Pérez-Jiménez, Mercedes M.Monje-Moreno, José M.Brokate-Llanos, Ana MaríaVenegas-Calerón, MónicaSánchez-García, AliciaSansigre, PaulaValladares, AmadorEsteban-García, SaraSuárez-Pereira, IreneVitorica, JavierRíos, José JuliánArtal-Sanz, MartaCarrión, Ángel M.Muñoz, Manuel J.2022-10-312022-10-312021-01-04Pérez-Jiménez MM, Monje-Moreno JM, Brokate-Llanos AM, Venegas-Calerón M, Sánchez-García A, Sansigre P, et al. Steroid hormones sulfatase inactivation extends lifespan and ameliorates age-related diseases. Nat Commun. 2021 Jan 4;12(1):49http://hdl.handle.net/10668/4311Aging 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.enAtribución 4.0 Internacionalhttp://creativecommons.org/licenses/by/4.0/LongevityAlzheimer diseaseFertilityAgingMutationSensory neuronsPhenotypeTestosteroneSteroidsSulfatasesLongevidadEnfermedad de alzheimerFertilidadEnvejecimientoMutaciónCélulas receptoras sensorialesFenotipoTestosteronaEsteroidesSulfatasasMedical Subject Headings::Diseases::Nervous System Diseases::Neurodegenerative Diseases::Tauopathies::Alzheimer DiseaseMedical Subject Headings::Organisms::Eukaryota::AnimalsMedical Subject Headings::Organisms::Eukaryota::Animals::Invertebrates::Helminths::Nematoda::Secernentea::Rhabditida::Rhabditoidea::Caenorhabditis::Caenorhabditis elegansMedical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Helminth Proteins::Caenorhabditis elegans ProteinsMedical Subject Headings::Diseases::Animal Diseases::Disease Models, AnimalMedical Subject Headings::Phenomena and Processes::Genetic Phenomena::Genetic Processes::Gene Expression Regulation::Epistasis, GeneticMedical Subject Headings::Anatomy::Urogenital System::Genitalia::GonadsMedical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::MiceMedical Subject Headings::Phenomena and Processes::Genetic Phenomena::PhenotypeMedical Subject Headings::Anatomy::Cells::Neurons::Neurons, Afferent::Sensory Receptor CellsMedical Subject Headings::Chemicals and Drugs::Polycyclic Compounds::SteroidsMedical Subject Headings::Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Hydrolases::Esterases::Sulfatases::Arylsulfatases::Steryl-SulfataseMedical Subject Headings::Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Hydrolases::Esterases::SulfatasesMedical Subject Headings::Phenomena and Processes::Physiological Phenomena::LongevityMedical Subject Headings::Psychiatry and Psychology::Psychological Phenomena and Processes::Mental Processes::Learning::CuesMedical Subject Headings::Anatomy::Cells::Germ CellsMedical Subject Headings::Phenomena and Processes::Reproductive and Urinary Physiological Phenomena::Reproductive Physiological Phenomena::FertilityMedical Subject Headings::Phenomena and Processes::Genetic Phenomena::Genetic Variation::MutationMedical Subject Headings::Chemicals and Drugs::Hormones, Hormone Substitutes, and Hormone Antagonists::Hormones::Gonadal Hormones::Gonadal Steroid Hormones::Testosterone Congeners::TestosteroneMedical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammalsresearch article33397961open access10.1038/s41467-020-20269-y2041-1723PMC7782729