we covered the subjective experiences of NMN users and its effects in animal experiments. Today, we will focus on the relationship between NMN and age-related diseases that people care about most.
1. NMN and Diabetes
Diabetes has become a major epidemic caused by modern lifestyles, with over 90% of patients suffering from Type 2 diabetes.
The exact cause of Type 2 diabetes remains unclear, but it is influenced by genetics, obesity, age, high-calorie diets, and other factors—though "obesity" is often blamed by default. Regardless of its cause, Type 2 diabetes is characterized by a combination of insulin resistance (mainly manifested as hyperinsulinemia and reduced glucose utilization) and insufficient insulin secretion. NMN improves diabetes primarily by addressing two key issues: alleviating impaired glucose tolerance and enhancing insulin sensitivity.
In patients with Type 2 diabetes, NAMPT-mediated NAD+ biosynthesis in metabolic organs is severely impaired. As we mentioned in the "mechanism section," NAD+ is essential for various biological processes such as human metabolism, stress response, and cell differentiation. Supplementing with NMN restores NAD+ levels in the body, thereby alleviating impaired glucose tolerance. Additionally, NAD+ is an activator of Sirt1; increased NAD+ levels activate Sirt1, which enhances insulin sensitivity, stimulates insulin secretion, and restores the expression of fatty acid β-oxidation genes—compensating for insufficient insulin secretion in diabetic patients.
2. NMN and Cardiovascular Diseases
Current research has focused heavily on NMN’s cardioprotective effects after surgery: Myocardial ischemia-reperfusion (I/R) injury is a potentially fatal post-surgical complication. It commonly occurs after open-heart surgery, coronary artery bypass grafting (CABG), percutaneous transluminal coronary angioplasty (PTCA), and thrombolytic therapy. When a coronary artery is acutely occluded and then reopens, ischemic myocardial tissue regains normal perfusion—but the damaging changes caused by ischemia worsen after reperfusion. This can lead to severe arrhythmia, heart failure, and sudden death, posing a life threat even after surgery. However, injecting NMN (500 mg/kg) within 30 minutes before surgery can effectively reduce the occurrence of this injury.
After entering the body, NMN mimics the process of endogenous ischemic preconditioning (IPC), thereby reducing the size of myocardial infarction following ischemia/reperfusion. Ischemic preconditioning is a powerful endogenous mechanism that activates Sirt1 and induces deacetylation of lysine residues in proteins (including p53). This protects the myocardium from damage caused by transient ischemia/reperfusion and reduces oxidative stress.
In addition, some studies suggest NMN can improve heart failure. Mitochondrial dysfunction in the heart leads to an increased NADH/NAD+ ratio (i.e., redox imbalance) and high protein acetylation—phenomena also observed in failing human hearts and mouse hearts with pathological hypertrophy. By stimulating the NAD+ salvage pathway to increase NAD+ levels, NMN normalizes redox balance, inhibits excessive acetylation of mitochondrial proteins and cardiac hypertrophy, and improves cardiac function during stress responses.
3. NMN and Alzheimer’s Disease
Alzheimer’s disease (AD) is an incurable, progressive, and fatal neurodegenerative disease. It causes massive death of nerve cells, significant atrophy and weight loss of brain tissue, and impairs memory and cognitive abilities. It is arguably the most feared age-related disease—with subtle onset symptoms, unclear pathogenesis, and poor drug efficacy—affecting countless people unknowingly.
The key pathological features of Alzheimer’s disease include:
- Deposition of neurotoxic β-amyloid (Aβ) in brain tissue and microvessels, leading to cell death;
- Hyperphosphorylation of tau protein, resulting in neurofibrillary tangles.
Even in its early research stages, NMN has shown promising results in addressing Alzheimer’s disease. The most direct evidence is that NMN restores memory, enhances learning ability, and improves cognitive function in AD model mice—and these effects were observed after just 10/28 days of administration.
