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Chun-Lei
Cheng, Zhen Wang, Dian-Dong Li, Institute of Medicinal
Biotechnology, Chinese Academy of Medical Sciences and Peking Union
Medical College, Beijing 100050, China
Tian-Qin Gao, Binzhou Medical College Affiliated Hospital,
Binzhou 256603, Shandong Province, China
Supported by the Major State Basic Research Development
Program of China (973 Program), No. G2000057010
Correspondence to: Professor Dian-Dong Li, Institute of
Medicinal Biotechnology, Chinese Academy of Medical Sciences and
Peking Union Medical College, 1 Tiantan XiLi, Beijing 100050,
China. ddli@public3.bta.net.cn
Telephone: +86-10-63165289
Fax: +86-10-63017302
Received: 2004-11-15
Accepted: 2004-12-03
Abstract
The insulin/insulin-like growth factor 1 (IGF-1) signaling
pathway is evolutionary conserved in diverse species including C.elegans,
saccharomyces cerevisiae, Drosophila melanogaster, rodents and
humans, which is involved in many interrelated functions that are
necessary for metabolism, growth and reproduction. Interestingly,
more and more research has revealed that insulin/IGF-1 signaling
pathway plays a pivotal role in the regulation of longevity.
Generally, disruption of the power of this pathway will extend
longevity in species ranging from C.elegans to humans. The
role of insulin/IGF-1 in longevity is probably related to stress
resistance. Although the underlying mechanisms of longevity are not
fully understood, the Insulin/IGF-1 signaling pathway has attracted
substantial attention and it will be a novel target to prevent or
postpone age-related diseases and extend life span. In this review,
we mainly focus on the similar constitution and role of
insulin/IGF-1 signaling pathway in C.elegans, saccharomyces
cerevisiae, rodents and humans.
� 2005
The WJG Press and Elsevier Inc. All rights reserved.
Key words: Insulin; Insulin-like growth factor 1; Longevity;
Caloric restricted
Cheng CL, Gao TQ, Wang Z, Li DD. Role of insulin/insulin-like growth
factor 1 signaling pathway in longevity. World J Gastroenterol
2005; 11(13): 1891-1895
http://www.wjgnet.com/1007-9327/11/1891.asp
INTRODUCTION
Why and how do we age? What regulates longevity? Researchers
have asked these questions for long, and some answers are finally
emerging. However, the underlying mechanisms of longevity remain
elusive.
Recently, some researchers have concluded that
the incidence of insulin resistance increases with age and type 2
diabetes can accelerate aging syndromes. Concomitant reduction in
plasma insulin and plasma glucose levels, which implies increased
sensitivity to insulin, emerges as a hallmark of increased longevity[1,2].
Interestingly, organisms including C.elegans, saccharomyces
cerevisiae, Drosophila melanogaster, rodents and humans have
similar insulin/insulin-like growth factor 1 (IGF-1) signaling
pathway and mutations in pathway extend life span[3].
Thus, the potential link between ageing and insulin/IGF-1 signaling
has attracted substantial attention.
Here we will review the evidence for the role of
insulin/IGF-1 signaling pathway in the control of longevity in
species ranging from C.elegans to humans.
Caenorhabditis elegans
The insulin/IGF-1 signaling pathway remains in the C.elegans.
The pathway is composed of proteins encoded by daf-2, age-1, akt-2,
daf-16 and daf-18, which not only regulate the dauer diapause and
reproduction but also influence the lifespan of the adult[4].
The gene daf-2 encodes insulin/IGF-1 receptor-like protein, which is
probably the ancestor of human insulin receptor, IGF-1 receptor and
insulin related receptor, because the predicted DAF-2 protein is 35%
identical to the human insulin receptor, 34% identical to the IGF-1
receptor, and 33% identical to the human insulin receptor-related
receptor[5].
Animals with weak daf-2 mutation age slowly and have an extended
lifespan compared to wild-type[5].
The downstream of the gene age-1, which encodes the protein similar
to the mammalian p110 catalytic subunit of PI3K, leads to a 65%
increase in mean life span[6].
