The first long-lived mutants: discovery of the insulin/IGF-1 pathway for ageing

Abstract

Inhibiting insulin/IGF-1 signalling extends lifespan and delays age-related disease in species throughout the animal kingdom. This life-extension pathway, the first to be defined, was discovered through genetic studies in the small roundworm Caenorhabditis elegans. This discovery is described here.

Figure 1.

The life cycle of C. elegans. Under replete conditions (green arrows), the C. elegans hermaphrodite hatches from the egg, passes through four developmental stages (L1–L4), and becomes a fertile adult. Under harsh environmental conditions (red arrows), including low food availability, crowding and elevated temperature, the animals enter the dauer diapause instead of becoming L3 larvae. When environmental conditions improve, the dauers exit from the dauer state to become L4s and then fertile adults.

Figure 2.

daf-2 and daf-16 regulate dauer formation and lifespan. When conditions are favourable during development, wild-type daf-2 inhibits the activity of daf-16, allowing growth to adulthood. Under harsh environmental conditions, daf-2 activity levels fall, allowing daf-16 activity to promote dauer formation. During adulthood, reducing daf-2 activity allows daf-16 to promote longevity. This genetic pathway was inferred from the mutant phenotypes of daf-2 and daf-16. Long-lived adults carrying relatively weak daf-2 mutations do not look like dauers, move actively and can be completely fertile. We now know that these genes act exclusively during adulthood to regulate adult lifespan, whereas they act during development to regulate dauer formation. daf-2 activity in the adult can be influenced by environmental signals, as the pathway can mediate the longevity effects of caloric restriction and it can extend lifespan in response to altered sensory cues. daf-2 encodes an insulin/IGF-1-receptor that inhibits DAF-16/FOXO transcriptional activity via a conserved protein kinase cascade that acts directly on DAF-16/FOXO. Active DAF-16/FOXO, in turn, influences lifespan by regulating a variety of cell protective and metabolic genes.