The influence of dietary fat source on liver and skeletal muscle mitochondrial modifications and lifespan changes in calorie-restricted mice

The Membrane Theory of Aging proposes that lifespan is inversely related to the level of unsaturation in membrane phospholipids. Calorie restriction (CR) without malnutrition extends lifespan in many model organisms, which may be related to alterations in membrane phospholipids fatty acids. During the last few years our research focused on studying how altering the predominant fat source affects the outcome of CR in mice. We have established four dietary groups: one control group fed 95 % of a pre-determined ad libitum intake (in order to prevent obesity), and three CR groups fed 40 % less than ad libitum intake. Lipid source for the control and one of the CR groups was soybean oil (high in n-6 PUFA) whereas the two remaining CR groups were fed diets containing fish oil (high in n-3 PUFA), or lard (high in saturated and monounsaturated fatty acids). Dietary intervention periods ranged from 1 to 18 months. We performed a longitudinal lifespan study and a cross-sectional study set up to evaluate several mitochondrial parameters which included fatty acid composition, H+ leak, activities of electron transport chain enzymes, ROS generation, lipid peroxidation, mitochondrial ultrastructure, and mitochondrial apoptotic signaling in liver and skeletal muscle. These approaches applied to different cohorts of mice have independently indicated that lard as a fat source often maximizes the effects of 40 % CR on mice. These effects could be due to significant increases of monounsaturated fatty acids levels, in accordance with the Membrane Theory of Aging.Supported by NIH grant 1R01AG028125 (to JJR, PN and JMV), Ministerio de Economía y Competitividad BFU2011-23578 (to JMV), Junta de Andalucía Proyectos de Excelencia grant P09-CVI-4887 (to JMV), Junta de Andalucía Proyectos Internacionales grant (to JMV), and BIO-276 (Junta de Andalucía and the University of Córdoba, to JMV). RdC is funded by the Intramural Research program of the NIA/NIH. JALD, JA, LFdR and EGC were funded by a predoctoral fellowship of the Spanish Ministerio de Educación and BIO-276. HK was funded by a predoctoral fellowship of the Agencia Española de Cooperación Internacional al Desarrollo and BIO-276. MCR and MdR were supported by BIO-276.Peer Reviewe