Fight Aging!

The practice of calorie restriction, reducing calorie intake to as much as 40% below ad libitum intake while still maintaining optimal micronutrient levels, is well demonstrated to slow aging in a range of species. Relative extension of life span is smaller as species life span increases, however, for reasons that make sense from an evolutionary perspective. It is unclear as to how the observed, sweeping changes to metabolism conspire to produce this differing outcome, however. Evidence to date suggests that increased autophagy is the primary mechanism by which reduced calorie intake produces benefits, but a full understanding remains to be achieved despite decades of research.

The altered metabolic state produced by calorie restriction is triggered by sensors detecting the availability of specific dietary components, such as the essential amino acid methionine. It is possible to create some fraction of the benefits of calorie restriction with a low methionine diet. Similarly, experiments have demonstrated that a reduced intake of various other amino acids can also produce some degree of benefits similar to those resulting from calorie restriction. Human trials of mild degrees of calorie restriction have been conducted, and analysis of that data continues years after the trials completed. There has been little comparable work on human trials of amino acid restriction, however.

Amino acid restriction, aging, and longevity: an update

Ever since the discovery that restricting laboratory rodent food consumption relative to their ad libitum (henceforth ad lib) feeding amount reliably extended their lives, prevented or delayed a host of diseases, and generally enhanced later life health, researchers have been seeking to discover the mechanisms by which such restriction works. One way to investigate this question is to determine whether a key feature of what we call the dietary restriction (DR) effect, that is, improved health, reduced disease, and extended longevity due to diminished food consumption, is to restrict various components of the diet as contrasted with simply reducing food consumption itself. By now, experimental reduction of all dietary macronutrients has been performed many times in addition to macronutrient components, particularly essential amino acids, in multiple species. Various diets, from low calorie to low protein to low methionine, branched-chain amino acids (BCAAs), or isoleucine formulations, have shown that dietary modulation can affect later life health in laboratory species. Whether these dietary enhancements of later life health will be translatable to humans is a question begging to be answered.

So far surveys of humans on plant-based low methionine or low sulfur amino acid (methionine + cysteine) diets have been reported to be associated with several beneficial health outcomes such as lower cardiometabolic risk factors or diabetes-related mortality. Short-term (4-12 weeks) clinical trials indicate that low sulfur amino acid diets as in most animal studies lead to weight loss, lower total cholesterol and LDL cholesterol, and other salubrious changes. The cancer field has been particularly interested in low methionine diets as both cell-based and preclinical studies confirm that cancer cells hunger for methionine. Yet short-term trials of medical methionine restriction, especially when combined other cancer therapies, have been generally less than successful largely because of low palatability of the diet. Clearly if low methionine or low sulfur amino acid diets are to be sustainable, the plant-based approach is more likely to be successful.

It is time to determine in human studies whether these low these amino acid restricting diets unlike chronic DR, are sustainable over the long-term and what the long-term health consequences might be. It is also important to discover how the diets affect mood, energy, and interact with other healthy-enhancing lifestyle or pharmaceutical interventions such as exercise or geroprotective drugs. We have reached the "translation stage" of biological aging research. It will be curious to see how successful that translation will be.