In today's open access paper, researchers report that long-term supplementation with nicotinamide riboside in mice, starting from mid-life and continuing into old age, slows the pace of osteoporosis. The extracellular matrix of bone tissue is constantly remodeled over time, broken down by osteoclasts and built up by osteoblasts. Osteoporosis is caused by a growing imbalance between these two processes that favors destruction over creation. Bones lose mass and become brittle as a result, eventually becoming a serious health issue.
Many mechanisms are proposed to contribute to osteoporosis. Chronic inflammation, for example, alters the behavior of bone cells in ways that favor the activity of osteoclasts. Senescent cells accumulate with age and the source of a great deal of inflammatory signaling. Selectively destroying senescent cells via senolytic treatments has been shown to reverse osteoporosis to some degree. Another related mechanism involves the formation of advanced glycation endproducts (AGEs) that cross-link matrix proteins. This also is thought to be related to the chronic inflammation of aging.
Of relevance to today's research materials, mitochondrial dysfunction is also implicated in the development of osteoporosis, via its effects on cell development and activities. Mitochondria are the power plants of the cell, and when the supply of chemical energy store molecules created by mitochondria is diminished, near all cell processes suffer in some way.
In recent years, loss of NAD+ has been identified as one of the proximate causes of this issue, this being an important component in the chemical engines that operate inside mitochondria. NAD+ levels fall with age, for reasons that are far from fully explored. Various approaches to NAD+ upregulation have been assessed in mice and human trials, mostly supplementation with compounds derived from vitamin B3 such as nicotinamide riboside. The results in humans have overall been mixed at best. Nonetheless, results such as this one continue to accumulate in mice.
Here we show that NAD+ supplementation by the NAD+ precursor nicotinamide riboside (NR) can restore a youthful number of osteoprogenitor cells and attenuate skeletal aging in female mice. These, along with the findings that the levels of NAD+ decline with age in osteoblast progenitors, strongly suggest that NAD+ is a major target of aging in osteoblastic cells. A decrease in NAD+ was also seen in bone marrow stromal cells from 15-month-old when compared to 1-month-old mice. In agreement with our findings, long-term administration of NMN increased bone mineral density in male C57BL/6 mice. In contrast, administration of NMN to 12-month-old mice for only 3 months was not sufficient to alter bone mass.
We also found that the protein levels of Nampt in osteoblastic cells from old mice were lower than in cells from young mice. These along with the findings that deletion of Nampt in mesenchymal lineage cells is sufficient to decrease bone mass support the premise that the age-associated decrease in NAD+ in osteoblast progenitors attenuates bone formation. Further support is provided by evidence that NR administration increases osteoprogenitor number and mineralizing surface in aging mice. In tissues such as muscle and intestine, progenitor cells are critical targets of the anti-aging effects of NR. Nonetheless, the systemic nature of NR treatment precludes definitive conclusion about the target cells responsible for the beneficial effects on the skeleton.
We and others have shown that osteoprogenitors from old humans or mice exhibit markers of cellular senescence. Elimination of senescent cells via genetic or pharmacologic manipulations increases bone mass in aged mice, suggesting that cellular senescence contributes to skeletal aging46. Our present findings that NR administration decreases markers of senescence in osteoblast progenitors from old mice provide strong support for the contention that a decline in NAD+ is a major contributor to the age-associated bone cell senescence. This contention is further supported by evidence that a decrease in NAD+ exacerbates replicative senescence in bone marrow-derived stromal cell cultures. NR administration also attenuates cellular senescence in brain and skin of aged mice. Interestingly, in macrophages and endothelial cells Cd38 expression can be induced by factors associated with the senescence-associated secretory phenotype (SASP), suggesting that cellular senescence re-enforces the decline in NAD+.
Based on the results of the present work, we propose that intrinsic defects in osteoblast progenitors that cause a decrease in NAD+ contribute to the age-related decline in bone formation and bone mass. Repletion of NAD+ with precursors such as NR, therefore, may represent a therapeutic approach to age-associated osteoporosis as it does for other age-related pathologies.