SIRT1 accelerates the progression of activity-based anorexia.

Food consumption is fundamental for life, and eating disorders often result in devastating or life-threatening conditions. Anorexia nervosa (AN) is characterized by a persistent restriction of energy intake, leading to lowered body weight, constant fear of gaining weight, and psychological disturbances of body perception. Herein, we demonstrate that SIRT1 inhibition, both genetically and pharmacologically, delays the onset and progression of AN behaviors in activity-based anorexia (ABA) models, while SIRT1 activation accelerates ABA phenotypes. Mechanistically, we suggest that SIRT1 promotes progression of ABA, in part through its interaction with NRF1, leading to suppression of a NMDA receptor subunit Grin2A. Our results suggest that AN may arise from pathological positive feedback loops: voluntary food restriction activates SIRT1, promoting anxiety, hyperactivity, and addiction to starvation, exacerbating the dieting and exercising, thus further activating SIRT1. We propose SIRT1 inhibition can break this cycle and provide a potential therapy for individuals suffering from AN.

Cellular energetics and mitochondrial uncoupling in canine aging.

The first domesticated companion animal, the dog, is currently represented by over 190 unique breeds. Across these numerous breeds, dogs have exceptional variation in lifespan (inversely correlated with body size), presenting an opportunity to discover longevity-determining traits. We performed a genome-wide association study on 4169 canines representing 110 breeds and identified novel candidate regulators of longevity. Interestingly, known functions within the identified genes included control of coat phenotypes such as hair length, as well as mitochondrial properties, suggesting that thermoregulation and mitochondrial bioenergetics play a role in lifespan variation. Using primary dermal fibroblasts, we investigated mitochondrial properties of short-lived (large) and long-lived (small) dog breeds. We found that cells from long-lived breeds have more uncoupled mitochondria, less electron escape, greater respiration, and capacity for respiration. Moreover, our data suggest that long-lived breeds have higher rates of catabolism and ß-oxidation, likely to meet elevated respiration and electron demand of their uncoupled mitochondria. Conversely, cells of short-lived (large) breeds may accumulate amino acids and fatty acid derivatives, which are likely used for biosynthesis and growth. We hypothesize that the uncoupled metabolic profile of long-lived breeds likely stems from their smaller size, reduced volume-to-surface area ratio, and therefore a greater need for thermogenesis. The uncoupled energetics of long-lived breeds lowers reactive oxygen species levels, promotes cellular stress tolerance, and may even prevent stiffening of the actin cytoskeleton. We propose that these cellular characteristics delay tissue dysfunction, disease, and death in long-lived dog breeds, contributing to canine aging diversity.