Increased Dietary Leucine Activates mTOR Signaling in Macrophages, Accelerating Atherosclerosis
Leucine is an essential amino acid, only obtained from the diet rather than synthesized by our cells. Leucine supplementation has been proposed as a way to slow the loss of muscle mass with age, as leucine processing becomes dysregulated with aging in a way that can be compensated for by adding more leucine to the diet. Whether this actually works is a matter for debate; the evidence is mixed. The question is never whether the mechanism exists, the question is whether it has a large enough effect size to matter.
Given this impetus for a greater intake of dietary leucine in later life, it is interesting to see the research noted here, in which higher dietary protein intake, and particularly leucine, is shown to accelerate atherosclerosis via effects on the behavior of macrophage cells. In the bigger picture, reduced protein intake slows aging, through methionine seems more important than leucine when it comes to triggering beneficial mechanisms based on nutrient sensing. One is left to consider these various opposing points of view, and look forward to a future of rejuvenation therapies that produce large enough reversals of degenerative aging make all of these present dietary considerations irrelevant.
Following 2020 research, in which scientists first showed that excess dietary protein increases atherosclerosis risk in mice, the next study conducted by this group delved deeper into the potential mechanism and its relevance to the human body. "We have shown in our mechanistic studies that amino acids, which are really the building blocks of the protein, can trigger disease through specific signaling mechanisms and then also alter the metabolism of these cells. For instance, small immune cells in the vasculature called macrophages can trigger the development of atherosclerosis."
Based on initial experiments in healthy human subjects to determine the timeline of immune cell activation following ingestion of protein-enriched meals, the researchers simulated similar conditions in mice and in human macrophages, immune cells that are shown to be particularly sensitive to amino acids derived from protein. Their work showed that consuming more than 22% of daily dietary calories through protein can negatively affect macrophages that are responsible for clearing out cellular debris, leading to the accumulation of a "graveyard" of those cells inside the vessel walls and worsening of atherosclerotic plaques overtime. Interestingly, the analysis of circulating amino acids showed that leucine - an amino acid enriched in animal-derived foods like beef, eggs and milk - is primarily responsible for abnormal macrophage activation and atherosclerosis risk.
"Perhaps blindly increasing protein load is wrong. Instead, it's important to look at the diet as a whole and suggest balanced meals that won't inadvertently exacerbate cardiovascular conditions, especially in people at risk of heart disease and vessel disorders." Researchers also notes that these findings suggest differences in leucine levels between diets enriched in plant and animal protein might explain the differences in their effect on cardiovascular and metabolic health.
It would be interesting to know the protein/leucine/methionine intake levels of exceptionally long lived people