Advancing age predisposes us to a number of neurodegenerative diseases, yet the underlying mechanisms are poorly understood. With some 70 million individuals affected, glaucoma is the world's leading cause of irreversible blindness. Glaucoma is characterized by the selective loss of retinal ganglion cells that convey visual messages from the photoreceptive retina to the brain. Age is a major risk factor for glaucoma, with disease incidence increasing near exponentially with increasing age. Treatments that specifically target retinal ganglion cells or the effects of aging on glaucoma susceptibility are currently lacking. On page 756 of this issue, Williams et al. (1) report substantial advances toward filling these gaps by identifying nicotinamide adenine dinucleotide (NAD+) decline as a key age-dependent risk factor and showing that restoration with long-term dietary supplementation or gene therapy robustly protects against neuronal degeneration.
Glaucomas are neurodegenerative diseases that cause vision loss, especially in the elderly. The mechanisms initiating glaucoma and driving neuronal vulnerability during normal aging are unknown. Studying glaucoma-prone mice, we show that mitochondrial abnormalities are an early driver of neuronal dysfunction, occurring before detectable degeneration. Retinal levels of nicotinamide adenine dinucleotide (NAD+, a key molecule in energy and redox metabolism) decrease with age and render aging neurons vulnerable to disease-related insults. Oral administration of the NAD+ precursor nicotinamide (vitamin B3), and/or gene therapy (driving expression of Nmnat1, a key NAD+-producing enzyme), was protective both prophylactically and as an intervention. At the highest dose tested, 93% of eyes did not develop glaucoma. This supports therapeutic use of vitamin B3 in glaucoma and potentially other age-related neurodegenerations.