Abstract:Aging is a multifactorial and tissue-specific process involving diverse alterations regarded as the "hallmarks of aging", which include genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion and altered intracellular communication. Virtually all these hallmarks are targeted by dietary olive oil, particularly by virgin olive oil, since many of its beneficial effects can be accounted not only for the monounsaturated nature of its predominant fatty acid (oleic acid), but also for the bioactivity of its minor compounds, which can act on cells though both direct and indirect mechanisms due to their ability to modulate gene expression. Among the minor constituents of virgin olive oil, secoiridoids stand out for their capacity to modulate many pathways that are relevant for the aging process. Attenuation of aging-related alterations by olive oil or its minor compounds has been observed in cellular, animal and human models. How olive oil targets the hallmarks of aging could explain the improvement of health, reduced risk of aging-associated diseases, and increased longevity which have been associated with consumption of a typical Mediterranean diet containing this edible oil as the predominant fat source.

In this paper we analyzed changes in hepatocyte mitochondrial mass and ultrastructure as well as in mitochondrial markers of fission/fusion and biogenesis in mice subjected to 40% calorie restriction (CR) for 18 months versus ad libitum-fed controls. Animals subjected to CR were separated into three groups with different dietary fats: soybean oil (also in controls),fish oil and lard. Therefore, the effect of the dietary fat under CR was studied as well. Our results show that CR induced changes in hepatocyte and mitochondrial size, in the volume fraction occupied by mitochondria, and in the number of mitochondria per hepatocyte. Also, mean number of mitochondrial cristae and lengths were significantly higher in all CR groups compared with controls. Finally, CR had no remarkable effects on the expression levels of fission and fusion protein markers. However, considerable differences in many of these parameters were found when comparing the CR groups, supporting the idea that dietary fat plays a relevant role in the modulation of CR effects in aged 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.

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Biological membranes adapt their phospholipid composition according to the major lipid source present in the diet. Different dietary sources may modify the lipid pattern and produce biochemical alterations in cells, especially in mitochondrial membranes. For example, sources of polyunsaturated fatty acids, such as soybean or fish oil, will generate membranes more susceptible to oxidative stress than will sources of saturated or monounsaturated fatty acids, such as animal fat or olive oil, respectively. Previous studies revealed that different dietary fats also influenced the mitochondrial levels of coenzyme Q (Q), a lipid present in all organisms. Apart from participating as an electron and proton carrier in the mitochondrial electron transport chain, Q serves numerous cellular functions including metabolism, antioxidant protection, and the regulation of signal transduction. We used a hepatocellular model of Hepa1‐6 cells treated with different lipid emulsions, and focused on the regulation of Q biosynthesis and the ultrastructure of the mitochondria. Our results indicate that treatment with unsaturated fatty acids increased Q levels, which corresponded to an increase in Q biosynthetic rate in the case of polyunsaturated fatty acids (PUFA) but not in the case of monounsaturated fatty acids (MUFA). Moreover, our results indicate that PUFA regulate the different Q isoforms, and promote the biosynthesis of Q10 over Q9 thus decreasing Q9/Q10 ratio. Since most of the cellular Q is located in mitochondria, the structure, number, size and distribution of this organelle greatly influences the overall content of Q in cells. We studied the ultrastructure and the abundance of mitochondria in order to evaluate whether the regulation of Q levels by fatty acids involved an alteration of mitochondrial ultrastructure and/or mitochondrial abundance. Electron microscopy micrographs of cells showed that cells treated with n‐3 PUFA showed significantly increased mitochondrial volume and the number of mitochondria per cell, explaining in part the increase of Q levels previously described. However, these alterations in the mitochondrial ultrastructure do not explain the alteration of the Q9/Q10 ratio. Further experiments focused on the mevalonate pathway showed that the alteration of the Q9/Q10 ratio can be explained by PUFA‐mediated inhibition of farnesyl diphosphate synthase, a key enzyme in this pathway. However, the observed increase of Q biosynthesis may implicate additional target(s). Immunostaining analyses reveal that PUFA exert an stimulatory effect on some of the COQ proteins involved in Q biosynthesis pathway. Further studies will be needed to fully understand the exact regulation that fatty acids exert on Q metabolism and mitochondrial ultrastructure.Support or Funding InformationBFU2015‐64630‐R and BFU2011‐23578 Projects from the Spanish Ministery of Economy. 1R01AG028125‐01A1 Project from NIH. FPU12/03398 Scholarship from the Spanish Ministery of Education, Culture and Sport.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.