Search Results (7)

Background: Chlorophyll (Chl), widespread in fruits and vegetables, has been shown to have numerous nutritional functions, including beneficial effects on obesity. However, whether Chl has an anti-aging effect remains unclear. Methods: Here, we studied the beneficial effects and mechanism of Chl on delaying aging using a Drosophila model. Results: The results showed that dietary supplementation of Chl in an appropriate dose (3.925 mg/L) significantly extended the lifespan (7.66–13.94%), improved climbing ability, increased CAT activity, reduced MDA content, enhanced stress resistance to starvation, heat stress, and cold shock in Drosophila. Notably, lifespan extension was not associated with dietary restriction, reproductive sacrifice, or circadian rhythm regulation. RNA-Seq analysis showed that Chl supplementation led to differential expression of 723 genes in female flies and 435 genes in male flies. KEGG analysis revealed that these differentially expressed genes were significantly enriched in the xenobiotic metabolism (XM) pathway. Within this pathway, phase II detoxifying enzyme genes associated with the CncC (Nrf2) signaling pathway (GstD10, GstE7, Ugt37A3, and AOX2) were significantly downregulated in both sexes. In contrast, protective target genes from the same pathway (cat, Mrp4, Hsp68) were significantly upregulated, as confirmed by qPCR. Conclusions: Taken together, our data indicate that Chl supplementation delays aging in Drosophila melanogaster via enhanced stress resistance and remodeling of the detoxification network. Full article

The probiotic bacteria Lactobacillus fermentum ZC529 (L.f ZC529) has been identified from the colon of the Diannan small-ear (DSE) pig, but its intestinal protective function still lacks investigation. Here, we established a dextran sodium sulfate (DSS)-induced intestinal oxidative stress model in both Drosophila and porcine small intestinal epithelial (IPEC-J2) cell lines to explore the anti-oxidative and anti-inflammatory effects of L.f ZC529. The data showed that the intestinal colonization of L.f ZC529 counteracted DSS-induced intestinal oxidative stress and excessive reactive oxygen species (ROS) generation by activation of the CncC pathway, a homology of the nuclear factor erythroid 2-related factor 2 (Nrf2) in mammalian systems. Moreover, L.f ZC529 supplementation prevented flies from DSS-induced intestinal barrier damage, inflammation, abnormal excretory function, and shortened lifespan. Finally, L.f ZC529 also attenuated DSS-induced intestinal injury in the IPEC-J2 cell line by activating the Keap1-Nrf2 signaling and inhibiting the NF-κB signaling pathways. Together, this study unraveled the profound intestinal protective function of L.f ZC529 and provides its potential application as a new antioxidant in improving animal intestinal health as well as in developing a new probiotic in the food industry. Full article

The modulation of insulin/insulin-like growth factor signaling (IIS) is associated with altered nutritional and metabolic states. The Drosophila genome encodes eight insulin-like peptides, whose activity is regulated by a group of secreted factors, including Ecdysone-inducible gene L2 (ImpL2), which acts as a potent IIS inhibitor. We recently reported that cncC (cncC/Nrf2), the fly ortholog of Nrf2, is a positive transcriptional regulator of ImpL2, as part of a negative feedback loop aiming to suppress cncC/Nrf2 activity. This finding correlated with our observation that sustained cncC/Nrf2 overexpression/activation (cncC^OE; a condition that signals organismal stress) deregulates IIS, causing hyperglycemia, the exhaustion of energy stores in flies’ tissues, and accelerated aging. Here, we extend these studies in Drosophila by assaying the functional implication of ImpL2 in cncC^OE-mediated metabolic deregulation. We found that ImpL2 knockdown (KD) in cncC^OE flies partially reactivated IIS, attenuated hyperglycemia and restored tissue energetics. Moreover, ImpL2 KD largely suppressed cncC^OE-mediated premature aging. In support, pharmacological treatment of cncC^OE flies with Metformin, a first-line medication for type 2 diabetes, restored (dose-dependently) IIS functionality and extended cncC^OE flies’ longevity. These findings exemplify the effect of chronic stress in predisposition to diabetic phenotypes, indicating the potential prophylactic role of maintaining normal IIS functionality. Full article

