Lsp2 links early-life diet to adult translation and lifespan in Drosophila

Abstract

Abstract Nearly a century ago, restricting diet during early-life periods was suggested to extend lifespan in rats and in Daphnia 1,2 . The effect of juvenile diet on adult physiology and lifespan has subsequently been described in other model organisms, including fruit flies 3–5 and mice 6–8 ; however, its mechanism remains poorly understood. Here, using Drosophila as a model, we show that restricting protein intake during the larval stage (early-life protein restriction; ePR) promotes adult lifespan by reducing the levels of storage proteins. Using stable-isotope tracing, we show that dietary amino acids obtained in the larval stage are retained into early adulthood, and are incorporated into ribosomal proteins in particular. This is mediated by larval serum protein 2 (Lsp2), a major storage protein, the expression of which is durably downregulated by ePR in the early adult stage. Genetic silencing of Lsp2 phenocopies ePR, attenuating ribosomal-protein abundance and translational activity in early adulthood, and extending lifespan. Restricting specific amino acids that are especially enriched in these storage proteins, such as phenylalanine and tyrosine, is sufficient to decrease the levels of early-life Lsp2 and promote longevity. These findings identify Lsp2 as a molecular carrier of nutritional history across developmental transitions, linking juvenile nutritional status to adult translational capacity and lifespan. Our study uncovers a previously unrecognized mechanism of nutritional memory that links early-life diet to lifelong organismal health.