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Brain IGF-1 receptors control mammalian growth and lifespan through a neuroendocrine mechanism.

Kappeler L, De Magalhaes Filho C, Dupont J, Leneuve P, Cervera P, Périn L, Loudes C, Blaise A, Klein R, Epelbaum J, Le Bouc Y, Holzenberger M - PLoS Biol. (2008)

Bottom Line: Thus, early changes in neuroendocrine development can durably modify the life trajectory in mammals.The underlying mechanism appears to be an adaptive plasticity of somatotropic functions allowing individuals to decelerate growth and preserve resources, and thereby improve fitness in challenging environments.Our results also suggest that tonic somatotropic signaling entails the risk of shortened lifespan.

View Article: PubMed Central - PubMed

Affiliation: INSERM U893, Hôpital Saint-Antoine, Paris, France.

ABSTRACT
Mutations that decrease insulin-like growth factor (IGF) and growth hormone signaling limit body size and prolong lifespan in mice. In vertebrates, these somatotropic hormones are controlled by the neuroendocrine brain. Hormone-like regulations discovered in nematodes and flies suggest that IGF signals in the nervous system can determine lifespan, but it is unknown whether this applies to higher organisms. Using conditional mutagenesis in the mouse, we show that brain IGF receptors (IGF-1R) efficiently regulate somatotropic development. Partial inactivation of IGF-1R in the embryonic brain selectively inhibited GH and IGF-I pathways after birth. This caused growth retardation, smaller adult size, and metabolic alterations, and led to delayed mortality and longer mean lifespan. Thus, early changes in neuroendocrine development can durably modify the life trajectory in mammals. The underlying mechanism appears to be an adaptive plasticity of somatotropic functions allowing individuals to decelerate growth and preserve resources, and thereby improve fitness in challenging environments. Our results also suggest that tonic somatotropic signaling entails the risk of shortened lifespan.

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Lifespan Analysis(A) Survival curves show that bIGF1RKO+/− mice, on average, outlived their control littermates, although the maximum lifespan was similar for mutants and controls.(B and C) Separate survival curves for males and females. Mean lifespan for bIGF1RKO+/− males was 966 ± 28 d versus 853 ± 43 d for male controls; Mean lifespan for bIGF1RKO+/− females was 888 ± 27 d versus 821 ± 36 d for female controls. Differences were significant in Cox's test for males, females, and for both sexes combined when curves were censored before week 140, 130, and 135, respectively.
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pbio-0060254-g006: Lifespan Analysis(A) Survival curves show that bIGF1RKO+/− mice, on average, outlived their control littermates, although the maximum lifespan was similar for mutants and controls.(B and C) Separate survival curves for males and females. Mean lifespan for bIGF1RKO+/− males was 966 ± 28 d versus 853 ± 43 d for male controls; Mean lifespan for bIGF1RKO+/− females was 888 ± 27 d versus 821 ± 36 d for female controls. Differences were significant in Cox's test for males, females, and for both sexes combined when curves were censored before week 140, 130, and 135, respectively.

Mentions: Constitutive inactivation of GHRH or GH receptors, as well as mutations impeding pituitary somatotroph development, increase longevity [6,9,35]. We therefore measured the lifespan of bIGF1RKO+/− and control mice. Survival curves showed that bIGF1RKO+/− mice had a significantly longer mean lifespan than control littermates (914 ± 21 d, n = 27 versus 836 ± 28 d, n = 42, p < 0.05) (Figure 6A). When we analyzed male and female mutants separately, we found similar increases in longevity (Figure 6B and 6C). However, the maximum life span was unchanged. The mortality rate for bIGF1RKO+/− mice up to 100 wk of age was six times lower than for controls (bIGF1RKO+/− 0.037 versus controls 0.238, p < 0.05). Thereafter, however, mortality rate of bIGF1RKO+/− increased sharply and was 55% higher for 121- to 140-wk-old bIGF1RKO+/− mice than controls in the same age range. Consequently, the inter-individual variation of lifespan was significantly lower for bIGF1RKO+/− mice than for controls (Figure S4). Thus, survival and mortality patterns in bIGF1RKO+/− mice under normal conditions were clearly affected. In contrast, we did not find differences in survival when mutants where challenged with acute oxidative stress (Figure S5), indicating that causes other than stress resistance were important for increased lifespan of bIGF1RKO+/− mice.


