Biochem. J. (2009) 418, 1–12 (Printed in Great Britain)
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doi:10.1042/BJ20082102
REVIEW ARTICLE
Insulin/IGF-like signalling, the central nervous system and aging
Susan BROUGHTON and Linda PARTRIDGE1
UCL Institute of Healthy Aging, GEE (Genetics, Evolution and Environment), University College London, Gower St., London WC1E 6BT, U.K.
Enormous strides in understanding aging have come from the
discovery that mutations in single genes can extend healthy lifespan in laboratory model organisms such as the yeast Saccharomyces, the fruit fly Drosophila melanogaster, the nematode worm
Caenorhabditis elegans and the mouse. IIS [insulin/IGF (insulinlike growth factor)-like signalling] stands out as an important,
evolutionarily conserved pathway involved in the determination
of lifespan. The pathway has diverse functions in multicellular
organisms, and mutations in IIS can affect growth, development,
metabolic homoeostasis, fecundity and stress resistance, as well
as lifespan. The pleiotropic nature of the pathway and the often
negative effects of its disruption mean that the extent, tissue
and timing of IIS manipulations are determinants of a positive
effect on lifespan. One tissue of particular importance for lifespan
extension in diverse organisms is the CNS (central nervous
system). Although lowered IIS in the CNS can extend lifespan, IIS
is also widely recognized as being neuroprotective and important
for growth and survival of neurons. In the present review, we
discuss our current understanding of the role of the nervous system
in extension of lifespan by altered IIS, and the role of IIS in
determination of neuronal function during aging. The nervous
system can play both endocrine and cell-autonomous roles in
extension of lifespan by IIS, and the effects of IIS on lifespan
and neuronal function can be uncoupled to some extent. Tissuespecific manipulation of IIS and the cellular defence mechanisms
that it regulates will better define the ways in which IIS affects
neuronal and whole-organism function during aging.
INTRODUCTION
profile and motor performance, as well as lowered incidence
of osteoporosis, cataract and ulcerative dermatitis [17]. Longlived invertebrate model organisms show similar improvements
in health. Drosophila lacking chico, the single fly IRS, show increased lifespan together with improved immune function [18]
and a slower decline in the one measure of behavioural health, negative geotaxis, so far examined [19]. Long-lived C. elegans with
mutations in age-1 (AGEing alteration-1), the gene encoding the
catalytic subunit of the worm PI3K (phosphoinositide 3-kinase),
or daf-2 (abnormal DAuer Formation-2), the gene encoding
the worm insulin/IGF-1 receptor, show improved thermotaxisassociative conditioning behaviour [20] and enhanced immunity
[21] with age. Inhibition of the IIS pathway in worms inhibits
tumour growth [22,23] and reduces the toxicity of aggregrateprone proteins in a worm model of Alzheimer’s disease [24], and
in humans the pathway is being targeted as a therapy for cancer
[25]. Thus inhibition of specific IIS components can improve
broad aspects of health in a range of model organisms and has
the potential to attenuate functional senescence and age-related
disease in humans.
The signalling mechanisms, biochemical changes and the
tissues that mediate the effects of lowered IIS on lifespan, health
and function are starting to be elucidated. Studies using systems
that allow temporal and spatial control of IIS manipulation, such as
feeding-induced RNAi (RNA interference) in the worm, RU486induced GAL4/UAS (upstream activation sequence) in the fly
The IIS [insulin/IGF (insulin-like growth factor)-like signalling]
pathway is ubiquitous in multicellular animals and probably
played a central role in the evolution of multicellularity itself
[1]. The pathway has diverse functions, and mutations that alter
IIS can have pleiotropic effects on growth [2–5], development
[6], metabolic homoeostasis [7] and fecundity [8–10]. Although
alterations in IIS can have severely detrimental effects, an obvious
one being diabetes in mammals, lowered IIS has emerged as an
important, evolutionarily conserved means of extending lifespan
in the nematode worm Caenorhabditis elegans, the fruit fly
Drosophila melanogaster and the mouse Mus musculus [11–15].
Improvements in public health and lifestyle in many developed
countries have resulted in increasing human life expectancy
[16]. Despite the increases in individual health that underlie this
trend, more people are hence living long enough to experience
aging-related disease and loss-of-function. It is thus important to
evaluate the health and function of long-lived model organisms as
they age, to determine whether interventions that extend lifespan
also have the potential to delay or attenuate aging-related disease
and functional senescence. Lowered IIS can indeed improve
health at older ages. For instance, long-lived mice that lack
IRS [IR (insulin receptor) substrate]-1, despite their mild insulin
resistance when young, maintain glucose homoeostasis better than
controls at older ages. They also show improvements in immune
Key words: aging, central nervous system, health, insulin/IGF
(insulin-like growth factor)-like signalling, lifespan, neuronal
survival.
Abbreviations used: CNS, central nervous system; DILP, Drosophila insulin-like peptide; FOXO, forkhead box O; dFOXO, Drosophila FOXO; GH, growth
hormone; HSF, heat-shock factor; IGF, insulin-like growth factor; IGF-1R, IGF-1 receptor; IIS, insulin/IGF-like signalling; INS, insulin-like peptides; IR, insulin
receptor; IRS, IR substrate; JH, juvenile hormone; JNK, c-Jun N-terminal kinase; mNSC, median neurosecretory cell; NPY, neuropeptide Y; Nrf2, nuclear
factor-erythroid 2 p45 subunit-related factor 2; PDK, phosphoinositide-dependent kinase; PI3K, phosphoinositide 3-kinase; PKB, protein kinase B; PTEN,
phosphatase and tensin homologue deleted on chromosome 10; dPTEN, Drosophila PTEN; SIRT, sirtuin; sNPF, short neuropeptide F; TOR, target of
rapamycin.
1
To whom correspondence should be addressed (email [email protected]).
c The Authors Journal compilation c 2009 Biochemical Society
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S. Broughton and L. Partridge
[26] and the Cre/lox system in the mouse [27], have begun
to refine the analysis, and it is becoming clear that specific
alterations of IIS in specific tissues and at specific times are
important determinants of the effect on lifespan of reduced IIS
activity. Although not yet investigated in mammals, lowered IIS in
invertebrate model organisms during the early adult period has
been found to be sufficient for lifespan extension, and to have no
effect on reproductive capacity [10,28–32]. It is thus possible to
extend lifespan while avoiding one major detrimental pleiotropic
effect, at least in invertebrates.
