A groundbreaking investigation, spearheaded by researchers at the USC Leonard Davis School of Gerontology, suggests that the well-documented benefits of a Mediterranean-style dietary regimen may be mediated by a previously overlooked molecular pathway, one that involves the intricate workings of minuscule proteins synthesized within the cell’s energy powerhouses, the mitochondria. While primarily recognized for their role in cellular energy production, mitochondria are increasingly understood by the scientific community to be active participants in intercellular communication, releasing signaling molecules that exert profound influences on metabolic processes, inflammatory responses, stress resilience, and the fundamental trajectory of aging.
The study’s findings indicate a compelling correlation between adherence to a Mediterranean diet and elevated circulating levels of two specific mitochondrial microproteins: humanin and SHMOOSE. These diminutive proteins have garnered attention in prior research for their protective attributes against both cardiovascular ailments and neurodegenerative conditions, a category of disorders characterized by the progressive deterioration of nerve cell function, exemplified by diseases such as Alzheimer’s. The research, led by Roberto Vicinanza, an instructional associate professor of gerontology at the USC Leonard Davis School, posits that these microproteins may function as crucial molecular intermediaries, effectively translating dietary intake into tangible impacts on cellular operations and the aging process. "These microproteins may act as molecular messengers that translate what we eat into how our cells function and age," Vicinanza explained, highlighting the emergent understanding of a novel biological pathway that could illuminate the potent effects of the Mediterranean diet.
The Mediterranean diet, a dietary pattern historically rooted in the eating habits of countries bordering the Mediterranean Sea, is characterized by its emphasis on whole, minimally processed foods. Its cornerstone components include generous portions of olive oil, a diverse array of fish, nutrient-rich legumes, an abundance of fruits and vegetables, and whole grains. Conversely, it generally advocates for the limitation of refined carbohydrates, heavily processed food products, and items laden with added sugars. This dietary blueprint has been consistently associated with a reduced incidence of cardiovascular disease, type 2 diabetes, cognitive decline, and premature mortality, a testament to its salutary effects on human health accumulated over decades of epidemiological and clinical observation. However, the precise cellular mechanisms underpinning these widespread benefits have remained a subject of ongoing scientific inquiry.
In this latest research endeavor, the investigative team meticulously analyzed blood samples drawn from a cohort of older adults whose dietary habits exhibited varying degrees of adherence to the Mediterranean eating pattern. A significant observation emerged: participants demonstrating the most rigorous compliance with the diet exhibited notably higher concentrations of both humanin and SHMOOSE in their bloodstream. Furthermore, these individuals also presented with lower levels of biomarkers indicative of oxidative stress. Oxidative stress is a detrimental cellular state that arises when the body’s antioxidant defense systems are overwhelmed by an excess of unstable molecules known as reactive oxygen species. This imbalance can lead to cellular damage, impacting proteins, lipids, and DNA, and is widely implicated in the aging process and the pathogenesis of numerous chronic diseases.
The study’s revelations further suggest that individual constituents of the Mediterranean diet may exert distinct influences on mitochondrial health. For instance, elevated consumption of olive oil, fish, and legumes was specifically linked to increased levels of humanin. Concurrently, a higher intake of olive oil, coupled with a reduced consumption of refined carbohydrates, was associated with augmented levels of SHMOOSE. Refined carbohydrates, commonly found in products like white bread and pastries, undergo processing that strips them of much of their natural fiber and micronutrients. Their rapid digestion can precipitate sharp spikes in blood glucose levels. Pinchas Cohen, Dean of the USC Leonard Davis School and a distinguished professor, who served as the senior author of the study, commented on the implications: "These findings suggest that specific components of the Mediterranean diet may directly influence mitochondrial biology. Humanin and SHMOOSE could serve as biomarkers for adherence to the Mediterranean diet and have clinical significance." The concept of a biomarker is crucial here; it represents a measurable biological indicator that can furnish insights into an individual’s health status, the presence of disease, or the body’s response to specific interventions or behaviors. In this context, humanin and SHMOOSE could potentially offer a quantitative method for assessing the extent to which an individual’s physiology is responding positively to a Mediterranean dietary approach.
This research builds upon more than two decades of pioneering work by Professor Cohen, who was instrumental in the discovery of peptides originating from mitochondria. Unlike the vast majority of human proteins, which are encoded by nuclear DNA within the cell’s nucleus, mitochondria possess their own distinct, albeit small, genome. This mitochondrial DNA is inherited independently of nuclear DNA. Humanin and SHMOOSE originate from brief segments of this mitochondrial genome, known as small open reading frames (sORFs). Previously, these sORFs were largely considered to be non-functional or of minimal importance, but contemporary research has revealed that a subset of them actively produce biologically active microproteins.
