Searchable abstracts of presentations at key conferences in endocrinology
Endocrine Abstracts (2009) 20 S5.2

ECE2009 Symposia IGF1 survival, proliferation and cancer (4 abstracts)

IGF, somatotropic plasticity and mammalian lifespan

Martin Holzenberger


INSERM, Paris, France.


During recent years, insulin and insulin-like growth factors have been implicated in the control of lifespan in a variety of species. In mammals, substantial reduction of somatotropic signals generally extends lifespan. We showed recently in a conditional mouse mutant relevant for humans, that lifespan can be prolonged by inhibiting IGF-I signaling selectively in the central nervous system. This effect occurred through changes in specific neuroendocrine pathways. Investigating the pathophysiological mechanism, we found that IGF receptors in the brain steered the postnatal development of the somatotropic axis, which in turn altered the individual growth trajectory. This led to reduced adult body size, delayed mortality and longer mean lifespan. Our work suggested that chronically low IGF-I and low growth hormone levels favor long lifespan and may postpone age-related mortality. Together with other recent reports, these results challenge the idea that administrating GH can slow down or even prevent aging.

We then investigated whether early postnatal nutrition may participate in controlling the plasticity of the somatotropic axis. Using cross-fostering in newborn mice we manipulated early nutrition, and showed that underfeeding delayed growth, whereas overfeeding accelerated it. In both cases, final body size was permanently altered. We found significant alterations in pituitary GH, plasma IGF-I and ALS, and in gene expression of hypothalamic GHRH during postnatal development, that were consistent with the observed phenotypes and that persisted throughout adulthood. Although limited to the early postnatal period, both under- and overfeeding led to metabolic abnormalities, including diminished adult glucose tolerance, defective insulin secretion in previously restricted, and insulin resistance in overfed mice. Both restricted and overfed mice also showed increased arterial blood pressure, suggestive of vascular impairment. Collectively, these findings indicate a significant link between early diet, somatotropic development and specific pathology in mice, suggesting that, together with other hormones like leptin, IGF-I may play a role in modulating hypothalamic stimulation of the developing somatotropic function.

We propose that the underlying mechanism of the described phenotypes is an adaptive plasticity of the somatotropic function. This concept is particularly interesting from an evolutionary point of view, since it may allow individuals to decelerate growth and preserve resources, and thereby improve fitness in challenging environments.

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