Researchers established that the mutated Indy gene helped fruit flies live longer. They have now explored what mechanisms lead to the longer life of the fruit fly. (Indy flies’ life span increased from an average life span of about 35 days to 70 days.)
The researchers decided the best way to try to understand how the Indy mutation might extend life span would be to study the differences in molecular changes between the Indy flies and normal flies throughout their entire life. By comparing the expression level of all genes in the Indy flies to that of normal flies, they made an important finding. Some of the genes involved in generating the power necessary for normal cell life were expressed at lower levels in the Indy flies.
This led to a decrease in free radicals and the damage they normally cause in the cell, but it surprisingly did not decrease the overall amount of energy in the cell. These studies provide evidence for possible interventions that can alter metabolism in a way that reduces free-radical or oxidative damage and extends life span, without some of the negative consequences normally associated with a change in metabolism.
As readers here know separately Genescient has a population of fruit flies that live 4.5 times longer than normal and have identified 700+ genes that are correlated to aging. Genescient Co-founder and Chairman Gregory Benford believes that they can use supplements and already FDA approved drugs and ingredients to stimulate those genes to rapidly get life extending and health enhancing effects widely available.
Long-lived Indy [I’m Not Dead Yet] induces reduced mitochondrial reactive oxygen species production and oxidative damage
Decreased Indy activity extends lifespan in D. melanogaster without significant reduction in fecundity, metabolic rate, or locomotion. To understand the underlying mechanisms leading to lifespan extension in this mutant strain, we compared the genome-wide gene expression changes in the head and thorax of adult Indy mutant with control flies over the course of their lifespan. A signature enrichment analysis of metabolic and signaling pathways revealed that expression levels of genes in the oxidative phosphorylation pathway are significantly lower in Indy starting at day 20. We confirmed experimentally that complexes I and III of the electron transport chain have lower enzyme activity in Indy long-lived flies by Day 20 and predicted that reactive oxygen species (ROS) production in mitochondria could be reduced. Consistently, we found that both ROS production and protein damage are reduced in Indy with respect to control. However, we did not detect significant differences in total ATP, a phenotype that could be explained by our finding of a higher mitochondrial density in Indy mutants. Thus, one potential mechanism by which Indy mutants extend life span could be through an alteration in mitochondrial physiology leading to an increased efficiency in the ATP/ROS ratio.