the dynamics and stage of aging, and then, you see, we will somehow get to eternal youth. 

Portal "Eternal youth" http://vechnayamolodost.ru
04.08.2015
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