Antioxidant genes and other mechanisms involved in the extended longevity of Drosophila

Abstract

We are engaged in a genetic analysis of the mechanisms responsible for the expression of the extended longevity phenotype (ELP) of Drosophila. This phenotype is characterized by a ca. 40% increase in mean and maximum life span. We have shown that the ELP is due to a delayed onset of senescence (DOS) in one of our selected strain (LA) relative to its control (RA) stain. A complete genetic analysis, identifying the role of each chromosome in the expression of the ELP in the LA strain, has been done. The recessive genes responsible have been localized to the 3rd chromosome (c3). Genes on other chromosomes are involved in the expression of the ELP but are not expressed in the absence of the c3 genes. There are epistatic effects as well. In addition, expression of the ELP requires raising the L animals under high larval density (HD) conditions; raising the same genotype under low density (L-LD) conditions leads to a normal life span. There exists a critical period in larval life during which the L-HD animal programs the expression of genes in the young adult. This takes the form of a coordinated increase in specific antioxidant mRNA levels and enzyme activities in the 5 day old L-HD adult, a time point which just precedes the DOS. These increases are functional, as shown by the fact that the L-HD animals show an increase in their resistance to exogenous paraquat at this same time. The control (R-HD and L-LD) strains do not show such elevations and shortly thereafter show a decrease in their paraquat resistance and other biomarkers which signal the normal onset of senescence. Destruction of catalase activity in L-HD animals results in a failure to express the paraquat resistance component of the ELP. Thus, the critical period events which take place in the larva lead to coordinated changes in antioxidant gene activities in the young adult, and bring about the DOS and the expression of the ELP. These events do not appear to be limited to one strain. Our data shows that the only stress factor or biochemical trait which distinguishes all of our independently derived L strains from their related control and short-lived strains is their enhanced resistance to exogenous paraquat. The down-regulation of the antioxidant defense gene system must be viewed as the proximal cause of the onset of senescence.