Aging limits neuronal regeneration from glia in the mouse retina.

Reprogramming resident glia into neurons holds great therapeutic promise for neurodegenerative diseases across the central nervous system, yet these strategies have been developed largely in young animals. Because aging is the primary risk factor for neurodegeneration, whether glia-to-neuron reprogramming remains effective in aged tissue is a critical unanswered question. Here, using the retina as an accessible part of the central nervous system, we show that aging is a major barrier to glia-to-neuron reprogramming in vivo. Across three transcription factor-based strategies, aged Müller glia exhibit consistently reduced neurogenesis. Single-cell transcriptomics reveal that aged glia fail to activate progenitor programs and instead adopt reactive and inflammatory states. Concurrently, the aged retina mounts an exacerbated neuroimmune response to injury. Immunomodulation with dexamethasone partially restores neurogenesis. Thus, aging imposes both glial-intrinsic and microenvironmental barriers to neuronal regeneration that can be partially overcome by immunomodulation.