NAD+ Metabolism in Cardiac Health, Aging, and Disease

NAD+ metabolism plays a crucial role in maintaining overall health, particularly cardiovascular health and the aging process. NAD+ is an essential molecule for numerous biochemical reactions, helping to provide energy to cells and protect them from oxidative stress damage. Recent research has shown that NAD+ depletion is associated with conditions such as cardiovascular diseases, aging, and various other disorders, highlighting the potential role of boosting NAD+ in disease treatment and prevention.

1. NAD+ Metabolism in the Heart and Circulation

In the heart, NAD+ is predominantly concentrated in the mitochondria, where most of the cellular redox reactions occur. However, NAD+ is also present in the cytoplasm and nucleus, where NAD+-derived metabolites and NAD+-dependent enzymes are involved in various cellular functions.

NAD+ Synthesis

Most organs, including the heart, cannot synthesize NAD+ de novo. Instead, cardiac cells produce active NAD+ from available substrates such as nicotinamide. Nicotinamide present in the cells is the end product of NAD+ degradation and serves as a substrate for NAD+ production through the enzyme NAMPT.

However, the recycling of NAD+ within the cells is not limitless, as nicotinamide is also frequently metabolized and excreted through urine. Therefore, dietary supplementation of NAD+ precursors is necessary to maintain NAD+ balance in the body.

Transport and Supply of NAD+

NAD+ cannot cross the cell membrane on its own due to its size and charge. Consequently, cells need to import NAD+ precursors to synthesize NAD+ internally. Among these, nicotinamide and nicotinic acid are the smallest molecules that can easily pass through the cell membrane. Nicotinamide riboside (NR) is transported into cells via nucleoside transport proteins. Nicotinamide mononucleotide (NMN) must also be metabolized before it can enter the cells.

NAD+ Consumption

The levels of NAD+ within the cells depend not only on its synthesis but also on its consumption rate. Enzymes such as sirtuins and PARPs utilize NAD+ in their reactions. Under stress conditions, these enzymes can consume large amounts of NAD+, affecting the levels of NAD+ in the cells.

In summary, NAD+ plays a crucial role in maintaining normal cardiac function and other cellular activities. Understanding the processes of NAD+ synthesis, transport, and consumption provides opportunities for developing new treatments for cardiovascular-related diseases.

2. NAD+ and Cardiovascular Risk Factors

Epidemiological and preclinical studies indicate that age and obesity are significant factors affecting health, including cardiovascular health.

NAD+ Dysregulation in Aging

Intracellular NAD+ levels gradually decline with age in various tissues and species, including humans. Specifically, in the heart, the reduction in NAD+ varies markedly across studies, with declines ranging from 0% to 65% in two-year-old mice. Stable NAD+ concentrations may decrease due to impaired NAD+ synthesis, increased activity of NAD+-degrading enzymes, or both. The reduction in NAD+ production may be linked to decreased expression of NAMPT, although this has not been clearly established in the heart.

Some evidence suggests that CD38 is a primary contributor to age-related NAD+ decline in mammals. Aged mice lacking CD38 exhibit increased NAD+ in multiple tissues. Similarly, a specific CD38 inhibitor can reverse age-related NAD+ depletion and improve various health aspects, including cardiac function in older mice. Interestingly, CD38 inhibition increases NAD+ through an NMN-dependent mechanism, indicating that, in addition to NAD+, NMN also serves as an alternative substrate for CD38. Since CD38 is primarily expressed in immune cells, its impact on NAD+ decline may vary depending on the abundance of immune cells in the tissue.

NAD+ Dysregulation in Obesity

Similar to other cell types, the energy status of cardiac cells is reflected in the NAD+/NADH ratio, and failure to maintain NAD+ levels can lead to metabolic imbalance, energy deficiency, and functional decline. Metabolic changes that occur during obesity can reduce NAD+ due to the accompanying chronic inflammatory state. This inflammation may decrease NAMPT expression, thereby reducing the activity of NAD+ recycling pathways in various tissues and organs, possibly including the heart. Mice lacking NAMPT in adipose tissue show severe adipose inflammation and insulin resistance, which can be improved with NMN. NMN administration stimulates NAD+ synthesis and can restore glucose control in obese mice.

NAD+ Dysregulation in Hypertension

Given that hypertension is closely linked to aging and obesity, both associated with NAD+ deficiency, NAD+ metabolism has emerged as a potential therapeutic target for hypertension. NAMPT expression has been found to be reduced in both clinical and experimental hypertension. Conversely, enhancing NAMPT expression protects mice from angiotensin II-induced hypertension. Increasing NAD+ synthesis through nicotinamide supplementation reduces systolic blood pressure in both mice and salt-sensitive rats. Although the exact mechanism of the antihypertensive effect is not yet clear, a reduction in inflammation may play an important role.

Overall, NAD+ regeneration strategies hold great potential for combating aging, improving cardiovascular health, and may be beneficial for patients with hypertension.

