By Robert Schinetsky

Branched-Chain Amino Acids (BCAA) are a special subclass of the essential amino acids. They gained notoriety several decades ago when researchers discovered that the BCAAs (leucine, isoleucine and valine) stimulate muscle protein synthesis -- the biological process that drives muscle recovery and growth.

Based on these findings, sports nutrition companies flooded the market with BCAA supplements with the allure of better performance, faster recovery, less soreness, and greater gains. However, as we’ve discussed countless times over the years, there are glaring errors with the body of BCAA supplement research.[1]

Not only may BCAAs have minimal impact on your performance, recovery or muscle growth, they may be linked to an increased risk of certain adverse outcomes, including insulin resistance and stroke.[2,3,4]

Recent studies give further evidence that certain BCAAs may contribute to an increased risk of disease and a shorter lifespan.

Which ones?

Let’s discuss.

BCAAs, Protein, and Longevity

Low BCAA intake has been associated with improved metabolic health and extended longevity in mice as well as higher survival rates and better performance in Alzheimer's disease models. [5,6,7] Decreased intake of BCAAs as well as the essential amino acids (EAAs) methionine, and tryptophan have also been shown to increase lifespan and improve markers of metabolic health in animal studies.[13]

While these findings may seem recent, research from over 50 years ago found evidence that people with obesity and insulin resistance had elevated circulating levels of BCAAs.[8] Various studies have shown that BCAAs can over stimulate the body’s insulin signaling machinery resulting in reduced insulin signaling.[9,10]

Additional animal research notes that BCAAs may induce insulin resistance, and limiting BCAAs can help prevent insulin resistance.[16,17] Insulin, insulin resistance, and the insulin/IGF-1 pathway impact age, and both animal and human studies suggest that healthy blood glucose levels and higher insulin sensitivity support healthy aging and longevity.[18]

Based on these findings, limiting protein/BCAA intake may be beneficial, and animal models indeed have shown that protein restricted diets support longevity in several ways, including[11,12]:

• Promoting glucose tolerance
• Enhancing insulin sensitivity
• Improving energy expenditure via beiging of white fat cells
• Decreasing the production of reactive oxygen species (ROS) by mitochondria

As you look closer into the research, though, it appears that certain members of the BCAA family may be more problematic than others.

Beware Excessive Isoleucine or Valine

The BCAAs (leucine, isoleucine, and valine) are typically consumed together as they are found alongside each other in all complete protein sources like red meat, fish, poultry, seafood, dairy, etc. While they are eaten together, they are broken down in different ways and have different impacts/outcomes on our physiology.

Diets where isoleucine is restricted reprograms liver and adipose metabolism, increasing hepatic insulin sensitivity and ketogenesis, and increasing energy expenditure, activating the FGF21-UCP1 axis. Reducing valine induces similar but more modest metabolic effects.

Interestingly, these effects are absent with low leucine. Based on these findings, it may be beneficial to limit isoleucine or valine intake in obese subjects seeking to improve metabolic health markers.[14]

For instance, recent research published in Nature Aging investigated the effects of reducing total amino acid protein intake or just isoleucine. Mice were fed a normal (non-reduced) calorie diet with either a 67% reduction of all amino acids or just isoleucine. Both diets improved indicators of aging rate. Researchers concluded the paper stating that low isoleucine diets “can promote aspects of healthy aging in aged mice and suggest that similar interventions might promote healthy aging in older adults.”[29]

Another recent mouse study provides further evidence that limiting certain BCAAs may be beneficial. Researchers found that valine, specifically, acutely and significantly elevated blood glucose by nearly 100%.[2] Note: For healthy, active individuals this may not be problematic, but for sedentary and/or obese individuals, spiking blood glucose levels can lead to future health problems, including hyperglycemia, insulin resistance, and type 2 diabetes.

