Cisd2 slows down liver aging and attenuates age‐related metabolic dysfunction in male mice

The liver plays a pivotal role in mammalian aging. However, the mechanisms underlying liver aging remain unclear. Cisd2 is a pro‐longevity gene in mice. Cisd2 mediates lifespan and healthspan via regulation of calcium homeostasis and mitochondrial functioning. Intriguingly, the protein level of Cisd2 is significantly decreased by about 50% in the livers of old male mice. This down‐regulation of Cisd2 may result in the aging liver exhibiting non‐alcoholic fatty liver disease (NAFLD) phenotype. Here, we use Cisd2 transgenic mice to investigate whether maintaining Cisd2 protein at a persistently high level is able to slow down liver aging. Our study identifies four major discoveries. Firstly, that Cisd2 expression attenuates age‐related dysregulation of lipid metabolism and other pathological abnormalities. Secondly, revealed by RNA sequencing analysis, the livers of old male mice undergo extensive transcriptomic alterations, and these are associated with steatosis, hepatitis, fibrosis, and xenobiotic detoxification. Intriguingly, a youthful transcriptomic profile, like that of young 3‐month‐old mice, was found in old Cisd2 transgenic male mice at 26 months old. Thirdly, Cisd2 suppresses the age‐associated dysregulation of various transcription regulators (Nrf2, IL‐6, and Hnf4a), which keeps the transcriptional network in a normal pattern. Finally, a high level of Cisd2 protein protects the liver from oxidative stress, and this is associated with a reduction in mitochondrial DNA deletions. These findings demonstrate that Cisd2 is a promising target for the development of therapeutic agents that, by bringing about an effective enhancement of Cisd2 expression, will slow down liver aging.