Tissue-specific manipulation of gene expression has identified
some of the evolutionarily conserved sites that play a role in
extension of lifespan by IIS [10,30,31,33–36]. Fat and neuronal
tissues appear to be particularly important. Fat-specific knockout
of the IR in mice [35] and overexpression of dPTEN [Drosophila
PTEN (phosphatase and tensin homologue deleted on chromosome 10)] or dFOXO [Drosophila FOXO (forkhead box O)] in
the fat body of flies [30,31] can extend lifespan. In worms, the
intestine, which serves as a fat storage organ, similarly plays a
prominent role [34]. Brain-specific knockout of the IRS-2 in mice
extends lifespan [36], as does ablation of mNSCs (median neurosecretory cells) that secrete insulin-like peptides in the brain of
flies [10]. Neuronal tissue has been implicated in the extension
of lifespan by lowered IIS in several studies in worms [33,34,37].
The discovery that the CNS (central nervous system) is involved
is perhaps not surprising given its role in co-ordination of
physiology and behaviour. In all three model organisms, the CNS
appears to play an endocrine role in controlling or co-ordinating
the release of insulin-like peptide, which so far have in general
been implicated as positive regulators of IIS, and therefore, if
anything, act to shorten lifespan [5,10]. On the other hand, the
often neuroprotective effect of IIS in the CNS itself [38,39]
presents an apparent paradox, since lowered IIS activity can both
compromise the integrity of the CNS and cause lifespan extension.
Thus the impact of lowered IIS on brain aging and function is
receiving increasing attention. In the present review, we discuss
what is known about the role of the CNS in IIS-related lifespan
extension in model organisms. We consider its endocrine role,
and the way in which cell-autonomous effects in the CNS itself
affect both neuronal and whole-organism survival and health. We
also discuss the probable future directions of work in this area,
including the implications of the findings for improving health
during aging in humans.
IIS AND AGING IN MODEL ORGANISMS
Before turning to the CNS, we will provide a brief summary
of IIS and its discovery as an evolutionarily conserved pathway
determining lifespan. The intracellular pathway (Figure 1), as so
far identified, is considerably more complex in mammals than in
the worm and the fly. In the two invertebrates, it consists of a
single insulin-like receptor, multiple insulin-like peptide ligands
and mainly single isoforms of the other signalling components.
In contrast, mammals have one insulin and two IGF ligands,
which regulate the activity of the insulin and IGF-1Rs (IGF-1
receptors) respectively. The IGF-1R and the IR, which has two
isoforms, are able to form homo- and hetero-dimers, resulting in
six types of receptor, although the physiological significance of
each is still unclear [40]. Along with multiple isoforms of the
downstream signalling components, which can also have tissuespecific expression patterns, there is potential for many layers
of IIS complexity in mammals [41]. In all three organisms, the
IIS pathway intersects with other signalling pathways, often with
more than one type of regulatory interaction and at more than one
c The Authors Journal compilation c 2009 Biochemical Society
point of the pathway. Two of these interacting pathways, TOR (target of rapamycin) and JNK (c-Jun N-terminal kinase), which have
been implicated particularly in response to nutrition and stress
respectively, are illustrated in Figure 2. The highly evolutionarily
conserved TOR pathway regulates protein synthesis and growth
in response to amino acids and growth factors [42]. Mutations that
lower the activity of this pathway can extend lifespan in worms
and flies [43,44], and IIS interacts at several points with TOR signalling to control lifespan in these organisms [43–45]. Increased
signalling in the JNK pathway, which is activated by stresses
including UV radiation and oxidative stress [46], can extend lifespan [47,48]. JNK phosphorylates many transcription factors including the key IIS effector, the forkhead transcription factor
FOXO, thus antagonizing IIS by causing nuclear localization of
FOXO.
The IIS pathway was first discovered to be involved in the
determination of lifespan in C. elegans. A screen for enhanced
longevity identified the age-1 mutation which was later mapped
to the catalytic subunit of PI3K [11,12,49]. Mutation of the
worm IR, encoded by the daf-2 gene, also extended lifespan,
and this extension required the presence of the worm forkhead
transcription factor DAF-16 [6,50–52]. In Drosophila, the
involvement of IIS in lifespan was discovered when mutations
in the single fly IR (termed dINR) and IRS, chico, were shown
to extend lifespan [13,15]. The evolutionary conservation in
mammals of the control of lifespan by the IIS pathway was
confirmed when it was found that disruption of either the insulin
or IGF pathways could extend the lifespan of mice [14,17,35,36].
This discovery has opened up the use of the much simpler and
shorter-lived invertebrate organisms to understand the role of IIS
in mammalian aging. Several types of cellular defence mechanism
have been implicated in mediating the effects of IIS on lifespan,
including xenobiotic detoxification [53–56], reduced protein
synthesis [57–59], autophagy [60], proteasomal activity [24,61]
and enhanced immunity [17,18,21,62,63]. The perturbations
of the IIS pathway that can extend lifespan, the downstream
signalling effectors involved, such as the forkhead transcription
factors, and the candidate downstream biochemical mechanisms
have been extensively reviewed recently [62,64–66].
THE CNS AND THE DETERMINATION OF LIFESPAN
BY LOWERED IIS
Individual tissues can contribute to the extension of lifespan by
producing secreted factors, such as the insulin ligands, that can act
at a distance (endocrine) or locally (paracrine), or on the secreting
cells themselves (autocrine). In addition, tissue-autonomous responses to lowered systemic IIS can occur. These may either result
in improved functioning of the tissue itself, which could contribute
to the survival of the whole organism (a cell-autonomous mechanism), or could cause the tissue to emit secreted factors. The
evidence so far suggests that the role of the CNS in IIS-related
lifespan extension is predominantly endocrine, but that cellautonomous effects may also play a role.
Endocrine regulation of lifespan
Worm, fly and mouse CNSs differ in structure, organization and
complexity, but, in all three model organisms, neuronal tissue
releases secreted factors that directly or indirectly modulate IIS
in distant tissues. Simplified models for this endocrine control of
lifespan are outlined in Figure 3, which illustrates how the CNS
and other endocrine tissues interact to regulate IIS at a distance and
thus co-ordinate aging in the whole organism. The evidence
supporting these models in each organism, the upstream control
Insulin/IGF-like signalling, the central nervous system and aging
Figure 1
3
The IIS pathway in worms, flies and mice
Signalling begins with the binding of an INS to an appropriate receptor which induces receptor dimerization and autophosphorylation of the cytoplasmic domain. Mice and other mammals have
three ligands (insulin, IGF-1 and IGF-2), whereas worms have 38 ligands and flies have seven ligands identified so far. In contrast, worms and flies have one receptor, whereas mice have three which
additionally can form heterodimers. The signal is then transduced either directly from the receptor (in worms and flies) or indirectly via the IRS (in worms, flies and mice) to PI3K (or AGE-1 in worms).
