Anti-age drug NMN can help combat COVID, published in the top journal Cell Discovery

New breakthrough! Chinese Academy of Sciences confirms that NMN, the “Anti-age drug”, can help combat COVID, published in the top journal Cell Discovery

Recently, the outbreak of Coronavirus in many places in China has caused considerable impact on people’s production and life. In order to reduce the impact of Coronavirus on human beings, scientists all over the world have devoted themselves to research and treatment of COVID-19, and among many studies, scientists have found that NAD+ precursors, represented by NMN, are an important and promising research direction.

In April 2020, a team of researchers from Harvard University discovered that NMN cocktail therapy can treat COVID-19, which refers to a solution of NMN as the main agent, together with betaine, zinc sulfate and sodium chloride. After NMN cocktail treatment, a severely infected patient with COVID-19 who had failed to respond to conventional treatments was discharged from the hospital after only 13 days, and other elderly patients with COVID-19 infection showed significant improvement in their symptoms [1].

After the first success of NMN in the treatment of COVID-19, scientists became interested in NMN and other NAD+ precursors to combat coronavirus, and in February 2021, a team from the Swiss Royal Institute of Technology published human clinics on cocktail therapy for COVID-19 and found that a cocktail package of NAD+ precursors and several other substances increased the recovery rate of COVID-19 patients by 40% [2]. Just recently, Sinclair, the “godfather of anti-aging”, published an article in Trends in immunology supporting the idea that increasing NAD+ levels can be effective in the prevention and treatment of COVID-19 [3].

Recently, a similar conclusion was reached in our own trial: a team from the Chinese Academy of Sciences, together with Peking University and Tsinghua University, published their preclinical study in Cell Discovery, one of China’s top and world-renowned academic journals, in which they found that NMN supplement has a NAD+-like effect on COVID-19, improving not only the NAD+ metabolism caused by infection with COVID-19, but also ameliorates the dysregulation of immune response and cell death-related gene expression and inhibits cell death [4].

NAD+ supplementation ameliorates coronavirus-induced lung injury

The researchers started with NAD+ and used the less toxic SARS-CoV-2 MASCp6 to infect mice with NAD+ (1 mg/g/day) to treat older mice (8-9 months) and younger mice (6-7 weeks), and used saline as a control group, and dissected the mice on the third day after infection.

Figure Note: Changes in lung parameters after NAD+ supplementation c: Inflammatory cell aggregation density d: Inflammatory cell aggregation area e: Airway obstruction ratio f: Airway obstruction area.

They found pathological features in the lungs of control aged mice, including severe inflammatory cell infiltration, alveolar septal thickening, hemolysis, epithelial damage, airway obstruction and cell death, while mice in the NAD+ supplemented group showed significantly reduced symptoms of inflammatory cell infiltration and airway obstruction in the lungs, and no signs of hemolysis. Unlike the aged mice, the case characteristics of young mice in the control group were relatively mild, while the symptoms in the NAD+ supplemented group were almost completely eliminated, but a large amount of virus was still present in the lungs as shown by qPCR and immunofluorescence detection, indicating that NAD+ supplement could alleviate the pathological damage caused by the virus, but not the replication of the virus.

NAD+ supplement ameliorates Covid19-induced gene expression changes

PARP family, the “downstream” of NAD+

The PARP family is a major consumer of NAD+, and the researchers examined PARP family gene expression in the lung and found that the reduction in PARP2 expression was almost completely restored in NAD+ supplemented mice. Unexpectedly, PARP9, PARP10 and PARP14 were further upregulated in NAD+ supplemented mice, suggesting that PARP9, PARP10 and PARP14 genes play an important role in protection against coronavirus infection.

Figure Note: Changes in PARP family gene expression

Based on the changes in PARP family genes after NAD+ supplement, the researchers concluded that the downregulation of PARP2 gene after infection COVID-19 is due to the upregulation of PARP9, PARP10, and PARP14 gene expression by the cells to defend against coronavirus infection, thus increasing the demand for NAD+, but the total amount of NAD+ is limited and therefore the PARP2 gene expression is selected to be downregulated to maintain the dynamic balance of NAD+.

NAD+ “upstream” – NAD+ synthesis-related genes

The researchers examined not only the “downstream” PARP genes of NAD+, but also the “upstream” genes related to NAD+ synthesis.

