Shorter life- and health-span, disturbed insulin-like growth factor signalling in cannabinoid receptor type-1 knockout mice

Cannabinoid receptor type-1 (Cnr1) signalling declines with age, which may contribute to the ageing process, as Cnr1 activity influences several hallmarks of ageing. Indeed, previous studies have shown that mice with a genetic deletion of Cnr1 (Cnr1^-/-) exhibit an early onset of brain ageing. However, it is not yet clear whether Cnr1 activity influences life span and the pace of bodily ageing. Thus, we asked whether the life- and health-span of Cnr1^-/- mice differs from their wild-type controls and whether their insulin-like growth factor 1 (IGF-1) and gonadotropin-releasing hormone (GnRH) signalling is affected. Comparison of survival curves revealed that the median survival time of Cnr1^-/- mice was lower than that of Cnr1^+/+ wild-type or Cnr1^+/- mice, similarly in both sexes. Frailty developed earlier and was more intense in both knockout and heterozygous animals than in their wild-type siblings, in males and females alike. Cnr1^-/- mice had reduced hypothalamic expression of GHRH and lower IGF-1 plasma levels - thus reduced IGF-1 signalling. Furthermore, we observed a reduced GnRH production and lower expression of elements of IGF-1 receptor signalling in the hypothalamus of knockout animals. The present study demonstrates that reduced CB1 receptor activity accelerates bodily ageing by reducing GnRH production. Furthermore, the lower IGF-1 signalling did not compensate for the early ageing phenotype of the knockout mice.