Worms and flies have a single IRS, whereas mice encode four (IRS-1–IRS-4). PI3K converts PIP2 [phosphatidylinositol (4,5)-biphosphate] into the second messenger PIP3 [phosphatidylinositol
(1,4,5)-triphosphate], and this activity is antagonized by the PTEN phosphatase (DAF-18 in worms). Elevated levels of PIP3 result in activation of PKB and PDK, and PDK then further phosphorylates
PKB, fully activating it. Flies have a single PKB, whereas worms have Akt 1, Akt 2 and SGK-1 (serum- and glucocorticoid-induced protein kinase-1), and mice have Akt 1, Akt 2 and Akt 3. Activated PKB phosphorylates the forkhead transcription factor (Forkhead TF) resulting in its exclusion from the nucleus, and thus its inactivation. Worms and flies contain a single forkhead transcription
factor (DAF-16 and FOXO respectively), whereas mice contain three [FKHR (Forkhead homologue 1), FKHRL1 (FKHR-like 1) and AFX (FOXO 4)]. Species-specific names for each pathway component
and whether they are singly or multiply encoded are indicated in the Figure.
of ligand release and the interactions with other endocrine tissues
and hormones are described.
Mammals
In mammals, the evidence supporting the endocrine regulation of
lifespan by IIS is abundant, although largely indirect. The hypothalamus in the mammalian brain is central to the regulation
of the somatotropic axis [GH (growth hormone)–IGF-1–insulin)
and the integration of many nutritional signals. The insulin-like
ligands, insulin and IGF-1, are mainly produced by the pancreas
and liver, with only a minor contribution from the brain [67].
Repression of the somatotropic axis controlling their release
extends lifespan in several mouse models and other mammalian
species (for a review, see [65]). For example, Snell and Ames
dwarf mice both have mutations that result in lack of GH and
other pituitary hormones resulting in similar phenotypes such as
small size and female sterility, and both are consistently long-lived
[68,69]. Mice with defects in GH function are also longlived. Both Lit/Lit mice, which have a mutation in the GHRHR
(GH-releasing hormone receptor), but no apparent effects on other
pituitary hormones, and mice with a complete knockout of the GH
receptor/binding protein gene, are long-lived [63,70]. Although
these animals differ in some phenotypes due to their different hormonal profiles, they share several traits including reduced IGF-1
signalling, enhanced peripheral insulin sensitivity and glucose
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S. Broughton and L. Partridge
stress-sensing JNK signalling pathway in neurons using the same
pan-neural driver was found to be sufficient to extend lifespan and
reduce the accumulation of oxidative damage in neurons [47].
Again, however, expression specifically in the DILP-producing
mNSCs was sufficient for the lifespan extension probably via the
regulation of dilp expression [48].
Nematode worms
Figure 2
Pathways interacting with IIS
(1) An evolutionarily conserved nutrient-sensing cascade involving the TOR kinase interacts with
IIS at multiple points in the pathway. Nutrients, predominantly amino acids, regulate the activity
of TOR which activates the S6 kinase (S6K), which is involved in the control of translation, cell
and organismal growth and cancer. Activated PKB activates the TOR pathway via its inhibition of
TSC1–TSC2 (tuberous sclerosis complex 1 and tuberous sclerosis complex 2). TOR signalling
via S6K also negatively feeds back on to IIS via an inhibition of PI3K activation. (2) The
conserved JNK pathway is activated in response to environmental factors such as UV radiation
and oxidative stress. JNK promotes nuclear localization of FOXO and activation of downstream
target genes, thus antagonizing IIS. Although the mechanism remains to be fully elucidated,
JNK may antagonize IIS via an inhibition of IRS and/or the direct phosphorylation of FOXO [48].
INR, insulin receptor.
tolerance which are thought to be important for lifespan extension
[64]. Mice heterozygous for an IGF-1R knockout are long-lived
[14], supporting the specific role for IGF-1 in the determination of
lifespan in mammals. The hypothalamus has thus been suggested
to be the site of the endocrine regulation of lifespan in mammals
[71].
Fruit flies
Drosophila is an important model in the study of the endocrine
regulation of aging in part because it has endocrine tissues that
resemble those of mammals (for a review, see [72]). mNSCs
in the pars intercerebralis region of the fly brain produce three
of the seven DILPs (Drosophila insulin-like peptides) and have
been suggested to be functionally equivalent to pancreatic β-cells
as producers of circulating insulin-like peptides for metabolic
homoeostasis [4]. In fact, gene-expression patterns and the cell
lineages giving rise to the mNSCs are very similar to those giving
rise to the β-cells of mammals, and there are similarities in development between the mNSCs and the mammalian anterior pituitary
and hypothalamic axis [73].
Genetic ablation of the mNSCs results in lifespan extension
presumably by reducing levels of circulating DILP-2, -3 and -5
[10]. Other studies in the fly have supported this endocrine
role of the mNSCs as the source of insulin-like peptides that
regulate aging in peripheral tissues. Expression of a dominantnegative form of p53 in the CNS using a pan-neural elavGAL
driver was sufficient for lifespan extension [74], but it was
not the case that this was due to an inhibition of neuronal
apoptosis as might be expected given the role of p53 in this
process [75]. Instead, expression in the DILP-producing mNSCs
alone was sufficient to extend lifespan, which correlated with
lowered levels of dilp2 transcript in the mNSCs and lowered
PI3K activity in the periphery [76]. Similarly, increases in the
c The Authors Journal compilation c 2009 Biochemical Society
In the worm, multiple insulin-like peptides (INS) are expressed in
many tissues throughout the body and act as receptor agonists or
antagonists [77,78]. Although this widespread expression could
suggest that INS have paracrine or autocrine effects in the tissue
in which they are expressed, some INS-expressing tissues play an
endocrine role in IIS-related lifespan extension.
