Macrophage migration inhibitory factor-knockout mice are long lived and respond to caloric restriction

Macrophage migration inhibitory factor (MIF) affects inflammation, glucose homeostasis, and cellular proliferation in mammals. Previously, we found that MIF was significantly elevated in multiple long-lived mouse models, including calorie restriction (CR), which led us to hypothesize that MIF might be important in the control of mammalian life span and be necessary for the life-extending effects of CR. To test this hypothesis, we examined the life span of mice with a targeted deletion of the Mif gene on a segregating B6 x 129/Sv background (MIF-KO) under ad libitum (AL) feeding and CR conditions. Control mice were generated by mating C57BL/6J females with 129/SvJ males to make an F1 hybrid, and crossing F1 males to F1 females to produce segregating F2 mice homozygous for the normal MIF allele. Not only did MIF-KO mice show a life span extension in response to CR, they were, unexpectedly, longer lived than controls under standard AL conditions. MIF-KO mice were significantly protected against lethal hemangiosarcoma, but more likely than controls to die of disseminated amyloid, an age-related inflammatory syndrome. Overall, these data refute the suggestion that MIF is required for the CR effect on life span, but raise the possibility that MIF may limit life span in normal mice.