Two more geroprotectors?
New potential "drugs for old age" suppress the production of heat shock proteins in cells
Maria Perepechaeva, "First-hand Science"
There is an opinion among scientists that aging is not so much a natural process as a disease. And the disease can be treated! For example, today researchers can already slow down aging in some organisms, such as nematodes, one of the favorite model objects for gerontological research. But what is good for a worm or a mouse may not work on humans, despite the fact that it is much more difficult to study the aging process in humans. But now scientists have developed a technique that allows testing potential geroprotectors on cell cultures, and have already discovered something new.
The dream of any person who has exchanged more than a dozen years is geroprotectors, "medicines for old age". But the search for such substances that can slow down the inexorable passage of time is fraught with a number of difficulties. It would seem that there is an easy way out – to use human cell cultures for experiments, but our body is more than a simple collection of different cells and tissues. So until recently, it was unclear how it was possible to study the complex multilevel aging process of an entire organism on individual cells.
The solution to this problem was suggested by the results of a recently published work, according to which the age of a person fairly accurately reflects the so–called transcriptome - the totality of all RNA molecules synthesized by the cell at the moment. (For those who forgot: ribonucleic acid (RNA) – the closest "relative" of DNA – serves as a matrix for protein synthesis and performs a number of other service functions, and a variety of non-coding RNAs are the main regulators of genes and genetic ensembles).
Therefore, researchers from Europe's largest medical university – the Swedish Karolinska Institute – turned to the project database Genotype-Tissue Expression containing a set of transcriptomes of donor tissues of different genders and ages. Using machine learning methods, they created a computer algorithm capable of distinguishing between "young" and "old" transcriptomes, as well as evaluating the geroprotective potential of certain substances when they affect the cell.
Applying this tool to the results of experiments on the effects of 1309 different compounds on human cell cultures, they were able to identify three dozen candidates for geroprotectors, including previously known ones. All candidate substances were tested on the same nematodes (roundworms) C.elegans, a favorite object for research. As a result, the effectiveness of already known geroprotectors, including the immunosuppressant rapamycin, as well as two new ones, monorden and tanespimycin, belonging to the group of heat shock protein 90 (Hsp90) inhibitors, was confirmed. These two compounds increased both the life expectancy of the subjects and their overall activity, which is considered as an indicator of health.
What can be associated with the noticeable geroprotective properties of these compounds? It is known that heat shock proteins have chaperone activity, i.e. the ability to bind to other molecules, stabilizing them. Even on the ribosome (protein factory), they bind to the growing protein chains of future proteins, protecting them from sticking and disintegration, and help to fold into the correct three-dimensional structure. Heat shock proteins are actively synthesized in the cell when exposed to high temperature and other stressful factors, giving it the opportunity to "survive" adverse conditions.
The Hsp90 protein is one of the most common members of this important family. Normally, it is associated with Hsf-1, the transcription factor of heat shock proteins, which, as the name suggests, activates the synthesis of the corresponding proteins in the cell when stress acts on the cell. However, neither is active in the complex. When monordene or tanespimycin is attached to Hsp90, Hsf-1 is released and begins its work.
Interestingly, the geroprotective effect of these compounds on humans may be even higher than on nematodes: it is known that Hsp90 inhibitors are able to suppress chronic inflammation, which plays an important role in our aging, as well as selectively cause the death of aging cells as senolytics.
Thus, inhibition of the Hsp90 protein can affect the cell through different mechanisms simultaneously. These substances are already being tested in clinical trials as anti-cancer drugs, and in the light of new data, they should also be tested as "anti-aging pills".
Article by Janssens et al. Transcriptomics-Based Screening Identifies Pharmacological Inhibition of Hsp90 as a Means to Defer Aging published in the journal Cell Reports.
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