Signaling networks in
Eric L. Greer1,2and Anne
1Department of Genetics, 300 Pasteur Drive,
2Cancer Biology Program, and 3Neurosciences
Program, Stanford University, Stanford, CA 94305,
*Author for correspondence
Journal of Cell Science 121, 407-412
Published by The Company of Biologists 2008
Aging – long considered to be solely the
result of wear and tear – is in fact regulated
by specific genetic pathways. Simple
changes in the environment (e.g. dietary
restriction) can drastically extend lifespan,
suggesting that several of these genetic
pathways control longevity in response to
changes in the surroundings. Here we
summarize the key signaling modules
identified so far that regulate aging and
Insulin and insulin-like signaling
The first example of a specific pathway
controlling longevity came from studies of
Caenorhabditis elegans. Mutations that
reduce the activity of the insulin receptor
DAF-2 (Kenyon et al., 1993; Kimura et al.,
1997) or the phosphoinositide 3-kinase
(PI3K) AGE-1 (Friedman and Johnson,
1988; Morris et al., 1996) extend lifespan in
adult worms by more than 100%. The
insulin receptor mediates its effects via the
PI3K-AKT/SGK signaling pathway, which
culminates in the negative regulation of the
Forkhead transcription factor FOXO/DAF-
16 (Brunet et al., 1999; Kops et al., 1999;
Lin et al., 1997; Ogg et al., 1997). Insulin
signaling regulates aging in a conserved
manner, from worms to mammals. In
Drosophila melanogaster, mutations in the
insulin receptor extend female lifespan by
~85% and mutation of the insulin-receptor
substrate (IRS) Chico causes an ~48%
increase in lifespan (Clancy et al., 2001;
Tatar et al., 2001). Overexpression of foxo
in Drosophila extends lifespan by ~15-52%
(Giannakou et al., 2004; Hwangbo et al.,
2004). In mice, animals that lack one allele
of the insulin-like growth factor 1 (IGF1)
receptor gene show a 26% increase in mean
lifespan (Holzenberger et al., 2003). The
insulin signaling pathway is important in a
variety of tissues to extend lifespan.
Mutation of the insulin receptor in adipose
tissue increases mouse lifespan by 18%
(Bluher et al., 2003), whereas a brain-
specific IRS2 knockout extends mouse
lifespan by ~18% (Taguchi et al., 2007).
Growth hormone signaling
In mice, the Snell and Ames dwarf
mutations, which are in the genes encoding
Cell Science at a Glance
(See poster insert)
Signaling Networks in Aging
Eric L. Greer and Anne Brunet
© Journal of Cell Science 2008 (121, pp. 407-412)
Dietary restrictionHormonal signaling
akt-1/2 / sgk-1
Cell cycle arrest
Cell cycle arrest
Cell cycle arrest
Telomere and genome maintenance
C.elegans genes shown to
affect lifespan are shown
beneath the equivalent
Proteins not yet shown to
affect ageing are shown
Journal of Cell Science
the pituitary transcription factors PIT1
(POU1F1) and PROP1, respectively, extend
lifespan by 42-67% (Brown-Borg et al.,
1996; Flurkey et al., 2001). The extension
in longevity in both mouse models is likely
to be due to defects in the ability of the
pituitary gland to secrete growth hormone
(GH), because mice that have a null
mutation in the GH receptor (GHR–/–) also
display an ~21-40% increase in lifespan
(Coschigano et al., 2003), whereas
transgenic mice that overexpress GH live
significantly shorter than wild-type mice
(Wolf et al., 1993). Interestingly, the Ames
dwarf mice and the GHR–/–mice have
reduced levels of circulating IGF1, fasting
insulin and glucose (Brown-Borg et al.,
1996; Coschigano et al., 2003), raising the
possibility that the increased longevity of
these mice is mediated by insulin/IGF1
Disruption of the expression of klotho, a
cell-surface protein whose extracellular
domain can act as a circulating hormone
(Shiraki-Iida et al., 1998), accelerates aging
in mice (Kuro-o et al., 1997). Conversely,
overexpression of klotho in mice leads to
an ~19-31% lifespan extension in one strain
of mice (Kurosu et al., 2005). The precise
mechanisms by which klotho extends
lifespan are still under investigation, but
klotho has been found to repress
insulin/IGF1 signaling (Kurosu et al., 2005)
and to regulate phosphate and calcium
homeostasis (Imura et al., 2007) by
affecting fibroblast growth factor 23
(FGF23) (Urakawa et al., 2006) and the
Na+/K+-ATPase (Imura et al., 2007).
