Maciel, Patricia, da Silva, Jorge Diogo, Teixeira-Castro, Andreia, Almeida, Dulce, Costa, Marta Daniela Araujo, Pereira-Sousa, Joana
[
International Worm Meeting,
2021]
Over the past few years evidence that contradicted aging as an inevitable phenomenon has surged, leading the scientific community to concentrate efforts to test drugs that effectively tackle aging. In parallel, this approach aimed to decrease the prevalence of a number of different disorders, such as neurodegenerative diseases, for which aging is a key risk factor. Here, the hypothesis that delaying aging is neuroprotective was assessed in a C. elegans model of Spinocerebellar Ataxia (SCA) Type 3, also known as Machado-Joseph disease (SCA3/MJD), the most common SCA worldwide. This neurodegenerative disease has a clear genetic cause, the abnormal expansion of a CAG triplet in the ataxin-3 gene. However, the contribution of additional genetic/environmental factors have been proposed to explain the variable disease phenotype. Lifespan-increasing mutations that are representative of well-known and conserved aging regulator mechanisms (insulin/IGF-1 signaling, dietary restriction, germline ablation and mitochondrial dysfunction) were introduced in the genetic background of the SCA3 nematode model. Their impact in key aspects of the disease was then assessed. Lifespan-extension improved the SCA3 motor phenotype if induced by altered nutrient sensing pathways, as is the case of the insulin/IGF-1 and mTOR signaling, but not when associated with other pathways, such as mitochondrial dysfunction and germline ablation. This challenges the idea that delaying aging is by itself beneficial and regarded a guaranteed therapy for these diseases. Additional experiments pointed to significant transcriptomic alterations in the proteostasis network caused by the downregulation of IGF-1/insulin signaling. However, not all insulin/IGF-1-dependent transcriptional responses seemed disease-modifying, suggesting that neuroprotective effects of aging can be restricted to more specific aging factors. Finally, chronic treatment of the C. elegans SCA3 model with insulin/IGF-1 signaling inhibitors also improved the motor phenotype, further demonstrating the therapeutic value of insulin/IGF-1 downregulation for the disease, increasing prospects for additional drug repurposing centered in this pathway. These results provide key insights to guide future therapeutic strategies for neurodegenerative diseases based on the manipulation of the aging process.