These effects need the integrity of daf-16, which can help the
formation of the dauer. Dauer diapause is a nonfeeding
stress-resistant larval state evolved for endurance and dispersal
under adverse conditions. The protein daf-16 is similar to a family
of mammalian forkhead transcriptional regulator (FOXO). Also, daf-16
encodes a member of the hepatocyte nuclear and plays a central role
in the regulation of lifespan[7].
Interestingly, daf-2 also regulates metabolism.
The mutation of daf-2 makes the higher expression of antioxidant
enzymes such as catalase and superoxide dismutase (SOD)[3,8].
The downstream gene of daf-2, age-1 mutation can protect the decline
of catalase with age. Also, DAF-16 is a key regulator of heat and
oxidative stress resistance, fat storage, development arrest,
fertility, and metabolism. Elevated stress resistance combined with
down-regulated central metabolism and reproduction may be
coordinated physiological states associated with slow aging[2].
Down-regulation of daf-2 signaling upon adult life-span and stress
resistance is independent of larval dauer and of adult reproduction.
There are 37 insulin-like ligands in the genome
of C.elegans and they mainly express in neurons, but are also
found in intestine, muscle, epidermis, and gonad[3].
The same signals from different tissues have different influence on
aging. The most important signal is located in the nervous system[9].
However, recently Libina et al., reported that DAF-16
activity in the intestine completely restores the longevity of
daf-16(-) germline-deficient animals, and increases the life spans
of daf-16(-) insulin/IGF-1-pathway mutants substantially. These
results indicate that DAF-16 may control two types of downstream
signals: DAF-16 activity in signaling cells upregulates DAF-16 in
specific responding tissues, possibly via regulation of insulin-like
peptides, and also evokes DAF-16-independent responses[10].
Drosophila melanogaster
In the fly D.melanogaster, the insulin/IGF-1 pathway is
constituted of insulin/IGF receptor INR, insulin receptor substrate
(IRS) CHICO, the PI3K Dp110/p60, and the PI3K target protein PKB (Akt),
which regulates growth, size and longevity[11].
The gene of IGF receptor inR is similar to the insulin
receptor gene and the IGF-1 receptor gene[12].
The mutation of inR in fly D.melanogaster can
significantly extend adult longevity. Interestingly, it has been
reported that a heteroallelic genotype InRp5545/InRE19
in females can lead to small, infertile and 85% longer life than
wild-type[3].
Also, the long-lived flies share some important characteristics with
wild-type adults that are in reproductive diapause, including
increased triglycerides and SOD and reduced synthesis of juvenile
hormone.
Clancy has reported that the life span of female D.melanogaster
is also extended by mutation of the IRS homolog chico[13].
Null mutation of the chico gene that encodes IRS increases
the life span of homozygous chico1/chico1 female fruit
flies by 48%. Interestingly, homozygous males are short-lived,
whereas heterozygous animals of both sexes have increased longevity
(≤36%
in females and 13% in males).
In D.melanogaster, insulin-like receptor
mediates phosphorylation of dFOXO, the equivalent of nematode daf-16
and mammalian FOXO3a. Recently, Tatar et al.[14],
have reported that dFOXO regulates D. melanogaster aging
when activated in the adult pericerebral fat body. Interestingly,
this limited activation of dFOXO reduces the expression of the
insulin-like peptide dilp-2 synthesized in neurons, and represses
endogenous insulin-dependent signaling in peripheral fat body. These
results suggest that autonomous and non-autonomous roles of insulin
signaling combine to control aging.
Rodents
The decrease of insulin/IGF-1 signaling pathway has also been shown
to extend longevity in several rodent models, which include murine
genetic models and caloric restricted (CR) rodents. The character of
these models again explains the role of insulin/IGF-1 pathway in
longevity.
The gene pit-1 and prop-1 in mice can code
transcription factor that regulates the development of pituitary.
The Snell dwarf (Pitdw/Pitdw)
mice and the Ames dwarf (Prop1df/Prop1df)
mice come from the homozygous mutation of gene locus pit-1
and prop-1, respectively. These mice are dwarfs but live
25-65% longer than wild type[15,16].