Mice lacking type 5 adenylyl cyclase
(AC5) have an ~32% increase in lifespan
compared with wild-type littermates (Yan
et al., 2007). AC5 probably transduces
signals emanating from a hormonal seven-
transmembrane-domain receptor, although
the identity of this receptor is unknown.
The increase in lifespan in AC5-deficient
mice correlates with decreased levels of
circulating GH, increased resistance to
oxidative stress and increased Raf-MEK-
ERK signaling (Yan et al., 2007). The
chronological lifespan of yeast expressing
a mutant form of adenylyl cyclase (CYR1)
or yeast overexpressing the MAP kinase
ERK2 is also increased, suggesting that
the relevance of this pathway to longevity
(Fabrizio et al., 2001; Yan et al., 2007).
conserved throughout evolution
In adult worms, mutations in TGF? (daf-7)
or in the TGF?
(TGF?R1) and DAF-4 (TGF?R2) extend
worm lifespan by 18-120% (Shaw et al.,
2007). TGF? signaling is mediated by two
SMAD transcription factors, DAF-8 and
DAF-14, which inhibit the action of
another SMAD transcription factor, DAF-
3 (SMAD3) (Shaw et al., 2007). DAF-3,
together with its co-activator DAF-5,
upregulates genes involved in cell cycle
arrest and apoptosis, a large number of
which are also regulated by the FOXO
transcription factor DAF-16 (Shaw et al.,
2007). Thus, the TGF? and the insulin
pathways might regulate lifespan by acting
on similar subsets of genes.
In worms, the loss-of-function mutation of
a cytochrome P450 (daf-9), a predicted
lifespan in a manner that is dependent on
DAF-12 (Gerisch et al., 2001; Jia et al.,
2002), a nuclear hormone receptor with
closest homology to LXR? (liver X
receptor alpha) in mammals. DAF-9 might
regulate the synthesis of a steroid ligand
that inhibits the receptor DAF-12 (Gerisch
et al., 2001; Jia et al., 2002). In line with
this prediction, the steroid dafachronic acid
is a ligand for DAF-12 that shortens the
lifespan of daf-9-mutant worms (Gerisch et
al., 2007). Conversely, another steroid,
pregnenolone, extends worm lifespan in a
DAF-12-dependent manner (Broue et al.,
2007). In flies, the steroid termed juvenile
hormone has been found to reverse the
lifespan extension caused by mutation of
the insulin-like receptor (Tatar et al., 2001).
In mammals, the effects of steroids or
steroid receptors on overall lifespan have
not been directly examined, but the steroid
dehydro epiandorosterone sulfate (DHEA-
S) has been found to be associated with
increased longevity in primates and
humans (Roth et al., 2002).
extremely potent regulators of lifespan,
perhaps because they coordinate the
longevity of several key organs by acting
in a systemic manner.
signaling pathways are
Nutrient sensing and signaling
intervention to delay aging is dietary
restriction (DR) – restriction of food intake
without malnutrition. Dissecting the
most efficient environmental
longevity has allowed the identification of
novel signaling pathways that regulate
The Sirtuin family of NAD-dependent
protein deacetylases was identified early
on as a key regulator of replicative lifespan
in yeast (Kaeberlein et al., 1999; Kennedy
et al., 1995). The role of Sirtuins in lifespan
is conserved in metazoans. An increased
number of copies of sir-2.1, a worm
ortholog of yeast SIR2, extends worm
lifespan by 15-50% (Tissenbaum and
Guarente, 2001) and expression of
Drosophila Sir2 extends fly lifespan by 18-
29% (Rogina and Helfand, 2004).