Specific sensory neurons have been found to influence lifespan
in a DAF-16/FOXO-dependent manner [79]. Ablation of a subset
of gustatory neurons resulted in lifespan extension that was found
to be dependent on daf-16 and had no effect in a daf-2 (encoding
the worm IR) mutant, suggesting that these neurons affect lifespan
by modulating IIS in distant tissues. In contrast, the lifespan extension due to ablation of olfactory neurons was found to be
only partially dependent on daf-16, suggesting the involvement
of unknown secreted factors. Although INS production has not
been directly examined, these sensory neurons are thought to be
the source of INS to regulate IIS in distant tissues [79].
Two tissues, the CNS and intestine, both respond to IIS and
contribute a further level of endocrine signalling that involves the
secretion of diffusible factors, possibly INS and unknown factors,
to regulate DAF-16 throughout the animal. Mosaic worms which
were composed of wild-type and mutant daf-2 cells were longlived despite containing many wild-type daf-2 cells, suggesting
that secondary factors were released that in turn controlled lifespan [80]. Most of these mosaics contained at least some neuronal
daf-2-mutant cells, and a specific role for neurons was later confirmed in a study which found that expression of wild-type age-1
(PI3K) or daf-2 in neurons, but not in intestine or muscle, could
completely rescue the extended lifespan phenotype of age-1or daf-2-mutant animals [33]. That other tissues in the body could
not respond with altered IIS because they were mutant, and that
such overexpression in a wild-type animal did not shorten lifespan,
supported the notion that the lifespan extension of age-1 or daf-2
mutants was due to lowered IIS in neurons alone and that diffusible
factors other than insulin-like ligands were secreted by neurons
to control lifespan [33].
In contrast, a study analysing the requirement for DAF-16
activity in specific tissues using various genetic methods reported
that DAF-16 activity in neurons accounts for only a small part of
the lifespan extension of daf-2 mutants, and a far greater effect was
due to expression of DAF-16 in intestinal cells [34]. This study
further suggested that DAF-16 activity in the intestine, and to a
lesser extent in neurons, controlled the production of a secondary
signal that regulated DAF-16 activity in distant cells. The discrepancy in how much of a contribution neuronal cells made to the
control of lifespan in these two studies could have been due to
non-specific effects of the various trangenes used, the modulation
of different IIS components (i.e. age-1, daf-2 or daf-16), or
variable endocrine effects of the tissue-specific manipulations
depending on the genotype of the rest of the worm. More recently,
a further analysis of the tissue-restricted and endocrine effects
of IIS using tissue-specific expression of new, wild-type age-1
transgenes to rescue the extended lifespan of age-1 mutant worms
and a wild-type daf-16 transgene to rescue the shortened lifespan of daf-16/age-1-mutant worms was performed [37]. Expression of the wild-type age-1 transgenes either in different subsets
Insulin/IGF-like signalling, the central nervous system and aging
Figure 3
5
Models for the endocrine regulation of aging by IIS in worms, flies and mice
(A) In worms, an endocrine pathway resulting from IIS in a number of different tissues is involved in the regulation of lifespan. Sensory neurons (gustatory and olfactory) express ins genes and
are thought to secrete INS and other factors in response to food and unknown environmental cues to regulate lifespan in both a DAF-16-dependent and non-dependent fashion in peripheral tissues
[79]. Two tissues, the CNS and intestine, subsequently respond to IIS and produce putative secondary signals, which could include other INS and unknown non-INS factors, to regulate DAF-16
activity throughout the body. The gonad is also involved in the determination of lifespan via the regulation of DAF-16 activity in the intestine. (B) DILPs 2, 3 and 5 produced by mNSCs in the pars
intercerebralis region of the brain are thought to be released into the circulatory system via neuronal contacts at the Drosophila heart [3] and activate the IR in peripheral tissues. Expression of these
DILPs is regulated by nutrient intake, JNK, p53 and sNPF. Fat tissue [both the pericerebral and abdominal fat bodies (FB)] is a direct target of the DILPs; down-regulation of IIS via expression of
dFOXO in fat extends lifespan [30,31] suggesting that both fat tissues produce secondary humoral factors that regulate aging in peripheral tissues. Pericerebral fat body IIS in turn can feedback on
to the mNSCs via an unknown secreted factor to down-regulate dilp expression in the mNSCs. Two other tissues have been implicated in the endocrine regulation of aging. The adult ring gland
comprises the corpora cardiaca which produces AKH (adipokinetic hormone) that is analogous to mammalian glucagon, and the corpora allata which produces JH, reduced levels of which sometimes
correlate with lifespan extension in IIS mutants, although direct evidence for its role is lacking. The mNSCs make direct contacts with the ring gland providing a possible neural control of JH
expression by the mNSCs. The female ovary produces the steroid hormone ecdysone (20E), reduced levels of which have been implicated in the control of lifespan [155]. Although a direct control
by IIS of 20E has been demonstrated in larvae [156], a link between IIS and 20E in adults has not yet been shown. (C) A very simplified model is provided to indicate that the CNS is central to the
control of the release of GH and its downstream effects including regulation of IGF-1 levels. Food intake results in the hypothalamus promoting hormone release from the pituitary. The hypothalamus
also produces NPY which feeds back to regulate food intake. The pituitary hormones, including LH (luteinizing hormone), FSH (follicle-stimulating hormone) and GH, cause increases in steroid sex
hormones from the gonad and IGF-1 predominantly from the liver. Food intake also results in increased insulin output from the pancreatic β-cells. The circulating insulin and IGF-1 then activate IIS
in peripheral tissues. Adipose tissue may be important in lifespan extension due to reduced IIS, although the mechanism is not known. Mice with a fat-specific knockout of the IR (FIRKO mice) are
long-lived, have reduced fat mass and do not show age-related obesity and metabolic changes although their food intake is normal [157]. In each model, broken lines indicate speculative elements
and red stars indicate IR/IGF-1R-mediated signalling.
of neurons or in the intestine could rescue the lifespan of age-1mutant animals in a graded fashion, suggesting that cells in these
tissues could act equally to produce endocrine factors. DAF-16
had less effect on the lifespan of daf-16/age-1-mutant animals
when expressed in either the CNS or the intestine than when
expressed in both tissues together, suggesting that the response
of multiple tissues to IIS is required for lifespan extension.
