Nicotinamide and NAD+ Boosting for Glaucoma Neuroprotection and Healthy Aging

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IntroductionGlaucoma is a chronic neurodegenerative eye disease marked by death of retinal ganglion cells (RGCs) and progressive visual field loss despite controlled intraocular pressure (IOP). Recent research highlights that RGCs have extraordinarily high metabolic demands (long unmyelinated axons, constant spiking) and sit at a “metabolic precipice,” making them vulnerable to age-related energy deficits and mitochondrial dysfunction () (). A key metabolic change in aging retinas is depletion of NAD+ (nicotinamide adenine dinucleotide), an essential coenzyme in mitochondrial energy production. Age-dependent NAD+ decline is documented in glaucoma models and is thought to render RGCs susceptible to “metabolic crisis” under stress () (). Accordingly, nicotinamide (NAM, the amide form of vitamin B3) and other NAD+ boosters have emerged as candidate neuroprotectants. NAM is a precursor in the NAD+ salvage pathway, and boosting NAD+ can enhance mitochondrial function, activate longevity enzymes, and buffer metabolic stress. Preclinical studies in glaucoma models and early clinical trials have begun to investigate whether NAD+ repletion can improve RGC resilience and slow vision loss () (). This article reviews the evidence from animal models and human studies, explains the proposed mechanisms (mitochondrial support, sirtuin activation, metabolic buffering) in the context of longevity biology, and discusses trial designs, outcomes, dosing, safety, adherence, and open questions about long-term use of NAM and other NAD+ boosters in glaucoma.NAD+ Metabolism in Retinal Ganglion CellsNAD+ is a ubiquitous coenzyme that facilitates ATP production via glycolysis and oxidative phosphorylation, and serves as a substrate for enzymes that regulate cell survival (sirtuins), DNA repair (PARPs), and stress responses () (). In RGCs – among the most energy-demanding neurons – NAD+ levels are critical for maintaining mitochondrial health and redox balance. In glaucoma models (DBA/2J mice), retinal NAD+ declines significantly with age, correlating with early mitochondrial dysfunction and vulnerability to IOP stress (). Bansal et al. showed that age-dependent NAD+ loss in DBA/2J RGCs “renders [them] vulnerable to a metabolic crisis following periods of high IOP” (). Similarly, human data suggest that metabolic dysregulation, including NAD+ depletion, contributes to glaucomatous neurodegeneration. Chiu et al. note that NAD+ depletion is a key feature of RGC stress and that nicotinamide supplementation—by replenishing NAD+—could counteract this “progressive depletion” and preserve mitochondrial function (). Nicotinamide is converted to NAD+ via the salvage pathway (NAM → NMN → NAD+), involving enzymes like NAMPT and NMNAT. Aging and stress can impair these enzymes, leading to an NAD+ deficit () (). NAD+ boosters also include nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN), which enter the same pathway. By elevating NAD+, these precursors support cellular bioenergetics and enable sirtuin (SIRT) activity, which normally helps sustain mitochondrial integrity and stress resistance () (). In glaucomatous RGCs, key NAD+-producing enzymes are downregulated and NAD+consumption (via PARP1) is upregulated, lead