Intergenerational Effects of Dietary Restriction and Insulin/IGF Signaling on Starvation Resistance and Reproductive Development

The roundworm C. elegans reversibly arrests larval development during starvation, but extended early-life starvation reduces reproductive success. Maternal dietary restriction (DR) buffers progeny from starvation as young larvae, preserving reproductive success. However, the developmental basis of reduced fertility following early-life starvation is unknown, and it is unclear how maternal diet modifies developmental physiology in progeny. We show here that extended starvation in first-stage (L1) larvae followed by unrestricted feeding results in a variety of developmental abnormalities in the reproductive system, including glp-1/Notch-sensitive germ-cell tumors and uterine masses that express neuronal and epidermal cell-fate markers. We found that maternal DR and reduced maternal insulin/IGF signaling (IIS) increase oocyte provisioning of vitellogenin lipoprotein, reducing penetrance of starvation-induced abnormalities in progeny, including tumors. Furthermore, we show that maternal DR reduces IIS in progeny, and that daf-16/FoxO and skn-1/Nrf, transcriptional effectors of IIS, are required in progeny for maternal DR to suppress starvation-induced abnormalities. daf-16/FoxO activity in somatic tissues is sufficient to suppress starvation-induced abnormalities, suggesting cell-nonautonomous regulation of reproductive system development. This work reveals that early-life starvation compromises reproductive development and that intergenerational insulin/IGF-to-insulin/IGF signaling mediates adaptation to nutrient availability.