3. Targeting NAD+ Metabolism in Experimental Models of Cardiovascular Disease

Research on the role of NAD+ in experimental models of cardiovascular disease has demonstrated the therapeutic potential of supplementing NAD+ precursors. Below is a summary of the key findings:

Ischemic Heart Disease and Myocardial Infarction:

Studies in mice have shown that supplementation with nicotinamide riboside (NR), a precursor of NAD+, before or after myocardial infarction helps reduce infarct size, improve systolic function, and restore cardiac function. This may be attributed to NR increasing the activity of the enzyme SIRT3, which helps protect cells against oxidative damage.

Post-Infarction Heart Failure:

In a mouse model of myocardial infarction, supplementation with NR or nicotinamide mononucleotide (NMN), another derivative of NAD+, reduces infarct size, improves systolic function, and limits post-infarction fibrosis. This could be related to NAD+ enhancing the activity of SIRT1 and SIRT3, which help control inflammation and oxidative stress.

Hypertrophic Cardiomyopathy:

In a mouse model of hypertrophic cardiomyopathy induced by hypertension, NR supplementation reduces cardiac hypertrophy, improves systolic function, and limits fibrosis in the heart muscle. This effect may be due to NR increasing the activity of SIRT3, which helps regulate oxidative stress and inflammation.

Arrhythmias:

In a mouse model of arrhythmia, NMN supplementation decreases the formation of infarcts and fibrosis in the heart muscle, as well as reduces the risk of life-threatening arrhythmias. This may be linked to NMN enhancing the activity of SIRT1 and SIRT3, which help regulate inflammation and oxidative processes.

Dilated Cardiomyopathy:

In a mouse model of dilated cardiomyopathy, NR supplementation improves systolic function, reduces chamber dilation, and limits fibrosis in the heart muscle. This effect may be related to NR increasing the activity of SIRT3, which helps control oxidative stress and inflammation.

In summary, animal studies suggest that supplementing NAD+ precursors such as NR and NMN has protective effects on the heart against various injuries, including ischemia, infarction, hypertrophy, arrhythmias, and heart failure. This is primarily due to these precursors increasing cellular NAD+ levels, which in turn activates key enzymes like SIRT1 and SIRT3, helping to regulate inflammatory and oxidative processes while protecting cardiac function.

4. NAD+ Supplementation in Humans

Researchers are focusing on investigating the effects of supplementing NAD+ or its precursors, such as NR, NMN, and nicotinamide, to extend lifespan and prevent or slow the aging process, as well as age-related diseases.

Clinical trials assessing NAD+ enhancement strategies beyond niacin primarily concentrate on NR. Although these trials often involve only a small number of subjects, they have demonstrated that NR supplementation is safe and does not cause any significant harmful side effects, while increasing NAD+ levels in the whole blood.

In fact, oral administration of NR for 5 to 9 days (with a dose escalation up to 1 g twice daily from day 3) resulted in increased NAD+ levels, improved mitochondrial respiration, and reduced the expression of pro-inflammatory cytokine genes in the peripheral blood mononuclear cells of hospitalized patients with advanced heart failure and reduced ejection fraction.

Nicotinamide is another safe NAD+ precursor that, unlike NA/niacin, does not cause flushing. Indeed, nicotinamide is well tolerated at relatively high doses over extended periods of several months or even years. For example, oral supplementation of nicotinamide for 12 months (1 g per day) is safe and effective for preventing non-melanoma skin cancer. In another large-scale trial, nicotinamide was safely administered for 5 years at a dose of 1.2 g/m² per day (up to a maximum of 3 g per day) to individuals at risk of developing type 1 diabetes, although no clinical efficacy was observed. Importantly, administering nicotinamide (1 or 3 g per day for 3 days) to patients undergoing cardiac surgery reduced troponin T levels, a marker of cardiac injury. Furthermore, observational studies indicate that diets rich in nicotinamide (and NA) are associated with lower blood pressure and reduced risk of cardiovascular mortality in humans.

However, it is important to note that most clinical studies on NAD+ and its precursors are small in scale and short in duration. Larger and longer-term studies will be necessary to fully evaluate the effects, appropriate dosages, and safety of NAD+ or its precursors in humans.

Additionally, further research is needed to explore the mechanisms of action and biological pathways through which NAD+ and its precursors exert their effects to better understand their potential for anti-aging and therapeutic benefits. Developing methods for measuring NAD+ levels in various tissues and cells is also crucial for monitoring and adjusting appropriate supplementation dosages.

In summary, supplementation with NAD+ or its precursors is considered a promising approach to combat aging and age-related diseases. While current clinical studies are limited, initial results are encouraging. More clinical research will be needed to fully assess the effects, dosages, and safety of NAD+ or its active precursors in humans.

In summary, NAD+ metabolism is not only a key factor in maintaining cardiovascular function but also plays an important role in slowing the aging process and preventing related diseases. Continued research on NAD+ and methods to enhance NAD+ levels in the body could open up new prospects for the treatment of chronic diseases and improve quality of life. Understanding the mechanisms of NAD+ metabolism will help us develop more effective prevention and treatment strategies in the future.

Source: ahajournals.org