Geroscope – automated search for geroprotectors
Scientists have shifted the "menial work" of searching for eternal life to robots
MIPT Press Service
Russian scientists from MIPT, in collaboration with Insilico Medicine, commissioned by the Center for Biogerontology and Regenerative Medicine, developed the GeroScope algorithm to search for geroprotectors – means that increase life expectancy – and tested the ten substances found with its help. The work was published in the American peer-reviewed journal Aging (Aliper et al., In search for geroprotectors: in silico screening and in vitro validation of signalome-level mimetics of young healthy state)
The process of creating medicines takes years of hard work and millions of dollars. Especially if you are looking for a means to combat aging, a multifactorial biological mechanism of body change. Thanks to computer modeling, it is possible to significantly reduce the time and cost of development.
"The aging of the population is one of the global problems facing humanity. The development of effective approaches for the creation of geroprotectors and their validation in relation to humans is an urgent challenge for biomedicine. We have proposed a possible approach that brings us closer to solving this problem," commented Alexey Moskalev, Corresponding Member of the Russian Academy of Sciences and Head of the Laboratory of Genetics of Aging and Longevity at MIPT.
Previously, the Oncofinder algorithm was created, which is focused on studying and analyzing the activation values of molecular pathways based on a comparison of gene expression in cancer and non-cancer cells, as well as at the level of a patient tissue sample. Based on it, the researchers developed the GeroScope algorithm, which allows comparing changes in the cells of young and old patients and searching for drugs with minimal side effects that compensate for these changes.
To do this, transcriptomic data (information that is read from DNA and transferred to RNA) were analyzed in young (donors aged 15-30 years) and old (donors older than 60 years) cell samples. Based on the data obtained using computer modeling, scientists were able to construct molecular pathways associated with aging. Molecular pathways are a sequence of reactions that lead to changes in the cell. The most common molecular pathways are involved in metabolism, signal transmission. GeroScope has modeled molecular pathways and analyzed cell reactions to various substances. Having selected 70 compounds from the database of geroprotective drugs, scientists using a new algorithm identified 10 substances that could have geroprotective properties in accordance with the model.
The GeroScope system analyzed the tissues of young and old patients, as well as cell lines. For experimental confirmation of the algorithm, scientists took human fibroblast stem cell lines (connective tissue cells). Two effects were studied: "rejuvenation" of cells and prolongation of viability.
At the beginning of the experiment, the parameters of viable cells were measured: the size, shape and complexity of the internal structure of the cell were estimated, etc. Then the cells were mixed with the test substance and the life support medium and maintained in this state for 6, 12 and 18 days. After that, the same parameters were measured as at the beginning of the experiment, as well as the level of associated β‑galactosidase, which is considered one of the markers of aging.
According to the results of the experiment, the studied 10 substances selected at the stage of computer modeling showed different results. For example, NDGA does not affect rejuvenation, but shortens life expectancy, Myricetin slightly rejuvenates, but greatly undermines life expectancy, EGCG has a strong rejuvenating effect, but dramatically reduces life expectancy. NAC is a very light rejuvenation, but a sharp increase in life expectancy, PD-98059 is a strong both effect*.
The predictions made using computer modeling were confirmed in human fibroblast cell cultures for several substances: PP-98059, NAC, Myricetin and EGCG. Some of these drugs are already actively sold as dietary supplements.
"This is a very good result for computer modeling. In the pharmaceutical industry, 92% of drugs that have been tested on animals fail in clinical trials. Being able to model biological effects with such precision is a breakthrough. PD-98059 and NAC proved to be the strongest geroprotectors. We hope that some of these drugs will be tested in humans in the near future using biologically significant biomarkers of aging," commented Alexander Zhavoronkov, Ph.D., Head of the Laboratory of Regenerative Medicine of the D. Rogachev National Research Center for Pediatric Hematology, Oncology and Immunology, Associate Professor at MIPT, Head of Insilico Medicine (Center for Breakthrough Technologies, Johns Hopkins University).
Thus, scientists have created and conducted an experimental test of the GeroScope algorithm to search for geroprotectors. A high correlation of the algorithm operation with experimental data was shown. In the future, GeroScope will be used to search for yet unknown substances with geroprotective effects.
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02.12.2016