Cytochrome b5 reductase and the control of lipid metabolism and healthspan

Abstract

Cytochrome b5 reductases (CYB5R) are required for the elongation and desaturation of fatty acids, cholesterol synthesis and mono-oxygenation of cytochrome P450 enzymes, all of which are associated with protection against metabolic disorders. However, the physiological role of CYB5R in the context of metabolism, healthspan and aging remains ill-defined. We generated CYB5R-overexpressing flies (CYB5R-OE) and created a transgenic mouse line overexpressing CYB5R3 (CYB5R3-Tg) in the C57BL/6J background to investigate the function of this class of enzymes as regulators of metabolism and age-associated pathologies. Gender- and/or stage-specific induction of CYB5R, and pharmacological activation of CYB5R with tetrahydroindenoindole extended fly lifespan. Increased expression of CYB5R3 was associated with significant improvements in several metabolic parameters that resulted in modest lifespan extension in mice. Diethylnitrosamine-induced liver carcinogenesis was reduced in CYB5R3-Tg mice. Accumulation of high levels of long-chain polyunsaturated fatty acids, improvement in mitochondrial function, decrease in oxidative damage and inhibition of chronic pro-inflammatory pathways occurred in the transgenic animals. These results indicate that CYB5R represents a new target in the study of genes that regulate lipid metabolism and healthspan. Increased activity of a single gene improves healthy lifespan of mice and flies, highlighting a new cellular pathway involved in aging. An international team of researchers led by Rafael de Cabo at the National Institutes of Health in Baltimore studied aging and disease progression in flies and mice genetically modified to overexpress antioxidant protein called cytochrome b5 reductase (CYB5R). These animals had modest improvements in lifespan, and mice had delayed tumor growth compared to controls in a model of liver cancer. Interestingly, the data suggest that this lifespan improvement was mediated by different biochemical pathways activated by calorie restriction, a well-studied longevity technique. Treatments or techniques that increase activity of the CYB5R pathway could thus be a viable alternative approach to lengthening healthy lifespan.