Researchers at Columbia University’s Vagelos College of Physicians and Surgeons have reported new findings that suggest rejuvenating aging neurons could slow the progression of amyotrophic lateral sclerosis (ALS). The study, led by Hynek Wichterle and Emily Lowry, was published in Nature Neuroscience on August 12.
Wichterle, co-director of Columbia’s Motor Neuron Center and professor of pathology and cell biology, proposed that restoring vulnerable neurons to a more youthful state might make them more resilient to ALS. Initially skeptical, Lowry took charge of the project with support from Project ALS. Early results were promising enough to attract further funding from the National Institutes of Health.
“It’s the first time that motor neurons have been rejuvenated in any kind of capacity,” said Wichterle. “The results provide compelling proof that we can revert adult neurons to a more immature state without compromising their normal function.”
The research team used gene therapy in mice with ALS to return their neurons to a younger state. This approach delayed symptom onset and increased neuronal resilience. “Our hope is that this work will open the door to future therapies for age-related neurodegenerative diseases,” said Lowry.
ALS typically affects adults between ages 55 and 75 by targeting motor neurons in the spinal cord, leading to progressive loss of movement and speech. Wichterle noted, “We know that even in people who are born with mutations that almost always cause ALS, the motor neurons do not degenerate for several decades. It’s the most direct evidence that the young motor neuron is much more resilient in the face of the disease.”
Previous attempts at cellular rejuvenation used Yamanaka reprogramming factors but risked making cells too immature for normal function—a problem for critical cells like motor neurons. Lowry explained, “If that happened with motor neurons, it could cause paralysis.”
Instead, Wichterle and Lowry focused on two transcription factors—ISL1 and LHX3—that are naturally active during early neuron development. By reactivating these factors using a viral gene delivery system developed by Tulsi Patel (now at Rutgers University), they restored some youthful properties to mature mouse neurons without affecting their essential functions.
While translating this strategy into human therapies faces challenges, ongoing research aims to identify specific genes controlled by ISL1 and LHX3 as potential drug targets. “The two factors control about 200 other genes in the motor neurons, but it’s possible that just one or two of those genes are sufficient and could be targeted with a drug,” said Lowry.
The researchers also hope their findings may apply to other neurodegenerative diseases such as Parkinson’s and Alzheimer’s.
As Lowry stated: “Everyone is looking for the fountain of youth.”
