Circadian alignment of early onset caloric restriction promotes longevity in male C57BL/6J mice

Caloric restriction (CR) prolongs lifespan, yet the mechanisms by which it does so remain poorly understood. Under CR, mice self-impose chronic cycles of 2-hour-feeding and 22-hour-fasting, raising the question whether calories, fasting, or time of day are causal. We show that 30%-CR is sufficient to extend lifespan 10%; however, a daily fasting interval and circadian-alignment of feeding act together to extend lifespan 35% in male C57BL/6J mice. These circadian effects of CR are independent of fasting duration and body weight. Aging induces widespread increases in gene expression associated with inflammation and decreases in expression of genes encoding components of metabolic pathways in liver from ad lib fed mice. CR at night ameliorates these aging-related changes. Thus, circadian interventions promote longevity and provide a perspective to further explore mechanisms of aging. Overall design: mRNA-seq circadian profiles generated for C57BL/6J male mice fed under 6 different feeding conditions and collected at 6 and 19 months of age. Liver samples were collected every 4h during 2 days (12 timepoints x 2 biological replicates x 6 feeding conditions x 2 ages, total 288 samples).