A new study from the laboratory of Levi Todd, PhD, at Upstate Medical University has found that aging significantly limits the ability of support cells in the retina, called glia, to be reprogrammed into new neurons; a discovery that has important implications for the future of regenerative medicine for age-related neurodegenerative diseases such as Alzheimer's, Parkinson's, and glaucoma.
The study, published in the Proceedings of the National Academy of Sciences (PNAS), is among the first to test whether glial reprogramming strategies, which have had success in young animals, still work in aged tissue. Because degenerative diseases of the brain and eye are overwhelmingly diseases of aging, the question is a critical one for the field.
The Todd Lab studies how the nervous system might repair itself after neurons are lost, rather than simply trying to prevent that loss in the first place.
That restoration strategy relies on glia, the cells that support and nourish neurons throughout the brain and retina. In some animals, including zebrafish and frogs, glial cells can naturally sense when neurons are lost and respond by reverting to a stem-cell-like state to generate replacements.
Only in the past decade has research shown that this same process can be triggered in the retinas of young mice. Todd noted that the broader field of glial reprogramming has grown rapidly since the original 2017 discovery that new retinal neurons could be generated from glia, but that growth has focused almost entirely on refining techniques in young animals.
"This whole concept of cell replacement therapy is usually for degenerative disorders, which are almost all age-related. Nobody yet has done anything in aged nervous system regeneration," Todd said. "We show that yeah, it can still work, so there's still hope. It's just going to be harder. And now we're finding approaches to overcome those challenges."
Using multiple transcription factor-based regeneration strategies, the team found that the efficiency of glial-to-neuron reprogramming is largely reduced with age. Todd pointed to two underlying factors. First, the neurons and glia a person is born with are cells they keep for life, unlike skin or liver cells that constantly turn over. Over time, these cells can become "tired” and lose plasticity seen in the young nervous system. Second, and more targetable, is a phenomenon known as 'inflammaging'.
Inflammation increases as you age. It's true for everything; it's why it's harder to diet when you're older and why healing is slower. It's also true in the brain and the retina.Dr. Levi Todd, PhD, Assistant Professor, Ophthalmology and Visual Sciences, Upstate Medical University
Dr. Todd also said, "Typically, the nervous system keeps out the immune system with the blood-brain barrier. You don't want the immune system in your brain, because the immune system is a blunt force. What we've been showing is that the barrier breaks down with age, and that exacerbates the difficulty of regeneration."
Todd's lab also points out a potential solution. Their research showed that dampening the immune system with anti-inflammatory steroids could partially restore the retina's regenerative response in aged neurons.
Looking ahead, the lab plans to pinpoint exactly which molecules and pathways drive this inflammatory block on regeneration, with an eye toward more precise therapies.
"The next step of this project is to figure out what exactly it is about inflammation that impacts regeneration," Todd said. "What are the molecules? Could you develop monoclonal antibodies that block a specific pathway to make regeneration better? If we can be more specific with our target, we could avoid broad immunosuppression, which can have negative side effects."
Todd also credited the graduate students who led the work.
"Our first three authors on this paper are all graduate PhD students in neuroscience. I'm very proud of the fact that they've already been able to contribute to a big story. I think as a scientist, in the long run your impact is going to be on all the scientists you train and the mentoring you do."
Other Upstate authors include Jugasmita Deka, Ying Han, Sucheta Bhattacharya, Samantha Sutton, Galina Bachay and William Brunken, PhD.
The full paper published in the September edition of PNAS can be found here.
Reference:
1. https://www.pnas.org/doi/10.1073/pnas.2612369123
(Newswise/MF)