Aging is typically seen as a driver of neurodegenerative diseases – but what if it could be harnessed as part of the solution? A new study, published in the journal Mechanisms of Ageing and Development, by researchers at ICVS suggests that.
Machado-Joseph Disease, or Spinocerebellar Ataxia Type 3, is caused by a genetic alteration in the gene coding for ataxin-3 protein. This mutation results in a protein with an abnormally long sequence of a specific amino acid, glutamine. The altered protein tends to form aggregates in neurons, impairing their function and potentially leading to cell death. Although the mutation is present from birth, symptoms – such as loss of coordination and motor function – appear in adulthood and progress with age, making aging a key factor in the onset and progression of the disease.
Using the model organism Caenorhabditis elegans, the team tested genetic alterations known to extend lifespan through different biological mechanisms. While all of these changes successfully increased longevity, only those related to nutrient-sensing pathways, such as mutations in the eat-2 gene (which mimics caloric restriction) and daf-2 (which reduces insulin/IGF-1 signaling), also led to improvements in motor symptoms associated with the disease.
“This study helped us understand that only specific aging-related pathways offer protective effects in the context of neurodegenerative diseases,” Marta Costa explained. “While this adds complexity to how we understand the biological mechanisms involved, it also provides valuable clues for developing more targeted and effective treatments.”
Based on these findings, the team went on to test a compound that inhibits the IGF-1 receptor and the insulin/IGF-1 signaling pathway. The treatment proved effective in reducing motor deficits in the animal model, further supporting the therapeutic potential of this molecular pathway.
This study (conducted by Marta Daniela Costa, Jorge Diogo Da Silva, Andreia Teixeira-Castro and Patrícia Maciel) opens new therapeutic perspectives for Machado-Joseph Disease by targeting specific biochemical pathways linked to aging, reframing aging as a strategic focus for future therapies.
