A new study suggests that the Mediterranean diet may protect the heart, brain and aging cells through a surprising biological mechanism involving tiny proteins produced by mitochondria, the structures responsible for generating most of the energy our cells need.
Researchers at the USC Leonard Davis School of Gerontology found that people who followed the Mediterranean diet more closely had higher levels of two mitochondrial microproteins called humanin and SHMOOSE. Both have previously been linked to protection against cardiovascular disease and neurodegeneration, the progressive deterioration of nerve cells that occurs in conditions such as Alzheimer’s disease.
The study, led by Roberto Vicinanza, USC Leonard Davis associate professor of gerontology, offers a possible explanation for how daily food choices influence cellular health and the aging process.
“These microproteins can act as molecular messengers that translate what we eat into how our cells function and age,” Vicinanza said. “It’s a new biological pathway that helps explain why the Mediterranean diet is so powerful.”
How the Mediterranean diet can protect aging cells
The Mediterranean diet emphasizes foods such as olive oil, fish, beans, lentils, fruits and vegetables. It has historically been associated with a lower risk of heart disease, type 2 diabetes, and cognitive decline. However, scientists are still working to understand exactly how this eating pattern produces its many health benefits.
To investigate, researchers examined blood samples from older people who followed the Mediterranean diet to varying degrees. Those whose eating habits most closely matched the diet had significantly higher concentrations of humanin and SHMOOSE.
They also showed lower indicators of oxidative stress, a process in which harmful molecules called reactive oxygen species overwhelm the body’s protective defenses. Over time, oxidative stress can damage proteins, DNA, and other cellular components, contributing to aging and chronic disease.
Interestingly, researchers found that certain foods were associated with different microproteins. Higher consumption of olive oil, fish and legumes were linked to increased humanin levels. Meanwhile, consuming olive oil and eating fewer refined carbohydrates were associated with higher SHMOOSE levels.
Refined carbohydrates include foods made with heavily processed grains and sugars, such as white bread, pastries, and many sugary snacks. These foods generally contain less fiber and fewer natural nutrients than their minimally processed counterparts.
“These results suggest that specific components of the Mediterranean diet may directly influence mitochondrial biology,” said USC Dean of the Leonard Davis School and USC Distinguished Professor Pinchas Cohen, lead author of the study. “Humanin and SHMOOSE could serve as biomarkers for adherence to the Mediterranean diet and have clinical significance.”
Biomarkers are measurable biological indicators that can provide information about a person’s health or physiological state. In this case, the researchers suggest that humanin and SHMOOSE could potentially help scientists understand how well a person’s diet aligns with healthy eating habits and how their cells respond.
Tiny mitochondrial proteins with powerful effects
The results extend a more than 20-year scientific effort to study small proteins produced by mitochondria. Cohen played a leading role in the discovery and study of these molecules, which are increasingly recognized as important players in cellular health.
Mitochondria are often described as the powerhouses of cells because they produce much of the energy needed for essential biological activities. But their role goes beyond energy production. They also help regulate metabolism, cellular responses to stress and processes associated with aging.
Unlike most proteins, which are produced using instructions stored in the DNA of the cell nucleus, mitochondrial microproteins come from genetic instructions contained in the mitochondria themselves.
These instructions are found in small segments of mitochondrial DNA called open reading frames. Some of these regions were once thought to be nonfunctional, but researchers have discovered that they can encode biologically active molecules.
One of the best understood is humanin, first identified by Cohen and fellow researchers in 2003. Subsequent studies have linked humanin to improved insulin sensitivity, improved cardiovascular health, increased longevity, and protection of cognitive abilities.
Insulin sensitivity refers to how effectively the body’s cells respond to insulin, the hormone that helps regulate blood sugar. Maintaining good insulin sensitivity is important for metabolic health and reducing the risk of type 2 diabetes.
Another intriguing microprotein is SHMOOSE (Small Human Mitochondrial ORF Over SErine tRNA), which was identified more recently by Cohen’s research team.
