Autoimmunity, calorie restriction, and core body temperature

PROJECT SUMMARY Calorie restriction (CR) is a balanced reduction of caloric intake that promotes healthy aging and longevity without causing malnutrition. Importantly, in earlier studies, CR was also found to reduce autoimmunity in several mouse models of lupus. A striking effect of CR in mice is the reduction of the core body temperature (Tb) during sleep, which is lowered by up to 10°C compared to mice fed ad libitum (AL). Here, we hypothesize that this amplified Tb reduction is crucial for the beneficial effects of CR. Consistent with this hypothesis, our preliminary results suggested that the CR-associated inhibition of lupus-like autoimmunity, especially kidney disease, is lost if mice are housed under conditions of thermoneutrality (TN, achieved at the ambient temperature of ~30°C), which does not allow body heat dissipation and hence prevents Tb reductions in CR mice. Thus, studies are proposed to investigate the effects of CR and TN on circadian Tb profiles in lupus mice at different disease stages, assess the long-term impact of CR and TN on lupus disease, and determine the effects of CR and TN on gene expression signatures in lupus kidneys and spleen using single cell and spatial transcriptomics. The proposed studies are highly significant, particularly for translational applications of CR in humans, since humans use behavioral thermoregulation (clothes, duvets, air conditioning) to live at TN.