Importantly, Sirtuin proteins mediate the
beneficial effects of DR on lifespan and
behavior in yeast, worms, flies and mice
(Chen et al., 2005; Lin et al., 2000; Rogina
and Helfand, 2004; Wang and Tissenbaum,
2006). Note that Sir2 is necessary for
increased lifespan induced by some, but
not all, methods of DR in yeast (Kaeberlein
et al., 2004; Lin et al., 2002). In mammals,
there are seven Sirtuin proteins. The role of
mammalian Sirtuin proteins in longevity
has not yet been entirely described, but
three pieces of recent evidence support a
conserved role for Sirtuins in mammalian
lifespan. First, Sirt6–/–mice display signs
of accelerated aging (Mostoslavsky et al.,
2006). Second, a polymorphism in the
human SIRT3 gene has been correlated
with increased survival in centenarians
(Rose et al., 2003). Third, Sirtuin proteins
are one of the targets of the polyphenol
compound resveratrol, which extends
lifespan of invertebrates and obese mice
(Baur et al., 2006; Viswanathan et al.,
2005; Wood et al., 2004).
The Sirtuin pathway intersects with the
insulin/IGF1 pathway. sir-2.1 lifespan
extension in worms is dependent on FOXO
(Tissenbaum and Guarente, 2001) and
deacetylates FOXO in mammalian cells
(Brunet et al., 2004; Daitoku et al., 2004;
Frescas et al., 2005; Motta et al., 2004; Van
Der Horst et al., 2004; Yang et al., 2005).
interacts with and directly
AMP-activated protein kinase (AMPK) is
an energy sensor that is activated in
response to low energy levels. AMPK
overexpression extends lifespan in worms
by ~13% (Apfeld et al., 2004; Greer et al.,
2007a). AMPK is necessary for worm
lifespan extension by one DR method in C.
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elegans (Greer et al., 2007a), but not
another (Curtis et al., 2006). The role of
AMPK in mammalian longevity is not
clear yet, but compounds that activate
AMPK have been proposed to act as DR
mimetics and can extend mouse lifespan
(Anisimov et al., 2005; Ingram et al.,
2004). AMPK is also activated by
resveratrol (Baur et al., 2006; Dasgupta
and Milbrandt, 2007; Zang et al., 2006).
AMPK acts in part via FOXO transcription
factors to extend lifespan in worms (Greer
et al., 2007a). In mammalian cells, AMPK
directly phosphorylates FOXO, which
suggests cross-talk between the AMPK
and the insulin/IGF1 pathways (Greer
et al., 2007b). AMPK activation in
mammalian cells is known to result in the
inhibition of target of rapamycin (TOR), a
protein kinase that regulates protein
translation (Inoki et al., 2003); so, part of
the effects of AMPK on longevity could
also be mediated by TOR (see below).
TOR and translation signaling
Mutation of TOR in worms extends
lifespan by 150% (Hansen et al., 2007;
Henderson et al., 2006; Vellai et al., 2003).
In addition, mutation of raptor (DAF-15),
a protein that forms a regulatory complex
with TOR, extends worm lifespan by
transcription is regulated by FOXO/DAF-
16 (Jia et al., 2004), highlighting the
intersection of the insulin receptor (IR) and
the TOR pathways. TOR regulates
translation through activation of p70S6K
and inhibition of the translation repressor
eIF4EBP. Recent studies have confirmed
the importance of regulation of translation
in longevity. Knocking down three
translational regulators, eIF4G, eIF4E and
eIF2B homologs, or p70S6K (RSKS-1) in
C. elegans extends worm lifespan (Hansen
et al., 2007; Henderson et al., 2006; Pan et
al., 2007; Syntichaki et al., 2007).
translation by a dominant-negative form of
TOR or its downstream target S6K extends
lifespan (Kapahi et al., 2004).
(Jia et al., 2004). Raptor
in flies, modulation of
FOXA/PHA-4, another transcription factor
of the Forkhead family, plays a central role
in the extension of longevity induced by
DR in worms (Panowski et al., 2007).
