The D. melanogaster transcription factor dFOXO is homologous to C. elegans daf-16 and to human FOXO3a. Regulated through insulin/IGF signaling, DAF-16 helps control dauer and aging. DAF-16 is known to affect aging through cell nonautonomous mechanisms, but we do not yet know which tissues are required to initiate this regulation or how these coordinate organism-wide senescence. D. melanogaster provides a useful complementary model to understand DAF-16/FOXO function. Flies with ubiquitous, constitutive mutations at the insulin-like receptor (InR) and insulin receptor substrate (chico) retard demographic and functional aging, Recently, dFOXO of D. melanogaster has been cloned and shown to control growth, stress resistance and starvation phenotypes. In new preliminary data we further show that conditional, tissue specific over-expression of dFOXO increases longevity in both males and females. Notably, senescence is slowed when dFOXO is expressed in adult fat body of the head, but not when expressed in abdominal fat body or in other tissues. Working from these observations we aim to understand how dFOXO regulates aging through tissue specific function. We shall (1) characterize endogenous functions of dFOXO in the head fat body and describe how this tissue differs from the fat body of the abdomen, (2) characterize how longevity induced by dFOXO-expression is influenced by diet restriction and by reproduction, (3) characterize through genetic analysis how longevity is affected by the interaction of dFOXO with the histone deactylase SIR2, with the translation factor binding protein 4e-BP, and with the insulin receptor substrate homolog chico and (4) elucidate candidate transcriptional and physiological targets of dFOXO associated with slow aging. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG024360-03
Application #
7110175
Study Section
Special Emphasis Panel (ZAG1-ZIJ-5 (M3))
Program Officer
Mccormick, Anna M
Project Start
2004-08-15
Project End
2009-07-31
Budget Start
2006-08-15
Budget End
2007-07-31
Support Year
3
Fiscal Year
2006
Total Cost
$338,543
Indirect Cost
Name
Brown University
Department
Biology
Type
Schools of Medicine
DUNS #
001785542
City
Providence
State
RI
Country
United States
Zip Code
02912
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