Lesson 16: NAD+ Copy Copy
NAD+
Nad+ is Nicotinamide adenine dinucleotide which is a co factor found in all living cells. Nicotinamide adenine dinucleotide, or NAD, is a coenzyme (a compound that certain enzymes need to work) in every cell that is crucial to the basic reactions in your cells that keep you alive. It occurs in two forms: NAD+ and NADH. To understand what NAD does in simple terms, think of NAD as a waiter that picks up an electron from one table and drops it off at another. The oxidized form, NAD+, grabs an electron from one molecule. While it has a hold on that electron, it becomes NADH. NADH donates that electron to another molecule, and it becomes NAD+ again. The simple act of shuffling electrons around helps your enzymes work, and those enzymes activate microscopic chemical reactions in your cells that keep them healthy and keep your whole body humming.
There are two forms :
Oxidized Nad = NAD+
Reduced Nad = NADH
Nad is more bioavailable when taken with co q10. Nad optimises mitochondria function. Niacin is a precursor of Nad and Tryptophan is a precursor to niacin and serotonin and melatonin. Niacin is B3 and is high in avocados. Another way which has gained huge popularity in the scientific community of directly boosting Nad+ is take a supplement called NR (Nicotinamide Riboside). A healthy thriving person with optimum mitochondria function will have a ratio of 700:1 (NAD:NADH)
What Is NAD+ and why is it Important for Aging and Health
You can’t live without the coenzyme NAD+, nicotinamide adenine dinucleotide. Here’s why it’s so important, how it was discovered, and how you can get more of it. NAD+, or nicotinamide adenine dinucleotide, is a coenzyme found in all living cells, and it’s required for the fundamental biological processes that make life possible. But NAD+ levels decline as we age. NAD+ has two general sets of reactions in the human body: helping turn nutrients into energy as a key player in metabolism and working as a helper molecule for proteins that regulate other biological activity. These processes are incredibly important because they are responsible for regulating oxidative stress and circadian rhythms while maintaining the health of DNA and keeping humans healthier for longer.
How NAD+ Powers Health, Life, And Aging
Open any biology textbook and you’ll learn about NAD+, which stands for nicotinamide adenine dinucleotide. It’s a coenzyme found in all living cells that’s required for the fundamental biological processes that make life possible, from metabolism to DNA repair. NAD+ is hard at work in the cells of humans and other mammals, yeast and bacteria, even plants. Nothing can live without NAD+, and low levels are often accompanied by negative health consequences.
Scientists have known about NAD+ since it was first discovered in 1906, and since then our understanding of its importance has continued to evolve. For example, NAD+ precursors played a role in mitigating pellagra, a fatal disease that plagued the American south in the 1900s. Scientists at the time identified that milk and yeast, which both contain NAD+ precursors, alleviated symptoms. Over time scientists have identified several NAD+ precursors — including nicotinic acid, nicotinamide, and nicotinamide riboside, among others — which make use of natural pathways that lead to NAD+. Think of NAD+ precursors as different routes you can take to get to a destination. All the pathways get you to the same place but by different modes of transportation.
Recently, NAD+ has become a prized molecule in scientific research because of its central role in biological functions, with research in animals tying NAD+ to notable benefits. The scientific community has been researching how NAD+ relates to overall health and age-related diseases. For example, a 2016 study found that mice and worms with degenerative muscles had improved muscle function when supplemented with NAD+ precursors. A 2017 study showed that mice supplemented with an NAD+ precursor experienced an increase in DNA damage repair, with tissue in two-year-old mice given the NAD+ precursor looking identical to tissue in three-month-old mice. And a 2018 study found that mice with NAD+ precursor supplementation had improved cognitive function, pointing to signs of therapeutic potential for Alzheimer’s disease. These are only some of the recent findings, all of which continue to inspire researchers to translate these findings to humans, exploring the potential for NAD+ to positively affect human health through supplementation.
So how exactly does NAD+ play such an important role? In short, it’s a coenzyme or “helper” molecule, binding to other enzymes to help cause reactions on the molecular level that produce positive outcomes on the everyday health level. NAD+ has two general sets of reactions in the human body: helping turn nutrients into energy as a key player in metabolism and working as a helper molecule for proteins that regulate other biological activity. But the body doesn’t have an endless supply of NAD+. In fact, it actually declines with age. The first studyshowing this decline, from 2012, examined human skin and established the coenzyme as vital to aging research. In 2015, another human study furthered this proof by showing similar NAD+ decline in the human brain.
