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bioRxiv · 10.1101/541730

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

Perez-Jimenez, M. M.·Sansigre, P.·Valladares, A.·Venegas-Caleron, M.·Sanchez-Garcia, A.·Monje, J. M.·Esteban-Garcia, S.·Suarez-Pereira, I.·Vitorica, J.·Rios, J. J.·Artal-Sanz, M.·Carrion, A. M.·Munoz, M. J.
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Abstract

Aging and fertility are two interconnected processes. From invertebrates to mammals, absence of the germline increases longevity by a still not fully understood mechanism. We find that loss of function of sul-2, the Caenorhabditis elegans steroid sulfatase (STS), raises the pool of sulfated steroid hormones and increases longevity. This increased longevity requires factors involved in germline-mediated longevity (daf-16, daf-12, kri-1, tcer-1 and daf-36 genes) and is not additive to the longevity of germline-less mutants. Noteworthy, sul-2 mutations do not affect fertility. Thus, STS inactivation affects the germline signalling process regulating longevity. Interestingly, sul-2 is only expressed in sensory neurons, suggesting a regulation of germline longevity by environmental cues. We also demonstrate that treatment with the specific STS inhibitor STX64, reproduces the longevity phenotype of sul-2 mutants. Remarkably, STS inhibition by either mutation or drug treatment ameliorates protein aggregation diseases in C. elegans models of Parkinson, Huntington and Alzheimer, as well as Alzheimer disease in a mammalian model. These results open the possibility of reallocating steroid sulfatase inhibitors for the treatment of aging and aging related diseases.

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Perez-Jimenez, M. M., Sansigre, P., Valladares, A., Venegas-Caleron, M., Sanchez-Garcia, A., Monje, J. M., Esteban-Garcia, S., Suarez-Pereira, I., Vitorica, J., Rios, J. J., Artal-Sanz, M., Carrion, A. M., Munoz, M. J.. 2019-02-06. Steroid hormones sulfatase inactivation extends lifespan and ameliorates age-related diseases. https://doi.org/10.1101/541730

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