Figure Note: Morris water maze test—The NMN group showed shorter escape latency than the non-NMN group. (Legend: Sham+saline; Aβ1-42+saline; Aβ1-42+NMN)
The specific mechanisms by which NMN improves Alzheimer’s disease are as follows:
1. Reducing β-amyloid (Aβ) production and deposition
After administering NMN to mice for 10 days, the levels of pro-inflammatory cytokines (IL-6, IL-1β, and TNFα) in the mice decreased significantly—proving NMN effectively suppresses neuroinflammation in the mouse brain. These reduced pro-inflammatory cytokines then inhibit Aβ production in the body.
Figure Note: NMN significantly reduced Aβ plaque formation in brain tissue. (Groups: Vehicle; NMN)
2. Reducing neuronal death and improving neurological function
NMN restores NAD+ and ATP levels, thereby reducing oxidative stress-induced neuronal death—specifically by eliminating reactive oxygen species (ROS) accumulation in the hippocampus of AD mice. Additionally, NAMPT-mediated NAD+ biosynthesis is the main source of NAD+ in excitatory neurons, which is crucial for neuronal survival and normal function. Increased NAD+ levels protect neurons through multiple mechanisms, including preventing mitochondrial damage, avoiding ATP depletion and glycolysis inhibition[9], and enhancing DNA repair[10].
Figure Note: Neuronal death rate was lower in the Aβ1-42 + NMN group (bottom left) than in the Aβ1-42 group (top right) [5]. (Groups: Control; Aβ1-42; Aβ1-42 + NMN; Aβ1-42 + NMN + 3AP)
The above covers NMN’s effects and mechanisms in improving age-related diseases. Beyond middle-aged and elderly populations, NMN is also particularly important for specific groups, such as:
- Athletes: Intense exercise requires large amounts of NAD+ to produce ATP;
- Aviation personnel: High-altitude radiation causes DNA damage, increasing cancer risk;
- High-altitude workers: To combat altitude sickness;
- Doctors and nurses: Night shifts easily lead to accumulated DNA damage.
While the above results are from animal models, human clinical trials of NMN are also progressing steadily. There are currently 4 ongoing clinical trials, with the earliest starting in 2016. One trial in the United States focuses on NMN’s effects on cardiovascular and metabolic functions, while three trials in Japan investigate NMN’s impact on human health—all have completed Phase I clinical trials.
On February 19 this year, Japan’s Shinkowa Pharmaceutical Co., Ltd. released the first interim report of its NMN clinical trial. Although no specific data was disclosed, the results showed that NMN has positive effects on human health, including upregulating Sirt1 protein and potentially aiding cancer treatment.
Perhaps in the near future, we will see the official results of these human clinical trials. We look forward to more surprises from NMN. 😘😘
References (Swipe Up to View)
[1] Yoshino, J., Mills, K.F., Yoon, M.J., and Imai, S. (2011). Nicotinamide mononucleotide, a key NAD(+) intermediate, treats the pathophysiology of diet- and age-induced diabetes in mice. Cell Metab. 14, 528–536.
[2] Sanada S, Komuro I, Kitakaze M (2011). Pathophysiology of myocardial reperfusion injury: preconditioning, postconditioning, and translational aspects of protective measures. Am J Physiol Heart Circ Physiol 301: H1723–1741.
[3] Yamamoto, T., Byun, J., Zhai, P., Ikeda, Y., Oka, S., and Sadoshima, J. (2014). Nicotinamide mononucleotide, an intermediate of NAD+ synthesis, protects the heart from ischemia and reperfusion. PLoS One 9, e98972.
[4] Stromsdorfer, K.L., Yamaguchi, S., Yoon, M.J., Moseley, A.C., Franczyk, M.P., Kelly, S.C., Qi, N., Imai, S., and Yoshino, J. (2016). NAMPT-mediated NAD(+) biosynthesis in adipocytes regulates adipose tissue function and multi-organ insulin sensitivity in mice. Cell Rep. 16, 1851–1860.
[5] Wang, X., Hu, X., Yang, Y., Takata, T., and Sakurai, T. (2016). Nicotinamide mononucleotide protects against beta-amyloid oligomer-induced cognitive impairment and neuronal death. Brain Res. 1643, 1–9.