Taken together, these studies suggest a model whereby sensory
neurons release INS and other factors in response to unknown
environmental cues to regulate IIS in distant tissues throughout
the worm. The CNS and intestine both respond to these secreted
factors in a DAF-2/DAF-16-dependent manner to regulate the
secretion of secondary diffusible factors that in turn regulate
DAF-16 independently of DAF-2 in distant tissues. Although the
identities of the diffusible factors are unknown, JNK and HSF
(heat-shock factor)-1 can regulate DAF-16 in a DAF-2-independent manner, and it has been suggested that interactions between
proteins regulating these pathways and IIS allow for the complex
co-ordination of DAF-16 activity throughout the worm [37].
Upstream factors regulating insulin-like ligand secretion
To what do the insulin-like peptide-producing cells respond to
regulate the secretion of insulin-like ligands in the invertebrate
model organisms and how does this compare with the control of
the mammalian somatotropic axis?
As described above, a role for olfactory and gustatory neurons
in the endocrine control of lifespan in worms has been identified,
but the environmental factors regulating them and the identity,
roles and target tissues of the INS released by these neurons
are unknown. In the fly, a role for gustatory sensory neurons in
IIS-related control of lifespan has not yet been tested. However,
signalling in olfactory neurons has been found to modulate
lifespan, indicating evolutionary conservation of this olfactory
mechanism [81]. Exposure to yeast odorants reduced the lifespan
of dietary-restricted flies and mutation of an odorant-receptor
molecule severely disrupted olfaction and extended lifespan in
fully fed flies [81]. Although the dependence on FOXO was not
tested, no changes in dilp or a FOXO target-gene expression were
detected in the odorant-receptor mutant, suggesting that, similarly
to worms, olfactory control of aging in flies may be, to a large
extent, IIS-independent.
The DILP-producing mNSCs of flies, however, have been found
to be regulated by a number of factors, some of which suggest
evolutionary conservation with mammals. As described above,
dilp2 expression is sensitive to various stresses via p53 and JNK
signalling. In addition, the mNSCs have been shown to respond to
nutrient intake to control the expression of dilp5, but not dilp2 and
dilp3 [5]. Interestingly, dilp2 and dilp3, but not dilp5, expression
c The Authors Journal compilation c 2009 Biochemical Society
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S. Broughton and L. Partridge
in the mNSCs and IIS in peripheral tissues have been found to
be regulated by sNPF (short neuropeptide F), the Drosophila
orthologue of mammalian NPY (neuropeptide Y) [82]. Similarly
to NPY, sNPF is expressed in the CNS and regulates food intake,
growth, metabolism and lifespan [83]. Rat insulinoma (INS-1)
β-cells similarly up-regulate insulin expression in response to
NPY administration, further supporting the evolutionary conservation of NPY/sNPF regulation of insulin-like ligand expression between flies and mammals [82]. DILP2 secretion by the
mNSCs has been found to be controlled by serotonergic neurons to
control growth [84]. A connection between 5-hydroxytryptamine
(serotonin) and IIS has also been observed in mammals, where
5-hydroxytryptamine had effects on insulin secretion by the
pancreas in rat and mouse models [85] and on IGF-1 release from
human granulosa cells [86]. Thus, similarly to the hypothalamus
in mammals, the mNSCs appear to be the site of the integration
of many signals to control insulin-like ligand secretion and
peripheral IIS.
involved [72]. Ecdysone in adult flies is produced in the ovarian
follicle cells and adult-specific ecdysone signalling has been
found to modulate lifespan in a sex-specific fashion, but it is not
yet known if it and reduced IIS affect lifespan by overlapping or
distinct mechanisms [90]. JHs are major developmental regulators
in insects which are also involved in adult female vitellogenesis,
oogenesis and entry into reproductive diapause in response to
changes in photoperiod or temperature. Although some studies
suggest that JH levels are involved in the regulation of lifespan
[91,92], low JH production does not always correlate with lifespan extension in IIS mutants [93]. The Drosophila IR is
expressed in the JH-producing gland (corpora cardiaca/corpora
allata) of adult Drosophila and the mNSCs make axonal contacts
with this gland, such that IIS has the potential to regulate JH
production, but further experiments are needed to confirm a direct
role in lifespan determination.
Summary
Other endocrine tissues and secondary factors
Other hormonal pathways and endocrine tissues appear to play
roles in mediating the lifespan-extending effect of reduced IIS.
Spatial analysis has identified fat as an important tissue for IIS-related lifespan extension. Fat-specific knockout of the IR in mice
[35] and fat-specific overexpression of dPTEN or dFOXO in
flies [30,31] can extend lifespan. As described above, DAF-16
activity in the intestine of worms results in longevity effects and
this tissue serves as a fat storage organ [34,37]. The endocrine
role of the intestine in worms is described in detail above. In flies,
both head and abdominal fat-body expression of dFOXO extended lifespan [30,31]. Head fat-body expression of dFOXO
resulted in lowered dilp2 expression in the mNSCs suggesting
that the increase of lifespan occurred via feedback by dFOXO
to regulate dilp expression in the mNSCs [30]. In contrast, dilp
expression was not affected by abdominal fat-body expression of
dFOXO [32]. It is therefore not clear whether lifespan extension
due to lowered IIS in fat tissue is mediated by a fat-body signal that
down-regulates dilp expression [30] or by some other mechanism
[32]. The evolutionary conservation of fat tissue in IIS-related
lifespan extension is thus well established. In all three organisms,
it is likely that secondary signals are released by fat tissue in
response to lowered IIS, but the identity of these putative signals
and the downstream effectors and mechanisms are unknown.
The gonad has been implicated in regulating the effect of
secreted insulin-like ligands on distant tissues. Removal of the
germline in the worm extended lifespan via an effect on DAF-16
activity in the intestine [34,87], and in the fly it extended
lifespan and lowered IIS as shown by up-regulation of FOXO
target genes [88]. Although these studies demonstrate the
evolutionary conservation of the gonadal regulation of lifespan,
it is probably not via the control of insulin-like peptide release at
least in flies. In germline-less flies, dilp expression was actually
increased, suggesting that the reduced IIS observed was due to a
modulation of insulin sensitivity by the gonad [88]. Interestingly,
transplantation of the ovaries of young mice into old females
extended the remaining lifespan of the recipient [89], supporting
the evolutionary conservation of the role of the gonad in
integrating lifespan and reproduction. As reduced reproduction
is not required to extend lifespan, but is often correlated with it,
a goal of future studies will be to determine how IIS can affect
lifespan and reproduction separately and co-ordinately.
