[Ageing, genetics and the somatotropic axis].
Research on ageing made a big leap forward when genes regulating lifespan were discovered about a decade ago. First isolated by screening the genome of the nematode Caenorhabditis elegans, most of these genes belong to an essential signalling pathway that is highly conserved during animal evolution. Orthologous genes in vertebrate species are the families of genes coding for insulin, insulin-like growth factors (IGF) and related proteins. Intensively studied and well-known for their pivotal roles in proliferation, differentiation, survival and metabolism of most cells, we now discover their multiples functions with respect to the control of longevity and their ability to modulate the cell's responses to oxidative stress, a major cause of cellular and organismal ageing. The activity of IGF signalling in mammals depends on a complex interplay of endocrine signals that together constitute the somatotropic axis. Accordingly, several components of this hormone axis, like growth hormone or growth hormone releasing hormone receptors, regulate efficiently animal longevity, which has been elegantly demonstrated by studies performed in genetically modified mouse models. From this and other work, it becomes increasingly clear that the control of ageing is a question of hormonal regulations. We here present several of these models and discuss the respective contributions of insulin and IGF signalling to the regulation of lifespan. We review data on the Klotho gene that acts on lifespan via surprising and not yet fully understood molecular mechanisms, connecting this new, hormone-like substance to IGF and insulin signalling. We further report recent evidence showing that human lifespan might be controlled in similar ways. Finally, we shed some light on clinical GH treatment in humans, from an endocrinologist's point of view.
Kappeler
Laurent
L
Inserm U.515, Hôpital Saint-Antoine, 184, rue du Faubourg Saint-Antoine, 75571 Paris Cedex 12, France. kappeler@st-antoine.inserm.fr
De Magalhaes Filho
Carlos
C
Le Bouc
Yves
Y
Holzenberger
Martin
M
D000375:Aging / Q000235:genetics*; D000818:Animals; D006728:Hormones / Q000235:genetics*; D019382:Human Growth Hormone / Q000235:genetics*; D006801:Humans; D007328:Insulin / Q000235:genetics; D008017:Life Expectancy; D008136:Longevity
D006728:Hormones; D007328:Insulin; D019382:Human Growth Hormone