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Insulin/IGF-1 paradox of aging: Regulation via AKT/IKK/NF-κB signaling
http://www.sciencedirect.com/science/ar ... 6809003234
"Ames and Snell dwarf mice lack GH whereas the Little mouse displays a mutation in the GHRH receptor gene [5,7]. GHRKO mice are also characterized by reduced body weight [6]. Each of these mouse strains exhibits a clear decline in the serum IGF-1 levels and this is responsible for dwarfish growth.
Interestingly, all these dwarf mice live longer than their wild type counterparts [5–8] with the extension of the lifespan varying between 20 and 70% in the different dwarf models. This is a striking evidence, present also in lower animals (see Section 2), indicating that the insulin/IGF-1 signaling enhances growth process during development but later in life can potentiate the aging process. This conserved pleiotropy has been called the insulin/IGF-1 paradox [9,10]."
"In humans, the evidence on the role of insulin/IGF axis in the aging process is still controversial and the clinical studies indicate that there may be several risks associated with GH treatment in healthy elderly people [17]."
"Caenorhabditis elegans is a nematode which has been broadly utilized in aging paradigms. C. elegans can enter a developmental diapause state, called the dauer larva, if it encounters harsh environmental conditions [23,24]. The endocrinesystem regulates the induction of alternatemetabolism and the formation of the dauer stage."
"In conclusion, the GH/insulin/IGF-1 axis, which has been conserved through evolution, supports the growth of the organism during the developmental phase but later in the lifespan, it can be viewed as a force driving the aging process. This pleiotropic function of the GH/insulin/IGF-1 pathway is mediated through the PI-3K/AKT signaling."
"The purpose of AKT signaling is to maintain the cellular homeostasis by regulating protein synthesis and survival processes, e.g. stress resistance[1]."
"AKT also regulates the gene expression by modulating the function of several transcription factors [1]. The FoxO family is the most important with respect to longevity regulation [29,30]."
"How does the activation of FoxO factors achieve this expansion of lifespan? FoxO factors can induce the expression of several antioxidative enzymes, e.g. catalase and SOD2, andstress resistance inducers [29,38]. Increased stress resistance is a hallmark of all long-lived mutant organisms [23,28]. FoxO factors play a key role in the maintenance of the energy metabolism in the whole body, especially glucose balance [39], which is important in metabolic dysfunctions. FoxOs can induce the expression of gluconeogenetic enzymes in liver. Furthermore, FoxO1 can regulate pancreatic beta cell proliferation and resistance against oxidative stress [40]. FoxO members have also a critical role in the regulation of the immune system [41] which may be an important function since immunosenescence is one of the key players in the aging process."
"Recently, Iwasaki et al. [66] demonstrated that insulin can exhibit a short-term anti-inflammatory response but later, there is a clear long-term potentiation of inflammatory responses induced by TNFα, at least in human hepatocyte cell lines."
"All these results imply that an elevated insulin/IGF-1 level could potentiate the NF-κB-dependent pro-inflammatory responses and support the inflamm-aging process [31,33,70]."
"Bertrand et al. [72] demonstrated that insulin acts through the NF-κB systemto induce the expression of TRAF2 which increases the basal and insulin-stimulated NF-κB activities and protects against apoptotic insults. In the brain, IGF-1 exerts neuroprotective activity against apoptotic insults and it has been considered to represent a putative novel treatment for neurodegenerative disorders. Heck et al. [75] indicated that IGF-1 elucidates the neuroprotection via the NF-κB signaling which is mediated by PI-3K signaling. All of these examples imply that NF-κB signaling is an important target of the somatotropic insulin/IGF-1 axis."
"The NF-κB system is an ancient pleiotropic* factor which has a variety of functions during the organism's lifespan. The NF-κB system participates in developmental processes, e.g. with the name Toll-Dorsal pathway it regulates the dorso-ventral patterning of Drosophila embryo [76].In addition to morphogenesis, NF-κB signaling also regulates the differentiation of several cell types, e.g. those of the immune system [48,77]. However, the main function of the NF-κB system is to organize and maintain the host defence against immune attacks and to recognize and trigger the repair process of injuries of the organism. Interestingly, GH/insulin/IGF-1 hormones can stimulate the function of immune system as well as they can also control local growth and differentiation processes via cytokine production [77,78]. As a matter of course, the NF-κB system is involved in several processes regulated by the insulin/IGF-1 axis."
*Affects genes in a chain-like fashion.
"The characteristic functions of the NF-κB system, e.g. the inhibition of apoptosis and autophagy and the activation of innate immunity responses, are ideal properties during the growth phase but they are a double-edged sword which can be responsible for several problems during the later phases of life."
"In mammals, there is some evidence to suggest that caloric restriction can suppress the insulin/IGF-1 axis [88] but the regulation may be more complex, since caloric restriction evokes many hormonal changes, e.g. the release of gluco-corticoids, which are powerful inhibitors of the NF-κB system and thus can suppress inflammatory responses [89]."
Be kind, I haven't conducted the study and I'm sensitive. Haha!
