Untangling determinants of health and lifespan

The impact of chronic caloric restriction (CR) on health and survival in model organisms is complex and its underlying molecular mechanisms are poorly understood. Genetic background, sex, degree of CR and diet composition are expected modifiers of survival outcomes of this intervention. A recent study in mice addressed the impact of diet composition and feeding patterns used in nonhuman primates. It was found that, while diet composition alone did not impact longevity, fasting and calories were determinant for increased survival. We use here a combined physiological, multi-omics (transcriptomics-metabolomics), and integrated pathway analyses to gain insight into core and specific pathways associated with liver healthspan and lifespan. Main findings show that liver longevity pathways associated with CR predominantly correspond to detoxification, molecular turnover-repair-maintenance, and energy supply processes. Differential responses on lifespan extension provided by the different feeding strategies unveiled a distinct pattern of longevity pathways that centered around amino acid, fatty acid and nucleic acid metabolisms. Glycine-serine-threonine metabolism was a unique metabolic hub associated with lifespan whereas short-chain fatty acids and essential PUFAs metabolism were unique to healthspan. Nonhuman primate serum metabolomics data essentially recapitulated key features in mice. This microarray study of liver gene expression from three feeding regimens, ad libitum (AL), 30% caloric restriction (CR), or meal-fed (MF), in male C57BL6/J mice examines the transcriptional effects on mice who were fed either an open source diet (NIA diet) low in sucrose and fat, or a sucrose-rich diet (WIS diet) composed of purified ingredients from five monts of age and for the remainder of their lives. There were from four to nine biological replicates for each of the six different combinations of diet and feeding regimens, for a total of forty-eight microarray samples.