Role of insulin/insulin-like growth factor 1 signaling pathway in
Chun-Lei Cheng, Tian-Qin Gao, Zhen Wang, Dian-Dong Li
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. 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
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.
Using DNA micro-array
analysis, Murphy et al.,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 up regulating a wide variety of genes, including cellular stress-response, antimicrobial
and metabolic genes, and by down regulating specific life-shortening genes. In
human, Barbieri et al., 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 agerelated agerelated 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.
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.
Association analysis between longevity in the Japanese population and polymorphic variants of genes involved in insulin
and insulin-like growth factor 1 signaling pathways
Experimental Gerotolgy, Volume 39, Issues 11-12,
November-December 2004, Pages 1595-98.
Proceedings of the Seventh International Symposium on the Neurobiology and Neuroendocrinology
of Aging, at http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T6J-4DGD4R7-1&_user=10&_rdoc=1&_fmt=&_orig=search&_sort=d&view=c&_version=1&_urlVersion=0&_userid=10&md5=b4a622a92f6e38fae3c9589fd1d5802c
Recent studies have demonstrated a significant association between mutations in genes involved in the insulin/IGF1 signaling
pathway and extension of the life span of model organisms. In this study which compared 122 Japanese semisupercentenarians
(older than 105) with 122 healthy younger controls, we examined polymorphic variations of six genes which are involved in
insulin/IGF1 signaling. These genes were FOXO1A, INSR, IRS1,
PIK3CB, PIK3CG, and PPARGC1A.
We investigated the possible association of each gene locus and longevity by haplotype-based association analyses using 18
SNPs from public databases and the published literature. One INSR haplotype, which was comprised of 2 SNPs in linkage
disequilibrium, was more frequent in semisupercentenarians than in younger controls.
, PHA-4 is also involved in longevity of caloric restricted diet;
· ^ "The gene for longevity, if you're a worm", ABC News (2007). Retrieved on 3
The activation of the Sirt1 gene is involved (work of David
A. Sinclair). Sir2 (in mammals known as the SIRT1), suppresses DNA
instability · ^ Sinclair DA, Guarente L. Extrachromosomal rDNA circles--a cause of aging in yeast. Cell. 1997 Dec 26;91(7):1033-42. PMID: