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Researchers at the USC Leonard Davis School of Gerontology have detailed how adherence to the Mediterranean diet is associated with higher circulating levels of mitochondrial microproteins that are linked to cardiovascular and neural health. The study, published in Frontiers in Nutrition, found that individuals with higher adherence to the diet had elevated levels of the proteins humanin and SHMOOSE, both of which are linked to protection against cardiovascular disease and neurodegeneration, as well as lower levels of biomarkers indicative oxidative stress. The findings suggest that mitochondrial signaling pathways produce cellular responses that influence aging and disease risk based on dietary intake.
“These microproteins may act as molecular messengers that translate what we eat into how our cells function and age,” said first author Roberto Vicinanza, MD, PhD, an associate professor of Gerontology at USC. “It’s a new biological pathway that helps explain why the Mediterranean diet is so powerful.”
The work builds on decades of research of mitochondria in the lab of Pinchas Cohen, MD, dean of USC Leonard Davis School of Gerontology, executive director of the Ethel Percy Andrus Gerontology Center.
Humanin and SHMOOSE are mitochondrial-derived microproteins that are encoded within mitochondrial DNA. Humanin has been associated with insulin sensitivity, vascular protection, and cognitive preservation, while SHMOOSE has been linked to neuronal protection and Alzheimer’s disease risk modulation. Together, these proteins are increasingly recognized as regulators of cardiometabolic and neurodegenerative health.
For this work, the researchers analyzed blood samples from 49 older adults and stratified participants based on adherence to the Mediterranean diet. “This study indicates (i) a positive association between adherence to the Med-Diet and circulating levels of mitochondrial microproteins SHMOOSE and Humanin supporting their role as potential mediators of Med-Diet benefits; (ii) a putative crosstalk between Humanin signaling and Nox2 activity, suggesting a novel cardioprotective mechanism of the Med-Diet,” the researchers wrote. The association between increased humanin levels and lower Nox2 activity points to the potential of diet may reduce oxidative stress, a significant driver of cardiovascular disease and aging.
The Mediterranean diet includes a focus on whole grains, legumes, fruits, vegetables, olive oil, fish, and moderate dairy intake, while limiting red meat and refined carbohydrates. These components provide polyphenols, unsaturated fatty acids, and other bioactive compounds that influence inflammation, lipid metabolism, and mitochondrial function. The researchers found that specific dietary components appeared to differentially influence the two microproteins. Olive oil consumption was associated with higher levels of both humanin and SHMOOSE, while fish and legumes were linked specifically to humanin. Lower intake of refined carbohydrates was associated with higher SHMOOSE levels.
“These findings suggest that circulating levels of mitochondrial microproteins may reflect bioenergetic adaptations to specific nutrient patterns characteristic of the Med-Diet,” the researchers wrote. They also connect these effects to known biochemical pathways, including SIRT1 activation and mitochondrial biogenesis, as well as AMPK signaling influenced by omega-3 fatty acids.
Humanin is known to reduce oxidative stress and improved endothelial function, which preserves of the health of arteries, veins, and capillaries. The study identified an inverse relationship between humanin and markers such as sNox2-dp and 8-iso-PGF2α, indicating that higher levels of humanin could suppress the production of reactive oxygen species which results in lower levels of inflammation.
In the brain, both humanin and SHMOOSE have been identified as protective against amyloid-related toxicity. Prior studies from the Cohen lab show that these microproteins can attenuate amyloid-β–induced neurotoxicity, building on prior research that has shown the Mediterranean diet is associated with better cognitive outcomes.
These studies have noted reductions in oxidative stress and inflammation, as well as improvements in metabolic and cardiovascular markers resulting from adherence to the Mediterranean diet, but the role of mitochondrial microproteins as mediators has not been broadly researched. This study provides a solid platform for further defining the roles played by humanin and SHMOOSE and could also be the underpinning of developing them as potential biomarkers of dietary adherence and biological response. Future work will also explore additional mitochondrial peptides and their interaction with dietary patterns.
The study noted that mitochondrial responses to diet may vary across individuals, providing the possibility of tailoring precision dietary interventions in the future to affect both aging and disease prevention at the molecular level.
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