Steroid hormones sulfatase inactivation extends lifespan and ameliorates age-related diseases
Mercedes M. Pérez‐Jiménez, José Manuel Monje, Ana María Brokate-Llanos, Mónica Venegas‐Calerón, Alicia Sánchez‐García, Paula Sansigre, Amador Valladares, Sara Esteban-García, Irene Suárez‐Pereira, Javier Vitórica, José Julián Ríos, Marta Artal‐Sanz, Ángel Manuel Carrión, Manuel J. Muñoz
Abstract
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.