Drosophila insulin-like peptide dilp1 increases lifespan and glucagon-like Akh expression epistatic to dilp2.
Aging Cell. 2018-12-03; 18(1): e12863
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Post S(1)(2), Liao S(3), Yamamoto R(2), Veenstra JA(4), Nässel DR(3), Tatar M(2).
(1)Department of Molecular Biology, Cell Biology and Biochemistry, Brown
University, Providence, Rhode Island.
(2)Department of Ecology and Evolutionary Biology, Brown University, Providence,
(3)Department of Zoology, Stockholm University, Stockholm, Sweden.
(4)Institut de Neurosciences Cognitives et Intégratives d’Aquitaine (CNRS
UMR5287), University of Bordeaux, Pessac, France.
Insulin/IGF signaling (IIS) regulates essential processes including development,
metabolism, and aging. The Drosophila genome encodes eight insulin/IGF-like
peptide (dilp) paralogs, including tandem-encoded dilp1 and dilp2. Many reports
show that longevity is increased by manipulations that decrease DILP2 levels. It
has been shown that dilp1 is expressed primarily in pupal stages, but also during
adult reproductive diapause. Here, we find that dilp1 is also highly expressed in
adult dilp2 mutants under nondiapause conditions. The inverse expression of dilp1
and dilp2 suggests these genes interact to regulate aging. Here, we study dilp1
and dilp2 single and double mutants to describe epistatic and synergistic
interactions affecting longevity, metabolism, and adipokinetic hormone (AKH), the
functional homolog of glucagon. Mutants of dilp2 extend lifespan and increase Akh
mRNA and protein in a dilp1-dependent manner. Loss of dilp1 alone has no impact
on these traits, whereas transgene expression of dilp1 increases lifespan in
dilp1 – dilp2 double mutants. On the other hand, dilp1 and dilp2 redundantly or
synergistically interact to control circulating sugar, starvation resistance, and
compensatory dilp5 expression. These interactions do not correlate with patterns
for how dilp1 and dilp2 affect longevity and AKH. Thus, repression or loss of
dilp2 slows aging because its depletion induces dilp1, which acts as a
pro-longevity factor. Likewise, dilp2 regulates Akh through epistatic interaction
with dilp1. Akh and glycogen affect aging in Caenorhabditis elegans and
Drosophila. Our data suggest that dilp2 modulates lifespan in part by regulating
Akh, and by repressing dilp1, which acts as a pro-longevity insulin-like peptide.
© 2018 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.