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Nicotinamide mononucleotide promotes osteogenesis and reduces adipogenesis by regulating mesenchymal stromal cells ...

nicotinamide mononucleotide nmn sirt1 adipogenesis mesenchymal stromal cells mscs

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#1 Engadin

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Posted 28 June 2019 - 11:54 AM


Nicotinamide mononucleotide promotes osteogenesis and reduces adipogenesis by regulating mesenchymal stromal cells via the SIRT1 pathway in aged bone marrow

 

 

F U L L   T E X T :   Cell Death & Disease

 

 

Abstract

 

Mesenchymal stromal cells (MSCs) can differentiate to various cell types including osteoblasts, chondrocytes, and adipocytes. This cellular flexibility contributes to widespread clinical use of MSCs in tissue repair. However, challenges remain in efficient cellular expansion of MSCs for stem cell therapy. Current MSC culture methods have resulted in reduced self-renewal of MSCs and compromised therapeutic outcomes. This study identifies that nicotinamide mononucleotide (NMN), a key natural NAD+ intermediate, effectively encourages MSC expansion in vitro and in vivo. The in vitro expanded MSCs had heightened osteogenesis, but reduced adipogenesis. Furthermore, NMN supplementation stimulated osteogenesis of endogenous MSCs, and protected bone from aging and irradiation induced damage in mice. Mechanistically, we found that NMN treatment upregulated SIRT1. Genetically overexpressing SIRT1 in MSCs by using Prx1 cre; ColA1flox-stop-flox-SIRT1 mice promoted osteogenesis and reduced adipogenesis in aged mice. Overall, our data demonstrate that NMN promoted MSC self-renewal with strengthened osteogenesis and reduced adipogenesis via upregulating SIRT1 in aged mice.

 

 

Introduction

 

Aging is predicted to be an increasingly serious health and financial problem worldwide1. Age-related disorders, such as tumor2,3, metabolic disease4, memory deterioration5, and immunologic degeneration6, are associated with declined regenerative capacity in rapidly dividing stem cells7. Nicotinamide mononucleotide (NMN), a key NAD+ intermediate which decreases with age in mammals8, is an efficient therapy against age-associated diseases9,10. NMN administration alleviates age-related type 2 diabetes, ischemia-reperfusion injury, and Alzheimer’s disease11,12. However, the underlying mechanism of NMN’s protective effect is still unknown. In this study, we explored NMN’s role in combating age-related disorders via regulating mesenchymal stromal cells (MSCs). MSCs are nonhematopoietic multipotent stem cells with regeneration capacity13. Loss in number or functionality of MSCs with age profoundly limits tissue regeneration14, However, most current MSC culture methods limits self-renewal potential and functionality of MSCs, leading to compromised therapeutic outcomes10,15.

 

Herein, we have investigated the effects and underlying mechanism of NMN on the expansion and differentiation of mouse MSCs in vitro and in vivo. We have found that NMN promotes MSC self-renewal during in vitro culture and in mice. We have further demonstrated that NMN activates Sirtuin1 (SIRT1), which is an NAD+-dependent deacetylase. NMN increases osteogenesis and reduces adipogenesis of MSCs via upregulating SIRT1 in aged mice.

 

 

..../....

 

 

T E X T   F R O M   O T H E R   S O U R C E :    Alive by Nature (ABN)

 

 

This study published April 81, 2019 found that 300 mg/kg a day of NMN in drinking water increased bone density and decreased fat in older mice.

Nicotinamide mononucleotide promotes osteogenesis and reduces adipogenesis by regulating mesenchymal stromal cells via the SIRT1 pathway in aged bone marrow.

 

Nicotinamide Riboside (NR) and Nicotinamide MonoNucleotide (NMN) are NAD+ precursors that can be used to increase NAD+ levels in the body and are being used in hundreds of studies for treating a wide range of age related diseases and have shown some benefit on increased lifespan.

 

Other NAD+ precursors such as Nicotinic Acid (Niacin), or Nicotinamide (NAM) are also quite effective at elevating NAD+ levels (at least in the liver), and are effective at treating some health conditions.

 

However, numerous studies have also found Niacin and NAM are quite often not as effective for treating health conditions and have not shown the same benefit for increased lifespan.

 

This study is one such example.

 

NMN doubled the Sirt1 in stem cells and this increased Sirt1 activity resulted in significantly increased bone growth and decreased fat.

 

 

Adding NAM actually prevents the increase in Sirt1 from NMN.

 

In this study, 300 mg/kg of NMN a day in the drinking water for 3 months resulted in:

 

  • Promotes osteogenesis (bone growth)
  • Decreases adipogenesis (growth of fat cells)
  • Increased Sirt1 expression required
  • Increased MSC (Stem cells)
  • Nicotinamide inhibits Sirt1 increase

 

Nicotinamide mononucleotide (NMN), a key NAD+ intermediate which decreases with age in mammals8, is an efficient therapy against age-associated diseases.

 

NMN increases osteogenesis and reduces adipogenesis of MSCs via upregulating SIRT1 in aged mice.

 

 

NMN Increased Bone Growth

 

fig4-g-600x410.png

Our findings reveal a potential connection between NMN treatment and remedy in osteoporotic and aging mice.

 

 

NMN Decreased Fat Growth

 

NMN is a valuable therapy for rescuing bone loss during aging.

 

These results indicate that NMN stimulates osteogenesis in aged mice.

 

 

fig4-o.png

 

 

NMN Increased Stem cells

 

These data suggest that NMN inhibits adipogenesis in aged mice.

 

Our results show that anti-aging agent NMN, can efficiently promote MSCs (stem cells) expansion in vivo.

 

 

NMN increases Sirt1

 

Our study establishes NMN as a promising potential therapy for MSCs expansion and rejuvenation of aged MSCs.

 

NMN promoted MSC self-renewal with strengthened osteogenesis and reduced adipogenesis via upregulating SIRT1 in aged mice.

 

We have further demonstrated that NMN activates Sirtuin1 (SIRT1), which is an NAD+-dependent deacetylase.

 

We demonstrate that SIRT1 protein is essential for NMN to control the osteoblast and adipogenic lineage differentiation.

 

 

NAM inhibits Sirt1

 

Mechanistically, SIRT1 protein upregulation plays an essential role in NMN’s regulation of bone-fat balance.

 

Mechanistically, we found that NMN treatment upregulated SIRT1.

 

 

fig-7-bcd-600x286.png

 

 

It has been known for several years that excess Nicotinamide (NAM) can act to inhibit Sirtuin activity. However it is unclear what impact excess NAM has in vivo, as it is either metabolized to NMN and NAD+ through the salvage pathway, or, methylated to MeNAM and excreted in the urine.

 

This study doesn’t really answer the question of whether NAM inhibits Sirtuins in vivo. But it is striking how completely the addition of NAM along with NMN shuts down the increased Sirt1 activation.

 

 

Conclusion

 

These results confirm that the SIRT1 is required for NMN to control osteogenesis and adipogenesis.  

 

In summary, we provide evidence for the novel role of NMN in regulating bone-fat imbalance through SIRT1 during skeletal aging.

 

Previous studies have shown that SIRT1 plays an important role in regulating osteogenesis and adipogenesis in human embryonic stem cells.

 

 

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#2 PandorasBox

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Posted 27 May 2020 - 04:57 PM

At that dose i would need 19 grams very expensive. So one should avoid naicinamide

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Also tagged with one or more of these keywords: nicotinamide mononucleotide, nmn, sirt1, adipogenesis, mesenchymal stromal cells, mscs

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