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

Abstract

AbstractAging and fertility are two interconnected processes. From invertebrates to mammals, absence of the germline increases longevity. Here we show that loss of function ofsul-2, theCaenorhabditis eleganssteroid 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-1anddaf-36genes) althoughsul-2mutations do not affect fertility. Interestingly,sul-2is 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 ofsul-2mutants. Remarkably, those treatments ameliorate protein aggregation diseases inC. 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.