Protein Restriction Slow Aging - Better Aging Series Part 3

In Part 2 of our Better Aging Series, we looked at three forms of dietary restriction: caloric restriction, prolonged fasting, and alternate-day fasting. These interventions have helped provide a framework for researchers to unravel the molecular details of how aging happens. But these dietary restrictions are quite extreme, and may not be practical for everyone. In this article, we will look at two less extreme forms of dietary restriction: protein restriction, and the Daniel fast.

Caloric intake in a typical balanced diet comes from three classes of macronutrients: carbohydrates, proteins, and fats. Studies show that restrictions in carbohydrate and fat intake have no effect on longevity. Protein restriction, however, appears to be a viable option, increasing maximum lifespan by up to 20% in 16 out of 18 reviewed studies in rodents. Given the 40% increase in lifespan found in many studies on calorie restriction, it appears that protein restriction accounts for approximately half of this effect. The most important factor determining the lifespan benefits of protein restriction in multiple species is the ratio of dietary protein to carbohydrate and fat intake. Very few studies on the effects of protein restriction have been conducted in humans, but benefits have been found, including reduced cancer incidence among individuals 65 years and younger.

Proteins are long chains of amino acids strung together, which then form a specific 3-dimensional shape. In humans, there are twenty different types of amino acids coded for by genes. However, other amino acids exist and are often the result of modifications on these twenty. It is not crystal clear whether it is the restriction of proteins as a group or the restriction of specific amino acids that causes the increase in lifespan. The amino acids tryptophan and methionine have both been implicated, but most studies focus on methionine restriction.

A study done by Caro and coworkers investigated the effect of 40% restriction of all dietary amino acids except methionine. It was demonstrated that such a regimen did not reduce mitochondrial reactive oxygen species generation and oxidative damage in mitochondrial DNA. This suggests that methionine is the only amino acid that has any effect on these biomarkers. Furthermore, methionine has been shown to be especially vulnerable to oxidation by reactive oxygen species, compared to other amino acids. Increased methionine intake increases LDL cholesterol oxidation and plasma homocysteine concentrations, which in turn increase the risk of cardiovascular disease and mortality. Methionine-restricted diets in humans are both feasible and tolerable, making these an appealing option for further testing in humans. Here is a list of foods highest in methionine from NutritionData.com. So, it appears that when protein intake is limited, pro-aging pathways are inhibited. What are the mechanisms involved? Two pathways of interest are GCN2 and mTOR.

Slow aging by activating the GCN2 pathway

The GCN2 pathway senses when certain essential amino acids are absent. Once this protein deficiency pathway is triggered, it stabilizes a transcription factor (ATF4) that activates genes implicated in extending lifespan. Additionally, activating GCN2 also reduces mTOR network activity, which I will discuss next.

Slow aging by inhibiting the mTOR pathway

When we eat protein (especially leucine-rich protein sources), it activates the mTOR pathway. This pathway is involved in cell growth, cell proliferation, and protein synthesis. This is why athletes, in fact, aim to stimulate it; it builds muscle and repairs tissue damaged in response to exercise. Athletes better eat their protein, right? However, as we age, this pathway becomes increasingly subject to deregulation and is implicated in various disease states like diabetes, obesity, and cancer. Therefore, it stands to reason that earlier in the lifespan, promoting mTOR activity would be beneficial for age-associated mating behaviors, like maintaining high-levels of muscle to display genetic fitness. But as one ages, suppressing its activity may be wise for long-term health. Of course, we do want to have an adequate level of muscle mass to maintain physical functioning during old age. So there appears to be a tradeoff between physical robustness and longevity.

My hope is that further research will reveal a way to circumvent this tradeoff so that we can aggressively promote the maintenance of lean muscle mass without sacrificing longevity. As you’ll see in my future posts, there are some strategies involving drug therapies that might just allow for us to have the best of both worlds, or at least the better of both worlds.

Here is a quote from Volter Longo of the Longevity Institute at University of Southern California, from an interview with The Low Histamine Chef

Please read the rest of that interview to hear the discussion on “ideal diet.”

Aging research has also investigated societies that elect to utilize different forms of dietary restriction in their culture, usually through adherence to a religious practice. Luckily, many religions do have forms of dietary restriction in their practices, and we have societies that adhere to those practices over long periods of time, sometimes a lifetime. These cultures provide a great resource for us to understand the effects of dietary restriction on health and aging.

Among the different forms of religious fasts that have been examined for their potential life-extending effects, the Daniel fast appears very promising for health and longevity. The modern-day Daniel fast is based on two stories in the Bible, and allows ad libitum intake of fruits, vegetables, whole grains, nuts, seeds, and oil, but forbids meats, preservatives, additives, sweeteners, flavorings, caffeine, and alcohol. This plan might be thought of as a more stringent form of the vegan diet. Studies note excellent mood and satiety (about 7.9 using a 10 point scale) with the Daniel fast, which is likely why compliance has been reported to be very high (>90%).

These compliance rates suggest that the Daniel fast is a practical intervention that people can apply to their life. The question remains as to whether non-religious people would show equal adherence if they don’t infuse the stories of the religion’s text with extramundane meaning.

Still, it has been observed that people who adhere to the Daniel Fast show statistically significant decreases in total cholesterol, LDL cholesterol, and blood pressure. Clinically meaningful decreases in insulin and C-reactive protein, as well as body fat and body weight, were also noted but in degrees that were not of statistical significance. Unfortunately, HDL cholesterol, commonly referred to as good cholesterol, also decreased. In general, the Daniel fast does appear to improve several biomarkers of overall health. It will be interesting to modify the Daniel fast so that HDL cholesterol is increased and see the how the effects of such a regimen compare to others.

There are currently no head-to-head trials directly comparing the effects of the different dietary interventions on lifespan itself, which precludes a definitive recommendation as to which dietary pattern is best for this purpose. For people wishing to put these regimens into practice, they should remember that their effects on lifespan have not yet been conclusively demonstrated. Nevertheless, the improvements they induce in surrogate measures of overall health may be enough reason for people to decide to try them out.

The next article in this series will explore how other aspects of lifestyle, like wine and exercise, influence aging.