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RESEARCH
 

I am interested in understanding the mechanisms underlying the onset of senescence in Drosophila. My approach to the problem was to construct an appropriate normal lived control strain and then to derive from it by artificial selection several very long lived strains. This model system insured that our manipulations had significantly affected the aging and senescence mechanisms while keeping the genomes of the two strains otherwise nearly identical, and thus suitable for comparison. We then examined these strains by a variety of techniques in order to identify and characterize the genetically altered processes responsible for the extended longevity. We demonstrated that the selected La long lived and the Ra normal lived progenitor strain age in the same manner, but that the significant increase in both the mean and maximum life span characteristic of the long lived strain comes about because of a delayed onset of senescence. The events that precipitate this delayed onset occur early in adult life when the animal specifically up-regulates its anti-oxidant defense systems, resulting in the enzymatic scavenging and destruction of reactive oxygen species (ROS). The animal further reduces its ROS load because its more efficient mitochondria have a significantly decreased rate of ROS production. In addition, the animal has a more efficient altered metabolism. Taken together, these gene based changes reduce the ROS load, which results in a lowered rate of oxidative damage to critical cells and cellular components, and thus a delay in the age at loss of function, or senescence.

We have evidence that the long-lived animal’s response to dietary restriction (DR) is significantly different from that characteristic of both weak and robust normal-lived strains. The normal lived strains respond to DR by significantly increasing their mean and maximum life span when fed a low yeast diet. The long lived strains do not show such a response but rather express the same extended longevity phenotype at all diets above starvation levels. Both the life span and the mortality patterns of the DR-induced normal strains is statistically equivalent to that of the long lived animals. We interpret these data as suggesting that our long lived (La) strain has a constituitive expression of the DR response. We plan to use this strain to help decipher the still-unknown mechanisms and pathways underlying the DR response in Drosophila.

By using ‘cybrids’ (animals whose nuclear and mitochondrial genomes are derived from different strains), we have determined that it is the mitochondria that determines the animal’s response to DR. We are now investigating the cell signaling pathways involved in this altered response, and are now using the appropriate strains in a critical test of this hypothesis. In this context, it is interesting to note that we have made trans-acting regulatory mutants that significantly increase or decrease this extended longevity; our data to date suggests they affect mitochondrial efficiency and so alter longevity. Clearly energy efficiency and allocation play an important role in longevity determination, and we are using our strains to explore this concept in some detail from the phenotypic to the molecular level.

 
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