How does NAD metabolism affect aging and longevity?

Highlights

• NAD levels decrease with age due to an imbalance between synthesis and degradation processes.
• Reduced NAD metabolism is linked to various physiological aging processes.
• NAD precursors protect against many aging-related diseases.
• Enhancing NAD metabolism may extend the lifespan of multiple species.

Summary

Nicotinamide adenine dinucleotide (NAD) is a crucial cofactor involved in numerous physiological processes, including metabolism, post-translational protein modifications, and DNA repair. In living organisms, a careful balance between NAD production and degradation regulates NAD levels. Recent studies have shown that NAD levels decline with age, and the deterioration of NAD metabolism promotes many age-related diseases, including metabolic disorders, neurodegenerative diseases, and various cancers. Conversely, boosting NAD metabolism, including dietary supplementation with NAD precursors, has been shown to prevent NAD decline and offer beneficial effects on aging and aging-related diseases. Moreover, several studies have demonstrated that activating NAD metabolism through genetic and/or nutritional factors can extend the lifespan of various species. Overall, it is evident that NAD metabolism plays a vital role in aging and longevity. In this review, we summarize the fundamental functions of the enzymes involved in NAD synthesis and degradation, as well as the consequences of their dysregulation during different stages of aging. Additionally, the article focuses on the role of NAD metabolism in extending the lifespan of various species, along with a discussion of the remaining challenges in this field of research.

Introduction

Nicotinamide adenine dinucleotide (NAD) is an essential cofactor involved in various biological processes, including metabolism, DNA repair, and gene expression (Canto et al., 2015; Magni et al., 2004). NAD was first discovered in 1906 as a co-enzyme involved in yeast fermentation (Harden and Young, 1906) and has been considered a classical metabolite. However, recent studies have highlighted the numerous roles of NAD metabolism in aging and longevity. It has been shown that NAD levels decline with age due to an imbalance between NAD synthesis and consumption. This decline in NAD levels is associated with many aging-related diseases, including metabolic disorders, cancer, and neurodegenerative diseases. Consequently, supplementing with NAD precursors through diet has been shown to restore NAD levels in aging tissues and offer beneficial effects on aging and aging-related diseases (Fang et al., 2017; Katsyuba and Auwerx, 2017; Rajman et al., 2018; Yoshino et al., 2017). Most notably, enhancing NAD metabolism has been demonstrated to extend the lifespan of various organisms, such as yeast, worms, flies, and rodents.

As a co-enzyme, NAD participates in numerous enzymatic reactions. Specifically, NAD plays a central role in regulating energy metabolism pathways, including glycolysis, fatty acid oxidation (β-oxidation), the tricarboxylic acid (TCA) cycle, and oxidative phosphorylation (Canto et al., 2015). The redox interaction between the oxidized form (NAD+) and the reduced form (NADH) regulates the enzymatic reactions of NAD-dependent enzymes in these pathways (Anderson et al., 2017; Magni et al., 2004). On the other hand, NAD is consumed in protein deacetylation and ADP-ribosylation processes by sirtuins and poly (ADP-ribose) polymerase (PARP) (Canto et al., 2015; Magni et al., 2004). NAD glycohydrolases, CD38 and CD157 (BST1), also consume NAD by converting it into ADP-ribose (ADPR) or cyclic-ADPR (Quarona et al., 2013). Based on these findings, NAD metabolism is believed to regulate various aging processes through these critical pathways (Figure 1). In mammals, NAD is synthesized via three pathways: 1) from tryptophan (Trp) in the de novo pathway, 2) from nicotinic acid (NA) in the Preiss-Handler pathway, and 3) from nicotinamide (NAM) in the salvage pathway. Additionally, nicotinamide riboside (NR) can also be used to generate NAD (Bieganowski and Brenner, 2004).

A growing body of evidence has demonstrated that NAD is a key molecule in regulating aging across different species. Recent studies have shown that intermediates of NAD metabolism, as well as NAD-related metabolites, possess unique biological functions in regulating aging and longevity. Moreover, new technologies such as metabolomics and genetically modified mice have advanced the understanding of NAD metabolic pathways. In this review, we will provide a comprehensive summary of current studies on NAD-synthesizing and NAD-consuming enzymes and their roles in aging. Additionally, we will focus on the role of NAD metabolism in regulating lifespan, along with a discussion of the remaining challenges in this field for future human applications.

