Shifting the Scales: NMN Mitigates Skeletal Aging by Promoting Healthy Bone-Fat Balance

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showing patient a spine xray; NMN Mitigates Skeletal Aging by Promoting Healthy Bone-Fat Balance

Affecting one in three women and one in five men over age 50, the breakdown and deterioration of bone known as osteoporosis contributes to significant increases in morbidity and mortality in older adults. As bones become more brittle with age, the skeletal system cannot fully support the body, leading to fractures, falls, and frailty with decreased independence and quality of life. 

While many factors contribute to skeletal aging, the reduced regenerative abilities of mesenchymal stromal cells (MSCs) may be a leading cause. These adult stem cells found in the bone marrow act as building blocks for skeletal tissue, as they can develop into bone cells called osteoblasts. However, with age, the cells that MSCs contribute to tend to shift — rather than creating more osteoblasts, they start to develop preferentially into adipocytes, or fat cells. With this change in bone-fat balance comes an increased risk of osteoporosis and fat accumulation, leading to worse health and chronic disease development with age. 

Although the number and functionality of MSCs do decline with age, researchers think there are some ways to combat this decline — and, with it, improve the bone-fat imbalance commonly seen in aging adults. One such way is with nicotinamide mononucleotide (NMN), a precursor to nicotinamide adenine dinucleotide (NAD+) — a vital coenzyme for cell function, energy production, and regulation of the aging process. In a recent study published in Cell Death and Disease, Song and colleagues looked at how NMN shifts the balance from fat-forming to bone-boosting in both cell-based and animal models of age, starting with its role in expanding MSC quantity and quality. As the inability of MSCs to regenerate is implicated in many other diseases, ranging from neurodegenerative to metabolic, this study suggests that NMN may be a promising therapy for combating much more than just osteoporosis.

xray of shoulder; As bones become more brittle with age, the skeletal system cannot fully support the body, leading to fractures, falls, and frailty with decreased independence and quality of life.

How aging cells contribute to bone-fat imbalance

As MSCs are long-lived cells, they are more prone to being affected by the aging process, leading to increased dysfunction and inability to regenerate. To create new and healthy bone cells throughout life, osteoblasts need to be continuously replaced with new bone cells that originate from MSCs. But, with age, there is a decline in MSC functionality that comes from inflammation and oxidative stress — the buildup of reactive compounds that damage cells and DNA — or reduced autophagy, our internal recycling program that removes toxic or dysfunctional cells from the body. This age-related damage is partly controlled by epigenetic changes — reversible modifications that don’t change the DNA sequence itself, but, rather, lead to alterations in gene activity based on how your body reads the DNA. With these epigenetic changes, MSCs deviate from their normal differentiation into osteoblasts, creating the bone-fat imbalance that is characteristic of skeletal aging and osteoporosis.

NMN tips the scales towards stronger bones

In this study, Song and colleagues look toward NMN to rebalance the scale between bone and fat, as declines in NAD+ levels are implicated in accelerated aging and chronic disease development — including osteoporosis. First, the research team administered NMN to a sample of MSCs from the bone marrow of mice, finding that the NAD+ precursor significantly boosted the expansion of MSCs in the cell culture, meaning they were able to regenerate successfully. Not only that, but NMN shifted the balance between bone-boosting osteogenesis and fat-forming adipogenesis. After applying NMN, the MSCs were much more likely to become osteoblasts than adipocytes, suggesting that NMN promotes bone formation. Additionally, essential genes involved in osteogenesis were markedly upregulated after NMN treatment.

From there, the researchers wondered if these results would translate from cells in a dish to mice. In a group of middle-aged mice, those who received NMN had more significant bone growth and less fat cell development, with increased markers of bone health, including thickness and density. With NMN treatment, the typical age-related reduction in bone growth was restored. 

The essential duo of NMN and SIRT1

Lastly, Song and colleagues looked at whether the compound SIRT1 (sirtuin-1) plays a role in how NMN boosts osteoblast and bone formation. Sirtuins are a family of proteins that play an essential role in health and longevity. When the activity of these so-called “longevity genes” decreases, aging and chronic disease can develop. As sirtuins are dependent on NAD+, NMN can boost the sirtuins’ activity by first increasing NAD+ levels. One of the sirtuins, SIRT1, is thought to be especially involved in bone health and metabolism, leading the research team to wonder if SIRT1 activity is necessary for NMN to promote osteogenesis and a healthy bone-fat balance — and, turns out, it is.

The same middle-aged mice who received NMN and saw bone-boosting benefits also doubled in SIRT1 activity in their MSCs compared to mice who didn’t get the NMN. Conversely, in NMN-treated cell cultures with their SIRT1 deleted, the MSCs experienced suppressed osteogenesis and increased adipogenesis, indicating that the sirtuin is required for NMN to do its bone-balancing job. Notably, mice who had their SIRT1 deleted did not survive long enough to be studied in this experiment, underlying the importance of this protein for health and longevity.

lab scientist doing research; nmn administration to stem cells boosted osteogenesis

Fighting skeletal aging, one osteoblast at a time

This study’s results promote NMN as a potential therapeutic option for diseases that result from MSC dysfunction and lack of regeneration with age, including osteoporosis. Through boosting NAD+ levels, supplemental NMN increases both SIRT1 activity and osteogenesis, effectively regulating the bone-fat imbalance that occurs with age and causes bone loss. As there is typically a shortage of MSC-rich bone marrow donations and some logistical issues with culturing MSCs in the lab, NMN may be an easier alternative for rescuing age-related bone loss. As the authors conclude, “Our study establishes NMN as a promising potential therapy for MSCs expansion and rejuvenation of aged MSCs.” Although this study didn’t test bone growth in humans, these results allude to NMN’s capabilities for fighting or preventing age-related bone loss and osteoporosis in the future.

Show references

Almeida M, O'Brien CA. Basic biology of skeletal aging: role of stress response pathways. J Gerontol A Biol Sci Med Sci. 2013;68(10):1197-1208. doi:10.1093/gerona/glt079

Song J, Li J, Yang F, et al. Nicotinamide mononucleotide promotes osteogenesis and reduces adipogenesis by regulating mesenchymal stromal cells via the SIRT1 pathway in aged bone marrow. Cell Death Dis. 2019;10(5):336. Published 2019 Apr 18. doi:10.1038/s41419-019-1569-2

Ullah I, Subbarao RB, Rho GJ. Human mesenchymal stem cells - current trends and future prospective. Biosci Rep. 2015;35(2):e00191. Published 2015 Apr 28. doi:10.1042/BSR20150025

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