[6] Yao, Z., Yang, W., Gao, Z., and Jia, P. (2017). Nicotinamide mononucleotide inhibits JNK activation to reverse Alzheimer disease. Neurosci. Lett. 647, 133–140.
[7] Long, A.N., Owens, K., Schlappal, A.E., Kristian, T., Fishman, P.S., and Schuh, R.A. (2015). Effect of nicotinamide mononucleotide on brain mitochondrial respiratory deficits in an Alzheimer’s disease-relevant murine model. BMC Neurol. 15, 19.
[8] Alano, C.C., Garnier, P., Ying, W., Higashi, Y., Kauppinen, T.M., Swanson, R.A. (2010). NAD+ depletion is necessary and sufficient for poly(ADP-ribose) polymerase-1-mediated neuronal death. J. Neurosci. 30: 2967–2978.
[9] Ying, W., Garnier, P., Swanson, R.A. (2003). NAD+ repletion prevents PARP-1-induced glycolytic blockade and cell death in cultured mouse astrocytes. Biochem. Biophys. Res. Commun. 308: 809–813.
[10] Wang, S., Xing, Z., Vosler, P.S., Yin, H., Li, W., Zhang, F., Signore, A.P., Stetler, R.A., Gao, Y., Chen, J. (2008). Cellular NAD replenishment confers marked neuroprotection against ischemic cell death: role of enhanced DNA repair. Stroke 39: 2587–2595.
[2] Sanada S, Komuro I, Kitakaze M (2011). Pathophysiology of myocardial reperfusion injury: preconditioning, postconditioning, and translational aspects of protective measures. Am J Physiol Heart Circ Physiol 301: H1723–1741.
[3] Yamamoto, T., Byun, J., Zhai, P., Ikeda, Y., Oka, S., and Sadoshima, J. (2014). Nicotinamide mononucleotide, an intermediate of NAD+ synthesis, protects the heart from ischemia and reperfusion. PLoS One 9, e98972.
[4] Stromsdorfer, K.L., Yamaguchi, S., Yoon, M.J., Moseley, A.C., Franczyk, M.P., Kelly, S.C., Qi, N., Imai, S., and Yoshino, J. (2016). NAMPT-mediated NAD(+) biosynthesis in adipocytes regulates adipose tissue function and multi-organ insulin sensitivity in mice. Cell Rep. 16, 1851–1860.
[5] Wang, X., Hu, X., Yang, Y., Takata, T., and Sakurai, T. (2016). Nicotinamide mononucleotide protects against beta-amyloid oligomer-induced cognitive impairment and neuronal death. Brain Res. 1643, 1–9.
[6] Yao, Z., Yang, W., Gao, Z., and Jia, P. (2017). Nicotinamide mononucleotide inhibits JNK activation to reverse Alzheimer disease. Neurosci. Lett. 647, 133–140.
[7] Long, A.N., Owens, K., Schlappal, A.E., Kristian, T., Fishman, P.S., and Schuh, R.A. (2015). Effect of nicotinamide mononucleotide on brain mitochondrial respiratory deficits in an Alzheimer’s disease-relevant murine model. BMC Neurol. 15, 19.
[8] Alano, C.C., Garnier, P., Ying, W., Higashi, Y., Kauppinen, T.M., Swanson, R.A. (2010). NAD+ depletion is necessary and sufficient for poly(ADP-ribose) polymerase-1-mediated neuronal death. J. Neurosci. 30: 2967–2978.
[9] Ying, W., Garnier, P., Swanson, R.A. (2003). NAD+ repletion prevents PARP-1-induced glycolytic blockade and cell death in cultured mouse astrocytes. Biochem. Biophys. Res. Commun. 308: 809–813.
[10] Wang, S., Xing, Z., Vosler, P.S., Yin, H., Li, W., Zhang, F., Signore, A.P., Stetler, R.A., Gao, Y., Chen, J. (2008). Cellular NAD replenishment confers marked neuroprotection against ischemic cell death: role of enhanced DNA repair. Stroke 39: 2587–2595.