Gene x environment interactions as drivers of lifespan variation in nematodes

Variation in lifespan is predicted from evolutionary theory, where selection may favor organisms that live longer and reproduce later in life or those that live shorter, but reproduce earlier. Proximal physiological causes may also explain variation in lifespan, with many processes linked to mitochondria predicted to influence longevity and chemical treatments that affect mitochondrial function causing increased lifespans. However, long-lived genetic variants may not benefit from these chemical treatments to the same degree. Here, we examined the effects of lifespan-enhancing phytochemicals (curcumin, carnosol, and rapamycin) on lifespan and healthspan in five genetic strains of the model nematode C. elegans with known variation in lifespan. Both the genetic strains and phytochemicals were associated with mitochondrial function. We found significant effects of genetic background (although not always as precited from previous studies), chemical treatment, and their interactions (GxE) that explained variation in lifespan. Contrary to our predictions, lifespan-enhancing phytochemicals had larger effects in genetic strains that were already long-lived. Healthspan (measured as worm activity) generally decreased with age, but in different ways for different genetic strains. For both lifespan and healthspan, genetic strain explained more variation than chemical treatment. There was a trade-off between healthspan and lifespan, such that strains that lived longer were generally less active across all ages. Together, our results support predicted trade-offs from evolutionary theory, while contradicting trade-offs predicted based on a biochemical “ceiling” to enhancing lifespan in long-lived genetic strains.