We know that there are three main pathways for NAD+ synthesis: ab initio synthesis, the Preiss-Handler pathway, and the remediation pathway. It was found that NAD+ supplement partially restored the downregulation of genes in the remediation pathway, while genes related to ab initio synthesis were not affected.

 Other genes

In addition, genes related to immunity and apoptosis such as Cd200r3, Cd200r4 and Apaf1 were found to be suppressed, suggesting that NAD+ supplement reduces excessive inflammation and cell death caused by infection with COVID-19 by regulating gene expression.

 NMN supplement also improved lung injury and reduced mortality.

Since NAD+ can treat COVID-19, does NMN, a precursor of NAD+, have similar therapeutic effects? For better experimental results, the researchers used the more virulent SARS-CoV-2 MASCp36 to infect aged mice (8-9 months), which were then treated with NMN and NAD+, respectively, where the dose of NMN was 500 mg/kg/day and the dose of NAD+ remained unchanged, and saline was used as a control.

The results showed that the control mice had severe inflammatory cell infiltration and alveolar septal thickening in the lungs, while this injury was significantly reduced in the NMN and NAD+ groups of mice. In addition, cell death was significantly inhibited in both the NMN and NAD+ groups, with inhibition rates of 72.0% and 73.9%, respectively. Surprisingly, 30% of the mice in the NMN group eventually survived, whereas all of the mice in the control group had died by day 8 post-infection.

Figure Note: Plot of survival rate of mice with time of infection.

In terms of gene expression, Cd200r3 expression was significantly reduced in both the NMN and NAD+ groups, but reduced expression of Cd200r4 and Apaf1 was only observed in the NMN group. These results suggest that NMN supplement has similar effects to NAD+, and in some aspects NMN performs better, not only reducing inflammatory damage in the lungs and inhibiting cell death, but even reducing mortality in infected animals.

NMN supplement partially ameliorates metabolic disorders caused by COVID-19

Not satisfied with this result, the researchers also investigated the protective effect of NMN in more depth through metabolomic analysis. Seventy-five metabolites were found to be altered in mice infected with COVID-19, 22 of which were upregulated and 53 downregulated. And after comparing the metabolites in the NMN group with the control group, it was found that the NMN group improved 23 of the 53 metabolites that were downregulated, including glutamine, asparagine, proline, choline and glycine.

Since the NMN supplement naturally involved testing for NAD+-related metabolites, it was found that NAD+, NMN, NR and NAM levels were all elevated. In addition, the researchers found that NMN supplement restored the effects of infection with COVID-19 on many metabolites, including pyruvate, yohimbe and malate in the citric acid cycle, tryptophan, kynurenine, and glucose. All evidence suggests that NMN supplement may partially ameliorate the metabolic disorders caused by infection with COVID-19.

Figure Note: Changes in metabolites associated with NAD+ after NMN supplementation.

Summary

Although the previous NMN cocktail therapy confirmed the ability of NMN to treat COVID-19, it was an isolated clinical case, which is not very strong and has no theoretical basis. Most other studies have focused on NAD+ for coronavirus, and although NMN is a direct precursor of NAD+, it cannot be concluded that NMN can also treat COVID-19.

This preclinical study by the CAS research team not only proved again that NMN can treat COVID-19, but also provided a solid theoretical basis for the role of NMN in treating COVID-19. Based on the good performance of NMN in reducing lung pathological damage and even death in mice infected with COVID-19, NMN may be used in clinical trials to treat patients with COVID-19.

References

[1] Huizenga,R. (2020). Dramatic Cytokine Storm Reversal with an Over the Counter NMN Cocktail.Available at SSRN 3581388.

[2] Altay, O.,Arif, M., Li, X., Yang, H., Aydın, M., Alkurt, G., …& Mardinoglu, A. (2021). Combined metabolic activators accelerates recoveryin mild-to-moderate COVID-19. Advanced Science, 8(17), 2101222.

[3] Zheng, M.,Schultz, M. B., & Sinclair, D. A. (2022). NAD+ in COVID-19 and ViralInfections. Trends in Immunology.

[4] Jiang, Y., Deng, Y., Pang, H., Ma, T.,Ye, Q., Chen, Q., … & Xu, Z. (2022). Treatment of SARS-CoV-2-inducedpneumonia with NAD+ and NMN in two mouse models. CellDiscovery, 8(1), 1-17.