Significance: Impaired neuronal bioenergetics and neuroinflammation are thought to play key roles in the progression of Alzheimer's disease (AD), but their interplay is not clear. AD mouse brains showed lower nicotinamide adenine dinucleotide (NAD ⁺ ) levels and alterations in inflammation. Treatment of AD mice with NR reduced neuroinflammation, attenuated DNA damage, and prevented cellular senescence. We present evidence that the beneficial effects of nicotinamide riboside (NR) are, in part, through a cyclic GMP-AMP synthase (cGAS)–stimulator of interferon genes (STING)-dependent pathway. DNA damage was increased in AD and attenuated by NR. Both cGAS–STING and NAD ⁺ pathways are potential therapeutic targets for AD.

Emerging findings suggest that compromised cellular bioenergetics and DNA repair contribute to the pathogenesis of Alzheimer’s disease (AD), but their role in disease-defining pathology is unclear. We developed a DNA repair-deficient 3xTgAD/Polβ ^+/− mouse that exacerbates major features of human AD including phosphorylated Tau (pTau) pathologies, synaptic dysfunction, neuronal death, and cognitive impairment. Here we report that 3xTgAD/Polβ ^+/− mice have a reduced cerebral NAD ⁺ /NADH ratio indicating impaired cerebral energy metabolism, which is normalized by nicotinamide riboside (NR) treatment. NR lessened pTau pathology in both 3xTgAD and 3xTgAD/Polβ ^+/− mice but had no impact on amyloid β peptide (Aβ) accumulation. NR-treated 3xTgAD/Polβ ^+/− mice exhibited reduced DNA damage, neuroinflammation, and apoptosis of hippocampal neurons and increased activity of SIRT3 in the brain. NR improved cognitive function in multiple behavioral tests and restored hippocampal synaptic plasticity in 3xTgAD mice and 3xTgAD/Polβ ^+/− mice. In general, the deficits between genotypes and the benefits of NR were greater in 3xTgAD/Polβ ^+/− mice than in 3xTgAD mice. Our findings suggest a pivotal role for cellular NAD ⁺ depletion upstream of neuroinflammation, pTau, DNA damage, synaptic dysfunction, and neuronal degeneration in AD. Interventions that bolster neuronal NAD ⁺ levels therefore have therapeutic potential for AD.

Mitochondrial dysfunction contributes to normal aging and a wide spectrum of age-related diseases, including neurodegenerative disorders such as Parkinson's disease and Alzheimer's disease. It is important to maintain a healthy mitochondrial population which is tightly regulated by proteolysis and mitophagy. Mitophagy is a specialized form of autophagy that regulates the turnover of damaged and dysfunctional mitochondria, organelles that function in producing energy for the cell in the form of ATP and regulating energy homeostasis. Mechanistic studies on mitophagy across species highlight a sophisticated and integrated cellular network that regulates the degradation of mitochondria. Strategies directed at maintaining a healthy mitophagy level in aged individuals might have beneficial effects. In this review, we provide an updated mechanistic overview of mitophagy pathways and discuss the role of reduced mitophagy in neurodegeneration. We also highlight potential translational applications of mitophagy-inducing compounds, such as NAD+ precursors and urolithins.

Metabolic dysfunction is a primary feature of Werner syndrome (WS), a human premature aging disease caused by mutations in the gene encoding the Werner (WRN) DNA helicase. WS patients exhibit severe metabolic phenotypes, but the underlying mechanisms are not understood, and whether the metabolic deficit can be targeted for therapeutic intervention has not been determined. Here we report impaired mitophagy and depletion of NAD⁺, a fundamental ubiquitous molecule, in WS patient samples and WS invertebrate models. WRN regulates transcription of a key NAD⁺ biosynthetic enzyme nicotinamide nucleotide adenylyltransferase 1 (NMNAT1). NAD⁺ repletion restores NAD⁺ metabolic profiles and improves mitochondrial quality through DCT-1 and ULK-1-dependent mitophagy. At the organismal level, NAD⁺ repletion remarkably extends lifespan and delays accelerated aging, including stem cell dysfunction, in Caenorhabditis elegans and Drosophila melanogaster models of WS. Our findings suggest that accelerated aging in WS is mediated by impaired mitochondrial function and mitophagy, and that bolstering cellular NAD⁺ levels counteracts WS phenotypes.