Insulin/IGF-1 paradox of aging: Regulation via AKT/IKK/NF-κB signaling
http://www.sciencedirect.com/science/ar ... 6809003234
"Ames and Snell dwarf mice lack GH whereas the Little mouse displays a mutation in the GHRH receptor gene [5,7]. GHRKO mice are also characterized by reduced body weight [6]. Each of these mouse strains exhibits a clear decline in the serum IGF-1 levels and this is responsible for dwarfish growth.
Interestingly, all these dwarf mice live longer than their wild type counterparts [5–8] with the extension of the lifespan varying between 20 and 70% in the different dwarf models. This is a striking evidence, present also in lower animals (see Section 2), indicating that the insulin/IGF-1 signaling enhances growth process during development but later in life can potentiate the aging process. This conserved pleiotropy has been called the insulin/IGF-1 paradox [9,10]."
"In humans, the evidence on the role of insulin/IGF axis in the aging process is still controversial and the clinical studies indicate that there may be several risks associated with GH treatment in healthy elderly people [17]."
"Caenorhabditis elegans is a nematode which has been broadly utilized in aging paradigms. C. elegans can enter a developmental diapause state, called the dauer larva, if it encounters harsh environmental conditions [23,24]. The endocrinesystem regulates the induction of alternatemetabolism and the formation of the dauer stage."
"In conclusion, the GH/insulin/IGF-1 axis, which has been conserved through evolution, supports the growth of the organism during the developmental phase but later in the lifespan, it can be viewed as a force driving the aging process. This pleiotropic function of the GH/insulin/IGF-1 pathway is mediated through the PI-3K/AKT signaling."
"The purpose of AKT signaling is to maintain the cellular homeostasis by regulating protein synthesis and survival processes, e.g. stress resistance[1]."
"AKT also regulates the gene expression by modulating the function of several transcription factors [1]. The FoxO family is the most important with respect to longevity regulation [29,30]."
"How does the activation of FoxO factors achieve this expansion of lifespan? FoxO factors can induce the expression of several antioxidative enzymes, e.g. catalase and SOD2, andstress resistance inducers [29,38]. Increased stress resistance is a hallmark of all long-lived mutant organisms [23,28]. FoxO factors play a key role in the maintenance of the energy metabolism in the whole body, especially glucose balance [39], which is important in metabolic dysfunctions. FoxOs can induce the expression of gluconeogenetic enzymes in liver. Furthermore, FoxO1 can regulate pancreatic beta cell proliferation and resistance against oxidative stress [40]. FoxO members have also a critical role in the regulation of the immune system [41] which may be an important function since immunosenescence is one of the key players in the aging process."
"Recently, Iwasaki et al. [66] demonstrated that insulin can exhibit a short-term anti-inflammatory response but later, there is a clear long-term potentiation of inflammatory responses induced by TNFα, at least in human hepatocyte cell lines."
"All these results imply that an elevated insulin/IGF-1 level could potentiate the NF-κB-dependent pro-inflammatory responses and support the inflamm-aging process [31,33,70]."
"Bertrand et al. [72] demonstrated that insulin acts through the NF-κB systemto induce the expression of TRAF2 which increases the basal and insulin-stimulated NF-κB activities and protects against apoptotic insults. In the brain, IGF-1 exerts neuroprotective activity against apoptotic insults and it has been considered to represent a putative novel treatment for neurodegenerative disorders. Heck et al. [75] indicated that IGF-1 elucidates the neuroprotection via the NF-κB signaling which is mediated by PI-3K signaling. All of these examples imply that NF-κB signaling is an important target of the somatotropic insulin/IGF-1 axis."
"The NF-κB system is an ancient pleiotropic* factor which has a variety of functions during the organism's lifespan. The NF-κB system participates in developmental processes, e.g. with the name Toll-Dorsal pathway it regulates the dorso-ventral patterning of Drosophila embryo [76].In addition to morphogenesis, NF-κB signaling also regulates the differentiation of several cell types, e.g. those of the immune system [48,77]. However, the main function of the NF-κB system is to organize and maintain the host defence against immune attacks and to recognize and trigger the repair process of injuries of the organism. Interestingly, GH/insulin/IGF-1 hormones can stimulate the function of immune system as well as they can also control local growth and differentiation processes via cytokine production [77,78]. As a matter of course, the NF-κB system is involved in several processes regulated by the insulin/IGF-1 axis."
*Affects genes in a chain-like fashion.
"The characteristic functions of the NF-κB system, e.g. the inhibition of apoptosis and autophagy and the activation of innate immunity responses, are ideal properties during the growth phase but they are a double-edged sword which can be responsible for several problems during the later phases of life."
"In mammals, there is some evidence to suggest that caloric restriction can suppress the insulin/IGF-1 axis [88] but the regulation may be more complex, since caloric restriction evokes many hormonal changes, e.g. the release of gluco-corticoids, which are powerful inhibitors of the NF-κB system and thus can suppress inflammatory responses [89]."
Be kind, I haven't conducted the study and I'm sensitive. Haha!
