Oral nicotinamide riboside raises NAD+ and lowers biomarkers of neurodegenerative pathology in plasma extracellular vesicles enriched for neuronal origin

Abstract

Declining nicotinamide adenine dinucleotide (NAD+) concentration in the brain during aging contributes to metabolic and cellular dysfunction and is implicated in the pathogenesis of aging‐associated neurological disorders. Experimental therapies aimed at boosting brain NAD+ levels normalize several neurodegenerative phenotypes in animal models, motivating their clinical translation. Dietary intake of NAD+ precursors, such as nicotinamide riboside (NR), is a safe and effective avenue for augmenting NAD+ levels in peripheral tissues in humans, yet evidence supporting their ability to raise NAD+ levels in the brain or engage neurodegenerative disease pathways is lacking. Here, we studied biomarkers in plasma extracellular vesicles enriched for neuronal origin (NEVs) from 22 healthy older adults who participated in a randomized, placebo‐controlled crossover trial (NCT02921659) of oral NR supplementation (500 mg, 2x /day, 6 weeks). We demonstrate that oral NR supplementation increases NAD+ levels in NEVs and decreases NEV levels of Aβ42, pJNK, and pERK1/2 (kinases involved in insulin resistance and neuroinflammatory pathways). In addition, changes in NAD(H) correlated with changes in canonical insulin–Akt signaling proteins and changes in pERK1/2 and pJNK. These findings support the ability of orally administered NR to augment neuronal NAD+ levels and modify biomarkers related to neurodegenerative pathology in humans. Furthermore, NEVs offer a new blood‐based window into monitoring the physiologic response of NR in the brain.

Neurometabolomic Impacts of Modeled Wildfire Smoke and Protective Benefits of Anti-Aging Therapeutics in Aged Female C57bl/6j Mice

“…After FDR correction (cut-off p<0.1), the main pathways affected included alanine, aspartate, and glutamate metabolism; purine biosynthesis; arginine biosynthesis; pyrimidine metabolism; and nicotinate and nicotinamide metabolism (Fig 2C , Table 1). The affected pathway of nicotinate and nicotinamide metabolism confirms the accuracy of pathway analysis employed, based on abundant literature showing that aging is associated with declines in NAD + reserves and biosynthesis (55)(56)(57)(58)(59)(60)(61)(62)(63)(64)(65). The nonoverlapping FA metabolites were added into the list containing overlapping metabolites and the new list was queried for pathway alterations.…”

Inhibiting tau-induced elevated nSMase2 activity and ceramides is therapeutic in an Alzheimer’s disease mouse model

“…Yet, to this date, experiments have not directly addressed these hypotheses. On the other hand, cumulative evidence supports the use of L1CAM as a target for the isolation of blood-borne nEVs, including the enrichment of EV and neuronal markers in L1CAM IP eluates from human blood as well as the correlation of EV cargo with brain disease states and therapeutic interventions [ 54 , 76 – 84 ], the recovery of GFP-positive EVs from the plasma of Nestin-GFP mice selectively expressing GFP in neurons [ 79 ], and the positive correlations between brain and nEV levels of pathological proteins in multiple AD mouse models [ 43 ]. In addition, proteomic analyses have detected L1CAM in EVs isolated from human brains [ 85 , 86 ] and that a high percentage of proteins carried by EVs isolated from human blood via L1CAM IP are highly expressed in the human brain and shared by EVs isolated from the conditioned media of human neurons in culture [ 83 , 87 ].…”

Fingerstick blood assay maps real-world NAD+ disparity across gender and age

“…In addition, previous studies showed that oral supplementation of NA 12 , NR [33][34][35] or NMN 17,36 can increase the blood NAD + level and lead to beneficial outcomes. However, the conventional quantification based on HPLC-MS or enzymatic cycling assays are time-and labor-intensive, hence limiting the up-scale and generalization of the NAD + blood test.…”