University of Campinas

Scientists found that a modified Mediterranean-style diet with low protein and just enough methionine helped mice live healthier lives while reducing body fat and frailty. Human data also linked lower animal protein intake to lower rates of obesity and Type 2 diabetes, suggesting the approach could benefit people as well.A mostly plant and fish based diet with low protein and carefully balanced levels of an amino acid found in foods like eggs, meat, and dairy helped mice stay healthier as they aged, according to new research from the University of Southern California. The diet increased healthspan, reduced body fat, and lowered frailty in older mice. The findings, published in Cell Metabolism, were supported by an analysis of dietary and health data from more than 200,000 people conducted by researchers from USC, the University of Toronto, and Harvard University. People who followed more plant focused eating patterns also showed lower rates of obesity and Type 2 diabetes. Together, the mouse and human findings suggest that a Mediterranean inspired "longevity diet" centered on mostly vegan or vegetarian foods with fish may offer important health benefits. According to senior author Valter Longo, the diet provides low but adequate amounts of methionine and other essential amino acids. A longevity diet inspired by the Mediterranean Longo has spent years studying how nutrition influences aging and disease. His previous work has focused on the traditional low protein, plant centered Mediterranean diets commonly found in parts of southern Europe, where people often live exceptionally long lives. Although these populations tend to have some of the world's longest life expectancies, they also experience relatively high levels of frailty in old age. Because plant foods naturally contain lower levels of essential amino acids than animal products, Longo developed a modified longevity diet that adds a small amount of methionine to determine whether it could reduce frailty while preserving the advantages of a plant focused eating pattern. To test the idea, researchers fed 20 month old mice one of four diets: a standard diet; a Western diet high in fats and sugars; a low carbohydrate ketogenic diet; or a low protein, methionine supplemented longevity diet (LDMM). The mice eating the LDMM consistently performed best. They experienced a longer healthspan (the portion of life spent in good health), carried less body fat, and showed fewer signs of frailty than mice on the other diets. "We expected different diets to produce different outcomes, but what really impressed us was how modulating just a single amino acid, methionine, in the longevity diet could produce such dramatic metabolic changes," said USC Leonard Davis Research Associate Maura Fanti, first author of the new study. "It points to the idea that amino acid composition, not just overall protein quantity, may be the target of strategic metabolic interventions." Metabolic health improved despite higher food intake The researchers also found several biological markers associated with improved cardiometabolic health in mice fed the LDMM. Among them were increased levels of GLP-1 and other signaling molecules involved in regulating metabolism and aging across many species. "There are, of course, differences in how these pathways are regulated between mice and humans, but seeing such coordinated changes across multiple metabolic hormones is genuinely encouraging, and we're very curious to know whether effects of similar magnitude would be seen in human studies," Fanti said. Longo highlighted another surprising result. Mice eating the LDMM consumed more food than any of the other groups and took in as many calories as the other diets, yet still lost body fat while maintaining lean muscle mass. Those benefits appeared only when methionine levels remained low but sufficient. Human data point to similar benefits The analysis of more than 200,000 people revealed a similar pattern. Participants who consumed the most animal protein, and therefore the highest levels of methionine and other essential amino acids, had higher rates of obesity and were twice as likely to have Type 2 diabetes compared with people who ate little or no animal protein. According to Longo, these differences remained even though people with the highest animal protein intake generally consumed fewer calories and otherwise had healthier diets. "This challenges the dogma that calorie reduction is necessary to lose weight, but it also tells us that we need to have clear understanding of the mechanisms," he said. "Too little methionine caused frailty, but too much methionine abolished the benefits of this diet, which was otherwise based on the diet of long-lived populations like the traditional Italian and Okinawa diets. … These results indicate that overall protein intake may be less important than specific amino acid intake." The research team says the next step is to test the LDMM in a controlled clinical trial involving people to determine whether the same health benefits can be achieved in humans. Study details and disclosures The study was led by researchers from the USC Leonard Davis School of Gerontology in collaboration with scientists from the University of Toronto, Harvard University, the University of Campinas, the Keck School of Medicine of USC, and Children's Hospital Los Angeles. Funding was provided by National Institute on Aging grant AG084485, National Institute of Health grant GR1045540, and the USC Edna Jones Chair Fund. Valter Longo has an equity interest in L-Nutra, a company that develops medical foods. Longo, Todd Morgan, and Sebastian Brandhorst have filed patents related to the Fasting-Mimicking Diet through the University of Southern California, which has licensed related intellectual property to L-Nutra and may receive royalty payments. Longo and Maura Fanti are also inventors on a U.S. provisional patent application covering aspects of the methods and findings described in the study.