1. NAD levels decrease with aging

Nicotinamide adenine dinucleotide (NAD) is a crucial coenzyme present in every living cell. It plays an essential role in numerous biological processes, including energy metabolism, DNA repair, and circadian rhythm regulation. However, one of the key findings in aging research is that NAD levels significantly decline with age.

As we age, the NAD levels in our bodies gradually decrease. Studies show that in a 50-year-old adult, NAD levels are roughly half of those in a 20-year-old. By the age of 80, NAD levels may drop to just 1-10% of youthful levels. This decline impacts many important physiological functions and is considered one of the primary causes of aging signs.

Several factors contribute to the age-related decline in NAD:

• Decreased production: The activity of enzymes involved in NAD synthesis, such as NAMPT, decreases with age, reducing the body’s ability to produce new NAD.
• Increased consumption: As we age, the body faces more oxidative stress and DNA damage. This activates enzymes like PARP and sirtuins, which consume more NAD to repair damage.
• Chronic inflammation: Mild, systemic inflammation in old age increases the activity of the enzyme CD38, which breaks down NAD.
• Metabolic imbalances: Energy metabolism disruptions in the elderly further contribute to reduced NAD reserves.

The decline in NAD affects many vital bodily functions:

• Reduced energy production: NAD is an essential coenzyme in cellular respiration and glycolysis. As NAD levels decrease, the cell’s ability to produce ATP diminishes.
• Weakened DNA repair: NAD is a substrate for the enzyme PARP, which is involved in DNA repair. A lack of NAD impairs the body’s ability to repair DNA damage.
• Circadian rhythm disruption: NAD plays a role in regulating the activity of clock genes. A decline in NAD contributes to circadian rhythm disorders in the elderly.
• Decreased sirtuin activity: Sirtuin proteins are crucial for cellular protection and anti-aging mechanisms. They require NAD to function effectively.

Understanding the role of NAD and its decline with age is a fundamental basis for developing interventions aimed at slowing the aging process and promoting healthy longevity.

2. NAD Metabolism and Organ Aging

NAD metabolism plays a crucial role in the aging process of various organs in the body. The decline in NAD levels with age affects the function of multiple organs, contributing to the onset of age-related diseases.

• Brain: NAD is essential for neuronal function and neuroprotection. The reduction of NAD in the aging brain decreases the energy production capacity of neurons, impacting memory and cognition. Additionally, NAD deficiency weakens the brain’s ability to protect neurons from oxidative stress and other damage. Research shows that NAD supplementation can improve cognitive function and protect neurons in models of Alzheimer’s disease.

• Cardiovascular System: NAD is vital for heart health, as it plays a role in energy production for cardiac muscle and regulates endothelial function in blood vessels. A decrease in NAD weakens the heart’s contraction ability and disrupts endothelial function, increasing the risk of cardiovascular diseases. Animal studies suggest that NAD precursors can improve heart function and reduce atherosclerosis.

• Skeletal Muscle: The decline in NAD contributes to the aging of the musculoskeletal system. NAD is necessary for muscle protein synthesis and the maintenance of muscle mass. With age, NAD deficiency reduces the muscle’s ability to regenerate and recover, leading to sarcopenia (the loss of muscle mass and strength in the elderly). NAD supplementation has been shown to improve muscle strength and mobility in aged mice.

• Liver: The liver plays a central role in metabolism and detoxification, and NAD is essential for liver function, participating in fatty acid oxidation and detoxification processes. The decline of NAD in the aging liver reduces lipid metabolism, leading to fat accumulation and increasing the risk of cirrhosis. Studies indicate that NAD supplementation can improve liver function and reduce fat accumulation in obese mice.

• Kidneys: NAD is necessary for normal kidney function. It is involved in energy production for renal tubular cells and protects the kidneys from ischemic injury. Age-related NAD decline increases the risk of chronic kidney disease. Animal studies have shown that NAD precursors can protect the kidneys from ischemic damage and improve kidney function in aged mice.

• Skin: NAD plays a key role in maintaining the structure and function of the skin. It is involved in the synthesis of collagen and elastin, two proteins essential for skin elasticity and firmness. The age-related decline in NAD contributes to skin aging, including the appearance of wrinkles and reduced elasticity. Research shows that NAD supplementation can improve skin structure and increase resistance to UV damage.