Nrf2 is the dominant cellular stress response factor that protects cells through transcriptional responses to xenobiotic and oxidative stimuli. Nrf2 malfunction is highly correlated with many human diseases, but the underlying molecular mechanisms remain to be fully uncovered. GATA4 is a conserved GATA family transcription factor that is essential for cardiac and dorsal epidermal development. Here, we describe a novel interaction between Drosophila Nrf2 and GATA4 proteins, i.e., cap‘n’collar C (CncC) and Pannier (Pnr), respectively. Using the bimolecular fluorescence complementation (BiFC) assay—a unique imaging tool for probing protein complexes in living cells—we detected CncC–Pnr complexes in the nuclei of Drosophila embryonic and salivary gland cells. Visualization of CncC–Pnr BiFC signals on the polytene chromosome revealed that CncC and Pnr tend to form complexes in euchromatic regions, with a preference for loci that are not highly occupied by CncC or Pnr alone. Most genes within these loci are activated by the CncC–Pnr BiFC, but not by individually expressed CncC or Pnr fusion proteins, indicating a novel mechanism whereby CncC and Pnr interact at specific genomic loci and coactivate genes at these loci. Finally, CncC-induced early lethality can be rescued by Pnr depletion, suggesting that CncC and Pnr function in the same genetic pathway during the early development of Drosophila. Taken together, these results elucidate a novel crosstalk between the Nrf2 xenobiotic/oxidative response factor and GATA factors in the transcriptional regulation of development. This study also demonstrates that the polytene chromosome BiFC assay is a valuable tool for mapping genes that are targeted by specific transcription factor complexes. Full article

Aging is the gradual deterioration of physiological functions that culminates in death. Several studies across a wide range of model organisms have revealed the involvement of FOXO (forkhead box, class O) transcription factors in orchestrating metabolic homeostasis, as well as in regulating longevity. To study possible dose- or tissue-dependent effects of sustained foxo overexpression, we utilized two different Drosophila transgenic lines expressing high and relatively low foxo levels and overexpressed foxo, either ubiquitously or in a tissue-specific manner. We found that ubiquitous foxo overexpression (OE) accelerated aging, induced the early onset of age-related phenotypes, increased sensitivity to thermal stress, and deregulated metabolic and proteostatic pathways; these phenotypes were more intense in transgenic flies expressing high levels of foxo. Interestingly, there is a defined dosage of foxo OE in muscles and cardiomyocytes that shifts energy resources into longevity pathways and thus ameliorates not only tissue but also organismal age-related defects. Further, we found that foxo OE stimulates in an Nrf2/cncC dependent-manner, counteracting proteostatic pathways, e.g., the ubiquitin-proteasome pathway, which is central in ameliorating the aberrant foxo OE-mediated toxicity. These findings highlight the differential dose- and tissue-dependent effects of foxo on aging, metabolic and proteostatic pathways, along with the foxo-Nrf2/cncC functional crosstalk. Full article

Sesamin, a major lignin in sesame seeds, possesses health-promoting properties. Sesamin feeding suppresses several aging-related phenotypes such as age-dependent accumulation of damaged proteins in the muscles and neuronal loss in the brains of Drosophila adults with high levels of reactive oxygen species. Sesamin promotes the transcription of several genes that are responsible for oxidative stress, although the underlying mechanism remains unclear. Here, we aimed to demonstrate that sesamin mediates its action through activation of a transcription factor, Nrf2 (Cnc in Drosophila), essential for anti-aging oxidative stress response. Nrf2/Cnc activation was determined using the antioxidant response element, Green Fluorescence Protein reporter, that can monitor Nrf2/Cnc-dependent transcription. We observed strong fluorescence in the entire bodies, particularly in the abdomens and brains, of adult flies fed sesamin. Interestingly, Nrf2/Cnc was strongly activated in neuronal cells, especially in several neuron types, including glutamatergic and cholinergic, and some dopaminergic and/or serotonergic neurons but not in GABAergic neurons or the mushroom bodies of flies fed sesamin. These results indicate that the anti-aging effects of sesamin are exerted via activation of Nrf2/Cnc-dependent transcription to circumvent oxidative stress accumulation in several types of neurons of adult brains. Sesamin could be explored as a potential dietary supplement for preventing neurodegeneration associated with accumulation of oxidative stress. Full article

The Keap1-Nrf2 system is an evolutionarily conserved defense mechanism against oxidative and xenobiotic stress. Its regulatory mechanisms, e.g., stress-sensing mechanism, proteasome-based regulation of Nrf2 activity and selection of target genes, have been elucidated mainly in mammals. In addition, emerging model animals, such as zebrafish, fruit fly and Caenorhabditis elegans, have been shown to have similar anti-stress systems to mammals, suggesting that analogous defense systems are widely conserved throughout the animal kingdom. Experimental evidence in lower animals provides important information beyond mere laboratory-confined utility, such as regarding how these systems transformed during evolution, which may help characterize the mammalian system in greater detail. Recent advances in genome projects of both model and non-model animals have provided a great deal of useful information toward this end. We herein review the research on Keap1-Nrf2 and its analogous systems in both mammals and lower model animals. In addition, by comparing the amino acid sequences of Nrf2 and Keap1 proteins from various species, we can deduce the evolutionary history of the anti-stress system. This combinatorial approach using both experimental and genetic data will suggest perspectives of approach for researchers studying the stress response. Full article