A plant- and fish-based, low-protein diet paired with small amounts of an amino acid commonly found in eggs, meat and dairy increased healthy lifespan and decreased frailty and fat mass in mice, according to a new USC study published today in the journal Cell Metabolism .
The researchers, led by Valter Longo of the USC Leonard Davis School of Gerontology, also worked with University of Toronto and Harvard University colleagues to analyze existing data on the diet and health of more than 200,000 people. The team found similar health advantages of a more plant-focused diet, including less obesity and Type 2 diabetes.
The combined data from mice and humans indicate that the best health outcomes may be obtained by following a "longevity diet" that's largely vegan or vegetarian, but with fish added, Longo said. The Mediterranean-inspired diet provides a small but sufficient amount of methionine and other essential amino acids.
A modified Mediterranean Diet
Longo has heavily studied the relationship between diets, health and longevity . Much of his work has focused on the low-protein, plant-focused Mediterranean diet, a staple of southern Europe's long-lived populations.
While these groups have some of the highest life expectancies in the world, they also experience high rates of frailty. As plant-based foods have lower amounts of essential amino acids than animal products, Longo developed a longevity diet supplemented with a small amount of the essential amino acid methionine to test its effects on frailty risk.
For the experiment, groups of 20-month-old mice were fed one of four diets: a standard diet; a Western diet high in fats and sugars; a low-carbohydrate ketogenic diet; or the low-protein, methionine-supplemented longevity diet (LDMM).
Mice that received the LDMM showed significantly better outcomes, including a longer healthspan (the portion of life spent in good health), reduced fat mass and less frailty.
"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."
Promising clinical potential
In addition, tests revealed several biomarkers of better cardiometabolic health in LDMM mice, including higher amounts of signaling molecules that affect metabolism and aging across species, such as GLP-1, Fanti said.
"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," she said.
Longo said one of the most remarkable findings was that mice on the LDMM could eat more food than any other group and as much calories as any other group and yet lose fat without losing lean body mass — but only when methionine levels were low but sufficient.
Additionally, human data showed that participants who ate the highest levels of animal protein — therefore consuming the highest amount of methionine and other essential amino acids — had a higher prevalence of obesity and twice the rate of diabetes compared with those consuming little to no animal protein. This persisted even though those eating more animal protein had a lower calorie intake and otherwise healthier nutrition, Longo said.
"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 next step the team hopes to pursue is a controlled clinical trial of the LDMM in humans, Longo and Fanti noted.
About this study
In addition to Longo and Fanti, other authors of the paper include Sebastian Brandhorst, Gerardo Navarrete, Arnold Diaz, Giacomo Giuliani, Dolly Chowdhury and Todd E. Morgan of the USC Leonard Davis School; Gabriel C. Antunes of the University of Campinas, Sao Paolo; Louis Dubeau of the Keck School of Medicine of USC; Valentina Villani and Laura Perin of Children's Hospital Los Angeles; Vasanti S. Malik of the University of Toronto; and Frank B. Hu of Harvard University.
The study was funded by National Institute on Aging grant AG084485, National Institute of Health grant GR1045540, and the USC Edna Jones Chair Fund.
Valter Longo has 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 at the University of Southern California. The University of Southern California has licensed its intellectual property to L-Nutra. As part of this license agreement, the university has the potential to receive royalty payments from L-Nutra.
Longo and Maura Fanti are inventors on a U.S. provisional patent application filed by the University of Southern California that covers aspects of the methods and findings described in this manuscript.
