DDS promotes longevity through a microbiome-mediated starvation signal.

The antibiotic diaminodiphenyl sulfone (DDS) is used in combination with other antibiotics as a first line treatment for leprosy. DDS has been previously reported to extend lifespan in Caenorhabditis elegans through inhibition of pyruvate kinase and decreased mitochondrial function. Here we report an alternative mechanism of action by which DDS promotes longevity in C. elegans by reducing folate production by the microbiome. This results in altered methionine cycle metabolite levels mimicking the effects of metformin and lifespan extension that is dependent on the starvation- and hypoxia-induced flavin containing monoxygenase, FMO-2.

Protective effect of 4,4'-diaminodiphenylsulfone against paraquat-induced mouse lung injury.

Although 4,4'-diaminodiphenylsulfone (DDS, dapsone) has been used to treat several dermatologic conditions, including Hansen disease, for the past several decades, its mode of action has remained a topic of debate. We recently reported that DDS treatment significantly extends the lifespan of the nematode C. elegans by decreasing the generation of reactive oxygen species. Additionally, in in vitro experiments using non-phagocytic human fibroblasts, we found that DDS effectively counteracted the toxicity of paraquat (PQ). In the present study, we extended our work to test the protective effect of DDS against PQ in vivo using a mouse lung injury model. Oral administration of DDS to mice significantly attenuated the lung tissue damage caused by subsequent administration of PQ. Moreover, DDS reduced the local expression of mRNA transcripts encoding inflammation-related molecules, including endothelin-1 (ET-1), macrophage inflammatory protein-1α (MIP-1α), and transforming growth factor-ß (TGF-ß). In addition, DDS decreased the PQ-induced expression of NADPH oxidase mRNA and activation of protein kinase Cµ (PKCµ). DDS treatment also decreased the PQ-induced generation of superoxide anions in mouse lung fibroblasts. Taken together, these data suggest the novel efficacy of DDS as an effective protective agent against oxidative stress-induced tissue damages.

DDS, 4,4'-diaminodiphenylsulfone, extends organismic lifespan.

DDS, 4,4'-diaminodiphenylsulfone, is the most common drug prescribed to treat Hansen disease patients. In addition to its antibacterial activity, DDS has been reported to be involved in other cellular processes that occur in eukaryotic cells. Because DDS treatment significantly enhances the antioxidant activity in humans, we examined its effect on lifespan extension. Here we show that DDS extends organismic lifespan using Caenorhabditis elegans as a model system. DDS treatment caused a delay in aging and decreased the levels of a mitochondrial complex. The oxygen consumption rate was also significantly lowered. Consistent with these data, paraquat treatment evoked less reactive oxygen species in DDS-treated worms, and these worms were less sensitive to paraquat. Interestingly enough, all of the molecular events caused by DDS treatment were consistently reproduced in mice treated with DDS for 3 mo and in the C2C12 muscle cell line. Structural prediction identified pyruvate kinase (PK) as a protein target of DDS. Indeed, DDS bound and inhibited PK in vitro and inhibited it in vivo, and a PK mutation conferred extended lifespan of C. elegans. Supplement of pyruvate to the media protected C2C12 cells from apoptosis caused by paraquat. Our findings establish the significance of DDS in lowering reactive oxygen species generation and extending the lifespan, which renders the rationale to examining the possible effect of DDS on human lifespan extension.

Protective effect of 4,4'-diaminodiphenylsulphone against oxidative stress but not to apoptotic stress in human diploid fibroblasts.

The antibiotic drug 4,4'-diaminodiphenylsulphone (DDS) is used to treat several dermatologic diseases, including Hansen's disease. This study confirmed the antioxidant nature of DDS in hydrogen peroxide (H(2)O(2))-induced oxidative stress and assessed its role in other apoptotic stresses in human diploid fibroblasts (HDFs). Oxidative stress was effectively reduced by DDS in a dose-dependent manner. Moreover, the oxidative stress-induced increases in the levels of the p53 and p21 proteins were inhibited by pre-treatment with DDS. In addition, H(2)O(2) and DDS increased the level of cytochrome P450 (CYP450) IIE1 in HDFs, implicating a role for DDS in H(2)O(2) scavenging via the activation of CYP450. DDS treatment increased the activity of catalase (CAT), glutathione peroxidase (GPx) and glutathione reductase (GR), as well as the GSH/GSSG ratio, indicating activation of the glutathione system against oxidative stress. However, DDS showed no protective effects on HDFs against other apoptotic stimuli, such as thapsigargin and staurosporine, suggesting that DDS would act only against oxidative stress. Therefore, in addition to its antibiotic function, DDS is a potent antioxidant against H(2)O(2)-induced oxidative stress in HDFs.

Suppression of ROS generation by 4,4-diaminodiphenylsulfone in non-phagocytic human diploid fibroblasts.

The action mode of 4,4-diaminodiphenylsulfone (DDS) is still under debate, although it has long been used in treatment of several dermatologic diseases including Hansens disease. In this study, we tested the effect of DDS as an antioxidant on paraquat-induced oxidative stress in non-phagocytic human diploid fibroblasts (HDFs). Overall, preincubation of HDFs with DDS prevented the oxidative stress and the resulting cytotoxic damages caused by paraquat in these cells. The specific effects of DDS in paraquat-treated HDFs are summarized as follows: a) reducing the expression of NADPH oxidase 4 (NOX4) by inhibiting paraquat-induced activation of PKC; b) inhibiting paraquat-induced decreases in mitochondrial complex protein levels as well as in membrane potentials; c) consequently, inhibiting the generation of cytosolic and mitochondrial superoxide anions. Taken together, these findings suggest that DDS would suppress the radical generation in non-phagocytic HDFs during oxidative stress, and that DDS might have the extended potential to be used further in prevention of other oxidative stress-related pathologies.