FOXA/PHA-4 mediates the increase in
lifespan of eat-2, a mutation that causes a
decreased eating rate in C. elegans and is
used to mimic DR (Avery, 1993; Lakowski
and Hekimi, 1998). FOXA/PHA-4 also
mediates the entire lifespan extension
caused by another DR method, in which
food is restricted in liquid medium
(Panowski et al., 2007). FOXA/PHA-4
promotes worm longevity by upregulating
a set of superoxide dismutase genes (sod-
1, sod-2, sod-4 and sod-5), whereas
FOXO/DAF-16 induces a different set of
superoxide dismutase genes (sod-1, sod-3
and sod-5) (Panowski et al., 2007).
DR-induced longevity is also mediated by
a member of the family of bZIP
transcription factors called SKN-1 in
worms (NRF1 in mammals). A mutation in
skn-1 decreases average lifespan in C.
elegans (An and Blackwell, 2003).
Expression of SKN-1 in two sensory
neurons in worms is necessary for lifespan
extension by DR where food is restricted
in liquid medium (Bishop and Guarente,
2007), which suggests that SKN-1 acts to
sense DR in these neurons. Interestingly,
SKN-1 has been proposed to act by
increasing the respiration rate in worms
(Bishop and Guarente, 2007).
Mitochondria and ROS signaling
Mitochondria have been proposed to act
as central organelles in the regulation of
because they control cellular energy
levels, reactive oxygen species (ROS)
production/detoxification and apoptosis,
all of which are crucially important in
aging (Wallace, 2005),
ETC components, Clk-1 and p66shc
One of the first pieces of evidence that
components of the electron-transport chain
(ETC) in mitochondria directly control
lifespan came from genetic studies in C.
elegans. Loss-of-function mutations in clk-
1, which encodes a protein required for the
biosynthesis of ubiquinone (coenzyme Q),
an essential cofactor in the ETC, extend
worm lifespan by 7-41% (Lakowski and
Hekimi, 1996). The extension caused by
(Lakowski and Hekimi, 1996) but might
act in the same pathway as DR, because the
clk-1 mutation does not further extend the
lifespan of eat-2-mutant worms (Lakowski
and Hekimi, 1998). Interestingly, mice that
lack one allele of the Clk1 gene live 15-
31% longer than wild-type mice (Liu et al.,
2005), which suggests that ubiquinone
plays a conserved role in lifespan
mutation appears to be
of insulin signaling
Mutation of the iron sulfur protein (ISP-1)
of the mitochondrial complex III increases
worm lifespan by 68-77% (Feng et al.,
2001). RNAi directed against several
other components of the ETC (nuo-2,
NADH/ubiquinone oxidoreductase; cyc-1,
cytochrome c oxidase), as well as against
mitochondrial ATP synthase (atp-3),
extends worm lifespan (Dillin et al., 2002;
Lee et al., 2003). This suggests that
reducing the energy production and/or
reducing the production of ROS associated
with electron transfer is crucial for lifespan
reductase; and cco-1,
In mice, the deletion of the gene encoding
p66shccauses an ~28% increase in mouse
littermates (Migliaccio et al., 1999).
Intriguingly, p66shcis present within the
mitochondrial intermembrane space and
oxidizes cytochrome c, thereby generating
ROS (Giorgio et al., 2005; Pinton et al.,
compared with wild-type
Stress-induced protein kinases: JNK
The activation of JNK, a MAP kinase
family member activated by oxidative
stress, extends longevity in worms and
flies (Oh et al., 2005; Wang et al., 2003).
The JNK pathway intersects with the
overexpression of JNK leads to a FOXO-
dependent increase in worm lifespan of
~23-37% (Oh et al., 2005). In flies, FOXO
is necessary for the lifespan extension of
mutants in which JNK is activated (Wang
et al., 2005).
The expression of another oxidative-stress-
induced protein kinase (MST-1) extends
worm lifespan by 7-18% in a FOXO-
dependent manner (Lehtinen et al., 2006).
phosphorylate FOXO in worms and
mammals and antagonize the effect of
insulin on FOXO by promoting FOXO
nuclear localization (Lehtinen et al., 2006;
Oh et al., 2005).
