We have recently described that mutations in
sul-2 gene, which encodes to the sulfatase of steroid hormone, or its inhibition with STX64 regulates aging and protein aggregation diseases. Our research has revealed that
sul-2 acts on sulfated steroid hormones in C. elegans, the orthologue to STS in humans.
sul-2 mutants have an increased pool of sulfated steroid hormones, increased life-span and ameliorate symptoms of protein aggregation diseases. The
sul-2 longevity depends on germline-mediated factors as
daf-16,
daf-12,
kri-1,
tcer-1 and
daf-36 genes, but fertility is not affected. Interestingly,
sul-2 is only expressed in sensory neurons, suggesting a regulation of sulfated hormones state by environmental cues. We managed to set up a treatment with the STX64, the specific STS inhibitor. STX64 in C. elegans increases longevity and ameliorates Alzheimer's, Parkinson's and Huntington's disease models. Furthermore, testosterone-derived sulfated hormones reproduce the longevity and protein aggregation diseases phenotypes of
sul-2, supporting that the presence of sulfated steroid hormones is the responsible of the phenotypes. Remarkably, oral STX64 treatment in acute and chronic Alzheimer's disease mammalian models suppresses the cognitive impairment and reduces the presence of senile plaques in the brain. STX64 is non-toxic in humans and together with our results open the possibility of reallocating steroid sulfatase inhibitors or derivates for the treatment of aging and aging related diseases.