Aging is the strongest known risk factor for neurodegenerative diseases, yet researchers still do not fully understand which molecular changes associated with getting older cause these conditions to develop.
Scientists have now identified a protein pathway that may help connect aging with the harmful protein buildup seen in disorders such as Huntington’s disease and amyotrophic lateral sclerosis (ALS).
Searching for the Link Between Aging and Brain Disease
A research team led by Professor Dr. David Vilchez at the CECAD Cluster of Excellence for Aging Research investigated this connection using the small nematode worm Caenorhabditis elegans. The researchers examined a signaling pathway that becomes increasingly active with age and contributes to the accumulation of abnormal proteins.
Their study, titled “The aging factor EPS8 induces disease-related protein aggregation through RAC signaling hyperactivation,” was published in Nature Aging.
The team concentrated on EPS8, an aging-associated protein, and the signaling pathways it controls. Previous research showed that EPS8 accumulates as worms grow older and activates damaging stress responses that shorten their lifespan.
EPS8 Drives Toxic Protein Buildup
The researchers found that higher EPS8 levels and increased activity in its signaling pathways promote pathological protein aggregation and neurodegeneration. Both are defining features of age-associated neurodegenerative conditions, including Huntington’s disease and ALS.
When the scientists reduced EPS8 activity, toxic protein aggregates no longer accumulated as readily. The treatment also helped preserve neuronal function in worm models of both diseases.
“We are delighted to uncover a molecular mechanism that could shed light on to how aging contributes to diseases like ALS and Huntington’s,” says first author Dr. Seda Koyuncu. “For years, we’ve known that age is the major common risk factor for different neurodegenerative diseases. However, how exactly age-related changes contribute to these diseases remains largely unknown. This study may contribute to filling in a part of that puzzle.”
Similar Results in Human Cells
EPS8 and the signaling molecules associated with it have been preserved throughout evolution and are also found in human cells. This allowed the researchers to determine whether the mechanism they observed in worms might also be relevant to human disease.
Reducing EPS8 levels in human cell models of Huntington’s disease and ALS produced results similar to those seen in C. elegans. The intervention prevented the accumulation of toxic protein aggregates in the cells.
“It’s incredibly exciting that the mechanisms we uncovered in C. elegans are also conserved in human cell models,” says Professor Dr. David Vilchez, highlighting how the use of simpler model organisms like the nematode worm can prove extremely useful to uncover disease mechanisms relevant to humans.
A Potential Target for Future Treatments
Scientists still do not know precisely how increased EPS8 activity causes toxic proteins to aggregate. Even so, the results address an important gap in neurodegenerative disease research by identifying a direct molecular connection between aging and neurodegeneration.
The findings also point to EPS8 and its signaling partners as possible targets for future therapies. Treatments aimed at this pathway could potentially slow or prevent the progression of ALS, Huntington’s disease, and other brain disorders associated with aging.
