Differential effects of lifespan-extending genetic manipulations in an animal model of MJD/SCA3

This is the authors' abstract. We don't add key points for this paper.

Aging is a natural biological process, but evidence suggests that some aspects of aging can be delayed and reduce the prevalence of neurodegenerative diseases, for which aging is a key risk factor. In a neuronal Caenorhabditis elegans model of a Polyglutamine disease-Spinocerebellar Ataxia Type 3 (SCA3), or Machado-Joseph disease (MJD)- we assessed the hypothesis that delaying aging is neuroprotective, investigating the effect of genetically manipulating multiple lifespan-determinant mechanisms. Lifespan-increasing mutations causing insulin/IGF-1 signaling downregulation, mitochondrial dysfunction, germline ablation and dietary restriction/innate immune activation had distinct impacts on MJD/SCA3 phenotypes, suggesting that not all genetic strategies of stalling aging are equally neuroprotective and challenging the idea that delaying aging is a guaranteed therapy for these diseases. Lifespan-extension improved the SCA3/MJD motor phenotype only when induced by altered nutrient-sensing pathways such as those mediated by insulin/IGF-1 and eat-2 signaling, but their effects on neuronal aggregation differed. These pathways exhibited differential proteostasis profiles, but both activated the heat shock response suggesting that they operate through partially independent mechanisms to confer neuroprotection. The therapeutic value of the insulin/IGF-1 downregulation was demonstrated through the chronic treatment of the SCA3/MJD model with an insulin/IGF-1 signaling inhibitor, underscoring the relevance of aging manipulations in guiding therapeutic strategies for these diseases. • Not all genetic strategies for delaying aging offer equal neuroprotection. • Downregulation of insulin/IGF-1 signaling and knockout of eat-2 enhance motor function in a C. elegans model of MJD/SCA3. • Both pathways converge on the activation of the heat shock response in the C. elegans MJD/SCA3 model. • Aging-delay interventions show therapeutic promise and may guide future treatments for neurodegenerative diseases.