Autoimmunity, calorie restriction, and core body temperature

The National Institute of Allergy and Infectious Diseases (NIAID) awarded San Diego Biomedical Research Institute $541,500 under the Allergy and Infectious Diseases Research program (CFDA 93.855) effective June 17, 2025, with a completion date of May 31, 2027. This Project Grant funds a two-year research initiative investigating the relationship between calorie restriction (CR), core body temperature reduction, and autoimmunity in lupus models. The research will produce scientific knowledge through multiple deliverables, including circadian body temperature profile analysis in lupus-affected mice under varying environmental conditions, long-term disease impact assessments, and advanced genomic analyses utilizing single-cell and spatial transcriptomics to characterize gene expression signatures in lupus-affected kidneys and spleen tissue.

The research specifically examines whether the immunosuppressive effects of calorie restriction depend on reduced core body temperature during sleep, with particular relevance to translational applications in human populations. By comparing standard housing conditions with thermoneutral environments that prevent body heat dissipation, the study will determine whether temperature reduction mechanisms are essential to calorie restriction's beneficial effects on lupus-like autoimmunity and kidney disease. The findings will advance scientific understanding of potential dietary and physiological interventions for autoimmune disease management and inform future clinical applications given human reliance on behavioral thermoregulation.

Abstract

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.