Simultaneous activation of the hydrogen sulfide biosynthesis genes (CBS and CSE) induces sex-specific geroprotective effects in Drosophila melanogaster.

Hydrogen sulfide (H2S) is one of the most important gasotransmitters that affect lifespan and provide resistance to adverse environmental conditions. Here we investigated geroprotective effects of the individual and simultaneous overexpression of genes encoding key enzymes of H2S biosynthesis - cystathionine-ß-synthase (CBS) and cystathionine-γ-lyase (CSE) on D. melanogaster model. Simultaneous overexpression of CBS and CSE resulted in additive (in males) and synergistic (in females) beneficial effects on median lifespan. Individual overexpression of CBS was associated with increased thermotolerance and decreased transcription level of genes encoding stress-responsive transcription factors HIF1 and Hsf, while individual overexpression of CSE was associated with increased resistance to paraquat. Simultaneous overexpression of both genes increased resistance to hyperthermia in old females or paraquat in old males. The obtained results suggest sex-specific epistatic interaction of CBS and CSE overexpression effects on longevity and stress resistance.

Transcriptomic Analysis of the Effect of Torin-2 on the Central Nervous System of Drosophila melanogaster.

Torin-2, a synthetic compound, is a highly selective inhibitor of both TORC1 and TORC2 (target of rapamycin) complexes as an alternative to the well-known immunosuppressor, geroprotector, and potential anti-cancer natural compound rapamycin. Torin-2 is effective at hundreds of times lower concentrations and prevents some negative side effects of rapamycin. Moreover, it inhibits the rapamycin-resistant TORC2 complex. In this work, we evaluated transcriptomic changes in D. melanogaster heads induced with lifetime diets containing Torin-2 and suggested possible neuroprotective mechanisms of Torin-2. The analysis included D. melanogaster of three ages (2, 4, and 6 weeks old), separately for males and females. Torin-2, taken at the lowest concentration being tested (0.5 µM per 1 L of nutrient paste), had a slight positive effect on the lifespan of D. melanogaster males (+4% on the average) and no positive effect on females. At the same time, RNA-Seq analysis revealed interesting and previously undiscussed effects of Torin-2, which differed between sexes as well as in flies of different ages. Among the cellular pathways mostly altered by Torin-2 at the gene expression level, we identified immune response, protein folding (heat shock proteins), histone modification, actin cytoskeleton organization, phototransduction and sexual behavior. Additionally, we revealed that Torin-2 predominantly reduced the expression of Srr gene responsible for the conversion of L-serine to D-serine and thus regulating activity of NMDA receptor. Via western blot analysis, we showed than in old males Torin-2 tends to increase the ratio of the active phosphorylated form of ERK, the lowest node of the MAPK cascade, which may play a significant role in neuroprotection. Thus, the complex effect of Torin-2 may be due to the interplay of the immune system, hormonal background, and metabolism. Our work is of interest for further research in the field of NMDA-mediated neurodegeneration.

Geroprotective potential of genetic and pharmacological interventions to endogenous hydrogen sulfide synthesis in Drosophila melanogaster.

Endogenous hydrogen sulfide (H2S) is a gasotransmitter with a wide range of physiological functions. Aging is accompanied by disruption of H2S homeostasis, therefore, interventions to the processes of H2S metabolism to maintain its balance may have geroprotective potential. Here we demonstrated the additive geroprotective effect of combined genetic and pharmacological interventions to the hydrogen sulfide biosynthesis system by overexpression of cystathionine-ß-synthase and cystathionine-γ-lyase genes and treatment with precursors of H2S synthesis cysteine (Cys) and N-acetyl-L-cysteine (NAC). The obtained results suggest that additive effects of genetic and pharmacological interventions to H2S metabolism may be associated with the complex interaction between beneficial action of H2S production and prevention of adverse effects of excess H2S production by Cys and NAC treatment.

Tissue-Specific Knockdown of Genes of the Argonaute Family Modulates Lifespan and Radioresistance in Drosophila Melanogaster.

