Effects Of Long - Term Supplementation Of NMN On Heart Function in Old Mice And Its Mechanism.

Although human life expectancy continues to increase, many aging-related diseases still inevitably affect the quality of life of the elderly. Among them, cardiovascular disease is still the main cause of death in the elderly. Age-related decline in cardiac function places a huge burden on the elderly population, and the development of therapeutics that can improve cardiac health in the elderly remains a top priority for maintaining human health.

Cardiomyocytes have high-density mitochondria, and the electron transport chain (ETC) on the inner membrane of mitochondria couples oxidative phosphorylation to produce Adenosine Triphosphate (ATP) for the contraction function of cardiomyocytes. Nicotinamide adenine dinucleotide (NAD+), the cofactor of complex I substrate catabolism on the ETC chain, is also the coenzyme of many dehydrogenases in the body. However, NAD+ availability in tissues may be limited during stress and natural aging. Therefore, rescuing mitochondrial NAD+ levels in cells may be an effective therapeutic approach to improve aging-associated heart diseases in humans.

Nicotinamide Mononucleotide (nicotinamide mononucleotide, NMN) is an important precursor of NAD+ in mammals, and its function is mainly reflected by NAD+. Cauliflower, beef and other foods are rich in NMN, and NMN can also be converted into NAD+ spontaneously in the body. Supplementing with NMN is an effective way to increase NAD+ levels in the body. Previous studies have confirmed that short-term administration of NMN has a significant therapeutic effect on obesity complications. Furthermore, NMN protects the heart from ischemia-reperfusion injury by preventing ischemia-induced NAD+ reduction. The latest research by the Chinese research team recently focused on evaluating the changes in cardiac function and exploring the underlying mechanism by constructing an aged mouse model and adding NMN to drinking water for 12 months, in order to use NMN as a solution to age-related heart disease. Drug candidates for functional defects.

1.Long-term supplementation of NMN improves aging-related phenotypes of mice: From 4 months old, add NMN [300mg/(kg d)] to drinking water to feed mice until 16 months old (A, B in Figure 1). Compared with the mice in the old group fed with conventional feeding, the growth rate of body weight of the mice in the experimental group was slowed down, and the body weight was lighter at the age of 16 months (P < 0. 01, P < 0. 01, C ~ E in Figure 1); OGTT suggested that compared with the 4-month-old young group mice, the glucose tolerance of the mice in the aged group decreased, while the glucose tolerance of the mice in the aged group added with NMN
Tolerance improved (P < 0. 05, P < 0. 01, F, G in Figure 1). These results suggest that long-term use of NMN can improve obesity and impaired glucose tolerance in aging mice.

A. Schematic diagram of mouse model construction; B. Schematic diagram of mouse feeding in experimental group; C. Schematic diagram of typical morphology of mice; D. Curve of mouse body weight gain; E. Curve of mouse body weight over time;
F. Oral glucose tolerance test; G. Area under the curve of blood glucose over time;∗ P < 0.01,∗∗ P < 0.001

2.Long-term supplementation of NMN increased the NAD+ level in the hearts of aged mice and improved heart function: the heart NAD+ content of the mice in each group was detected, and it was found that compared with the 4-month-old mice, the heart NAD+ content of the 16-month-old mice was significantly lower, while NMN could To some extent, the NAD+ level in the hearts of aged mice was restored (P < 0.001, P < 0.01, Figure 2A). In addition, echocardiography found that compared with young mice, the E/A ratio, LVEF, and LVFS of aged mice were all decreased (P values were < 0.001, < 0.001, < 0.01, respectively, B ~ E in Figure 2) , and NMN treatment can significantly improve the above indicators. The above results indicated that long-term supplementation of NMN increased cardiac NAD+ in aged mice and at the same time alleviated the decline of cardiac systolic and diastolic function during aging.

A. Cardiac NAD+ level; B. Representative echocardiography; C. Ratio of ventricular early diastolic to late diastolic blood flow velocity; D. Left ventricular ejection fraction; E. Left ventricular short-axis shortening;∗ P < 0.01,∗∗ P < 0.001

3.NMN relieves oxidative stress in aged hearts and restores mitochondrial quality: Compared with young mice, the content of MDA in the myocardium of aged mice was significantly increased (P < 0.01), the activity of SOD decreased (P < 0.001), and the level of carbonylated protein increased (P < 0. 01), while the above indicators were improved in aged mice supplemented with NMN (P values were < 0. 05, < 0. 01, < 0. 05, respectively, A ~ D in Figure 3). Detection of myocardial ATP content and mtDNA copy number found that myocardial ATP production and mtDNA number in aged mice were both reduced (P < 0. 001, P < 0. 001, E, F in Figure 3), indicating that the mitochondrial quality of aged mice was affected. However, the myocardial ATP content and mtDNA of the mice in the experimental group recovered to a certain extent. These results suggest that NMN can attenuate oxidative stress and mitochondrial damage in mouse hearts during aging.

During aging, NAD+ levels decrease with age, and NMN, as a key intermediate for intracellular NAD+ synthesis, has attracted the attention of relevant researchers. Studies have reported that short-term administration of NMN can alleviate obesity-related metabolic disorders induced by high-fat diet in mice. Studies have also found that NMN has a protective effect on the cognitive and memory functions of both glucose-reperfused rats after hypoglycemia and sleep-deprived mice. Not only that, NMN can also improve cardiac function in mice undergoing ischemia-reperfusion injury and aortic coarctation. However, for different disease models, the usage and dosage of NMN are different. In this study, referring to other studies, NMN [300mg / (kg d) ] was added to the drinking water for 12 months, and it was confirmed that long-term administration of NMN can alleviate the metabolic-related physiological decline caused by aging mice, such as increased body weight and glucose tolerance damaged. And it was found that this usage and dosage were tolerable to mice, and no obvious adverse reactions were observed. In view of the decline of central function in the aging process and its importance to the longevity and quality of life of the elderly population, this study considers that long-term administration of NMN can be used as an NAD+ supplement for anti-aging intervention, especially for the heart.

DataType: 1
Title: Effects and mechanisms of long-term NMN supplementation on cardiac function in aged mice
Author-Author: Guo Ruiqing; Cai Ling; Zhang Zilong; Zhang Xiaopeng;
Source-Title: Journal of Medical Research
Year: 2023
PubTime - Publication time: 2023-01-15
Keyword-Keywords: aging; nicotinamide mononucleotide; cardiac function; mitochondria

Tag: NMN

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