Longevity via Methionine Restriction Depends on Autophagy
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The practice of calorie restriction involves reducing dietary calorie intake while still obtaining optimal levels of necessary micronutrients. In near all species tested to date this greatly enhances health and slows all measures of aging. In mice, for example, maximum life spans of up to 40% greater than normal are exhibited in calorie restriction studies. In longer-lived species the degree of life extension obtained is smaller, but the health benefits still large. There is no medical technology at present that can provide anywhere near same degree of improvement in long and short term measures of health to humans, based on the evidence to date. Nonetheless, lifelong calorie restriction in humans is not expected to provide more than a 7% gain in life span.

The mechanisms of action by which calorie restriction works are much debated despite having been under intense investigation for more than a decade: inroads have been made and evidence gathered, but there is still plenty to argue over when it comes to which of the known mechanisms are more important. There is a strong case to be made for low levels of visceral fat tissue to be important in long-term health, however: if you simply surgically remove visceral fat from mice they live significantly longer. Another well studied mechanism is the metabolic reaction to low levels of methionine, an essential amino acid that is not manufactured in the body but must be obtained from diet. Methionine restriction that does not reduce calorie intake but in which diet is structured to include only minimal safe levels of methionine produces similar results to calorie restriction in rodents.

Autophagy is also known to be a mechanism of importance in calorie restriction and methionine restriction, both of which spur increased levels of autophagy. In fact there is some evidence to suggest that calorie restriction depends on autophagy to work its benefits. But what is autophagy? It is the name given to housekeeping processes that minimize the presence of damaged cellular components by recycling them. Many of the methods of extending life and slowing aging in laboratory animals discovered over the past twenty years have also been shown to involve increased levels of autophagy. If we consider that aging is just a matter of damage accumulation, then this makes sense.

In the paper quoted below researchers join another dot in this mass of evidence by showing that methionine restriction, like calorie restriction, requires autophagy to produce benefits - which goes some way to reinforcing its claim as one of the primary mechanisms involved in calorie restriction. This work was carried out in yeast, which is normally a good reason to wait until someone reproduces it in mammals before commenting, but in the case of calorie restriction there has been a very good correspondence between its behavior in yeast, flies, nematode worms, and mammals. As in one, so in all the others.

Lifespan Extension by Methionine Restriction Requires Autophagy-Dependent Vacuolar Acidification

Health- or lifespan-prolonging regimes would be beneficial at both the individual and the social level. Nevertheless, up to date only very few experimental settings have been proven to promote longevity in mammals. Among them is the reduction of food intake (caloric restriction) or the pharmacological administration of caloric restriction mimetics like rapamycin. The latter one, however, is accompanied by not yet fully estimated and undesirable side effects. In contrast, the limitation of one specific amino acid, namely methionine, which has also been demonstrated to elongate the lifespan of mammals, has the advantage of being a well applicable regime. Therefore, understanding the underlying mechanism of the anti-aging effects of methionine restriction is of crucial importance.

With the help of the model organism yeast, we show that limitation in methionine drastically enhances autophagy, a cellular process of self-digestion that is also switched on during caloric restriction. Moreover, we demonstrate that this occurs in causal conjunction with an efficient pH decrease in the organelle responsible for the digestive capacity of the cell (the vacuole). Finally, we prove that [this] autophagy-dependent vacuolar acidification is necessary for methionine restriction-mediated lifespan extension.

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