Recent studies have revealed the significant contribution of mitochondrial dysfunction and disrupted energy metabolism to the pathogenesis of osteoarthritis. Impaired mitochondrial function leads to the accumulation of reactive oxygens species, which contribute to cartilage degradation and chondrocyte apoptosis...Compounds capable of modulating mitochondrial metabolism and improving mitochondrial function, such as nicotinamide riboside and pyrroloquinoline quinone, have also been investigated in the context of osteoarthritis. These compounds promote mitochondrial biogenesis, enhance mitochondrial respiration, and reduce oxidative stress and inflammation in chondrocytes, ultimately preserving the integrity of the cartilage matrix...

In our study, NAM prevented osteoblast DNA damage and cell death caused by oxidative stress. Therefore, NAM can prevent the acceleration of musculoskeletal aging caused by oxidative stress.In summary, the present study shows that NAM significantly enhances osteoblast differentiation by relieving mitochondrial oxidative stress. NAM increases mitochondrial respiration and the expression of antioxidant enzymes via SIRT3, FOXO3A and PGC1A activation, facilitating osteoblast differentiation both in normal physiological conditions and under oxidative stress. On the basis of this study, NAM could be a therapeutic or prophylactic drug to improve bone health or therapeutic agent for the bone diseases caused by reactive oxygen species (ROS).

Our studies demonstrate that administration of NR during pregnancy in mice can prevent severe developmental defects caused by genetic inhibition of NAD production. In view of the multiple clinical syndromes already linked to defective NAD production, our findings raise hope of their attenuation and perhaps prevention.

Our data suggest that NR administration in compromised hematopoietic systems (NAD+ depleted system) drives cell-intrinsic changes of the HSC compartment together with an overall reduction in circulating inflammatory cytokines. However, once the aged system has been exposed to NR, the effects of removing the supplementation may have undesirable consequences. Thus, once a deficient system is exposed to NAD+ supplementation, to maintain the benefits we have demonstrated, the regimen may need to be sustained long-term...Our results showed significant alterations in lineage commitment of HSCs after NR treatment, with enhanced lymphoid potential. This correlated with changes in inflammatory cytokines and transcriptional alterations of the HSCs. While transplantation of aged NR-treated HSCs reproduced the enhanced lymphoid output seen in the transcriptional profiles, the changes in potential are not sustained after NR withdrawal in the aged mice, and the rebound phenotype appear to exacerbate aging phenotypes. Our results highlight the importance of the duration of NR exposure and the timing of initial exposure to derive robust, balanced lineage outputs from HSCs.

With age, hematopoietic stem cells (HSC) undergo changes in function, including reduced regenerative potential and loss of quiescence, which is accompanied by a significant expansion of the stem cell pool that can lead to haematological disorders. Elevated metabolic activity has been implicated in driving the HSC ageing phenotype. Here we show that nicotinamide riboside (NR), a form of vitamin B3, restores youthful metabolic capacity by modifying mitochondrial function in multiple ways including reduced expression of nuclear encoded metabolic pathway genes, damping of mitochondrial stress and a decrease in mitochondrial mass and network-size. Metabolic restoration is dependent on continuous NR supplementation and accompanied by a shift of the aged transcriptome towards the young HSC state, more youthful bone marrow cellular composition and an improved regenerative capacity in a transplant setting. Consequently, NR administration could support healthy ageing by re-establishing a more youthful hematopoietic system.

Age-related osteoporosis is caused by a deficit in osteoblasts, the cells that secrete bone matrix. The number of osteoblast progenitors also declines with age associated with increased markers of cell senescence...We found decreased levels of NAD+ in osteoblast progenitor cultures from old mice, associated with increased acetylation of FoxO1 and markers of cell senescence. The NAD+ precursor nicotinamide riboside (NR) abrogated FoxO1 and β-catenin acetylation and several marker of cellular senescence, and increased the osteoblastogenic capacity of cells from old mice. Consistent with these effects, NR administration to C57BL/6 mice counteracted the loss of bone mass with aging. Attenuation of NAD+ levels in osteoprogenitor cultures from young mice inhibited osteoblastogenesis in a FoxO-dependent manner. In addition, mice with decreased NAD+ in cells of the osteoblast lineage lost bone mass at a young age. Together, these findings suggest that the decrease in bone formation with old age is due, at least in part, to a decrease in NAD+ and dysregulated Sirt1/FoxO/β-catenin pathway in osteoblast progenitors. NAD+ repletion, therefore, represents a rational therapeutic approach to skeletal involution