Subject(s)
Antibodies, Monoclonal, Humanized/administration & dosage , Hidradenitis Suppurativa/drug therapy , Interleukin-17/antagonists & inhibitors , Quality of Life , Adult , Antibodies, Monoclonal, Humanized/adverse effects , Female , Hidradenitis Suppurativa/complications , Hidradenitis Suppurativa/diagnosis , Hidradenitis Suppurativa/immunology , Humans , Injections, Subcutaneous , Interleukin-17/immunology , Male , Middle Aged , Pilot Projects , Severity of Illness Index , Treatment OutcomeABSTRACT
Some years ago we applied simultaneously an identical regime of selection for late-life reproduction to several normal-lived sister lines (Ra and Rb) so as to produce several selected long-lived sister lines (La and Lb). The long-lived La and Lb sister lines had statistically identical longevity phenotypes and paraquat resistance phenotypes; however, we noticed some statistically different responses of the two strains at the biochemical level. Extensive work with the La strain showed that transcriptional alterations in antioxidant gene expression are robustly associated with its extended longevity. We decided to critically test the assumption of phenotypic equivalence by subjecting the Lb strain to the same series of molecular assays as was the La strain. The two sister strains are characterized by significantly different mechanisms and patterns of antioxidant gene expression, antioxidant enzyme activity, and oxidative damage. We find that the Lb strain appears to depend on the transcriptional activation of different genes than does the La strain, and on a post-translational up-regulation of at least one other antioxidant defense gene. The phenotypic equivalence observed at the organism level need not hold at the molecular genetic level. This finding suggests that there is more than one molecular mechanism by which antioxidant defense genes can bring about an increased resistance to oxidative stress. The theoretical and empirical implications of these findings are discussed.
Subject(s)
Drosophila/genetics , Drosophila/metabolism , Longevity/genetics , Longevity/physiology , Animals , Antioxidants/metabolism , Catalase/genetics , Drug Resistance/genetics , Female , Gene Expression , Lipid Peroxidation , Male , Oxidative Stress , Paraquat/toxicity , Phenotype , RNA, Messenger/genetics , RNA, Messenger/metabolism , Selection, Genetic , Superoxide Dismutase/genetics , Superoxide Dismutase/metabolismABSTRACT
Patterns of antioxidant gene expression and of oxidative damage were measured throughout the adult life span of a selected long-lived strain (La) of Drosophila melanogaster and compared to that of their normal-lived progenitor strain (Ra). Extended longevity in the La strain is correlated with enhanced antioxidant defense system gene expression, accumulation of CuZnSOD protein, and an increase in ADS enzyme activities. Extended longevity is strongly associated with a significantly increased resistance to oxidative stress. Reverse-selecting this long-lived strain for shortened longevity (RevLa strain) yields a significant decrease in longevity accompanied by reversion to normal levels of its antioxidant defense system gene expression patterns and antioxidant enzyme patterns. The significant effects of forward and reverse selection in these strains seem limited to the ADS enzymes; 11 other enzymes with primarily metabolic functions show no obvious effect of selection on their activity levels whereas six other enzymes postulated to play a role in flux control may actually be involved in NADPH reoxidation and thus support the enhanced activities of the ADS enzymes. Thus, alterations in the longevity of these Drosophila strains are directly correlated with corresponding alterations in; 1) the mRNA levels of certain antioxidant defense system genes; 2) the protein level of at least one antioxidant defense system gene; 3) the activity levels of the corresponding antioxidant defense system enzymes, and 4) the ability of the organism to resist the biological damage arising from oxidative stress.