Research in Scientific Reports also found that, among BCAAs, isoleucine restriction stands out as the most potent means of improving metabolic health markers when it comes to tweaking a subject’s protein/amino acid intake.[19,24] In fact, researchers have identified “... isoleucine as a key regulator of metabolic health and the adverse metabolic response to dietary BCAAs, and suggest reducing dietary isoleucine as a new approach to treating and preventing obesity and diabetes.”[24]

Recently, a March 2024 meta‐analysis of 32,845 subjects was conducted to evaluate the relationships between BCAAs and hypertension. Published in the Journal of the American Heart Association, researchers found that “... increased levels of 3 BCAAs positively correlated with an increased risk of hypertension. Particularly, elevated isoleucine level is a causal risk factor for essential hypertension.[15]

Leucine for Muscle & Longevity

Leucine elicits the strongest anabolic response of any amino acid (including its BCAA brethren isoleucine and valine) by potently stimulating mTOR which directly enhances muscle protein synthesis (MPS) while preventing muscle protein breakdown. Overtime, this supports muscle growth (hypertrophy).[20,21]

Increased muscle mass is associated with greater resiliency and longevity, but building bigger, stronger muscles isn’t the only way by which leucine supports healthy aging.

In models of atherosclerosis, leucine uniquely demonstrates anti‐atherogenic properties through reducing macrophage triglyceride content to decrease macrophage foam cell formation, a critical step in the development of atherosclerosis.[22] Previous research from 2018 also found that leucine, in particular, is associated with improved markers of atherosclerosis.[23]

In cases where leucine was restricted, researchers have noted increased fat gain. But, when they limited isoleucine, and to a lesser degree valine, glucose tolerance improved.[24]

Leucine may also be cardioprotective. A mouse model of myocardial ischemia and reperfusion injury found that treatment with leucine improved the damage caused by myocardial I/R injury by promoting mTOR activity and mitochondrial fusion on prediabetic hearts in mice.[25]

Myocardial ischemia occurs when the blood flow through one or more of your coronary arteries is decreased. The low blood flow decreases the amount of oxygen your heart muscle receives. Researchers noted a decrease in reactive oxygen species (ROS) production when the mice were given leucine, suggesting that the king of amino acids can prevent enhanced ROS production followed by the loss of mitochondrial function due to I/R injury in wild-type and HFD-induced obese mice

Takeaway

The research surrounding BCAAs is intriguing, but can be confusing, especially for casual fitness enthusiasts. On one hand, they are essential -- our bodies cannot make them, and they are required for protein synthesis, hormone production, and other biological processes. On the other hand, research shows that elevated levels of BCAAs (especially isoleucine and valine) are associated with a number of unwanted conditions.

Researchers also aren’t entirely sure whether these adverse outcomes are the direct result of BCAAs or indirect by way of changes that happen to a person’s physiology and lifestyle habits, including energy balance, inflammation, and liver functions.[4,26,27] In fact, just last year, researchers stated that the “connection between plasma BCAA levels and stroke has not been thoroughly explored due to potential biases such as confounders or reverse causality; hence, it is unknown if BCAAs have a causal influence on the risk of stroke.”[4]

A separate 2023 review published in Frontiers in Nutrition concluded that the “...negative effects of BCAAs on longevity and insulin resistance were mostly observed in high-fat diet-fed subjects or obese individuals…there is still no definite conclusion on the specific conditions under which BCAAs and insulin resistance extend life, shorten life, or do not change lifespan, and there is still no credible and comprehensive explanation for the different effects of BCAAs and insulin resistance on lifespan.”[28]

If you want to err on the side of caution, aim to consume the majority of your BCAAs from whole food sources (lean proteins, like chicken, fish, lean red meat, etc.). Regarding free from amino acid supplementation, L-Leucine offers what you’re looking for from BCAA supplements (increased protein synthesis, decreased muscle breakdown, etc.), and it supports cardiovascular health and anti-aging (as we discussed above)! ^†

This is why AML PostWorkout includes 5g L-Leucine and NO isoleucine or valine. ^† 

<sup>† These statements have not been evaluated by the Food and Drug administration. This product is not intended to diagnose, treat, cure, or prevent any disease.

© Published by Advanced Research Media, Inc. 2024
© Reprinted with permission from Advanced Research Media, Inc.</sup>

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