In Caenorhabditis elegans, ablation of germline stem cells (GSCs) extends lifespan, but also increases fat accumulation and alters lipid metabolism, raising the intriguing question of how these effects might be related. Here, we show that a lack of GSCs results in a broad transcriptional reprogramming in which the conserved detoxification regulator SKN-1/Nrf increases stress resistance, proteasome activity, and longevity. SKN-1 also activates diverse lipid metabolism genes and reduces fat storage, thereby alleviating the increased fat accumulation caused by GSC absence. Surprisingly, SKN-1 is activated by signals from this fat, which appears to derive from unconsumed yolk that was produced for reproduction. We conclude that SKN-1 plays a direct role in maintaining lipid homeostasis in which it is activated by lipids. This SKN-1 function may explain the importance of mammalian Nrf proteins in fatty liver disease and suggest that particular endogenous or dietary lipids might promote health through SKN-1/Nrf.
Understanding how animals age may help us to prevent age-related or chronic diseases, such as type 2 diabetes and cancer. The tiny nematode worm known as C. elegans is widely used as a model to study aging and has enabled researchers to identify factors that can slow down the aging process. Like other animals, these worms contain female and male sex cells that originate from cells called germline stem cells. The normal lifespan of C. elegans is less than three weeks, but when the germline stem cells are removed, the worms can live for much longer.
Reproduction requires a lot of energy, which is typically ‘stored’ in molecules of fat. Animals utilize their fat reserves and release this energy by breaking the fat molecules down into smaller molecules as part of their ‘metabolism’. Worms that have had their germline stem cells removed have altered fat metabolism, and it is thought that this may contribute to their increased lifespan. These worms have increased levels of a protein called SKN-1, which alters fat metabolism and helps to protect cells from toxic molecules and other stresses.
SKN-1 works by regulating the activity (or ‘expression’) of many genes in cells, but it is not clear how this increases the lifespan of the worms. Steinbaugh et al. studied mutant worms that were lacking SKN-1. Unlike normal worms, when the germline stem cells were removed from the mutants, their lifespan did not increase. Further experiments analyzed the genes that are switched on by SKN-1, and identified many that are involved in fat metabolism, in degrading other proteins, and in detoxifying harmful molecules. The experiments also found that SKN-1 reduces the overall amount of fat stored in the body.
Next, Steinbaugh et al. investigated how SKN-1 stops fat from being stored. During reproduction, cells in the gut produce yolk—which is rich in fats—that will be provided to germ cells to nourish the developing embryo. Worms lacking germline stem cells are not able to reproduce, but they continue to make yolk. Steinbaugh et al. found that the build up of the yolk activates SKN-1, which in turn inhibits the further accumulation of fats.
Steinbaugh et al.'s findings show that SKN-1 can be activated by fat molecules and plays a direct role in controlling the amount of fat stored in the body of the worms. A future challenge will be to identify the specific fat molecules that activate SKN-1, which could provide a model for understanding how specific fats in human diets could have wide-ranging health benefits.