Small RNAs are essential to coordinate many cellular processes, including the regulation of gene expression patterns, the prevention of genomic instability, and the suppression of the mutagenic transposon activity. These processes determine the aging, longevity, and sensitivity of cells and an organism to stress factors (particularly, ionizing radiation). The biogenesis and activity of small RNAs are provided by proteins of the Argonaute family. These proteins participate in the processing of small RNA precursors and the formation of an RNA-induced silencing complex. However, the role of Argonaute proteins in regulating lifespan and radioresistance remains poorly explored. We studied the effect of knockdown of Argonaute genes (AGO1, AGO2, AGO3, piwi) in various tissues on the Drosophila melanogaster lifespan and survival after the γ-irradiation at a dose of 700 Gy. In most cases, these parameters are reduced or did not change significantly in flies with tissue-specific RNA interference. Surprisingly, piwi knockdown in both the fat body and the nervous system causes a lifespan increase. But changes in radioresistance depend on the tissue in which the gene was knocked out. In addition, analysis of changes in retrotransposon levels and expression of stress response genes allow us to determine associated molecular mechanisms.

Polyphenols as Potential Geroprotectors.

Significance: Currently, a large amount of evidence of beneficial effects of diets enriched with polyphenols on various aspects of health has been accumulated. These phytochemicals have a geroprotective potential slowing down the pathological processes associated with aging and ensuring longevity. In this study, a comprehensive analysis was conducted to determine the adherence of individual polyphenols to geroprotector criteria. Data from experimental models, clinical trials, and epidemiological studies were analyzed. Recent Advances: Sixty-two polyphenols have been described to increase the life span and improve biomarkers of aging in animal models. They act via evolutionarily conserved molecular mechanisms, including hormesis and maintenance of redox homeostasis, epigenetic regulation, response to cellular damage, metabolic control, and anti-inflammatory and senolytic activity. Epidemiological and clinical studies suggest that certain polyphenols have a potential for prevention and treatment of various diseases, including cancer, metabolic disorders, and cardiovascular conditions in humans. Critical Issues: Among the reviewed phytochemicals, chlorogenic acid, quercetin, epicatechin, genistein, resveratrol, and curcumin were identified as compounds with the highest geroprotective potential. However, there is a lack of unambiguous information on the effectiveness and safety of polyphenols for increasing health span, preventing and treating aging-associated diseases in humans. Future Directions: Further research is needed to fully understand the effects of polyphenols considering their long-term consumption, metabolic modification and bioavailability, complex interactions between different groups of polyphenols and with other phytochemicals, as well as their effects on individuals with different health status. Antioxid. Redox Signal. 40, 564-593.

Deletions of the cystathionine-ß-synthase (CBS) and cystathionine-γ-lyase (CSE) genes, involved in the control of hydrogen sulfide biosynthesis, significantly affect lifespan and fitness components of Drosophila melanogaster.

The gasotransmitter hydrogen sulfide (H2S) is an important biological mediator, playing an essential role in many physiological and pathological processes. It is produced by transsulfuration - an evolutionarily highly conserved pathway for the metabolism of sulfur-containing amino acids methionine and cysteine. Cystathionine-ß-synthase (CBS) and cystathionine-γ-lyase (CSE) enzymes play a central role in cysteine metabolism and H2S production. Here we investigated the fitness components (longevity, stress resistance, viability of preimaginal stages, and reproductive function parameters) in D. melanogaster lines containing deletions of the CBS and CSE genes. Surprisingly, in most tests, CSE deletion improved, and CBS worsened the fitness. Lines with deletion of both CBS and CSE demonstrated better stress resistance and longevity than lines with single CBS deletion. At the same time, deletion of both CBS and CSE genes causes more serious disturbances of reproductive function parameters than single CBS deletion. Thus, a complex interaction of H2S-producing pathways and cellular stress response in determining the lifespan and fitness components of the whole organism was revealed.

Molecular mechanisms of exceptional lifespan increase of Drosophila melanogaster with different genotypes after combinations of pro-longevity interventions.

Aging is one of the global challenges of our time. The search for new anti-aging interventions is also an issue of great actuality. We report on the success of Drosophila melanogaster lifespan extension under the combined influence of dietary restriction, co-administration of berberine, fucoxanthin, and rapamycin, photodeprivation, and low-temperature conditions up to 185 days in w1118 strain and up to 213 days in long-lived E(z)/w mutants. The trade-off was found between longevity and locomotion. The transcriptome analysis showed an impact of epigenetic alterations, lipid metabolism, cellular respiration, nutrient sensing, immune response, and autophagy in the registered effect.