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 ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG021953-04
Application #
7038301
Study Section
Geriatrics and Rehabilitation Medicine (GRM)
Program Officer
Mccormick, Anna M
Project Start
2003-04-01
Project End
2008-03-31
Budget Start
2006-04-01
Budget End
2007-03-31
Support Year
4
Fiscal Year
2006
Total Cost
$373,692
Indirect Cost
Name
Brown University
Department
Biology
Type
Schools of Medicine
DUNS #
001785542
City
Providence
State
RI
Country
United States
Zip Code
02912
Flatt, Thomas; Min, Kyung-Jin; D'Alterio, Cecilia et al. (2008) Drosophila germ-line modulation of insulin signaling and lifespan. Proc Natl Acad Sci U S A 105:6368-73
Min, Kyung-Jin; Yamamoto, Rochele; Buch, Susanne et al. (2008) Drosophila lifespan control by dietary restriction independent of insulin-like signaling. Aging Cell 7:199-206
Bergland, Alan O; Genissel, Anne; Nuzhdin, Sergey V et al. (2008) Quantitative trait loci affecting phenotypic plasticity and the allometric relationship of ovariole number and thorax length in Drosophila melanogaster. Genetics 180:567-82
Flatt, Thomas; Heyland, Andreas; Rus, Florentina et al. (2008) Hormonal regulation of the humoral innate immune response in Drosophila melanogaster. J Exp Biol 211:2712-24
Min, Kyung-Jin; Flatt, Thomas; Kulaots, Indrek et al. (2007) Counting calories in Drosophila diet restriction. Exp Gerontol 42:247-51
Min, Kyung-Jin; Tatar, Marc (2006) Drosophila diet restriction in practice: do flies consume fewer nutrients? Mech Ageing Dev 127:93-6
Min, Kyung-Jin; Tatar, Marc (2006) Restriction of amino acids extends lifespan in Drosophila melanogaster. Mech Ageing Dev 127:643-6
Min, Kyung-Jin; Hogan, Meghan F; Tatar, Marc et al. (2006) Resource allocation to reproduction and soma in Drosophila: a stable isotope analysis of carbon from dietary sugar. J Insect Physiol 52:763-70
Zerofsky, Melissa; Harel, Ephat; Silverman, Neal et al. (2005) Aging of the innate immune response in Drosophila melanogaster. Aging Cell 4:103-8