Among nematodes, flies and mice, the rate of aging is modulated by hormones. In nematodes, mutation at the insulin/IGF pathway in a few cells is sufficient to slow aging. We found an analogous system in D. melanogaster where mutant insulin/IGF receptor (InR) leads to deficiency in juvenile hormone (JH). These mutants are dwarf, sterile and long-lived, all apparently due to deficient JH. These findings resonate with dwarf mice that are long-lived and deficient in several pituitary hormones. Here is a common theme where the a small set of cells regulate secondary hormones with the potential to modulate aging. It is now of great importance to discover how insulin/IGF regulates these secondary hormones, and how these endocrines affect senescence. ? Research in this proposed project will exploit the powerful tools of Drosophila to develop fundamental insights on how mutation of InR increases life span. ? First, molecular analysis will dissect the qualities of the specific InR mutant alleles that confer increased life span. Do these alleles merely affect the quantity of INR protein, do they alter the tissue specificity of InR transcription, or do they alter a specific senescence related quality of the INR product? These studies will compare sequences of many types of alleles, describe expression patterns and transcript quality, and examine the ability of P-element remobilized alleles to rescue phenotypes. ? Second, the project will investigate whether JH deficiency arises because InR mutant genotypes have delayed development of endocrine tissue or because a mature endocrine tissue fails to receive adequate activation signals. This work will use Gal4/UAS lines with conditional expression of insulin-like ligands or of InR.
Our third aim will address the JH hypothesis directly by developing a regulated JH-negative strain with a new TetOn system to drive juvenile hormone esterase. These studies will establish how InR modulates JH and whether JH deficiency is sufficient to increase life span of InR mutant adults. ? Finally, with the JH-negative reagents and the set of InR mutants alleles, the project will explore how JH and InR affect somatic features that shape life span. In a comprehensive experimental design, we shall assess qualifies of stress resistance, central metabolism and mitochondria function to determine which feature best predicts variance in life span ? ?
