Fight Aging!

Proteins are made up of amino acids. It is known that reducing only protein in the diet, while maintaining the same calorie intake, produces a modest slowing of aging. Some of the beneficial effects of reduced calorie intake, such as upregulation of autophagy and improved cell maintenance, are triggered by sensing protein levels rather than other components of diet. The sensor mechanisms are more specific than simply protein as a whole, however, and can be triggered by reducing levels of individual essential amino acids, meaning amino acids that are required for protein synthesis in cells, but must be consumed because they are not manufactured in the body. A good deal of work has gone into assessing the effects of lower levels of the essential amino acid methionine in the diet, for example, finding that this captures a sizable fraction of the benefits of reduced calorie intake.

In today's open access paper, researchers compare overall protein restriction (all dietary amino acids) with restriction of only the essential amino acid isoleucine, in both cases maintaining an overall calorie intake equivalent to that of a non-restricted diet. Old mice are given these different diets, and the researchers present a great deal of data on the outcomes. Restriction in older individuals doesn't help with muscle loss and frailty, which is interesting given that long-term calorie restriction does slow the progression of age-related loss of muscle mass and strength. Restricting only isoleucine produces greater benefits by some metrics, but doesn't reduce cellular senescence in tissues, unlike protein restriction. Overall, it is an interesting data set, though as ever we should remember that evidence strongly suggests that calorie restriction and its equivalents are much less effective at extending life span in long-lived mammals than in short-lived mammals.

Restricting dietary protein or dietary isoleucine improves metabolic health in aged mice

An appealing alternative to reducing calories may be manipulating dietary macronutrients. Contrary to the conventional wisdom that calories from different sources are equivalent, a number of retrospective and prospective clinical trials have found that eating diets with lower levels of protein is associated with lower rates of age-related diseases including cancer and diabetes, and an overall reduction of mortality in those under age 55. While the effect of long-term protein restriction (PR) on human aging has not been tested in a randomized clinical trial (RCT), short-term RCTs in overweight or diabetic humans has found that protein restriction (PR) promotes metabolic health. Finally, PR diets have been repeatedly shown to increase the healthspan and lifespan of model organisms, including flies and rodents.

We and others have shown that much like calorie restriction (CR), restriction of specific nutrients, including total protein, the three branched-chain amino acids leucine, isoleucine, and valine, or isoleucine alone, can promote lifespan and metabolic health in animal models. While CR is less efficacious when starting in late life, the effects of interventions restricting amino acids in late life on healthy aging is unknown. Here, we investigate the metabolic, molecular, and physiological effects of consuming diets with a 67% reduction of either all amino acids (Low AA) or of isoleucine alone (Low Ile) in male and female C57BL/6J.Nia mice starting at 20 months of age.

We find that both diets reduce adiposity in aged mice; however, these diets decreased lean mass, and did not show significant improvements in frailty or fitness. The glucose tolerance of both male and female mice consuming Low Ile and Low AA diets were improved. We also observed a moderate increase in energy expenditure and respiratory exchange ratio induced by the two dietary interventions. In the hearts of aged female mice, Low Ile reversed age-associated changes in heart rate and stroke volume, returning cardiac function to similar levels as observed in young mice. We found that both Low AA and Low Ile diets promoted a more youthful molecular cardiac profile, preventing age-dependent increases in phosphatidylglycerols. These results demonstrate that Low AA and Low Ile diets can improve aspects of metabolic health in aged mice of both sexes, and has positive effects on cardiac health in aged females, suggesting that these dietary interventions are translationally promising for promoting healthy aging even in older people.