In flies, other secondary signals such as the lipophilic hormones,
ecdysone and JH (juvenile hormone) [9,90], which play important
roles during insect development, have been suggested to be
c The Authors Journal compilation c 2009 Biochemical Society
Recent advances in aging research have confirmed the neuroendocrine regulation of IIS-related lifespan extension but many
questions remain, including the following. (i) Which specific
insulin-like peptides modulate IIS in each responsive tissue?
(ii) What are the cues and mechanisms controlling their secretion
and action? (iii) What are the roles of binding proteins in targeting
and/or modulating the activity of the insulin-like peptides?
(iv) What are the secondary factors released in response to IIS
by other endocrine tissues?
Next, we consider the CNS as a tissue that responds to IIS and
discuss how cell-autonomous effects in the CNS itself affect both
neuronal and whole-organism survival and health.
Cell-autonomous effects of IIS in the CNS
Although the brain has long been thought to be insulin-insensitive,
the IIS pathway has been found to play roles in many aspects of
CNS development and function in diverse organisms, including
axonal guidance [94], neurogenesis [38], neuronal survival and
protection from apoptosis [39] and cognition [95]. Thus the CNS
is also a downstream target of IIS with cell-autonomous responses
that could affect neuronal survival and neurodegenerative disease,
and CNS function. These processes could all ultimately affect the
aging of the whole organism.
The role of IIS in neuronal survival and CNS function
In mammals, adult brain function and integrity require a constant
input of trophic factors from local (e.g. glial cells) and peripheral
sources including steroid hormones and growth factors such
as insulin and IGF-1 that cross the blood–brain barrier [96].
Both insulin-like ligands are neurotrophic since they can support
neuronal growth, survival and differentiation in the absence of
other growth factors [67]. Insulin and IGF-1Rs are expressed
throughout the brain, but most abundantly in specific regions such
as the cerebral cortex, hippocampus, thalamus, hypothalamus,
spinal cord and retina [97]. In the adult CNS, the activation of IIS
by insulin and IGF-1 is stimulatory to neuronal survival via the
action of PI3K to directly inhibit apoptosis [98,99]. The mechanism involves the activation of PKB (protein kinase B; also
known as Akt), which protects against apoptosis by inactivating
proteins involved in the apoptotic machinery [100,101], inhibiting GSK-3β (glycogen synthase kinase-3β) [102], inactivating
downstream transcription factors, such as FOXO [103], and downregulating the transcriptional activity of p53 [104]. In addition
Insulin/IGF-like signalling, the central nervous system and aging
to promoting the survival of neurons, IIS is beneficial to CNS
function. The IR is involved in synaptic plasticity [105,106]
and plays a modulatory role in learning and memory [107].
Signalling via the IR is also involved in the maintenance
of synapses that contributes to brain circuit formation and
experience-dependence plasticity [108], and mice with reduced
IGF-1 levels showed impaired performance of a hippocampaldependent spatial memory task [95].
However, the roles and mechanisms of action of insulin and
IGF-1 in the CNS have not been fully elucidated and it appears
that both ligands can in some circumstances be inhibitory to
neuronal survival. High levels of insulin in the brain are associated
with neurotoxicity, which is thought to be due to increased production of free radicals and elevated oxidative stress [109]. Insulin
has also been found to induce neuronal cell death at physiologically high or low glucose concentrations in an in vitro rat hippocampal culture system [110]. Likewise, IGF-1 has been proposed
to be capable of inhibiting neuronal survival in some circumstances, via the negative regulation of SIRT (sirtuin) 1 expression
[111,112]. Sirtuins are NAD+ -dependent protein deacetylases that
regulate gene expression (for reviews, see [113–115]), and their
overexpression in yeast and worms has been found to extend
lifespan, which in the worm requires the FOXO transcription
factor [116,117]. In mammals, of the seven members of the Sir2
family, SIRT1 is the closest to yeast Sir2 [118] and has been
shown to have a protective effect on the survival of neuronal
cells [119]. The balance of positive and negative effects of IGF1 on neuronal survival would thus depend on metabolic status
and NAD levels [111]; however, the mechanism by which IGF-1
regulates SIRT1 and its relevance to neuronal survival is unknown.
SIRT1 itself has also recently been shown to have both pro- and
anti-aging functions [120]. Inhibition of SIRT1 in mice resulted
in a shortened lifespan, but also decreased IGF-1 signalling and
enhanced resistance to oxidative stress of neuronal cells [120].
Sirtuin biology adds another layer of complexity that will affect
the outcome of IIS manipulations on neuronal survival.
Impact of lowered IIS on natural neurodegeneration and functional
senescence
The study of natural age-related neurodegeneration and its relationship to age-related functional decline (functional senescence) and IIS is in its infancy. In humans, normal aging is
associated with a decline in plasma levels of IGF-1 [121], which
is associated with neuronal aging and neurodegeneration, and
even healthy older people tend to show mild cognitive deficits
[96]. In contrast, plasma insulin levels tend to increase with age
due to progressive peripheral insulin resistance which can result in
neurotoxic levels of insulin in the brain [109,122]. Thus reduced
IIS in the CNS resulting from lower levels of peripheral IGF-1
and increased IIS due to hyperinsulinaemia during normal aging
are both associated with brain senescence in humans [123].
Results are beginning to emerge from studies in the model
organisms that specific IIS genetic manipulations can ameliorate
some forms of behavioural senescence, suggesting that they have
the potential to reduce neurodegeneration or improve neuronal
function with age. For instance, although the nervous system of
C. elegans shows few signs of degeneration during normal aging,
old animals do display behavioural defects [124] that could in part
be due to compromised CNS functioning at late ages. Long-lived
age-1 and daf-2 mutants show improved thermotaxis learning
behaviour, a type of associative conditioning, with age which was
suggested to be due to increased resistance to neuronal stresses
and disease [20,125]. Changes in locomotor activity did not appear
to be involved, suggesting that the improved learning behaviour
7
of these animals was due to enhanced associative conditioning.
However, the long-lived animals did show increased thermal
perception compared with controls, which could have contributed
to their improved thermotaxis-learning behaviour.
In Drosophila, although gross changes in CNS integrity with
normal aging have also not been reported, specific neuronal
cell types have been found to degenerate with age, which correlates with the senescence of experience-dependent behaviours
modulated by these neurons [126], and flies show AMI (agerelated memory impairment) [127]. The chico1 mutation in flies
has been shown to slow age-related decline in motor function
[19], suggesting that lowered IIS has the potential to ameliorate
CNS-based declines. However, the functional measure used in
the study was negative geotaxis and it is not known whether the
improvement in this behaviour was due to attenuated age-related
degeneration of the CNS or in other organ systems required for
climbing ability, such as muscle.