Also, they are deficient in serum growth hormone (GH), thyroid
stimulating hormone, and prolactin as well as for IGF-I, which is
secreted by liver cells upon stimulation with GH. Furthermore, dwarf
mice with high plasma GH but a 90% lower IGF-I [GH receptor/binding
protein (GHR/BP) null mice] live longer than the wild-type mice[17].
Taken together, these studies suggest that the reduction in plasma
IGF-I is responsible for a major portion of the life-span increase
in dwarf, GH-deficient, and GHR/BP null mice[18].
Recently, very strong support for the role of
insulin/IGF-1 signaling pathway in the control of mammalian aging
and for the involvement of this pathway in longevity of IGF-1
deficient mice was provided by Hsieh et al.[19,20].
It was shown that in the Snell dwarf mice, GH deficiency would lead
to a decreased IRS-2 pool level, decrease in PI3K activity and its
association with IRS-2 and decreased docking of p85a
to IRS-2. The authors conclude that the Pit- 1 mutation may
result in physiological homeostasis that favors longevity, and that
the Snell dwarf mutant conforms to the nematode longevity paradigm.
To investigate whether IGF-1R also controls
longevity in mammals, Holzenberger et al.[21],
inactivated the IGF-1R gene in mice (Igf1r). Using heterozygous
knockout mice because null mutants are not viable, they report that
Igf1r+/-
mice live on average 26% longer than their wild-type littermates (P<0.02).
Female Igf1r+/-
mice live upto 33% longer than wild-type females (P<0.001),
whereas the equivalent male mice show an increase in life span by
16%, which is not statistically significant. Also, long-lived Igf1r+/-
mice do not develop dwarfism, their energy metabolism is normal, and
their nutrient uptake, physical activity, fertility and reproduction
are unaffected. The spontaneous tumor incidence in the aging cohort
of Igf 1r+/-
mice was similar to that in wild-type controls. It is very important
that these Igf 1rt+/-
mice, and mouse embryonic fibroblasts
derived from them, were more resistant to oxidative stress than
controls, a known determinant of aging. At the molecular level, IRS
and the p52 and p66 isoforms of Shc, both main substrates of IGF-1
receptor, showed decreased tyrosine phosphorylation. p66Shc
mediated cellular responses to oxidative stress[22].
Two main pathways the extracellular-signal regulated kinase/mitogen-activated
protein kinase pathway and the phosphatidylinositol 3-kinase
(PI3K)-Akt pathway were downregulated in Igf 1r+/-
mice. These results indicate that the IGF-1 receptor may be a
central regulator of mammalian life span.
Using the Cre-loxP system, Bluher et al.[23],
created mice with fat-specific disruption of the insulin receptor
gene (FIRKO mice) and the extension of longevity was observed in
this model. These mice have low fat mass, loss of the normal
relationship between plasma leptin and body weight, and are
protected against age-related and hypothalamic lesion-induced
obesity, and obesity-related glucose intolerance, although their
food intake is normal. Both male and female FIRKO mice were found to
have an increase in mean life span of approximately 134 d (18%),
with parallel increases in median and maximum life spans. Extended
longevity in FIRKO mice was associated with a shift in the age at
which age-dependent increase in mortality risk becomes appreciable
and a decreased rate of age-related mortality, especially after 36
mo of age. In FIRKO mice, the resistance to obesity, despite normal
food intake, suggests that metabolic rate is increased, rather than
decreased[24].
The authors believe that decreased fat mass could lead to a decrease
in oxidative stress in FIRKO mice. Another possibility is that the
increased longevity in these mice is the direct result of altered
insulin signaling[25].
Shimokawa et al.[26],
designed another transgenic rat model that can be used to elucidate
a role for insulin /IGF-1 or their overlapping signaling pathways in
the modulation of longevity in mammals. These transgenic rats were
produced from founders created by introducing a fusion gene into rat
embryos. Transgenic offspring expressed the rat GH anti-sense RNA in
the pituitary gland, spleen, and thymus but not in the lung, liver,
heart, kidney, or testes. Male rats homozygous for the transgene (tg/tg)
had a reduced number of pituitary GH cells, a lower plasma
concentration of IGF-1, and a dwarf phenotype. Heterozygous rats (tg/-)
had an intermediate phenotype in plasma IGF-1, food intake, and body
weight between tg/tg and control (-/-) rats. The life span of tg/tg
rats was 5-10% shorter than -/- rats. In contrast, the life span of
tg/- rats was 7-10% longer than -/- rats. It was found that tumors
caused earlier death in tg/tg rats; in contrast, tg/- rats had
reduced non-neoplastic diseases and a prolonged life span.
