Cell Cycle 10:6, 904-911; March 15, 2011; © 2011 Landes Bioscience
904 Cell Cycle volume 10 issue 6
Key words: aging, calorie restriction,
dietary restriction, resveratrol,
life span, Sir2, takeout, genomics,
Abbreviations: DR, dietary restriction;
JH, juvenile hormone; GSEA, gene
set enrichment analysis
*Correspondence to: Nicola Neretti and Stephen L.
Helfand; Email: Stephen_Helfand@Brown.edu and
was used to identify genes and pathways
involved in calorie restriction/dietary
restriction (DR) life span extension in
Drosophila. Starting with a gene centric
analysis comparing the changes in com-
mon between DR and two DR related
molecular genetic life span extending
manipulations, Sir2 and p53, lead to a
molecular confirmation of Sir2 and p53’s
similarity with DR and the identification
of a small set of commonly regulated
genes. One of the identified upregulated
genes, takeout, known to be involved in
feeding and starvation behavior, and to
have sequence homology with Juvenile
Hormone (JH) binding protein, was
shown to directly extend life span when
specifically overexpressed. Here we show
that a pathway centric approach can be
used to identify shared physiological
pathways between DR and Sir2, p53 and
resveratrol life span extending interven-
tions. The set of physiological pathways
in common among these life span extend-
ing interventions provides an initial step
toward defining molecular genetic and
physiological changes important in life
span extension. The large overlap in
shared pathways between DR, Sir2, p53
and resveratrol provide strong molecular
evidence supporting the genetic studies
linking these specific life span extending
multiple comparison approach using
whole genome transcriptional arrays
Comparative transcriptional pathway bioinformatic analysis of dietary
restriction, Sir2, p53 and resveratrol life span extension in Drosophila
Michael Antosh,2,3 Rachel Whitaker,1 Adam Kroll,1 Suzanne Hosier,1 Chengyi Chang,1 Johannes Bauer,4 Leon Cooper,2,3
Nicola Neretti1,2,* and Stephen L. Helfand1,*
1Department of Molecular Biology, Cell Biology and Biochemistry; Division of Biology and Medicine; Sidney Frank Life Sciences Building; 2Institute for Brain
and Neural Systems; 3Department of Physics; Brown University; Providence, RI USA; 4Department of Biological Sciences;
Southern Methodist University; Dallas, TX USA
(DR) is one of the most robust and well-
known life span and health span extend-
ing interventions so far described. Despite
DR’s clear efficacy in a wide range of
organisms including yeast, nematodes,
flies, spiders, fish and mammals, the diffi-
culty in maintaining a DR diet in humans
has severely limited its practical therapeu-
tic use.1-10 The search for more applicable
DR-like interventions has focused on
understanding the molecular and physi-
ological changes underlying DR’s life span
extending effects. One such approach is
through the examination of transcrip-
tional changes.11 Whole genome transcrip-
tional arrays provide an unbiased method
for investigating the molecular mecha-
nisms of complex biological phenomena.
Results and Discussion
Comparative whole genome transcrip-
tional profiling identifies takeout as a
new gene involved in longevity deter-
mination. Whole genome transcriptional
profiling of DR flies shows a large number
of changes in gene expression (>2,000).11
Among this large group of genes are those
associated with life span extension as well
as genes that change in response to the
reduction in caloric or dietary intake, but
are not involved in mediating life span.
For example, the nearly universal decrease
in fertility that accompanies DR is not
directly related to life span extension in
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