Some mammals with reduced activity of the somatotropic
axis, such as long-lived Ames dwarf mouse and the GHRKO
(GH receptor knockout) mouse [68,128], have improved memory
retention with age [129,130]. For the Ames mouse, these improvements in cognitive function could be due to increased local
production of IGF-1 that has been found to occur in the hippocampus in response to the low circulating levels of this ligand
[131]. Interestingly, long-lived mNSC-ablated flies show an
attenuated decline in negative geotaxis behaviour and increased
levels of dilp4 (S. Broughton and L. Partridge, unpublished work).
This dilp is not expressed in the mNSCs, and preliminary data
suggest that it is expressed at low levels in the brain. Thus some
IIS manipulations may result in specific compensatory increases
in insulin-like ligands that protect the CNS from the neurotoxic
effects of reduced systemic IIS.
Given the neurotoxic effect of age-related hyperinsulinaemia
in mammals, it is also possible that reducing the expression or
activity of specific components of the IIS pathway that mediate
the response to insulin in the mammalian brain could have neuroprotective effects that ameliorate natural neurodegeneration. This
hypothesis is supported by the finding that a brain-specific
knockout of IRS-2 in mice was sufficient for lifespan extension
[36]. However, it is not known whether these mice are in fact
protected from age-related neurodegeneration or whether they
display any improvements in brain function with age compared
with control animals.
Impact of lowered IIS on neurodegenerative disease
The dysregulation of IIS in the CNS is also thought to play a major
role in the pathology of neurodegenerative diseases, which are
associated either with low serum IGF-1 levels or with high levels,
resulting in IGF-1 resistance. For example, most results indicate
that insulin and IGF-1 resistance are linked to the development of
late-onset forms of Alzheimer’s disease and neurodegeneration
associated with Type 2 diabetes (for reviews, see [132–135]).
Many potential mechanisms may exist to mediate this connection,
which is in general poorly understood, but several studies have
suggested that insulin and IGF-1 may directly affect the molecular
pathologies underlying neurodegenerative disease. On the one
hand, some studies suggest that insulin and IGF-1 signalling
may protect against such pathologies. Insulin and IGF-1 are both
involved in the control of β-amyloid metabolism, involved in
the pathogenesis of Alzheimer’s disease in a complex manner,
and it has been suggested that the pathogenic event triggering
Alzheimer’s disease is the development of IGF-1 resistance at the
blood–brain barrier [132]. Furthermore, the hippocampus of
the long-lived Ames mice, which has been shown to produce
c The Authors Journal compilation c 2009 Biochemical Society
8
S. Broughton and L. Partridge
IGF-1 locally, was found to be resistant to the deleterious effects of
β-amyloid peptide [136]. On the other hand, more recent studies
suggest that reductions in insulin signalling which extend lifespan
may actually confer a protective effect against abnormal protein
aggregation in neurodegenerative disease. In a worm model of
Alzheimer’s disease, lowered IIS resulted in reduced toxicity
of the Aβ-(1–42) [amyloid β-peptide (1–42)] via the regulation of
the downstream transcription factors HSF-1 and DAF-16, which
mediate cellular detoxification mechanisms [24]. Modulation of
the IIS pathway could also affect neurodegenerative disease by its
regulation of TOR kinase, which has been shown to modulate the
neurotoxicity of aggregrate-prone proteins such as polyglutamine
expansions and mutant tau that are involved in fly and mouse
neurodegenerative disease models [137,138]. Hence the effects of
insulin and IGF-1 dysregulation on neurodegenerative processes
appear to be complex and may have positive or deleterious
effects, possibly depending upon the level and mechanism of
dysregulation.
Impact of lowered IIS in the CNS on whole-organism aging
The cell-autonomous effects of lowered IIS in the CNS, described
above, whether beneficial or deleterious to neuronal survival,
could affect the survival of the whole organism via an effect
on the integrity and functioning of the CNS with age. Before we
discuss the evidence that beneficial effects on neuronal survival
in the CNS contribute to IIS-related lifespan extension, it should
be noted that the relationship between neurodegeneration and
lifespan is far from clear. For instance, although neurodegeneration is usually associated with shortened lifespan [139], a
Drosophila mutant displaying neurodegeneration and behavioural
deficits was found to have a normal lifespan [140]. This suggests
that the two processes can be uncoupled in some circumstances
and raises the possibility that some degree of neurodegeneration
or reduced CNS function could occur in long-lived IIS mutants
without impinging on the lifespan of the organism.
Some long-lived IIS mutants, however, have been found to show
improved cognitive or behavioural function with age, such as
the Ames dwarf mouse described above, suggesting that lowered
peripheral IIS can have beneficial effects on the CNS; however,
it is not known whether these putative effects in the CNS are
required for or contribute to the extended lifespan of these animals.
In worms, lowered IIS in neurons alone was suggested to be sufficient for lifespan extension in one study [42], and in another it
was found to have an effect in combination with lowered IIS in
other tissues [37]. Despite some discrepancies, these studies suggested that endocrine outputs from the CNS played a large part
in the lifespan extension, and it is not known to what extent cellautonomous responses to lowered IIS in neurons contribute. In
flies, there is as yet no direct evidence to suggest that downregulating IIS in the CNS has cell-autonomous effects that are
either sufficient for or contribute to lifespan extension.
The most direct evidence comes from the Irs2 brain-specific
knockout mice. The global knockout of Irs2 resulted in shortened
lifespan due to progressive diabetes [17,141], but when the deletion was brain-specific, the mice were long-lived despite the
obesity and insulin resistance that also resulted from this mutation
[36]. As described above, these Irs2 brain-specific knockout mice
were suggested to be long-lived because they were protected
from the neurotoxic effects of age-related increases in insulin
levels [36]. If true, this would suggest that enhanced neuronal
survival or function due to lowered IIS can contribute to lifespan
extension in some circumstances. However, the peripheral effects
on insulin resistance and obesity of the Irs2 brain-specific
knockout [36] raises the possibility that altered neuroendocrine
c The Authors Journal compilation c 2009 Biochemical Society
function could play a part in the lifespan extension. Indeed, IRS2 in a subpopulation of hypothalamic neurons plays an insulinresponsive role in energy homoeostasis and growth [142], and the
activity of the IR in the brain has been shown to regulate white
adipose tissue mass and glucose levels in mice [143].
