E. N. Plyusnina

Gadd45 proteins: relevance to aging, longevity and age-related pathologies.

The Gadd45 proteins have been intensively studied, in view of their important role in key cellular processes. Indeed, the Gadd45 proteins stand at the crossroad of the cell fates by controlling the balance between cell (DNA) repair, eliminating (apoptosis) or preventing the expansion of potentially dangerous cells (cell cycle arrest, cellular senescence), and maintaining the stem cell pool. However, the biogerontological aspects have not thus far received sufficient attention. Here we analyzed the pathways and modes of action by which Gadd45 members are involved in aging, longevity and age-related diseases. Because of their pleiotropic action, a decreased inducibility of Gadd45 members may have far-reaching consequences including genome instability, accumulation of DNA damage, and disorders in cellular homeostasis - all of which may eventually contribute to the aging process and age-related disorders (promotion of tumorigenesis, immune disorders, insulin resistance and reduced responsiveness to stress). Most recently, the dGadd45 gene has been identified as a longevity regulator in Drosophila. Although further wide-scale research is warranted, it is becoming increasingly clear that Gadd45s are highly relevant to aging, age-related diseases (ARDs) and to the control of life span, suggesting them as potential therapeutic targets in ARDs and pro-longevity interventions.

Increase of Drosophila melanogaster lifespan due to D-GADD45 overexpression in the nervous system.

The GADD45 protein family plays an important role in stress signaling and participates in the integration of cellular response to environmental and physiological factors. GADD45 proteins are involved in cell cycle control, DNA repair, apoptosis, cell survival and aging, and inflammatory response by complicated protein–protein interactions. In Drosophila melanogaster a single D-GADD45 ortholog (GG1086) has been described. Our data show that overexpression of the D-GADD45 gene in the nervous system leads to a significantly increase of Drosophila lifespan without a decrease in fecundity and locomotor activity. The lifespan extension effect is more pronounced in males than in females, which agrees with the sex-dependent expression of this gene. The longevity of D. melanogaster with D-GADD45 overexpression is apparently due to more efficient recognition and repair of DNA damage, as the DNA comet assay showed that the spontaneous DNA damage in the larva neuroblasts is reduced with statistical significance.

The role of D-GADD45 in oxidative, thermal and genotoxic stress resistance

There is a relationship between various cellular stress factors and aging. In earlier studies, we demonstrated that overexpression of the D-GADD45 gene increases the life span of Drosophila melanogaster. In this study, we investigate the relationship between D-GADD45 activity and resistance to oxidative, genotoxic and thermal stresses as well as starvation. In most cases, flies with constitutive and conditional D-GADD45 overexpression in the nervous system were more stress-resistant than ones without overexpression. At the same time, most of the studied stress factors increased D-GADD45 expression in the wild-type strain. The lifespan-extending effect of D-GADD45 overexpression was also retained after exposure to chronic and acute gamma-irradiation, with doses of 40 сGy and 30 Gy, respectively. However, knocking out D-GADD45 resulted in a significant reduction in lifespan, lack of radiation hormesis and radioadaptive response. A dramatic decrease in the spontaneous level of D-GADD45 expression was observed in the nervous system as age progressed, which may be one of the causes of the age-related deterioration of organismal stress resistance. Thus, D-GADD45 expression is activated by most of the studied stress factors, and D-GADD45 overexpression resulted in an increase of stress resistance.

The effects of pectins on life span and stress resistance in Drosophila melanogaster

