Chapter 188
Branched-Chain Amino Acids
Although an 80 percent reduction in methionine intake may be required to maximize its metabolic benefits in mice, 40 percent was enough to reduce free radical formation in mitochondria and oxidative damage to mitochondrial DNA. On average, vegans consume 47 percent less methionine than meat eaters. Perhaps that is one of the reasons for the health benefits attributed to a plant-based diet. For example, in obese mice, short-term methionine deprivation can achieve a 60 percent reduction in fat mass in two weeks, despite increased calorie intake and reduced physical activity (apparently by activating an “unproductive cycle” in which fat is simultaneously created and broken down).
Perhaps, then, it is the lower methionine intake that makes vegans, on average, 20 kilos lighter than people who eat a conventional diet. Even vegans who weigh the same as typical omnivores have only half the diabetes risk, which is consistent with an analysis from 2022 that followed about 15,000 adults in the United States for 17 years and found that those who consumed the most methionine had more than twice the risk of dying from diabetes.
On average, U.S. women eat twice as much methionine as they need, and American men three times as much. In view of the cardiovascular risk associated with higher methionine intake, public health researchers say the optimal methionine intake is around the recommended intake. Just as I do not advocate a low-protein diet, but rather a diet with the recommended protein intake, it is not necessary to eat a low-methionine diet; it is enough simply not to eat too much methionine. Based on what we know today, simply lowering methionine intake to the recommended amount has “great potential to reduce oxidative stress in tissues and extend healthy lifespan in humans …”.
Cysteine and Glycine
A large portion of the methionine we eat is converted in the body into another amino acid, cysteine. Since separately administered cysteine negates some of the benefit in animals with methionine restriction, it may be that cysteine does the dirty work for methionine. While cysteine could be an accomplice, the amino acid glycine is used to help the body usher methionine out of the system. I share more about both in see.nf/cysteineglycine. In short, you raise your blood glycine levels in exactly the same way you lower methionine and cysteine levels: by eating more plants.
Branched-Chain Amino Acids
The effect of protein restriction cannot be fully reproduced by methionine restriction alone, because even if you remove every amino acid from the diet except methionine, that still has a number of positive effects, such as reducing free radical production and oxidative DNA damage. The three branched-chain amino acids (BCAAs)—isoleucine, leucine, and valine—are also not above suspicion.
In the megastudy with 25 different dietary variants, the consequences for health and longevity were inversely related to BCAA levels in the blood, meaning the lowest levels were associated with the longest and healthiest lives. Intervention studies showed that a high-BCAA diet shortens the lifespan of mice, while BCAA restriction in fruit flies and mice increases lifespan and delays frailty. The researchers concluded that “limiting dietary BCAA content may be a key to a long and healthy life.”
That fits the picture well, since BCAAs are potent activators of the aging enzyme mTOR, which I covered in detail in Part I. Dampening mTOR signaling is seen as “crucial for improved health and lifespan,” since mTOR suppression is a “reliable molecular transducer for dietary anti-aging signals.” Lower BCAA intake may explain not only the longevity of the people of Okinawa, but also why a condition like acne was rare or nonexistent there, since pimples are the visible manifestation of increased mTOR activity. Maple syrup disease can provide insights into possible cognitive effects.
The irreversible breakdown of branched-chain amino acids in the body is tightly regulated. In babies born with a rare congenital defect in detoxifying BCAAs, the urine smells sweet, and later they can suffer encephalopathy, brain swelling, and death. The disease clearly shows that large BCAA excesses are dangerous for the brain, raising the question of whether mildly elevated levels could also be neurotoxic. In a mouse model of Alzheimer’s, cognitive performance worsened on a diet high in BCAAs, while it improved on a low-BCAA diet. This is consistent with a Mendelian randomization analysis that found that people born with a genetic predisposition for higher isoleucine levels were significantly more likely to develop Alzheimer’s, but a meta-analysis of eight cohort studies found that higher levels of BCAAs (including isoleucine) were associated with a lower risk of dementia.
Surprisingly, the literature on BCAAs is rife with contradictions; studies have found that BCAAs have harmful, no, or beneficial effects on aging and age-related diseases depending on the context. For example, an observational study found that higher BCAA intake was associated with significantly lower all-cause mortality. “With such high complexity,” a recent article on BCAAs and aging summed up, “one is unlikely to agree on a conclusion about the overall benefit or harm of BCAAs in older adults.” But at least for the effects of BCAAs on metabolism, we have human intervention studies and can document beneficial or harmful effects in one direction or the other.
BCAAs and Insulin Resistance
Insulin resistance is the cause of prediabetes and type 2 diabetes. Meta-analyses of prospective cohort studies showed that even in nondiabetics, insulin resistance and the elevated blood sugar that can result from it are associated with premature death. (Background on insulin resistance and what it does can be found in the chapter “Low Insulin Index” in my book How Not to Diet.) Insulin resistance, the inability of the body to respond sufficiently to the blood-sugar-lowering hormone insulin, can be caused by the intake of saturated fats (see.nf/insulin) and by the intake of branched-chain amino acids. A BCAA breakdown product has been shown to stimulate the uptake and accumulation of fat in muscle cells, which interferes with insulin signaling.
In obese mice, reducing BCAA intake led to a reduction in insulin resistance, drastic fat loss even without calorie reduction, and restoration of metabolic health, whereas a high-BCAA diet led to obesity in mice. In humans, an “overwhelming” number of studies have consistently shown that levels of branched-chain amino acids in blood and urine are linked to insulin resistance. In fact, elevated blood BCAA levels—the so-called BCAA signature—are a hallmark of obesity and diabetes. That does not necessarily mean that taking in less BCAA helps, because there are other factors that influence blood levels.
Yes, BCAAs can cause insulin resistance, but insulin resistance also appears to lead to rising BCAA levels, because it reduces the breakdown of BCAAs, which in some cases results in a reinforcing feedback loop that can spiral out of control. But epidemiology is not in agreement here. Even the microbiome has been invoked, when a twin study showed that a fecal transplant from a heavier twin raises blood BCAA levels in mice more than a fecal transplant from the lighter twin. But the proof is in the pudding. Just as you can make someone insulin resistant by giving them fat into the bloodstream, you can do that with BCAAs, too. A dose of butter can cause insulin resistance in just a few hours, and you can do that as well by chugging down a protein drink made of pure whey and water.