Humanin stands as one of the most extensively researched among these molecules. It was first identified by Cohen and his collaborators in 2003. Subsequent investigations have established its association with a range of beneficial effects, including enhanced insulin sensitivity, protection of the cardiovascular system, increased lifespan, and the preservation of cognitive function. Later, Cohen’s laboratory identified SHMOOSE (Small Human Mitochondrial ORF Over SErine tRNA), a microprotein that has been linked to brain health. Notably, a specific genetic variant of SHMOOSE has been associated with an increased susceptibility to Alzheimer’s disease, while its typical form appears to offer neuroprotection, shielding neurons from damage attributed to amyloid protein accumulation. Amyloid is a protein that can aggregate abnormally in the brain, forming plaques, which are a hallmark pathological feature of Alzheimer’s disease. Professor Cohen remarked on the growing significance of these molecules: "These peptides are emerging as key regulators of aging biology. They connect mitochondrial function to diseases like Alzheimer’s and heart disease and now, potentially, to nutrition."
The study also uncovered a potential connection between humanin and Nox2, an enzyme involved in the generation of reactive oxygen species. While reactive oxygen species play essential roles in normal cellular signaling and immune responses, an overproduction can lead to tissue damage and exacerbate oxidative stress. The findings revealed that higher levels of humanin were correlated with reduced Nox2 activity, suggesting that humanin may play a role in mitigating oxidative damage, thereby offering an additional layer of protection for the heart and vasculature. The researchers propose that the Mediterranean diet might confer cardiovascular protection through a dual mechanism: by directly reducing oxidative stress while simultaneously augmenting the production of mitochondrial microproteins that help to dampen harmful cellular processes. "This could represent a new cardioprotective mechanism of the Mediterranean diet," Vicinanza noted.
Beyond the laboratory, Vicinanza has actively championed the Mediterranean diet, advocating for its recognition not only for its health benefits but also for its cultural significance and environmental sustainability. His collaboration with the Municipality of Pollica in Italy, an officially recognized UNESCO Mediterranean Diet emblematic community, contributed to the establishment of the International Day of the Mediterranean Diet at the United Nations. Observed annually on November 16th, this day aims to elevate global awareness of the Mediterranean diet’s multifaceted importance – encompassing health, culture, and environmental considerations. Vicinanza views this mission as deeply aligned with the broader implications of the new research. "We’re connecting centuries-old dietary traditions with cutting-edge molecular biology," he stated, emphasizing how healthy eating patterns, largely devoid of ultra-processed foods, reflect ancestral human diets and may foster an environment to which mitochondria, considered ancient cellular organelles due to their evolutionary origins from symbiotic bacteria over a billion years ago, are inherently adapted. Cellular organelles are specialized compartments within cells that perform specific functions, and mitochondria’s ancient lineage underscores their fundamental role in cellular life.
It is important to acknowledge the observational nature of this study, which, despite its significant findings, was relatively small in scale. Consequently, it identified associations between dietary habits and microprotein levels but could not definitively establish a causal link. Various other factors, including physical activity levels, overall health status, medication regimens, genetic predispositions, and general lifestyle choices, could have influenced the observed results. Nevertheless, these findings represent a crucial step forward in the emerging field of precision nutrition. This innovative approach seeks to leverage an individual’s biological data, genetic makeup, metabolic profile, and other unique characteristics to formulate personalized dietary recommendations that move beyond generalized nutritional advice.
In the future, humanin, SHMOOSE, and related mitochondrial microproteins may serve as valuable tools for scientists, enabling them to pinpoint which specific dietary patterns are eliciting beneficial cellular responses in individual patients. Subsequent research will be crucial to determine whether modifying a person’s diet can directly elevate the levels of these peptides and, importantly, whether such increases translate into a demonstrable reduction in disease risk. "Our goal is to move from observing associations to understanding causality," Vicinanza articulated, expressing the aspiration to harness these newly identified pathways for the development of nutritional strategies that promote healthy aging at the molecular level.
The study titled "Mediterranean diet adherence is associated with mitochondrial microproteins Humanin and SHMOOSE; potential role of the Humanin-Nox2 interaction in cardioprotection" was published on March 9, 2026, in the journal Frontiers in Nutrition. Co-authors on this research include Junxiang Wan and Kelvin Yen from the USC Leonard Davis School, alongside Vittoria Cammisotto, Francesco Violi, and Pasquale Pignatelli from Sapienza University of Rome. Funding for this work was provided 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).
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