Amino-acid imbalance explains extension of lifespan by dietary restriction in Drosophila

Abstract

In a number of organisms, dietary restriction has been shown to extend lifespan at the expense of reduced fecundity. An example of competition for limited resources, the thinking generally goes, as nutrients are reallocated from reproduction to somatic maintenance. Grandison et al. now demonstrate that, in Drosophila, dietary restriction does not induce reallocation, because different amino acids limit lifespan and fecundity. They find that fecundity in long-life flies can be rescued by the addition of methionine alone. Long lifespan and high fecundity can thus occur simultaneously, without dietary restriction itself, by adjustment of the ratio of amino acids in the diet. These findings imply that humans might be able to enjoy the benefits of reduced food intake, without the downsides, by adjustment of dietary nutrients. Dietary restriction extends healthy lifespan in diverse organisms but reduces fecundity; this is thought to be because of an adaptive reallocation of nutrients from reproduction to somatic maintenance. Here, the nutrients producing the responses of lifespan and fecundity to dietary restriction in Drosophila are identified. Adding essential amino acids to the dietary restriction condition increased fecundity and decreased lifespan; furthermore, addition of methionine alone rescued fecundity. Dietary restriction extends healthy lifespan in diverse organisms and reduces fecundity1,2. It is widely assumed to induce adaptive reallocation of nutrients from reproduction to somatic maintenance, aiding survival of food shortages in nature3,4,5,6. If this were the case, long life under dietary restriction and high fecundity under full feeding would be mutually exclusive, through competition for the same limiting nutrients. Here we report a test of this idea in which we identified the nutrients producing the responses of lifespan and fecundity to dietary restriction in Drosophila. Adding essential amino acids to the dietary restriction condition increased fecundity and decreased lifespan, similar to the effects of full feeding, with other nutrients having little or no effect. However, methionine alone was necessary and sufficient to increase fecundity as much as did full feeding, but without reducing lifespan. Reallocation of nutrients therefore does not explain the responses to dietary restriction. Lifespan was decreased by the addition of amino acids, with an interaction between methionine and other essential amino acids having a key role. Hence, an imbalance in dietary amino acids away from the ratio optimal for reproduction shortens lifespan during full feeding and limits fecundity during dietary restriction. Reduced activity of the insulin/insulin-like growth factor signalling pathway extends lifespan in diverse organisms7, and we find that it also protects against the shortening of lifespan with full feeding. In other organisms, including mammals, it may be possible to obtain the benefits to lifespan of dietary restriction without incurring a reduction in fecundity, through a suitable balance of nutrients in the diet.