An overexpression screen for mutants with modified rates of age-dependent functional change in Drosophila melanogaster

Analysis of the mechanisms of aging has been advanced by finding single gene mutation which affect life span in model organisms, such as Drosophila melanogaster and C. elegans. Understanding genetic changes associated with age-dependent functional decline are also vital for elucidating the mechanisms of aging, and may predict mutations which affect life span. This study expands on current methods for screening longevity mutations in Drosophila by assaying phenotypic changes in aged adult flies. Several lines of evidence implicate the nervous system as critical to regulation of life span, thus mutations are made via ectopic overexpression of random genes in neural cell lineages using the GAL4-UAS system. The age-dependent behaviors used to assay functional change in aged adults were negative geotaxis response, heat stress sensitivity, and temperature sensitive paralysis. Other recorded phenotypes include lethality, physical defects and increased mortality under normal environmental conditions. 1868 mutations were screened, 36 were lethal and 245 were behaviorally phenotypic. Functional analysis of phenotypic versus non-phenotypic mutations identified gene families affecting age-dependent functional decline by altering neural function. Specific analysis of two mutations demonstrates the utility of the screen in uncovering mutations that change functional decline and life span. A mutation that activated expression of both Aats-asp and NMDA1 demonstrated it was possible to correlate accelerated functional decline with a decrease in life span and slowed functional decline with an increase in lifespan. A different mutation that increased expression of dsc1, a sodium channel homologue, accelerated functional decline and shortened life span when used to affect several different neural populations. However increasing expression in dsc1 in glial cell lineages slowed functional decline and may have increased life span. The results support a glial and non-neural endogenous adult expression pattern of dsc1. Thus, this screen provides a framework for launching further investigations into the mechanisms of physiological aging affecting age-dependent functional decline and possibly mortality.