Nicotinamide and Mitochondrial Rescue: Can Metabolic Therapy Restore Function?

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Excerpt:
Nicotinamide and Mitochondrial Rescue: Can Metabolic Therapy Restore Function?Glaucoma is a leading cause of irreversible vision loss, often progressing even when intraocular pressure (IOP) is controlled. A growing body of evidence highlights that retinal ganglion cells (RGCs) are particularly vulnerable to metabolic stress, notably from chronic depletion of nicotinamide adenine dinucleotide (NAD+), a coenzyme essential for mitochondrial energy production (). Nicotinamide (NAM), a form of vitamin B3 and an NAD+ precursor, has therefore emerged as a promising neuroprotective therapy. In animal models and early human studies, NAM supplementation has shown significant preservation of RGC integrity and function () (). This article reviews recent randomized clinical trials of high-dose NAM (with or without pyruvate) and discusses how NAD+ repletion might “rescue” stressed but viable RGCs. It also covers dosing considerations, safety, heterogeneity of responses, patient selection, and ongoing research.Metabolic Basis of Glaucoma and NAD+ RepletionRGCs have extremely high metabolic demands and rely on robust mitochondrial function. In glaucoma, aging and chronic stress trigger progressive NAD+ depletion in RGCs. NAD+ is a key cofactor in oxidative phosphorylation and in pathways (like sirtuins and DNA repair) that support cell survival () (). When NAD+ levels fall, RGCs experience bioenergetic failure, elevated oxidative stress, and susceptibility to apoptosis. Nicotinamide supplementation can replenish NAD+ via the NAD+ salvage pathway. This helps maintain mitochondrial ATP production and activates survival enzymes (e.g. SIRT1) while preventing over-activation of PARP1 (a DNA repair enzyme that can otherwise deplete NAD+) () (). In short, restoring NAD+ may revive “silent” RGCs. For example, electroretinographic studies show that NAM-treated glaucoma patients have larger photopic negative response (PhNR) amplitudes – an objective measure of inner retinal (RGC) function – compared to placebo (). These studies suggest NAM protects against early mitochondrial dysfunction and can boost RGC activity even after onset of disease. In animal glaucoma models, high-dose nicotinamide robustly preserved RGC morphology and prevented vision loss (). Together, these findings support the idea that stressed but not-yet-dead RGCs can be metabolically “rejuvenated” by NAD+ repletion.Clinical Trial Evidence for NicotinamideSeveral recent randomized trials have tested high-dose nicotinamide (with or without pyruvate) in glaucoma patients. Key outcomes include electrophysiology (pattern or photopic ERG) and visual function tests (visual field). Nicotinamide supplements alone (high-dose): A crossover trial in Australia randomized 57 patients with treated primary open-angle glaucoma to receive high-dose NAM (1.5 g/day for 6 weeks, then 3.0 g/day for 6 weeks) versus placebo, then crossed over (). In this study, inner retinal function improved significantly on NAM. The PhNR amplitude (Vmax) increased by ~14.8% on NAM (vs 5.2% on placebo, p=0.02), and the PhNR/b-wave ratio increased ~12.6% on NAM (p=0.002) (). Notably, 23% of patients on NAM showed PhNR improvements beyond natural variability, compared to only 9% on placebo (). There was also a trend for better visual fields: 27% of eyes improved ≥1 dB in mean deviation on NAM versus only 4% on placebo (p=0.02) (). Compliance was excellent (
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Видео Nicotinamide and Mitochondrial Rescue: Can Metabolic Therapy Restore Function? канала Glaucoma, Vision & Longevity: Supplements Science