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.
Cho
Sung Chun
SC
Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul 110-799, Korea.
Park
Moon Cheol
MC
Keam
Bhumsuk
B
Choi
Jung Min
JM
Cho
Yunje
Y
Hyun
Soonsil
S
Park
Sang Chul
SC
Lee
Junho
J
D000375:Aging / Q000187:drug effects; D000818:Animals; D000975:Antioxidants; D017173:Caenorhabditis elegans / Q000502:physiology*; D002460:Cell Line; D003622:Dapsone / Q000494:pharmacology*; D008136:Longevity / Q000187:drug effects*; D024101:Mitochondrial Proteins / Q000187:drug effects; D018482:Muscle, Skeletal / Q000166:cytology / Q000187:drug effects; D010101:Oxygen Consumption / Q000187:drug effects; D010269:Paraquat / Q000494:pharmacology; D011770:Pyruvate Kinase / Q000037:antagonists & inhibitors / Q000235:genetics; D017382:Reactive Oxygen Species
D000975:Antioxidants; D024101:Mitochondrial Proteins; D017382:Reactive Oxygen Species; D003622:Dapsone; D011770:Pyruvate Kinase; D010269:Paraquat