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. The forkhead box O (FoxO) transcription factors attenuate Wnt/β-catenin signaling and the proliferation of osteoprogenitors, thereby decreasing bone formation. The NAD⁺-dependent Sirtuin1 (Sirt1) deacetylates FoxOs and β-catenin in osteoblast progenitors and, thereby, increases bone mass. However, it remains unknown whether the Sirt1/FoxO/β-catenin pathway is dysregulated with age in osteoblast progenitors. 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.

与年龄有关的骨质疏松症是由成骨细胞（分泌骨基质的细胞）缺乏引起的。成骨细胞祖细胞的数量也随着年龄的增长而下降，这与细胞衰老标志物的增加有关。Forkhead box O (FoxO) 转录因子减弱 Wnt/β-catenin 信号传导和骨祖细胞的增殖，从而减少骨形成。NAD ⁺依赖性 Sirtuin1 (Sirt1) 使成骨细胞祖细胞中的 FoxOs 和 β-catenin 去乙酰化，从而增加骨量。然而，尚不清楚在成骨细胞祖细胞中，Sirt1/FoxO/β-catenin 通路是否会随着年龄的增长而失调。我们发现老年小鼠成骨细胞祖细胞培养物中 NAD ⁺水平降低，这与 FoxO1 乙酰化和细胞衰老标志物的增加有关。NAD⁺前体烟酰胺核苷 (NR) 消除了 FoxO1 和 β-连环蛋白乙酰化以及细胞衰老的几种标志物，并增加了老年小鼠细胞的成骨能力。与这些效果一致，对 C57BL/6 小鼠施用 NR 可抵消随年龄增长而导致的骨量损失。来自年轻小鼠的骨祖细胞培养物中 NAD ⁺水平的减弱以 FoxO 依赖性方式抑制成骨细胞生成。此外，成骨细胞谱系细胞中NAD ⁺降低的小鼠在年轻时失去了骨量。总之，这些发现表明，随着年龄的增长，骨形成的减少至少部分是由于成骨细胞祖细胞中 NAD ⁺的减少和失调的 Sirt1/FoxO/β-catenin 通路。NAD ⁺因此，补足代表了一种合理的骨骼退化治疗方法。