Understanding the relationship between NAD metabolism and organ aging opens the door to developing treatments aimed at slowing the aging process and preventing age-related diseases. Maintaining stable NAD levels may be a critical strategy for “anti-aging the body” and improving overall health as we grow older.

3. NAD Metabolism and Longevity

The relationship between NAD and longevity has been extensively studied in recent years. A growing body of scientific evidence suggests that maintaining stable NAD levels can contribute to extending lifespan and improving the quality of life in old age.

NAD is involved in many biological pathways related to the regulation of lifespan:

• Sirtuins: NAD is a necessary substrate for the activity of sirtuin proteins, particularly SIRT1 and SIRT3. These proteins play crucial roles in cell protection, DNA repair, and metabolism regulation. Sirtuin activity declines with age due to the decrease in NAD, contributing to the aging process.
• mTOR: NAD helps regulate the activity of mTOR (mechanistic target of rapamycin), a central protein kinase in the regulation of cell growth and metabolism. Inhibiting mTOR is believed to be beneficial for longevity, and NAD may contribute to this process.
• AMPK: NAD activates AMPK (AMP-activated protein kinase), a key energy sensor in cells. AMPK activation is linked to increased lifespan by improving metabolism and enhancing stress resistance.

Numerous animal studies have demonstrated the connection between NAD and longevity:

• Research on the roundworm C. elegans shows that boosting NAD synthesis can extend lifespan by up to 10%.
• In mice, supplementation with NAD precursors such as NMN (nicotinamide mononucleotide) or NR (nicotinamide riboside) has been shown to extend lifespan and improve health in old age.
• Studies on fruit flies indicate that enhancing the activity of NAMPT, a key enzyme in NAD synthesis, can prolong lifespan.

NAD extends lifespan through various mechanisms:

• Improved mitochondrial function: NAD is essential for efficient energy production in mitochondria. Maintaining stable NAD levels helps improve mitochondrial function, boost ATP production, and reduce oxidative stress.
• Enhanced DNA repair: NAD is a substrate for the PARP enzyme involved in DNA repair. Maintaining sufficient NAD levels enhances the ability to repair DNA damage, reducing the accumulation of mutations with age.
• Gene expression regulation: Through its interaction with sirtuins, NAD regulates the expression of many genes related to aging and longevity.
• Metabolic improvement: NAD helps maintain metabolic balance, improve insulin sensitivity, and enhance fatty acid oxidation, which are critical for overall health and longevity.
• Reduced chronic inflammation: NAD has anti-inflammatory effects by inhibiting NF-κB and other inflammatory pathways. Reducing chronic inflammation is an important factor in promoting healthy aging.

Based on the understanding of NAD’s role in aging and longevity, several strategies have been proposed to boost NAD levels and potentially extend lifespan:

• NAD precursor supplementation: NMN and NR are the most studied NAD precursors. They can be metabolized into NAD in the body and have shown promising results in preclinical studies.
• Inhibition of NAD-degrading enzymes: Inhibitors of CD38 and PARP are being explored as a way to reduce NAD degradation and maintain stable NAD levels.
• Enhancing NAMPT activity: Research is ongoing to find ways to boost the activity of NAMPT, a key enzyme in the NAD recycling pathway.
• Lifestyle modifications: Diets rich in NAD precursors (such as salmon, mushrooms, and soybeans), regular exercise, and caloric restriction have been shown to enhance NAD levels.

However, it is important to note that most research on NAD and longevity is still in the preclinical stage. More clinical studies in humans are needed to determine the efficacy and safety of NAD-boosting strategies for extending human lifespan.

The relationship between NAD and longevity is a promising area of research in anti-aging medicine. Understanding NAD’s role in biological processes related to aging opens the door to developing new interventions aimed at promoting healthy longevity. However, caution and further research are needed to ensure the safety and effectiveness of these methods in humans. Maintaining stable NAD levels through a healthy lifestyle, possibly combined with reasonable supplementation, may be a key strategy to “anti-age” the body and optimize health as we grow older.

Tài liệu tham khảo: Science.org, Link.springer.com, Onlinelibrary.wiley.com, Pmc.ncbi.nlm.nih.gov, Sciencedirect.com