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

Dietary restriction (DR) extends healthy lifespan in diverse organisms, and reduces fecundity 1,2. DR is widely assumed to induce adaptive reallocation of nutrients from reproduction to somatic maintenance, aiding survival of food shortages in nature 3-6. Long life under DR and high fecundity under full feeding would thus be mutually exclusive, through competition for the same, limiting nutrients. We tested this idea, by identifying the nutrients producing the responses of lifespan and fecundity to DR in Drosophila. Adding essential amino acids to a DR diet increased fecundity and decreased lifespan, similar to full feeding, with other nutrients having little or no effect. However, methionine alone increased fecundity as much as full feeding, but without reducing lifespan. Reallocation of nutrients therefore does not explain the DR responses. Lifespan was reduced by amino acids, particularly essential amino acids. Hence an imbalance in dietary amino acids away from the ratio optimal for reproduction shortens lifespan during full feeding and limits fecundity during DR. Reduced activity of the insulin/Igf signaling pathway extends lifespan in diverse organisms 7, and it protected against the shortening of lifespan with full feeding. In other organisms, including mammals, it may be possible to obtain the benefits for lifespan of DR without reduced fecundity, through a suitable balance of nutrients in the diet.