The Mediterranean diet, which is rich in healthy fats from olive oil and nuts, has long been associated with longer and healthier lives compared to diets heavy in fast food, meat, and dairy. However, the cellular mechanisms underlying this benefit have remained unclear. A team of researchers led by Stanford School of Medicine has now made one of the first connections between monounsaturated fatty acids (healthy fats) and lifespan at a cellular level, shedding light on the intricate relationship between diet, fats, and longevity.
While fats are generally considered detrimental to health, previous studies have indicated that certain types of fats, or lipids, can actually be beneficial. The researchers discovered that oleic acid, one of the fats found in the Mediterranean diet, increases the abundance of two crucial cellular structures called organelles. Additionally, it provides protection to cellular membranes from oxidative damage, a chemical reaction that can be harmful. This protective effect of oleic acid proved to be significant, as worms fed a diet rich in this fatty acid lived approximately 35% longer than those on standard worm diets.
Interestingly, one of the organelles, known as lipid droplets, acted as a sort of crystal ball, accurately predicting the remaining lifespan of individual worms based on their abundance. Worms with a higher number of lipid droplets tended to live longer compared to those with fewer droplets.
Senior author of the study, Professor Anne Brunet, Ph.D., who holds the Michele and Timothy Barakett Professorship of Genetics at Stanford School of Medicine, expressed their long-standing interest in understanding how diet influences lifespan. They are intrigued by the possibility of observing a similar association between lipid droplets and longevity in mammals and humans. These findings suggest that a fat-focused approach may hold promise for improving human health and extending lifespan.
The research, led by Dr. Katharina Papsdorf, was published in Nature Cell Biology on May 1.
A fat by (many) other names
Understanding the distinctions between “good cholesterol” and “bad cholesterol” and how to promote one over the other can be perplexing for many. In general, monounsaturated fats, present in plant-based foods like avocados, olive oil, and nuts, are considered relatively healthy. On the other hand, saturated fats and solid trans fats, which remain solid at room temperature, can elevate the risk of heart disease and other health issues. Fats and oils are composed of fatty acids, while lipids encompass fats, oils, fatty acids, and cholesterol.
In their research on longevity, Papsdorf and her team employed a minute roundworm called C. elegans. These worms, measuring about 1 millimeter in length, typically live for approximately 18 to 20 days. In their natural habitat, they reside in soil and feed on bacteria found on decomposing plant matter. In a laboratory setting, they move in leisurely arcs across specially prepared dishes containing bacteria. C. elegans reproduces rapidly, is cost-effective and easy to maintain, and their genomes and neural networks have been fully mapped, making them an ideal model for studying aging and disease.
Papsdorf and her colleagues conducted a comparison by feeding the worms bacteria grown on laboratory dishes supplemented with either oleic acid or a structurally similar compound known as elaidic acid. Elaidic acid is a monounsaturated trans fatty acid (trans fats = bad!) found in margarine and dairy products, and it is known to be unhealthy for humans. Unlike oleic acid, it lacks a kink in its molecular structure.
“We observed that the number of lipid droplets in the worms’ intestinal cells increased when they were exposed to oleic acid, and this was correlated with an extension of lifespan,” explained Brunet. “In contrast, exposure to elaidic acid did not increase the number of lipid droplets and had no effect on longevity.”
Lipid droplets serve as reservoirs for storing fats within cells and play a central role in cellular metabolism, regulating when, where, and whether the fats are utilized as energy by the cell. The accumulation of these droplets was pivotal to the impact of oleic acid. Blocking the genes responsible for producing proteins involved in droplet formation restored the worms’ lifespans to normal levels.
Alongside tracking the numbers of lipid droplets, the researchers also observed an increase in the quantity of peroxisomes in the intestinal tissue of worms exposed to oleic acid. Peroxisomes contain enzymes that participate in metabolism and oxidation.
Lipid droplet and peroxisome numbers are typically higher in younger animals and naturally decline with age, suggesting some form of co-regulation. Furthermore, these numbers can vary among individuals. Papsdorf discovered that among young worms fed a standard diet, those with higher lipid droplet counts lived slightly longer than genetically identical worms of the same age with fewer droplets, and this difference was statistically significant. The effect was even more pronounced among older worms; middle-aged worms with greater lipid droplet numbers lived an average of 33% longer than their genetically identical counterparts.
“Interestingly, calorie restriction has also been associated with longevity in animals and humans,” Brunet remarked. “But studies have shown that, among calorie-restricted mice, it is often the fattest individuals that live the longest. This suggests fat has a dual aspect. Some aspects are very negative, but other aspects can be positive.”
Avoiding ‘lipid oxidation’
Additionally, the researchers demonstrated that supplementing with oleic acid reduced the occurrence of lipid oxidation, a chemical reaction that damages cellular membranes. In contrast, elaidic acid increased lipid oxidation. Brunet emphasized the detrimental nature of membrane oxidation, stating, “Membrane oxidation is very bad news for an organism. Cell membranes can start to leak and malfunction, triggering a cascade of adverse biological effects.”
This study represents the first indication that lipid droplets and peroxisomes are co-regulated through a biological pathway that responds to the presence of beneficial monounsaturated fatty acids. Moreover, it suggests that protecting cellular membranes from oxidation could potentially delay the aging process.
Brunet acknowledged that further research is required to determine the applicability and mechanisms of these findings in humans. While the presence of lipid droplets in mammalian tissue often signifies obesity and other health issues, it is possible that droplets of a particular size, shape, or within a specific tissue may have varying effects on health. Understanding these distinctions in the context of disease and longevity is an essential aspect that needs to be explored further.