Immunological analysis revealed a smaller population and lower
activity of splenic natural killer cells in homozygous tg/tg rats.
The present data on a reduction in plasma glucose and insulin in the
transgenic rats suggested a similarity between daf-2 and age-1
mutants in nematodes for the insulin signaling pathway and provided
evidence that an optimal level of the GH-IGF-1 axis function needs
for longevity in mammals.
CR extends longevity in organisms from yeast to
mice and postpones or prevents a remarkable array of diseases and
age-dependent deterioration, without causing irreversible
developmental or reproductive defects[27].
Interestingly, CR increases life span of rodents up to 35-40%.
Furthermore, CR rodents encompass changes in both insulin and IGF-1
signaling and levels. These animals have lower insulin, glucose and
IGF-1 levels, several-fold decrease fat stores, and boosted immune
system and defenses against free radicals damage. Low insulin levels
in CR animals suggest increased insulin sensitivity[28].
Indeed, when stimulated with similar levels of insulin, CR rodents
have improved ability to increase peripheral glucose uptake, to
promote glycogen synthesis and to suppress hepatic glucose
production compared to ad libitum fed animals. Thus, the reduced
levels of plasma IGF-I in dwarf mice may contribute to disease
prevention and life-span extension by simulating CR or more severe
starvation conditions. Consistent with this notion is the role of
IGF-I in reversing the protection of CR against carcinogen-induced
bladder cancer. Apoptosis in the tumor is decreased 10-fold in CR
mice in which the levels of IGF-I are restored, indicating that the
activation of antiapoptotic pathways contributes to tumor incidence[29].
Interestingly, de Cabo et al.[30],
described a valuable in vitro model for the study of CR.
They use sera obtained from either Fisher 344 rats or Rhesus monkeys
that were fed ad libitum (AL) or CR diets to culture various cell
types. They show that treatment of cultured cells with CR sera
caused reduced cell proliferation, enhanced tolerance to oxidants
and heat, and heightened expression of stress-response genes. These
phenotypic features mirror the effects of CR in
animals. Supplementation of CR serum with insulin
and IGF-1 partially restored the proliferative and stress-response
phenotype that was seen in cells cultured with AL serum, indicating
that reduced levels of insulin and IGF-1 likely contribute to the
CR-related effects.
Human
Although human ageing is more complicated than C.elegans and
rodents, centenarian, sporadic mutations, and diseases studies have
given significant insight on the role of the insulin/IGF-1 signaling
in human longevity. In humans, insulin sensitivity normally declines
during aging, and insulin resistance is an important risk factor
associated with a variety of intermediate phenotypes (hypertension,
atherosclerosis, obesity) strongly affecting morbidity, disability,
and mortality among the elderly
[3,31].
Roth et al.[32],
reported that the most people with insulin levels live longer. More
recently, data from 466 healthy subjects with a wide age range
(range 28-110 years) demonstrated a significant reduction of insulin
resistance in subjects 90-100 year old[33].
These data suggest an intriguing peculiarity of this age category
and indicate that an efficient insulin response has an impact on
human longevity.
Interestingly, polymorphisms at IGF-IR, PI3KCB,
IRS-1, FOXO1A have been investigated[34].
IGF-I plasma levels, which decrease significantly with age, are
affected by the polymorphisms at IGF-IR and PI3CKB
genes, both alone and in combination. In particular, individuals
bearing at least one allele A at the IGF-IR locus (IGF-IR A+)
have lower plasma IGF-I levels than the rest of the population.
Also, IGF-IR A+
subjects are found in increased proportion in long-lived
individuals. Moreover, genotype combinations of an A allele at the IGF-IR
locus and a T allele at the PI3CKB locus (A+/T+
subjects) affect IGF-I plasma levels (having A-/T-
individuals the highest free IGF-I plasma levels), as well as
longevity, and the proportion of A+/T+
subjects significantly increased among long-lived individuals.
