Mediterranean diet may boost tiny proteins that protect the heart and brain

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 discovered that people who more closely followed the Mediterranean diet had higher levels of two mitochondrial microproteins called humanin and SHMOOSE. Both have previously been linked to protection against cardiovascular disease and neurodegeneration, the gradual deterioration of nerve cells that occurs in conditions such as Alzheimer's disease.

The study, led by USC Leonard Davis Instructional Associate Professor of Gerontology Roberto Vicinanza, offers a possible explanation for how everyday food choices influence cellular health and the aging process.

"These microproteins may 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 May Protect Aging Cells

The Mediterranean diet emphasizes foods such as olive oil, fish, beans, lentils, fruits, and vegetables. It has consistently 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 wide-ranging health benefits.

To investigate, the researchers examined blood samples from older adults who followed the Mediterranean diet to different 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, the researchers found that certain foods were associated with different microproteins. Higher consumption of olive oil, fish, and legumes was linked to increased humanin levels. Meanwhile, olive oil consumption and eating fewer refined carbohydrates were associated with higher levels of SHMOOSE.

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 naturally occurring nutrients than their minimally processed counterparts.

"These findings suggest that specific components of the Mediterranean diet may directly influence mitochondrial biology," said USC Leonard Davis School Dean and USC Distinguished Professor Pinchas Cohen, the study's senior author. "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 eventually help scientists understand how closely someone's diet aligns with healthy eating patterns and how their cells respond.

Tiny Mitochondrial Proteins With Powerful Effects

The findings extend a scientific effort spanning more than 20 years to investigate small proteins produced by mitochondria. Cohen has played a leading role in discovering and studying these molecules, which are increasingly recognized as important participants in cellular health.

Mitochondria are often described as the powerhouses of cells because they produce much of the energy required for essential biological activities. But their role extends beyond energy production. They also help regulate metabolism, cellular stress responses, and processes associated with aging.

Unlike most proteins, which are produced using instructions stored in the DNA inside the cell's nucleus, mitochondrial microproteins originate from genetic instructions within mitochondria themselves.

These instructions are found in small segments of mitochondrial DNA known as open reading frames. Some of these regions were once considered 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 associated humanin with improved insulin sensitivity, better 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 healthy 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 because of its possible role in protecting the brain. Scientists have found 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 involving amyloid, a protein that can accumulate abnormally in the brains of people with Alzheimer's.

"These peptides are emerging as key regulators of aging biology," Cohen said. "They connect mitochondrial function to diseases like Alzheimer's and heart disease and now, potentially, to nutrition."

A Hidden Mechanism for Protecting the Heart

The scientists also identified a potentially important connection between humanin and an enzyme called Nox2, which helps generate reactive oxygen species.

Although these molecules have useful roles in normal cell signaling and immune defense, excessive production can contribute to oxidative stress and damage blood vessels and other tissues.

The 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 offering an additional layer of cardiovascular protection.

Based on these findings, the researchers propose that the Mediterranean diet could support heart health in two complementary ways. The diet may help reduce oxidative stress directly while also supporting 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 extends beyond investigating its effects inside the body. He has also worked to promote this traditional eating pattern internationally as a way to support human health, cultural heritage, and environmental sustainability.

As part of those efforts, he collaborated with the Municipality of Pollica in Italy, which is recognized as a UNESCO Mediterranean Diet emblematic community.

That collaboration helped support the establishment of the International Day of the Mediterranean Diet through the United Nations.

Observed every year on November 16, the international event is intended to draw attention to the Mediterranean diet's health benefits as well as its cultural traditions and environmental significance.

For Vicinanza, the new findings reinforce the relationship between traditional food practices and modern discoveries about how the body functions.

"We're connecting centuries-old dietary traditions with cutting-edge molecular biology," Vicinanza said. "It supports the idea that healthy eating patterns with little to no ultra-processed foods reflect how humans have eaten over long periods and may create conditions to which mitochondria -- ancient cellular organelles -- are likely adapted."

Could Tiny Proteins Help Unlock Healthier Aging?

Although the findings are promising, the researchers emphasize that the study was relatively small and observational. That means it identified relationships between dietary habits and biological measurements but could not determine whether eating a Mediterranean diet directly caused the differences in microprotein levels.

Other factors, including participants' overall health and lifestyle, could also influence the results.

Nevertheless, the discovery opens an intriguing 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 those 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 funded 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 PRIN 2022 grant 000031_23_PP_PIGNATELLI_PRIN_2022-B53D23021240006 (to Pignatelli).