A decrease in NAD+ contributes to the loss of osteoprogenitors and bone mass with aging

• Published in: npj aging and mechanisms of disease 2021-04, Vol.7 (1), p.8-8, Article 8
• Main Authors: Kim, Ha-Neui, Ponte, Filipa, Warren, Aaron, Ring, Rebecca, Iyer, Srividhya, Han, Li, Almeida, Maria
• Format: Article
• Language: English
• Subjects: 631/80/509; 692/699/2743/316/801; Acetylation; Age; Aging; Biomedical and Life Sciences; Biomedicine; Bone growth; Bone mass; Bone matrix; Cell Physiology; Forkhead protein; FOXO1 protein; Geriatrics/Gerontology; Human Physiology; NAD; Neurosciences; Osteoblastogenesis; Osteoblasts; Osteogenesis; Osteoporosis; Osteoprogenitor cells; Senescence; SIRT1 protein; Transcription factors; Wnt protein; β-Catenin
• ISSN: 2056-3973; 2056-3973
• DOI: 10.1038/s41514-021-00058-7

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.