Biology Reference
In-Depth Information
energy homeostasis and protein quality control. But it also remains possible
that fatty acids themselves serve as hormonal signals that coordinate other
events. Exploring the interface between metabolism and longevity will cer-
tainly be an exciting area of future research.
Importantly, gonadal longevity also requires the DAs produced in the
somatic gonad and other tissues, which work through DAF-12 to promote
longevity in at least two ways (
Gerisch et al., 2001; Rottiers et al., 2006;
Yamawaki et al., 2010
). First, DA and DAF-12 facilitate DAF-16/FOXO
nuclear localization and activity within the intestine, a major fat depot
and metabolic organ (
Berman & Kenyon, 2006; Gerisch et al., 2007
).
DAF-16/FOXO is a powerful regulator of longevity well known to be acti-
vated by reduced IIS, but appears to be independently regulated in gonadal
longevity. Second, DAF-12 and DAF-16 share responsibilities for transcrib-
ing a set of life span-enhancing genes (
McCormick, Chen, Ramaswamy, &
Kenyon, 2012
). Yet the mechanism of crosstalk between DAF-16/FOXO
and DA/DAF-12 and how DA/DAF-12 regulates longevity has remained
obscure until recently.
If germline removal requires DAF-12 signaling, then it could be
predicted to activate this signaling axis. Indeed, Shen and coworkers recently
showed that germline removal results in increased
daf
-
36
/Rieske oxygenase
expression, heightened production of the DAs and augmented DAF-12
transcriptional activity (
Shen, Wollam, Magner, Karalay, & Antebi,
2012
). In particular, DA/DAF-12 signaling turns on expression of its
let
-
7
family microRNA targets including
mir
-
84
and
mir
-
241
, previously impli-
cated in developmental timing circuits. Importantly, just as DA/DAF-12 are
required for long life, removal of these microRNAs also abrogrates gonadal
longevity. This requirement is specific as microRNA deletion has no effect
on longevity due to reduced IIS or mitochondrial function. Evidence
suggests that
mir
-
84
and
mir
-
241
downregulate at least two inhibitors of
DAF-16/FOXO, namely the AKT-1 kinase and the LIN-14 nuclear factor.
Consequently, both DAF-12 and DAF-16 become activated by DA to pro-
mote longevity programs. Interestingly, LIN-14 had previously been impli-
cated in life span regulation; knockdown of the gene extends life, while
lin
-
4
mutation, which leads to excess LIN-14, shortens life span (
Boehm & Slack,
2005
). Longevity was shown to be
daf
-
16
dependent, but additive with lon-
gevity from decreased
daf
-
2
/InsR signaling, suggesting a parallel pathway.
Additionally, AKT-1 had been previously shown to prevent longevity
through IIS
by
phosphorylating
and
inhibiting DAF-16/FOXO
(
Paradis & Ruvkun, 1998
).
