Genetic Ducklings: Putting aging genes in a row
Authors: Davenport R. John 
Published: August 2003

No gene is an island; they collaborate with each other to execute biological processes such as aging. To understand such phenomena, scientists must sort out exactly how they work together. New results shed light on how one longevity gene fits into a cellular pathway already linked to aging. Although many components in the pathway are well known, its presumptive downstream targets have remained elusive.

Previous work has indicated that a number of
Caenorhabditis elegans
genes--including
daf-2
,
age-1
, and
daf-16
--team up as part of an insulin-like signaling pathway that governs life-span in worms and other animals (see
"Growing Old Together"
). The
daf-2
gene activates
age-1
, which triggers a cascade of events that thwarts
daf-16
. That gene encodes a protein that is thought to regulate the transcription of other genes based on its similarity to the forkhead family of mammalian transcription factors. But no one has identified the genes that DAF-16 presumably controls. The new work indicates that
daf-16
activates transcription of
old-1,
a gene that can lengthen the life-span of worms when it is overproduced.

Murakami and Johnson first looked within the
old-1
gene for sequences that forkhead-binding proteins grab when they regulate genes; they found six such sequences. To determine whether
daf-16
activates
old-1
production, the researchers linked the gene for green fluorescent protein (GFP) to the tail end of
old-1
using standard genetic engineering techniques and assessed quantities of the fusion protein by measuring GFP fluorescence. They also used a polymerase chain reaction technique to assess the amount of
old-1
messenger RNA (mRNA). As normal worms age or face stresses such as ultraviolet (UV) light, heat, or starvation, the production of
old-1
mRNA and protein increases, the researchers found. Perhaps
old-1
provides extra resistance against these environmental insults, the researchers suggest. For comparison, they studied worms carrying a life-shortening mutation that cripples
daf-16
. After exposure to UV light, heat, or starvation, these worms produce
old-1
mRNA in lower quantities than do worms with normal
daf-16
. Together, these results suggest that
daf-16
normally increases the amount of old-1.

The group also probed whether
old-1
follows the
age-1
and
daf-2
genes in the insulin-like signaling pathway, as expected if
old-1
is controlled by
daf-16
. Mutations in either
age-1
or
daf-2
that extend longevity ramp up production of
old-1
mRNA. Furthermore, destruction of
old-1
mRNA by means of a technique called RNA interference in worms with defective
age-1
and
daf-2
counteracts the life-span extension normally afforded by these mutations. These observations are consistent with a scenario in which
old-1
lies downstream of the other genes in the pathway.

The
old-1
gene is the first potential target of
daf-16
to be identified, but the exact relation between them isn't yet clear. Worms with a life-shortening mutation in
daf-16
do not live longer when they also carry multiple chromosomal copies of
old-1
, which normally results in overactivation of the gene. In a simple genetic scheme, the observation that the
daf-16
mutation trumps overproduction of
old-1
indicates that
old-1
precedes
daf-16
in the pathway. But because
daf-16
normally spurs
old-1
output,
old-1
might not be abundant in the mutant, where
daf-16
is defective. Nailing down this issue requires further work, but the potential extension of the pathway will undoubtedly lure researchers deeper into it.

--R. John Davenport; suggested by Matt Kaeberlein

S. Murakami, T. E. Johnson, The OLD-1 positive regulator of longevity and stress resistance is under DAF-16 regulation in
Caenorhabditis elegans.
Curr. Biol.
11
, 1517-1523 (2001).
[Abstract]
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