Assessing dementia conversion in patients with mild cognitive impairment (MCI) remains challenging owing to pathological heterogeneity. While many MCI patients ultimately proceed to Alzheimer’s disease (AD), a subset of patients remain stable for various times. Our aim was to characterize the plasma metabolites of nineteen MCI patients proceeding to AD (P-MCI) and twenty-nine stable MCI (S-MCI) patients by untargeted metabolomics profiling. Alterations in the plasma metabolites between the P-MCI and S-MCI groups, as well as between the P-MCI and AD groups, were compared over the observation period. With the help of machine learning-based stratification, a 20-metabolite signature panel was identified that was associated with the presence and progression of AD. Furthermore, when the metabolic signature panel was used for classification of the three patient groups, this gave an accuracy of 73.5% using the panel. Moreover, when specifically classifying the P-MCI and S-MCI subjects, a fivefold cross-validation accuracy of 80.3% was obtained using the random forest model. Importantly, indole-3-propionic acid, a bacteria-generated metabolite from tryptophan, was identified as a predictor of AD progression, suggesting a role for gut microbiota in AD pathophysiology. Our study establishes a metabolite panel to assist in the stratification of MCI patients and to predict conversion to AD.

Nonalcoholic fatty liver disease (NAFLD) and its more severe form, nonalcoholic steatohepatitis (NASH), are the most common chronic liver diseases worldwide. However, drugs to treat NAFLD and NASH are an unmet clinical need. This study sought to provide evidence that Cisd2 is a molecular target for the development of treatments targeting NAFLD and NASH. Several discoveries are pinpointed. The first is that Cisd2 dosage modulates the severity of Western diet-induced (WD-induced) NAFLD. Specifically, Cisd2 haploinsufficiency accelerates NAFLD development and exacerbates progression toward NASH. Conversely, an enhanced Cisd2 copy number attenuates liver pathogenesis. Secondly, when a WD is fed to mice, transcriptomic analysis reveals that the major alterations affecting biological processes are related to inflammation, lipid metabolism, and DNA replication/repair. Thirdly, among these differentially expressed genes, the most significant changes involve Nrf2-mediated oxidative stress, cholesterol biosynthesis, and fatty acid metabolism. Finally, increased Cisd2 expression protects the liver from oxidative stress and reduces the occurrence of mitochondrial DNA deletions. Taken together, our mouse model reveals that Cisd2 plays a crucial role in protecting the liver from WD-induced damages. The development of therapeutic agents that effectively enhance Cisd2 expression is one potential approach to the treatment of WD-induced fatty liver diseases.

Cisd2 (CDGSH iron sulfur domain 2) is a pro-longevity gene that extends the lifespan and health span of mice, ameliorates age-associated structural damage and limits functional decline in multiple tissues. Non-alcoholic fatty liver disease (NAFLD), which plays an important role in age-related liver disorders, is the most common liver disease worldwide. However, no medicines that can be used to specifically and effectively treat NAFLD are currently approved for this disease. Our aim was to provide pathological and molecular evidence to show that Cisd2 protects the liver from age-related dysregulation of lipid metabolism and protein homeostasis. This study makes four major discoveries. Firstly, a persistently high level of Cisd2 protects the liver from age-related fat accumulation. Secondly, proteomics analysis revealed that Cisd2 ameliorates age-related dysregulation of lipid metabolism, including lipid biosynthesis and β-oxidation, in mitochondria and peroxisomes. Thirdly, Cisd2 attenuates aging-associated oxidative modifications of proteins. Finally, Cisd2 regulates intracellular protein homeostasis by maintaining the functionality of molecular chaperones and protein synthesis machinery. Our proteomics findings highlight Cisd2 as a novel molecular target for the development of therapies targeting fatty liver diseases, and these new therapies are likely to help prevent subsequent malignant progression to cirrhosis and hepatocellular carcinoma.