The Drosophila melanogaster gene insulin-like receptor (InR) is homologous to mammalian insulin receptors as well as to Caenorhabditis elegans daf-2, a signal transducer regulating worm dauer formation and adult longevity. We describe a heteroallelic, hypomorphic genotype of mutant InR, which yields dwarf females with up to an 85% extension of adult longevity and dwarf males with reduced late age-specific mortality. Treatment of the long-lived InR dwarfs with a juvenile hormone analog restores life expectancy toward that of wild-type controls. We conclude that juvenile hormone deficiency, which results from InR signal pathway mutation, is sufficient to extend life-span, and that in flies, insulin-like ligands nonautonomously mediate aging through retardation of growth or activation of specific endocrine tissue.
SummaryHypomorphic mutants affecting the Drosophila insulin/ IGF signal pathway are reported to increase longevity in females but not in males. To understand this sexdifference, we conducted a large-scale demographic study with three new isogenic strains of alleles at chico , the insulin-receptor substrate homologue. We verify that female dwarf homozygotes ( ch 1 / ch 1 ) and normal-sized heterozygotes ( ch 1 /+) are long-lived, as originally reported. We find for the first time that male heterozygotes are longlived relative to wildtype, by about 50%. The life span of male ch 1 / ch 1 is similar to that of wildtype but these dwarf males age at a slow demographic rate. The levels of demographic frailty and of age-independent mortality are elevated in ch 1 / ch 1 males, counteracting the effect of slow aging upon life expectancy. Mortality deceleration occurs amongst the oldest-old wildtype adults, as seen in many organisms. Remarkably, in similarly sized cohorts of male and female ch 1 / ch 1 and of male ch 1 /+ mortality deceleration is absent. Mortality deceleration is a phenotype of chico .
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