BioMarin HQ/courtesy of BioMarin BioMarin Pharmaceuticals has published positive results in the New England Journal of Medicine from its Phase III clinical trial of valoctocogene roxaparvovec. BioMarin HQ/courtesy of BioMarin BioMarin Pharmaceuticals has published results in the New England Journal of Medicine from its Phase III clinical trial of valoctocogene roxaparvovec. The investigational gene therapy is intended for the treatment of adults with severe hemophilia A. Hemophilia A is an X-linked genetic disorder caused by insufficient levels of Factor VIII, a blood protein responsible for proper clotting. Because of this deficiency, people with hemophilia A have difficulty stopping the flow of blood from wounds. Those with the condition are prone to prolonged bleeding episodes after surgeries, dental procedures, injury or trauma, and can experience bruising and bleeding of the mucous membranes. Hemophilia A is considered to be severe when there is less than 1% of normal Factor VIII clotting activity, and it is associated with spontaneous bleeding, which can occur in any organ system. Currently, patients with hemophilia A are treated with prophylactic infusions of replacement factor VIII administered intravenously, sometimes two to three times per week, accumulating to 100 to 150 infusions per year. BioMarin Pharmaceuticals is looking to change the treatment landscape with its single-dose genetic therapy. The results of BioMarin Pharmaceuticals Therapy for Hemophilia A In the published results, BioMarin Pharmaceuticals shared that after a single infusion of valoctocogene roxaparvovec, patients experienced substantially reduced annualized bleeding rates, reduced Factor VIII utilization and increased Factor VIII activity. Additionally, 90% of patients dosed had either no treated bleeds or fewer treated bleeds after infusion as compared to Factor VIII prophylactic treatment. At weeks 49 and 52 following treatment, 88% of participants had a median Factor VIII activity of 5 IU/dL or higher, a change that is associated with lessened severity of the disease. “Breakthrough bleeding represents a high burden of disease management and an unmet medical need for many people. I am encouraged that during the first year of treatment, 90% of study participants had either zero treated bleeds or fewer treated bleeds post-infusion than with factor VIII prophylaxis,” said Margareth C. Ozelo, MD, Ph.D., director of Hemocentro UNICAMP, University of Campinas and lead principal investigator of the GENEr8-1 study. “These results reflect the potential for sustained hemostatic bleed control with this gene therapy for hemophilia A.” Valoctocogene roxaparvovec has been studied longer than any other gene therapy for hemophilia A, according to BioMarin Pharmaceuticals. The therapeutic has a favorable tolerability and safety pro no participants developing inhibitors to Factor VIII, malignancy or thromboembolic events. Common adverse events associated with the therapeutic included headache, arthralgia and nausea, as well as a moderate rise in liver enzymes, which was not associated with any long-lasting clinical events. Potential benefits of BioMarin’s valoctocogene roxaparvovec include zero bleeds for patients, avoiding the use of prophylactic therapy and providing a one-time treatment to control the disease. BioMarin Pharmaceuticals has other clinical studies underway in its comprehensive gene therapy program for the treatment of hemophilia A, including a dose-escalation study of valoctocogene roxaparvovec. This study involves dosing participants who have pre-existing AAV5 antibodies, which demonstrate immunity against gene therapy and evaluating the therapeutic in patients with active or prior Factor VIII inhibitors. Featured Jobs on BioSpace