Revealing the Cellular Effects of the Mediterranean Diet

People who follow the Mediterranean diet — which is rich in fats from olive oil and nuts — tend to live longer and healthier lives than others who eat primarily fast foods, meat and dairy products. But it wasn’t clear on a cellular level why the diet was so beneficial.

Researchers led by Stanford University School of Medicine have found one of the first cellular links between healthy fats — known as monounsaturated fatty acids — and lifespan in laboratory worms. The findings suggest a complex relationship between diet, fat, and longevity.

“Fat is generally thought to be bad for health,” said genetics professor Anne Brunet, PhD. “But some studies have shown that certain types of fats, or lipids, can be beneficial.”

Researchers learned that one of the fats found in the Mediterranean diet, oleic acid, increases the number of two major cellular structures, or organelles, and protects cell membranes from damage caused by a chemical reaction called oxidative stress. This protective effect has a big payoff: The researchers found that worms fed food rich in oleic acid lived about 35% longer than those fed standard worming rations.

Amazingly, one of the organelles, known as fat droplets, acted as a de facto crystal ball, predicting with increasing accuracy how many days each animal would live.

“The number of lipid droplets in individual worms tells me the remaining lifespan of the animal,” said research scientist Katharina Babsdorf, PhD. “Worms with more fat droplets live longer than those with fewer droplets.”

Brunette, professor of genetics at the Michelle and Timothy Barakett School, is the lead author of the study, which was published May 1 in the journal. Nature Cell Biology. Papsdorf is the lead author of the research.

“For years, we’ve been very interested in learning how diet affects lifespan,” Brunet said. “It would be interesting to see if we see a similar association between lipid droplets and longevity in mammals and humans. These findings suggest that there may be a fat-based strategy to improve human health and longevity.”

Ghee by (many) other names

Anyone who has ever struggled to remember the difference between “good cholesterol” and “bad cholesterol” and how to layer one over the other will know that the language of fat can be confusing. In general, most of the monounsaturated fats found in plant foods like avocados, olive oil, and nuts are relatively healthy. Saturated fats and trans fats — which are solid at room temperature — can increase your risk of heart disease and other health complications. Fats and oils are composed of fatty acids. Lipids include fats, oils, fatty acids, and cholesterol.

Papsdorf and her colleagues used a small worm called C. elegans in their studies of longevity. The worms, which are about 1 mm long, usually live about 18 to 20 days. In the wild, they live in the soil and feed on bacteria found in decaying plant matter. In the lab, they cruise in lazy arcs across the surface of specially prepared lab dishes filled with bacteria. C. elegans reproduces quickly, is cheap and easy to keep, and its genomes and neural networks have been fully mapped, making it a good model for studying aging and disease.

“The worms allowed us to track molecular changes that occur with changes in diet, and to determine which of these changes affect lifespan,” Babsdorf said.

Babsdorf and her colleagues compared the effect of feeding worm bacteria grown in lab dishes supplemented with oleic acid versus a structurally similar compound called elaidic acid. Lydic acid is a monounsaturated fatty acid (trans fat = harmful!) found in margarine and dairy products and known to be unhealthy for humans. It lacks the twist in the structure of the molecule found in oleic acid.

“We’ve seen that the numbers of lipid droplets in the intestinal cells of worms increase if the worms are exposed to oleic acid, and this is associated with an extended life span,” Brunet said. “In contrast, exposure to elaidic acid did not increase the number of lipid droplets and had no effect on longevity.”

Fat droplets are reservoirs in which cells store fat. It plays a central role in cellular metabolism – regulating when, where, and whether fats are used as energy for the cell. Droplet accumulation was a critical factor in the effect of oleic acid. Gene blocking of droplet-making proteins reduced the animals’ lifespan to the normal range.

In addition to tracking the numbers of lipid droplets, the researchers observed an increase in the number of peroxisomes in the intestinal tissues of the worms exposed to oleic acid. Peroxisomes contain enzymes involved in metabolism and oxidation.

The numbers of lipid droplets and peroxisomes are higher in younger animals and naturally decrease with age, indicating that they are jointly regulated. It can also vary between individuals. Papsdorf found that among young worms fed a normal diet, those with higher numbers of fat droplets lived slightly, but statistically significant, longer than genetically identical animals of the same age with fewer droplets. The effect was more pronounced among the older animals; Middle-aged worms with more lipid droplets lived an average of 33% longer than their genetically identical peers.

“Interestingly, calorie restriction has also been associated with longer life in animals and humans,” Brunet said. “But studies have shown that among calorie-restricted rats, it is often the fattest individuals who live the longest. This suggests that fat has a double aspect. Some aspects are very negative, but other aspects can be positive.”

Avoid fat oxidation

Finally, researchers have shown that oleic acid supplementation reduces a chemical reaction called lipid peroxidation, which damages cellular membranes. In contrast, elaidic acid increased lipid oxidation. “Membrane oxidation is very bad news for the organism,” Brunet said. “Cell membranes can begin to leak and fail, which can cause a cascade of adverse biological effects.”

The researchers’ findings are the first to suggest that lipid droplets and peroxisomes are jointly regulated by a biological pathway that responds to the presence of beneficial monounsaturated fatty acids, and that aging can be avoided by protecting cellular membranes from oxidative stress.

“There is still a lot of research to be done to see if and how these findings apply to humans,” Brunet said. “Often when one sees fatty droplets in mammalian tissue, it is an indication of obesity and other health issues. But it is possible that droplets of a certain size or shape or in a particular tissue can have varying health effects. We need to understand what characterizes them in the context of disease and longevity. “.