Brain IGF-1 receptors control mammalian growth and lifespan through a neuroendocrine mechanism.

Kappeler L, De Magalhaes Filho C, Dupont J, Leneuve P, Cervera P, Périn L, Loudes C, Blaise A, Klein R, Epelbaum J, Le Bouc Y, Holzenberger M - PLoS Biol. (2008)

Lifespan Analysis(A) Survival curves show that bIGF1RKO+/− mice, on average, outlived their control littermates, although the maximum lifespan was similar for mutants and controls.(B and C) Separate survival curves for males and females. Mean lifespan for bIGF1RKO+/− males was 966 ± 28 d versus 853 ± 43 d for male controls; Mean lifespan for bIGF1RKO+/− females was 888 ± 27 d versus 821 ± 36 d for female controls. Differences were significant in Cox's test for males, females, and for both sexes combined when curves were censored before week 140, 130, and 135, respectively.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2573928&req=5

pbio-0060254-g006: Lifespan Analysis(A) Survival curves show that bIGF1RKO+/− mice, on average, outlived their control littermates, although the maximum lifespan was similar for mutants and controls.(B and C) Separate survival curves for males and females. Mean lifespan for bIGF1RKO+/− males was 966 ± 28 d versus 853 ± 43 d for male controls; Mean lifespan for bIGF1RKO+/− females was 888 ± 27 d versus 821 ± 36 d for female controls. Differences were significant in Cox's test for males, females, and for both sexes combined when curves were censored before week 140, 130, and 135, respectively.
Mentions: Constitutive inactivation of GHRH or GH receptors, as well as mutations impeding pituitary somatotroph development, increase longevity [6,9,35]. We therefore measured the lifespan of bIGF1RKO+/− and control mice. Survival curves showed that bIGF1RKO+/− mice had a significantly longer mean lifespan than control littermates (914 ± 21 d, n = 27 versus 836 ± 28 d, n = 42, p < 0.05) (Figure 6A). When we analyzed male and female mutants separately, we found similar increases in longevity (Figure 6B and 6C). However, the maximum life span was unchanged. The mortality rate for bIGF1RKO+/− mice up to 100 wk of age was six times lower than for controls (bIGF1RKO+/− 0.037 versus controls 0.238, p < 0.05). Thereafter, however, mortality rate of bIGF1RKO+/− increased sharply and was 55% higher for 121- to 140-wk-old bIGF1RKO+/− mice than controls in the same age range. Consequently, the inter-individual variation of lifespan was significantly lower for bIGF1RKO+/− mice than for controls (Figure S4). Thus, survival and mortality patterns in bIGF1RKO+/− mice under normal conditions were clearly affected. In contrast, we did not find differences in survival when mutants where challenged with acute oxidative stress (Figure S5), indicating that causes other than stress resistance were important for increased lifespan of bIGF1RKO+/− mice.

Bottom Line: Thus, early changes in neuroendocrine development can durably modify the life trajectory in mammals.The underlying mechanism appears to be an adaptive plasticity of somatotropic functions allowing individuals to decelerate growth and preserve resources, and thereby improve fitness in challenging environments.Our results also suggest that tonic somatotropic signaling entails the risk of shortened lifespan.

View Article: PubMed Central - PubMed

Affiliation: INSERM U893, Hôpital Saint-Antoine, Paris, France.

ABSTRACT
Mutations that decrease insulin-like growth factor (IGF) and growth hormone signaling limit body size and prolong lifespan in mice. In vertebrates, these somatotropic hormones are controlled by the neuroendocrine brain. Hormone-like regulations discovered in nematodes and flies suggest that IGF signals in the nervous system can determine lifespan, but it is unknown whether this applies to higher organisms. Using conditional mutagenesis in the mouse, we show that brain IGF receptors (IGF-1R) efficiently regulate somatotropic development. Partial inactivation of IGF-1R in the embryonic brain selectively inhibited GH and IGF-I pathways after birth. This caused growth retardation, smaller adult size, and metabolic alterations, and led to delayed mortality and longer mean lifespan. Thus, early changes in neuroendocrine development can durably modify the life trajectory in mammals. The underlying mechanism appears to be an adaptive plasticity of somatotropic functions allowing individuals to decelerate growth and preserve resources, and thereby improve fitness in challenging environments. Our results also suggest that tonic somatotropic signaling entails the risk of shortened lifespan.

Show MeSH
Related in: MedlinePlus