The composition of diet is one of the major determining factors for lifespan. The dietary pectins are known to have anti-inflammatory properties and may influence aging and longevity. Here we demonstrate the lifespan-extending effect of the low methyl esterified (LM) commercial pectins CU701 and AU701 in wild-type strain of Drosophila melanogaster. The high methyl esterified (HM) pectin CU201 did not affect lifespan. LM pectin did not increase lifespan of males with a mutation in the Toll adaptor Myd88 gene and in both males and females with a mutation in the NF-κB ortholog Relish. LM pectin CU701 increased imagoes survival in stress conditions (oxidation, hyperthermia and starvation). However, the fertility of LM and HM pectins treated flies decreased. The treatment of the imagoes with LH and HM pectins induced the activation of whole-body expression of genes involved in DNA repair (D-GADD45, mei-9, spn-B), apoptosis (wrinkled/hid) and heat shock response (hsp70Aa). In contrast, the expression of proinflammatory PARP-1 gene decreased. In the intestines LH and HM pectins induced the mRNA expression of the NF-κB-dependent antimicrobial genes Defensin, Drosomycin and Metchnikowin. These results indicate that the observed lifespan-extending effect of the LM pectins may be mediated by intracellular pathways that involve NF-κB signalling and activation of stress resistance genes.

Geroprotective Effects of Activation of D-GADD45 DNA Reparation Gene in Drosophila Melanogaster Nervous System

The expre ssion of D-GADD45 gene involved in DNA reparation in Drosophila melanogaster decreases with age. Overexpression of D-GADD45 in the drosophila nervous system prolongs the median and maximum life span without deterioration of the quality of life parameters (fertility and neuromuscular activity). The life span prolongation effect is due to more effective DNA reparation, as spontaneous level of DNA aberrations in the nerve tissue of larvae with D-GADD45 overexpression is reduced signifi cantly.

Exhaustive data mining comparison of the effects of low doses of ionizing radiation, formaldehyde and dioxins

BackgroundIonizing radiation in low doses is the ubiquitous environmental factor with harmful stochastic effects. Formaldehyde is one of the most reactive household and industrial pollutants. Dioxins are persistent organic pollutants and most potent synthetic poisons effective even at trace concentrations. Environmental pollutants are capable of altering the expression of a variety of genes. To identify the similarities and differences in the effects of low-dose ionizing radiation, formaldehyde and dioxin on gene expression, we performed the bioinformatic analysis of all available published data.ResultsWe found that that in addition to the common p53-, ATM- and MAPK-signaling stress response pathways, genes of cell cycle regulation and proinflammatory cytokines, the studied pollutants induce a variety of other molecular processes.ConclusionsThe observed patterns provide new insights into the mechanisms of the adverse effects associated with these pollutants. They can also be useful in the development of new bio-sensing methods for detection of pollutants in the environment and combating the deleterious effects.

Influence of preparations containing phytoecdysteroids and plant steroid glycosides on the life span and stress resistance of Drosophila melanogaster

The clarification of the molecular mechanisms of the effect of a plant adaptogen’s active substance is a topical study direction. In the present work, we studied the effect of phytopreparations containing the Serratula coronata L. phytoecdysteroids (20-hydroxyecdysone and inocosterone) or the Trigonella foenumgraecum L. steroid glycosides (dioscin and protodioscin) on the expression of stress-response genes, stress resistance, and the life span of the Drosophila melanogaster. It was demonstrated that phytopreparations activate the mechanisms of antioxidant protection (Sod1), but reduce the level of induction of DNA repair (XPF and Rad51) and the apoptosis (Hid) genes. At the same time, the studied phytopreparations have a moderate adaptogenic and geroprotective effects associated with activation of the hormesis mechanisms.

The analysis of the survivorship curves in Drosophila melanogaster with D-GADD45 overexpression

It is well known that GADD45 overexpression in the nervous system leads to the increased longevity in Drosophila. In this study, we performed an approximation of survivorship curves in Drosophila with GADD45 overexpression using the Gompertz distribution. We showed that the life span prolongation is caused by the alteration of R parameter, reflecting the mortality rate at the beginning of adult life, and not by the alteration of another Gompertz distribution parameter, α, reflecting the exponentially growing mortality rate. In addition, we analyzed the survivorship curves in the case of radiation hormesis (the phenomenon of life span extension under the exposure to low doses of radiation) and confirmed the regularity stated above. On the basis of this regularity, we concluded it promising to search for geroprotectors among the substances decreasing the R parameter, which is easier to assess than the full survivorship curve.