The human body is composed of approximately 37 trillion cells, and each of these billions of cells relies on NAD+ to fulfill its physiological "responsibilities" and thereby maintain the normal operation of the organism. Without NAD+, the heart cannot pump blood through veins, the lungs cannot inhale air, and the neurons in the brain cannot generate excitatory signals. It is no exaggeration to say that without this crucial molecule, all vital organs of the human body would cease to function. NAD+ is like the fuel required for a car to operate, providing core power for the stable functioning of the complex "organism" that is the human body.
David Sinclair, Co-Director of the Center for the Biology of Aging at Harvard Medical School, stated: NAD+ is a core substance for maintaining a youthful state in the human body and one of the indispensable molecules for sustaining life activities. Without it, the human body would lose vital signs within 30 seconds.
I. What is the Nature of NAD+?
To understand the role of NAD+, it is first necessary to clarify the core concept of NAD. NAD is the abbreviation of nicotinamide adenine dinucleotide, which is a type of coenzyme. As an essential component that assists various enzymes in catalyzing redox reactions, it mainly undertakes the function of electron transfer in the human body.
Based on whether it carries electrons to be transferred, NAD can exist in two forms: NAD+ and NADH. Among them, NADH is in the reduced state, while NAD+ is in the oxidized state. These two forms are like the two sides of a coin; they have similarities yet also possess unique and irreplaceable roles. The core difference between them is that NADH carries one more positively charged hydrogen atom (H) and two negatively charged electrons than NAD+. Since these two forms can be converted into each other in the human body, NAD+ is often used to refer to the entire NAD system in daily expressions.
NAD+ also has another name - Coenzyme I, and its full name is nicotinamide adenine dinucleotide. It is widely distributed inside all cells of the human body, participates in thousands of biological catalytic reactions, and is an indispensable coenzyme in the human body. Fluctuations in NAD+ levels may directly affect the status of other key functions of the body and are closely related to the human aging process.
II. What Roles Does NAD+ Play in the Human Body?
The core role of NAD+ and NADH is to participate in the aerobic metabolism of glucose in cells, providing the energy necessary for maintaining life activities and supporting various behavioral activities of the human body. The aerobic glycolysis of cells mainly includes three links: glycolysis, tricarboxylic acid cycle, and electron transport chain.
In these three links, during the glycolysis and tricarboxylic acid cycle stages, NAD+ acts like a "transport train": after receiving electrons, it is converted into NADH, and then transports the electrons and biological hydrogen to the third link - the electron transport chain on the inner mitochondrial membrane. Immediately afterward, an electron transfer process called "oxidative phosphorylation" is initiated, which ultimately produces 3 energy molecules (ATP). ATP is not only a direct manifestation of energy but also a carrier of energy, serving as the main source and storage form of energy in the human body.
To ensure that this electron transfer "power station" can continuously supply energy to the human body and guarantee the normal operation of the electron transfer "channel" - NAD+, the human body has evolved two NAD+ synthesis pathways: the de novo synthesis pathway and the salvage synthesis pathway. The human body continuously consumes a large amount of substances and energy to synthesize sufficient NAD+ through these two pathways, ensuring that the electron transfer process is not hindered.
Regrettably, however, these two complementary synthesis pathways are ineffective in the face of aging: as the human body ages, the content of NAD+ will inevitably decrease.
On July 9, 2023, the Chini team from the medical school affiliated with Mayo Clinic published a review article titled "The Mechanism of NAD: Its Role in Cellular Senescence and Organismal Aging" in the journal Aging Cell. The article points out that in the de novo synthesis pathway, an oxidase IDO1 that should have been inhibited is abnormally activated during the aging process, thereby decomposing L-tryptophan, a key raw material required for NAD+ synthesis. In addition, since the de novo synthesis pathway is also an important mechanism for regulating the function of macrophages, the abnormal activation of IDO1 will also affect the normal function of the immune system.
At the same time, the content of NAMPT (a rate-limiting enzyme) and NMNAT (a key transferase) in the salvage synthesis pathway gradually decreases with aging, which further restricts the efficiency of NAD+ salvage synthesis. While synthesis is hindered, cells also need to consume additional NAD+ to repair damaged or disordered cellular components caused by aging. For example, the DNA repair enzyme PARP1 consumes a large amount of NAD+ to repair DNA damage that occurs with age, leading to a decrease in NAD+ levels in the body.
In addition, a large number of studies have confirmed that NAD+ also participates in thousands of biochemical reactions such as cellular metabolism, oxidation reactions, and protein transcription. Its specific roles are reflected in the following aspects:
Improve the level of cellular energy supply through the tricarboxylic acid cycle (TCA) pathway;
Activate longevity genes through the Sirtuins pathway to play a role in delaying aging;
Achieve the repair of DNA damage through the PARPs pathway;
Maintain chemical signal transmission between the nucleus and mitochondria to slow down the rate of cellular senescence;
Inhibit lipid peroxidation reactions to protect the structural integrity of mitochondria and cells;
Promote the synthesis of the neurotransmitter dopamine, stimulate muscle growth, and play a positive role in improving the symptoms of Parkinson's disease;
Promote the biosynthesis of norepinephrine and serotonin, which is helpful for alleviating depression and Alzheimer's disease;
Regulate autoimmune diseases by adjusting immune responses and restoring the normal structure of tissues.
