Steroid hormones sulfatase inactivation extends lifespan and ameliorates age-related diseases

Aging and fertility are two interconnected processes. From invertebrates to mammals, absence of the germline increases longevity. Here we show that loss of function of sul-2, the Caenorhabditis elegans steroid sulfatase (STS), raises the pool of sulfated steroid hormones, increases longevity and ameliorates protein aggregation diseases. This increased longevity requires factors involved in germline-mediated longevity (daf-16, daf-12, kri-1, tcer-1 and daf-36 genes) although sul-2 mutations do not affect fertility. Interestingly, sul-2 is only expressed in sensory neurons, suggesting a regulation of sulfated hormones state by environmental cues. Treatment with the specific STS inhibitor STX64, as well as with testosterone-derived sulfated hormones reproduces the longevity phenotype of sul-2 mutants. Remarkably, those treatments ameliorate protein aggregation diseases in C. elegans, and STX64 also Alzheimer's disease in a mammalian model. These results open the possibility of reallocating steroid sulfatase inhibitors or derivates for the treatment of aging and aging related diseases. Sul-2 is a steroid sulfatase in c.elegans. Here the authors show that, in the absence of sul-2 enzymatic activity, worm lifespan is increased, and that chemical inhibition ameliorates symptoms of neurodegenerative disorders in worms and mice.

Automated summary

The study demonstrates that loss of function of the steroid sulfatase sul-2 in Caenorhabditis elegans increases lifespan and ameliorates protein aggregation diseases, through mechanisms involving factors related to germline-mediated longevity. Sul-2 is predominantly expressed in sensory neurons, suggesting regulation by environmental cues.