Brain IGF-1 receptors control mammalian growth and lifespan through a neuroendocrine mechanism.
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.
Kappeler
Laurent
L
INSERM U893, Hôpital Saint-Antoine, Paris, France.
De Magalhaes Filho
Carlos
C
Dupont
Joëlle
J
Leneuve
Patricia
P
Cervera
Pascale
P
Périn
Laurence
L
Loudes
Catherine
C
Blaise
Annick
A
Klein
Rüdiger
R
Epelbaum
Jacques
J
Le Bouc
Yves
Y
Holzenberger
Martin
M
D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western; D001831:Body Temperature; D001921:Brain / Q000378:metabolism*; D004734:Energy Metabolism / Q000235:genetics / Q000502:physiology; D005260:Female; D005298:Fertility / Q000235:genetics / Q000502:physiology; D013006:Growth Hormone / Q000378:metabolism; D007150:Immunohistochemistry; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008136:Longevity / Q000235:genetics / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009490:Neurosecretory Systems / Q000378:metabolism*; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone; D017526:Receptor, IGF Type 1