Inserm researchers, working with an American team, have shown that the IGF-1 receptor is involved in the control of body temperature from the brain. Furthermore, the activity of this receptor is modulated by calorie intake and is associated with neuroprotection and longevity. This research will help provide a better understanding of the beneficial effects of diet on diseases related to aging.
Inhibition of the IGF pathway associated with longevity and neuroprotection
A few years ago, Martin Holzenberger’s team* had demonstrated that a reduction in the activity of IGF (insulin-like growth factor), involved in the regulation of several biological processes, could increase resistance to stress and significantly extend lifespan in mice. Recently, Saba Aïd* successively deactivated the IGF-1 receptor specifically in the neurons of the central nervous system and demonstrated that this intervention effectively protected the brain from serious diseases, such as neuron loss following brain ischemia or Alzheimer's disease. Since these discoveries, researchers have been investigating other functions of neuronal IGF signaling.
The IGF pathway controls body temperature from the brain
This research has just led to the publication of a new study, resulting from close cooperation with a Californian team from the Scripps Research Institute. It places the IGF signaling pathway at the center of an extensive and complex regulation system, linking nutrition - and, in particular, calorie intake - to energy expenditure balance and maintenance of body temperature. This regulation intersection may represent one of the mechanisms connecting IGF hormonal activity to longevity.
In order to reach these conclusions, the researchers used mice presenting different targeted mutations affecting this signaling pathway. They subjected the animals to a restricted-calorie diet that resulted in decreased energy expenditure and a lower body temperature, at the same time increasing their lifespan. Comparison of several mutant mouse models clearly demonstrated that IGF plays a major role in maintaining temperature and that this activity is primarily exerted in the brain, particularly in the preoptic region of the hypothalamus. This part of the central nervous system represents a regulation platform for numerous homeostatic functions, such as energy metabolism, physical activity and sleep, as well as circadian rhythms in general. However, specific inactivation of the IGF-1 receptor in other regions of the brain shows that the neuronal circuits located upstream of the hypothalamus also make a significant contribution to these regulation mechanisms. Until now, the latter were not suspected of being involved in core temperature control and energy expenditure. Researchers are now focusing more closely on these prosencephalic regions in order to also understand their role in aging and longevity.
IGF may be the link between regulation of energy balance, aging and neurodegeneration
Although humans do not have the extraordinary capacity of mice to very quickly vary their body temperature - a capacity that is primarily down to their small size - coupling of calorie intake (and nutrition in general) to energy expenditure via the central IGF signaling pathway could well occur in the same way in humans. Hypothalamic regulation of energy balance is thought to be modulated via IGF signals in this region of the brain and may have effects not only on aging and longevity, but also on the development of diseases related to aging, such as neurodegenerative conditions, particularly Alzheimer’s disease. It should also be noted that Jean-Christophe François (from this team) has just shown that inhibition of IGF signaling in all the tissues of adults also produces other benefits, in particular increasing the resilience of energy metabolism in the course of circadian rhythms between food intakes and periods of rest.
This research could contribute to the development of preventive measures
*Inserm Unit 938 /Sorbonne University, Saint Antoine Research Center, Paris
R. Cintron-Colon et coll. The insulin-like growth factor 1 receptor regulates hypothermia during calorie restriction. PNAS 2017, 114: 9731-9736.