SHMOOSE has attracted particular interest due to its possible role in protecting the brain. Scientists have discovered that a genetic variant of SHMOOSE is associated with an increased risk of Alzheimer’s disease. The normal version, meanwhile, appears to help protect neurons from damage related to amyloid, a protein that can build up abnormally in the brains of people with Alzheimer’s disease.
“These peptides emerge as key regulators of the biology of aging,” Cohen said. “They link mitochondrial function to diseases like Alzheimer’s and heart disease and now, potentially, to nutrition.”
A hidden mechanism to protect the heart
The scientists also identified a potentially important link between humanin and an enzyme called Nox2, which helps generate reactive oxygen species.
Although these molecules play a useful role in normal cell signaling and immune defense, excessive production can contribute to oxidative stress and damage blood vessels and other tissues.
Researchers observed that people with higher humanin levels tended to have lower Nox2 activity. This relationship raises the possibility that humanin helps limit damaging oxidative processes, potentially providing an additional layer of cardiovascular protection.
Based on these results, the researchers propose that the Mediterranean diet could promote heart health in two complementary ways. Diet can directly help reduce oxidative stress while promoting the production of mitochondrial microproteins that influence pathways involved in cellular damage.
However, the observed associations do not establish that the diet directly increases these proteins or that the proteins themselves prevent cardiovascular disease.
“This could represent a new cardioprotective mechanism of the Mediterranean diet,” Vicinanza said.
Bringing the Mediterranean diet to a global audience
Vicinanza’s interest in the Mediterranean diet goes beyond the study of its effects on the body. He has also worked to promote this traditional way of eating internationally as a way to support human health, cultural heritage and environmental sustainability.
As part of these efforts, he collaborated with the municipality of Pollica in Italy, recognized as an emblematic community of the Mediterranean diet by UNESCO.
This collaboration helped support the creation of the International Day of the Mediterranean Diet through the United Nations.
Observed annually on November 16, this international event aims to draw attention to the health benefits of the Mediterranean diet as well as its cultural traditions and environmental importance.
For Vicinanza, the new findings strengthen the relationship between traditional dietary practices and modern discoveries about how the body works.
“We combine centuries-old food traditions with cutting-edge molecular biology,” Vicinanza said. “This supports the idea that healthy eating habits with little or no ultra-processed foods reflect the way humans have eaten over long periods of time and may create conditions to which mitochondria – ancient cellular organelles – are likely adapted.”
Could Tiny Proteins Help Age Healthier?
Although the results are promising, the researchers point out that the study was relatively limited and observational. This means that it identified relationships between dietary habits and biological measures, but could not determine whether a Mediterranean diet directly caused the differences in microprotein levels.
Other factors, including participants’ overall health and lifestyle, could also influence the results.
Nonetheless, this discovery opens an exciting possibility for the emerging field of precision nutrition, which seeks to develop dietary recommendations based on an individual’s biological characteristics and needs.
If future research confirms that dietary changes can reliably influence humanin, SHMOOSE, and related microproteins, these molecules could potentially become useful tools for evaluating nutritional interventions and developing more personalized strategies for healthy aging.
The next step is to determine whether adopting a Mediterranean-style diet actually increases these proteins and whether these changes lead to measurable improvements in cardiovascular health, brain function, or disease risk.
“Our goal is to move from observing associations to understanding causality,” Vicinanza said. “If we can harness these pathways, we may be able to design nutritional strategies that promote healthy aging at the molecular level.”
The work was supported by the USC Daryl and Irwin Simon Nutrition for Alzheimer’s Disease Prevention Research Fund (to Vicinanza), the Hanson-Thorell Family Research Award (to Vicinanza), National Institutes of Health grant P30AG094848 (to Cohen), and the PRIN 2022 grant. 000031_23_PP_PIGNATELLI_PRIN_2022-B53D23021240006 (to Pignatelli).
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