New research finds that reducing the intake of one amino acid, isoleucine, by two-thirds improves lifespan, weight and health in middle-aged mice without reducing calorie intake. The findings suggest that limiting isoleucine levels in the diet may be key to healthy aging.
What you eat has a huge impact on your health and longevity. However, adhering to a calorie-restricted diet can be difficult, raising interest in interventions that mimic calorie-restricted diets without reducing calorie intake.
Research into the benefits of protein-restricted diets shows that lower protein intake is associated with a reduced risk of age-related disease and death, as well as improved metabolic health. Now, while exploring alternatives to calorie-restricted diets, UW-Madison researchers have found that reducing the intake of one amino acid in mice can extend their lifespan, making them leaner, less frail, and less susceptible to cancer.
Dudley Lamming, corresponding author of the study, said: "We like to say that calories are more than just calories. Different ingredients in the diet have other values and effects besides their function as calories, and we have been looking at one ingredient that many people may be eating too much of."
That ingredient is isoleucine, one of nine essential amino acids. Data from an earlier study of Wisconsinites' health found that people with higher body mass indexes (BMI) tended to consume more isoleucine, which is abundant in foods such as eggs, dairy, soy protein and many meats.
To further investigate the health effects of isoleucine, the researchers fed male and female genetically distinct mice one of three amino acid-defined diets. The control diet contained all 20 common amino acids, reflecting a natural diet that derived 21% of calories from protein. Other diets either reduced all amino acids or only 67% of isoleucine. These three foods have the same fat content, that is, they are isocaloric.
When the study began, the mice were about six months old, roughly equivalent to humans in their 30s, and they ate as much as they wanted.
"Quickly, we saw that the mice on the low-isoleucine diet lost fat -- they became more muscular and lost fat," Laming said. "In contrast, the mice on the low-amino acid diet initially became leaner but gained weight and fat again."
The researchers found that mice fed a low-isoleucine diet lived longer than those in the control group; male mice lived an average of 33 percent longer and female mice lived an average of 7 percent longer. In addition to increased longevity, "healthspan" has also improved. In low-isoleucine-fed male mice, there was a strong inverse correlation between lifespan and indicators of frailty related to body condition, including tail stiffness, fur color, and incidence of tremors. In control-fed females, lifespan was strongly positively correlated with beard loss, hair loss, and spinal curvature (kyphosis), whereas in females with reduced isoleucine intake, these deficits were negatively correlated with lifespan.
Notably, diets that reduced intake of all amino acids, including isoleucine, improved healthspan in both sexes to the same degree of frailty as the low-isoleucine diet, but did not extend lifespan in both sexes.
"Previous studies have shown that starting in very young mice, low-calorie, low-protein or low-amino acid diets can extend lifespan," Laming said. "We started with mice that were already starting to age. It's interesting and encouraging that even changing dietary habits as they approach middle age can have such a large impact on lifespan and what we call 'healthspan.'"
Mice with reduced isoleucine intake consumed significantly more calories than their counterparts, possibly because they were trying to increase their isoleucine intake, the researchers said. But they also burned more calories and lost and maintained leaner weight simply by adjusting their metabolism, not by exercising more.
The mice also had better blood sugar control, and male mice had less age-related prostate enlargement. While cancer was the leading cause of death in the genetically diverse mice used in the study, male mice fed low isoleucine had fewer tumors.
The mechanisms by which reducing isoleucine intake are beneficial to health are not well understood and require further study. Additionally, more research is needed to determine whether limiting isoleucine intake has negative effects and to examine how optimal levels of the amino acid vary with age and gender.
"We found that female mice benefited less than male mice, and we may be able to use this to find the mechanism," Laming said. "
The researchers noted several limitations of the study. They only looked at a single level of restriction, while other studies of calorie- and protein-restricted diets suggest that different strains and genders of mice may respond best to different levels of restriction. Furthermore, to maintain the diet isocalorically, the reduction in amino acids in the low-amino acid diet is balanced by additional carbohydrates, and the reduction in isoleucine is balanced by non-essential amino acids.
To complicate matters further, humans require isoleucine to stay alive. It is an oxygen-carrying pigment within red blood cells that helps make hemoglobin and is required for important functions such as muscle protein synthesis, energy production, and immune system support.
"We can't switch everyone to a low-isoleucine diet," Laming said. "But narrowing these benefits down to a single amino acid brings us closer to understanding the biological process and may lead to potential interventions in humans, such as isoleucine-blocking drugs."
The research was published in the journal Cell Metabolism.