Recently, Anisimov et al.[35],
firstly reported that mutation located downstream to daf-16 in human
insulin signal transduction system is associated with longevity.
They invested a group of 137 elderly individuals and concluded that
a greater frequency of the apolipoprotein C-III-455C allele was
correlated with aging (P<0.005). Also, it is worth noting
that centenarians display lower degree of resistance to insulin and
lower degree of oxidative stress as compared with elderly persons
before 90 years[36].
Moreover, Ruiz-Torres and Soares de Melo Kirzner compared ageing
parameters of young (up to 39 years) and old (over 70 years)
individuals having similar IGF-1 blood levels, the result was that
old males with IGF-1 levels similar to young ones do not show the
age-dependent decrease in serum testosterone and lean body mass, nor
the increase in fat body mass. This provides powerful evidence on
the important life-potential role of this peptide[37].
DISCUSSION
From the data presented, the insulin/IGF-1 pathway has the similar
characters in C.elegans, D.melanogaster, rodents and
humans, which include the constitution of the gene, the role in
regulation of aging and longevity. All these can be concluded that
the pathway exists long ago and the mechanism of aging is
evolutionarily conserved.
Reviewing the available data on the benefits and
adverse effects of caloric restriction and genetic modifications
Longo and Finch suggested three categories of drugs which may have
the potential to prevent or postpone age-related diseases and extend
life span: drugs that (1) stimulate dwarf mutations and therefore
decrease pituitary production of GH; (2) prevent IGF-1 release from
the liver, or (3) decrease IGF-1 signaling by the action on either
extracellular or intracellular targets[18].
According to this, Anisimov concluded and reported that effects of
antidiabetic biguanides seems to be more adequate in the prevention
of age-related deteriorations in glucose metabolism and in insulin
signaling pathway as well as in such important for longevity
parameters as a fertility and a resistance to oxidative stress and
tumorigenesis than those induced by caloric restriction and genetic
manipulations[25].
Although, the insulin/IGF-1 pathway can regulate
the life span in different species, the molecular mechanism largely
remains unknown. The most possible is that the pathway can enhance
the stress resistance. Murakami et al., reported that
fibroblasts from Snell dwarf mice show resistance to a variety of
forms of lethal injury, including ultraviolet light, heat, paraquat,
H2O2,
and the toxic metal cadmium. This cellular stress resistance may
lead to resistance to late-life diseases and frailty, and thereby
increase longevity[38].
Using DNA microarray analysis, Murphy et al.[39],
found the insulin/IGF-I pathway not only do cells function
non-autonomously to regulate life span but also exert their effect
on life span by upregulating a wide variety of genes, including
cellular stress-response, antimicrobial and metabolic genes, and by
downregulating specific life-shortening genes. In human, Barbieri et
al.[36],
suggest that centenarians may have been selected for appropriate
insulin regulation as well as for the appropriate regulation of
tyrosine hydroxylase gene, whose product is rate limiting in the
synthesis of catecholamines, stress-response mediators. It was shown
that catecholamine may increase free radical production through
induction of the metabolic rate and auto-oxidation in diabetic
animals[25,40].
On the other hand, although the insulin/IGF-1
pathway is evolution conserved, the pathway in mammals is more
complicated than other low animals. While disruption of the
insulin/IGF-1 receptor in nematodes and flies increases lifespan
significantly, mammals with genetic or acquired defects in insulin
signaling pathway are at a risk for age-related diseases and
increased mortality. This contradiction can be explained by the
acquisition of more complicated metabolic pathways in mammalians
over evolution. Mammals have insulin/IGF-1 receptors in many organs,
but their functions are opposite if they are located in the central
nervous system or in the periphery; whereas lower species have
insulin/IGF-1 receptors signaling mainly through the nervous system.
Furthermore, mammalians have different and very specific receptors
for insulin and IGF-1, with distinct pathways and diverse functions[41].
Human longevity is mysterious. Though we have
found the role of insulin/IGF-1 pathway in regulation of longevity,
further investigation would shed light on the molecular mechanism of
the pathway so that we will get more methods to decrease the
age-related diseases and everyone will be centenarians.
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