Interestingly, in contrast with the global knockout of IRS-2 [36],
homozygous global deletion of Irs1, which is also expressed in the
brain, extended the lifespan of mice and improved some aspects
of health, such as glucose homoeostasis and markers of skin,
bone, immune and motor function [17]. It will be very interesting
and important to determine the cognitive status of these mice as
well as the brain-specific Irs2-knockout mice [36] as they age
under variable environmental conditions. Taken together, these
results reflect the tissue-specific roles and differential coupling
to downstream signalling components of the IRS proteins in
mammals [41], and indicate that modulation of specific IIS components can either contribute to, or be sufficient for, lifespan
extension under certain conditions. However, the degree to
which enhanced neuronal survival or function due to altered IIS
contributes to lifespan extension is still unclear.
Putative CNS-specific mechanisms contributing to IIS-related lifespan
extension
If we assume that in some circumstances lowered IIS can
contribute to lifespan extension by promoting neuronal survival
and functioning of the nervous system with age, what are the
candidate cell-autonomous mechanisms mediating the response?
Indirect evidence has implicated autophagy. Autophagy is crucial
for cell survival under extreme conditions, by providing energy
via the catabolysis of cytoplasmic components [144]. It was first
identified as a potential longevity assurance mechanism downstream of IIS because it is required for the lifespan extension
of IIS-mutant worms [60], although it is not known whether
autophagy specifically in the CNS is required for the lifespan
extension of these animals. In flies, reduced autophagy is associated with short lifespan and neurodegeneration [139], suggesting that it is required for the basic maintenance and survival of
neurons. Promoting levels of autophagy in neurons alone was
sufficient to extend lifespan and increase resistance to oxidative
stress, possibly via the prevention of age-dependent accumulation
of damage in neurons [145]. As autophagy is predominantly
regulated by the TOR pathway, lowered IIS can induce it via the
reduced action of PDK (phosphoinositide-dependent kinase) 1/
PKB on TOR kinase [146]. However, the unexpected finding that
a mouse model of Hutchinson–Gilford progeria showed extensive
basal activation of autophagy and metabolic changes usually
associated with lifespan extension suggests that chronic activation
of this pathway can be pro-aging [147], and that an optimal,
intermediate level of autophagy is required for lifespan extension.
Comparative microarray analysis of long-lived IIS mutant
animals has identified a number of other evolutionarily conserved
molecular processes, including xenobiotic detoxification, reduced
protein synthesis and enhanced immunity, which are candidates
for mechanisms mediating IIS-related lifespan extension [62].
Little direct experimentation has so far been performed to test
the array-based predictions that these mechanisms are sufficient
to extend lifespan, but it was recently shown that up-regulation
of Keap1 (Kelch-like ECH-associated protein 1)/Nrf2 (nuclear
factor-erythroid 2 p45 subunit-related factor 2) signalling in the fly
and SKN-1 (SKiNhead 1) in the worm extends lifespan [148,149].
Nrf2 transcription factor and its specific repressor Keap1 mediates
cellular responses to oxidative stresses and xenobiotics in flies.
Activation of signalling by reduced expression of keap1 resulted
in increased tolerance to oxidative stress and extension of lifespan
Insulin/IGF-like signalling, the central nervous system and aging
[149]. In the worm, phase-two detoxification mechanisms which
provide defence against oxidative stress are regulated by the Nrf2related SKN-1, the expression of which is required for lifespan
extension due to dietary restriction in worms [150]. SKN-1 is
directly inhibited by IIS, mutations in SKN-1 suppressed IISrelated lifespan extensions, and increased expression of SKN-1extended lifespan [148].
Although less is known about whether modulation of any
of these mechanisms in the CNS plays a part in promoting
neuronal or whole-organism survival, some indirect evidence does
exist. Although it is not known how reducing protein synthesis
might contribute to lifespan extension, it has been shown that
it confers resistance to heat stress on worms [58], leading to
the suggestion that the mechanism is connected to the activity of
protein chaperones [62]. Ubiquitous overexpression of such HSFs
can extend lifespan in both worms [151,152] and flies [153], and
recently the expression of HSFs restricted to the CNS in flies
was found to be sufficient to extend lifespan [154]. Alternatively,
reduced protein synthesis may result in an increase in autophagy,
up-regulation of which in neurons, as described above, has been
shown to be sufficient for lifespan extension [145].
CONCLUSIONS AND FUTURE PERSPECTIVES
The often beneficial effect of IIS on neuronal survival and CNS
function has presented an apparent paradox, since lowered IIS activity has the potential to both compromise the integrity of the CNS
and extend lifespan. However, the potential for IIS in the CNS to
have both negative and positive effects, together with the tissue
and timing requirements and the sensitivity to environmental
conditions of the lifespan-extending IIS manipulations, suggests
that no paradox exists. Moreover, the finding that a Drosophila
mutant with significant neurodegeneration and behavioural
deficits has a normal lifespan [140] illustrates that neurodegeneration and mortality are only loosely coupled. This finding
raises the possibility that IIS manipulations may not always be
beneficial to CNS integrity and functioning even when they extend
lifespan, if positive effects of lowered IIS on peripheral organ
systems outweigh any negative effects in the CNS.
Although some aspects of health have been shown to be
improved, the functional status with age of many long-lived
animals remains to be determined. Thus, in the short term, there
is a great need for investigations to determine the relationships
between neurodegeneration, behavioural and cognitive function
and lifespan. In the longer term, the discovery of the cellular and
biochemical mechanisms mediating altered functioning of the
CNS in long-lived animals will further the identification of potential therapeutic targets of functional senescence and neurodegenerative disease.
The discoveries made in worms, flies and mice on the extension
of lifespan by lowered IIS suggest that manipulation of the
right signalling component in the right tissue in the adult can
extend lifespan with few detrimental effects or even improved
health and function. Together with the identification of possibly
evolutionarily conserved tissue-specific longevity assurance
mechanisms, this raises the exciting possibility that future
research will identify pharmacological targets and interventions
capable of extending lifespan and maintaining the function of the
nervous system during aging.
ACKNOWLEDGEMENTS
We thank M. Piper, F. Kerr and M. Hodges for comments on the manuscript, and
D. Withers for helpful suggestions prior to submission.
9
FUNDING
Our work is supported by the Wellcome Trust [grant number 066750/A/01/Z].
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