JNK and MST-1 directly
Genome surveillance pathways
DNA repair and telomere maintenance
Mutations in a number of DNA repair
genes (XPD, ATM, WRN, BLM, TOP3B
and POLG) cause premature aging,
suggesting that repair of nuclear and
mitochondrial DNA lesions is crucial for
the normal lifespan of an organism. This
subject is comprehensively reviewed
Journal of Cell Science 121 (4)
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elsewhere (Lombard et al., 2005).
Interestingly, mutations in humans in
some of these DNA repair genes (XPD,
ATM, BLM and WRN) and in a gene
encoding a protein involved in nuclear
architecture (lamin A) are responsible for
syndromes, in which patients display signs
Giovannoli et al., 2003; Eriksson et al.,
2003; Navarro et al., 2006). Telomere
maintenance is also crucial for a normal
lifespan. Telomere synthesis requires both
telomerase reverse transcriptase (TERT)
and telomerase RNA component (TERC).
Mice lacking TERC (mTR–/–) display
signs of accelerated aging at the sixth
generation (Rudolph et al., 1999). The fact
that rapid aging is only observed in later
generations of telomerase-deficient mice
suggests that it is the telomere length or
accumulation of DNA damage, rather than
the absence of the enzyme, that causes
premature aging. Although it is clear that
maintenance pathways are necessary for
normal lifespan, an important issue that
remains to be addressed is whether the
overexpression of genes involved in DNA-
repair or telomere-maintenance pathways
would be sufficient to extend lifespan.
known as progeroid
premature aging (De Sandre-
DNA repair and telomere
Tumor suppressors and antagonistic
Tumor suppressors are likely to help
promote longevity by preventing cancer.
Intriguingly, a few examples have indicated
that tumor suppression might occur at the
‘antagonistic pleiotropy’ theory of aging.
For example, a mouse mutant that has
constitutively activated p53 develops fewer
tumors but also shows signs of rapid aging
(Tyner et al., 2002). Mice overexpressing
p44, a truncated activating version of p53,
also have shortened lifespans (Maier et al.,
dominant-negative form of p53 in flies
extends lifespan by 32-58% (Bauer et al.,
2005). A potential explanation for these
findings is that the cellular responses
triggered by activated p53 (cellular
senescence) act as potent barriers against
cancerous lesions but also have deleterious
‘Antagonistic pleiotropy’ is not seen in all
suppressors. For example, transgenic mice
that express extra copies of p53 exhibit
tumor resistance but age normally (Garcia-
Cao et al., 2002; Matheu et al., 2007).
of longevity, illustrating the
Moreover, expression of a
in tissues (Campisi, 2005).
models expressing tumor
Transgenic mice that express both p53 and
the tumor suppressor p19Arfeven display a
16% extension in lifespan (Garcia-Cao et
al., 2002; Matheu et al., 2007). Similarly,
the tumor suppressor p16Ink4a
cellular senescence, but does not shorten
overall lifespan, when overexpressed in
mice (Matheu et al., 2004). These findings
indicate that, under some circumstances,
tumor-suppressor genes can prevent cancer
and extend lifespan.
Genetic and environmental manipulations
have revealed that aging is regulated by
specific signaling pathways. However,
whether these signaling pathways exert
their effects in all tissues or regulate aging
in specific ‘master’ tissues that then affect
aging systemically or are the rate-limiting
organs for longevity remains to be
determined for most pathways. Genome-
wide RNAi screens in C. elegans have
identified numerous genes that affect
lifespan (Chen et al., 2007; Curran and
Ruvkun, 2007; Hamilton et al., 2005;
Hansen et al., 2005; Lee et al., 2003).
Whether additional signaling modules
regulating lifespan in other species exist
will be interesting to determine. The
identification of aging-signaling pathways
has expanded the number of potential
targets for small molecules that could
stimulate longevity pathways or inhibit
aging pathways. Compounds that affect
aging could help prevent a wide range of
diseases that are age-dependent, including
cancer and neurodegenerative diseases.
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