A Mediterranean-style diet may influence aging through an unexpected biological pathway involving tiny proteins produced inside mitochondria, according to a new study led by researchers at the USC Leonard Davis School of Gerontology.
Mitochondria are best known as the structures that generate energy inside cells, but scientists increasingly recognize that they also release chemical signals that affect metabolism, inflammation, stress responses, and aging.
The researchers found that older adults who followed a Mediterranean diet most closely had higher blood levels of two mitochondrial microproteins called humanin and SHMOOSE. Both have previously been associated with protection against cardiovascular disease and neurodegeneration, the gradual loss of nerve cell function seen in conditions such as Alzheimer's disease.
The study was led by Roberto Vicinanza, an instructional associate professor of gerontology at the USC Leonard Davis School.
"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 Influence Aging
The Mediterranean diet emphasizes olive oil, fish, legumes, fruits, vegetables, whole grains, and other minimally processed foods. It generally limits refined carbohydrates, heavily processed products, and foods high in added sugar.
Decades of research have linked this eating pattern to a lower risk of cardiovascular disease, type 2 diabetes, cognitive decline, and premature death. However, scientists are still working to identify the cellular processes that may produce those benefits.
For the new study, the research team examined blood samples from older adults who followed the Mediterranean diet to different degrees. Participants with the strongest adherence had significantly higher concentrations of humanin and SHMOOSE.
They also had lower indicators of oxidative stress, a form of cellular damage caused when unstable molecules known as reactive oxygen species overwhelm the body's protective systems. Persistent oxidative stress can injure proteins, fats, and DNA and has been associated with aging and many chronic diseases.
Olive Oil, Fish, and Legumes Showed Strong Links
The findings suggest that individual parts of the Mediterranean diet may contribute differently to mitochondrial health.
Higher consumption of olive oil, fish, and legumes was associated with increased levels of humanin. Olive oil and a lower intake of refined carbohydrates were linked to higher levels of SHMOOSE.
Refined carbohydrates include foods such as white bread, pastries, and many sugary products that have been stripped of much of their natural fiber and nutrients. They are digested quickly and can produce sharp increases in blood sugar.
"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."
A biomarker is a measurable biological sign that can provide information about health, disease, or how the body is responding to a behavior or treatment. In this case, the two microproteins could potentially help researchers measure how strongly a person's body is responding to a Mediterranean eating pattern.
Tiny Proteins Hidden in Mitochondrial DNA
The study builds on more than 20 years of research led by Cohen, who helped pioneer the discovery of peptides produced by mitochondria.
Most familiar human proteins are made from instructions contained in the DNA inside the cell nucleus. Mitochondria, however, carry a small amount of their own genetic material, inherited separately from nuclear DNA.
Humanin and SHMOOSE come from short sections of the mitochondrial genome known as small open reading frames. These regions were once thought to have little or no function, but researchers now know that some of them produce biologically active microproteins.
Humanin is among the most extensively studied of these molecules. Cohen and his colleagues first identified it in 2003. Subsequent research has connected it to improved insulin sensitivity, cardiovascular protection, longer life span, and the preservation of cognitive function.
Cohen's laboratory later discovered SHMOOSE (Small Human Mitochondrial ORF Over SErine tRNA), which has been linked to brain health. One genetic variant of SHMOOSE has been associated with a greater risk of Alzheimer's disease, while the normal form appears to help shield neurons from damage related to amyloid.
Amyloid is a protein that can accumulate abnormally in the brain and form plaques, one of the major biological features associated with Alzheimer's disease.
"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 Possible New Form of Heart Protection
The researchers also identified a possible connection between humanin and Nox2, an enzyme involved in producing reactive oxygen species.
Although reactive oxygen species play useful roles in normal cell signaling and immune defenses, excessive production can damage tissues and increase oxidative stress.
Higher humanin levels were associated with lower Nox2 activity. This relationship suggests that humanin could help limit oxidative damage and provide added protection for the heart and blood vessels.
The researchers propose that the Mediterranean diet may protect the cardiovascular system in two complementary ways. It may directly reduce oxidative stress while also increasing mitochondrial microproteins that help restrain damaging cellular pathways.
"This could represent a new cardioprotective mechanism of the Mediterranean diet," Vicinanza said.
Taking the Mediterranean Diet to the Global Stage
Vicinanza has also worked to promote the Mediterranean diet beyond the laboratory, presenting it as a model not only for health, but also for culture and environmental sustainability.
He has collaborated with the Municipality of Pollica in Italy, a UNESCO Mediterranean Diet emblematic community, to support the creation of the International Day of the Mediterranean Diet at the United Nations.
The observance will take place each year on November 16. Its goal is to increase awareness of the Mediterranean diet's health, cultural, and environmental importance around the world.
Vicinanza said that mission reflects the broader implications of the new findings.
"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."
Cellular organelles are specialized structures that perform specific jobs inside cells. Mitochondria are considered ancient because scientists believe they evolved from bacteria that entered into a cooperative relationship with early cells more than a billion years ago.
A Step Toward Precision Nutrition
The study was relatively small and observational. That means it identified associations between diet and microprotein levels but could not prove that following the Mediterranean diet directly caused those biological changes.
Other factors, including physical activity, overall health, medication use, genetics, and lifestyle, could also have influenced the findings.
Even with those limitations, the results point toward a developing field known as precision nutrition. This approach aims to use biological measurements, genetics, metabolism, and other personal characteristics to design dietary recommendations that are more individualized than standard nutrition advice.
Humanin, SHMOOSE, and related mitochondrial microproteins could eventually help scientists determine which dietary patterns are producing beneficial cellular effects in a particular person.
Future studies will test whether changing a person's diet can directly raise levels of these peptides and whether those increases result in a measurable reduction in 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."
About the Study
The study, "Mediterranean diet adherence is associated with mitochondrial microproteins Humanin and SHMOOSE; potential role of the Humanin-Nox2 interaction in cardioprotection," was published March 9, 2026, in Frontiers in Nutrition. Coauthors included Junxiang Wan and Kelvin Yen of the USC Leonard Davis School and Vittoria Cammisotto, Francesco Violi and Pasquale Pignatelli of Sapienza University of Rome.
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).