In short, NAD+ is crucial for maintaining the overall health and physiological balance of the human body. It is involved in processes such as metabolism, redox reactions, DNA maintenance and repair, gene stability guarantee, and epigenetic regulation.
Therefore, the human body has a great demand for NAD+. NAD+ in cells continuously undergoes the processes of synthesis, decomposition, and recycling to maintain the stability of NAD+ levels in cells. However, during the aging process, the balance between the synthesis and decomposition of NAD+ is disrupted, and the consumption rate exceeds the synthesis rate, ultimately leading to a decrease in NAD+ levels in the body.
Hassina Massudi and a research team from the University of New South Wales found that a decrease in NAD+ levels is associated with age-related changes. Their research data shows that in the age group of 40-60 years old, the level of NAD+ in the human body will decrease by as much as 50%. Low levels of NAD+ can cause a variety of age-related health problems, such as muscle degradation, mental decline, increased pigmentation, and hair loss, which are collectively referred to as "aging" degenerative symptoms.
III. What Harms Does a Decrease in NAD+ Levels Bring?
The level of NAD+ in the body directly determines the rate of the aging process. Abnormal changes in NAD+ homeostasis can be observed in almost all age-related diseases, including neurodegenerative diseases, diabetes, and cancer.
The Chini team mentioned in the review "The Mechanism of NAD: Its Role in Cellular Senescence and Organismal Aging" that abnormal NAD metabolism is one of the important manifestations and risk factors of cardiovascular diseases. A decrease in NAD+ levels will affect the energy supply of the heart, thereby disrupting the normal blood-pumping function of the heart. In age-related diseases such as cancer, short telomere syndrome, and fibrosis, NAD+-related metabolic disorders are also important pathological mechanisms.
In addition, low levels of NAD+ can damage the structure of normal DNA, interfere with the process of protein synthesis, and induce mitochondrial dysfunction, accelerating the process of cellular senescence.
In 2019, the classic textbook in the field of aging biology, Biochemistry and Cell Biology of Ageing, summarized the achievements of decades of aging research and concluded that the core mechanisms of aging are two factors: oxidative free radical damage and a decrease in NAD+ levels.
A large number of studies have shown that a decrease in NAD+ levels has a causal relationship with a variety of age-related diseases, including cognitive decline, inflammatory reactions, cancer, metabolic diseases, sarcopenia, and neurodegenerative diseases. Fortunately, however, many age-related diseases can be alleviated or even reversed by restoring NAD+ levels.
IV. What Effects Does Supplementing NAD+ Have?
In February 2021, scholars such as Anthony J. Covarrubias and Rosalba Perrone from the Buck Institute for Research on Aging systematically sorted out the scientific research literature related to NAD+ and published the research results in Nature Reviews Molecular Cell Biology, a sub-journal of Nature. The researchers pointed out that as the human body ages, the level of NAD+ in the body will gradually decrease. By directly supplementing absorbable NAD+ to increase the level of NAD+ in the body, positive benefits can be brought to organs and tissues such as the brain, cardiovascular system, liver, and muscles. In this article, the authors also organized the research data related to NAD+ into visual charts.
A paper published in the journal Translational Medicine of Aging demonstrated the positive therapeutic value of increasing NAD+ levels with age. The paper clearly states: "Supplementing NAD+ can be used as a potential treatment plan to address aging and various diseases, thereby improving the quality of life of the growing elderly population."
In 2021, American researchers selected two substances that may increase NAD+ levels - NADH and NMN - to conduct research, and published the research results in the academic journal Journal of Functional Foods. The study found that NADH can significantly increase the level of NAD+ in the body. Compared with NMN, NADH is more effective in increasing NAD+ levels. At the same time, it can also promote alcohol metabolism and play an intervention role in early liver damage caused by acute alcohol exposure.
In July 2021, a research team from the University of Cambridge published a groundbreaking research paper in Cell Death & Disease, a sub-journal of Nature. Through research, they found that NAD+ is a molecule crucial for human health and the aging process, and people who take NAD+ precursors have a relatively lower risk of developing Alzheimer's disease.
In August 2022, the international top academic journal Nature Nanotechnology published an important paper by a research team from the University of Wisconsin-Madison - "NAD(H)-Loaded Nanoparticles for Efficient Sepsis Therapy via Modulating Immune and Vascular Homeostasis". The study confirmed that NADH can not only efficiently supplement the NAD+ levels in various cells and effectively improve cellular energy supply but also inhibit inflammatory reactions, prevent pyroptosis and apoptosis induced by inflammation, and play an important role in maintaining immune homeostasis and protecting vascular endothelial cells from damage. The paper also mentions at the end that NADH has potential application value in the treatment of COVID-19 and organ transplantation.
Overall, the normal operation of every cell, organ, and tissue in the human body is inseparable from the participation of NAD+. Increasing NAD+ levels can bring various benefits to various organs of the body:
Brain: Optimize brain function and prevent neurodegenerative diseases;
Vascular system: Promote the formation of new blood vessels and increase capillary density and blood flow;
Liver: Improve liver function, reduce hepatic steatosis, and enhance liver regeneration capacity;
Muscles: Reduce muscle atrophy, enhance mitochondrial function, and improve physical activity ability;
Pancreas: Improve the function of β cells, increase insulin secretion, and reduce inflammatory reactions;
Adipose tissue: Reduce the risk of dyslipidemia and prevent insulin resistance;
Inflammation regulation: Alleviate inflammatory reactions and improve the function of immune cells.
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