Difficulties of finding the pill of immortality (2)

Invertebrates as model systems for screening small molecules promoting longevity

(Continued. See the beginning of the article here.)

Due to various factors, especially the ease of genetic manipulation and the similarity of physiology with human physiology, mice have become the most popular mammalian model organism in the biology of aging. However, due to the high maintenance costs and the relatively long lifespan of mice, large-scale objective screening using this organism is not feasible. Based on the understanding that many signaling pathways associated with aging have been preserved during evolution even in very different species, short-lived invertebrate models have been used for such screening. Caenorhabditis elegans nematodes, characterized by a short lifespan of about 3 weeks, ease of cultivation and genetic manipulation, as well as well-described biological parameters, represent a very attractive model for chemical screening conducted to identify compounds that modulate life expectancy and age phenotypes. To date, the most extensive screening of life-extending small molecules has been conducted by Petrascheck et al., who analyzed the effect of 88,000 compounds on the longevity of nematodes. They identified 115 molecules that significantly increase the lifespan of these organisms. An interesting fact is that the structure of one of these compounds resembles the structure of an antidepressant that affects the signaling mechanism mediated by the neurotransmitter serotonin. Subsequently, they found that the serotonin receptor antagonist mianserin, also used as an antidepressant, when used at a certain concentration increases the lifespan of nematodes, presumably through mechanisms associated with a low-calorie diet. In the study of 19 compounds known to have an impact on human physiology, Evason et al. It was found that the anticonvulsant drugs ethosuximide, trimethadione and 3,3-dietil-2-pyrrolidinone in certain dosages delayed the manifestations of age-related changes and increased the life expectancy of C.elegans.

In search of mimetics of a low-calorie diet using a bioinformatic approach, Calvert et al. drugs that induce changes in gene expression similar to changes in expression associated with a low-calorie diet were analyzed and 11 small molecules with the desired property were identified. An interesting fact is that of the five drugs tested, four – rapamycin (at a dose of 10 microns), allantoin (250 microns), trichostatin A (100 microns) and LY-294002 (100 microns) – provided an increase in life expectancy and an increase in healthy life expectancy in wild-type C.elegans nematodes. However, they had no effect on the longevity of eat-2 mutants, which are a genetic model of a low-calorie diet. This indicates that the life-prolonging effect of these drugs is indeed mediated by mechanisms related to a low-calorie diet.

Alavez et al. published data according to which amyloid-binding compounds support protein homeostasis and increase the lifespan of C.elegans. Exposure to the amyloid-binding dye thioflavin T (ThT) at a dose of 50 or 100 microns on adult wild-type nematodes increased average life expectancy by 60% and maximum life expectancy by 43-78%. ThT therapy reduced beta-amyloid aggregation and preserved the integrity of muscle tissue in C.elegans with simulated Alzheimer's disease, which led to a decrease in the proportion of paralyzed worms. ThT-mediated suppression of protein aggregation and increased lifespan depended on molecular chaperones, autophagy, proteosomal function, heat shock protein proteostasis regulator-1 (HSF-1) and transcription factor SKN-1 24. Structurally similar to ThT compounds also increase the lifespan of nematodes by 40%, but at significantly lower concentrations than ThT. Moreover, exposure to other protein aggregates binding compounds, such as curcumin (100 microns) and rifampicin (10-100 microns) increased the lifespan of nematodes by 45%. These results highlight the importance of proteostasis in the lifespan and healthy lifespan of nematodes and provide further incentive in the development of proteostasis-supporting interventions to suppress the aging process and the development of age-related diseases.

Fruit flies of Drosophila melanogaster are another simple model suitable for screening potential anti-aging compounds. Researchers have at their disposal a wide variety of drosophila genetic lines with different lifespans suitable for validating the effectiveness of the compound in relation to different genetic profiles. Just like the nematodes C.elegans, drosophila have a short lifespan, and there are a large number of genetic tools that allow research into the mechanisms of action of promising compounds. The first study demonstrating the possibility of increasing life expectancy with the help of a chemical compound was conducted by Kang et al., who showed that the addition of 4-phenylbutyrate to the feed of flies – a drug that has many effects, including inhibiting histone deacetylase – at a dose of 5-10 mM significantly increased both median and maximum life expectancy, without adversely affecting mobility, stress resistance and reproductive function. A later study described the screening of protein kinase inhibitors for increasing the lifespan of fruit flies. 17 of the 80 tested inhibitors significantly increased life expectancy without affecting the amount of food consumed, which indicates the non-involvement of a low-calorie diet. In this regard, the results of a recent study conducted by Slack et al. indicate that the weakening of the activity of the RAS-Erk-ETS-mediated signaling mechanism leads to a decrease in the activity of the signaling pathway mediated by insulin/insulin-like growth factor, and provides an increase in the lifespan of fruit flies. Trametinib (1.56-15.6 microns), which is a highly specific MEK inhibitor that weakens signals below RAS, can increase the life expectancy of female fruit flies by 12% (p=1.92 × 10-10), and at higher doses (156 microns) improves survival at later stages of life. Trametinib effectively increases life expectancy even when added to the feed of middle-aged individuals. These and similar data for other drugs – an increase in the lifespan of mice with rapamycin therapy started in middle age, see below – indicate that anti-aging drugs can be effective for humans even when used in adulthood, which avoids their potential side effects on the development process.

Continuation: Mammalian Rapamycin Target Protein Inhibitor (mTOR)