The history of NAD+ research, and its recent establishment in the science of aging, has opened the floodgates for scientists to investigate how humans can maintain their NAD+ levels and get more of it.
What is the history of NAD+?
NAD+ was first identified by Sir Arthur Harden and William John Young in 1906 when the two aimed to better understand fermentation — in which yeast metabolize sugar and create alcohol and CO2. It took nearly 20 years for more NAD+ recognition, when Harden shared the 1929 Nobel Prize in Chemistry with Hans von Euler-Chelpin for their work on fermentation. Euler-Chelpin identified that the structure of NAD+ is made up of two nucleotides, the building blocks for nucleic acids, which make up DNA. The finding that fermentation, a metabolic process, relied on NAD+ foreshadowed what we now know about NAD+ playing a critical role in metabolic processes in humans. Euler-Chelpin, in his 1930 Nobel Prize speech, referred to NAD+ as cozymase, what it was once called, touting its vitality. “The reason for our doing so much work on the purification and determination of the constitution of this substance,” he said, “is that cozymase is one of the most widespread and biologically most important activators within the plant and animal world.”
Otto Heinrich Warburg — known for “the Warburg effect” — pushed the science forward in the 1930s, with research further explaining NAD+ playing a role in metabolic reactions. In 1931, the chemists Conrad A. Elvehjem and C.K. Koehn identified that nicotinic acid, a precursor to NAD+, was the mitigating factor in pellagra. United States Public Health Service Doctor Joseph Goldberger had previously identified that the fatal disease was connected to something missing in the diet, which he then called PPF for “pellagra preventive factor.” Goldberger died before the ultimate discovery that it was nicotinic acid, but his contributions led to the discovery, which also informed eventual legislation mandating the fortification of flours and rice on an international scale. The next decade, Arthur Kornberg, who later won the Nobel Prize for showing how DNA and RNA are formed, discovered NAD synthetase, the enzyme that makes NAD+. This research marked the beginning of understanding the building blocks of NAD+. In 1958, the scientists Jack Preiss and Philip Handler defined what’s now known as the Preiss-Handler pathway. The pathway shows how nicotinic acid — the same form of vitamin B3 that helped cure pellagra — becomes NAD+. This helped scientists further understand the role of NAD+ in the diet. Handler’s work largely focused on malnutrition and its role in disease, including pellagra, which later earned him the National Medal of Science from President Ronald Reagan, who cited Handler’s “outstanding contributions to biomedical research…furthering the state of American science.” While scientists had now realized that NAD+ played a crucial role in overall health, they had yet to discover its intricate impact on a cellular level. Forthcoming technologies in scientific research combined with comprehensive recognition of the coenzyme’s importance ultimately encouraged scientists to study NAD+ as a part of the aging process.
NAD+ and the Aging Process
Our current understanding of the importance of NAD+ really began in the 1960s. Using nuclear extracts from hen liver, French scientist Pierre Chambon identified a process called Poly ADP-ribosylation, where NAD+ is broken down into two component parts, one of which (nicotinamide) gets recycled, while the other (ADP-ribose) meets up with a protein to repair cells. This research formed the foundation of the field of PARPs, or poly (ADP-ribose) polymerases, a group of proteins that rely on NAD+ to function and regulate DNA repair, among other biological functions. PARPs are similar to another group of proteins called sirtuins in that they both only function in the presence of NAD+. Sirtuins have been called “the longevity genes” and “guardians of the genome” for their role in regulating cellular health and, as a result, aging. Sirtuins are a group of proteins that were first discovered in the 1970s but their dependence on NAD+ wasn’t realized until the 1990s. Elysium co-founder and MIT biologist Leonard Guarente identified that SIR2, a sirtuin in yeast, extended the life of the yeast only when it was activated by NAD+.
This finding provided further understanding about NAD+ and aging. Knowing that NAD+ plays a role in metabolism by turning nutrients into energy and then that sirtuins rely on NAD+ to function created a clear link between sirtuins and metabolism. It also clued scientists in on a crosstalk between biological functions, i.e., that metabolism is intricately related to other biological processes that are critical to health. This meant changes in NAD+ levels could make or break other vital functions in the body. It also inspired more research on a topic previously overlooked. “There are maybe 12,000 papers on sirtuins now. At the time we discovered the NAD+ dependent deacetylase activity the number of papers was in the 100s,” Guarante’s said. Humans get NAD+ from their diet via foods made up of amino acids that are also precursors to NAD+. However, NR is the most efficient precursor to NAD+. If NAD+ precursors are different routes you can take to get to a destination, NR is the best available route. Scientists worked toward creating a better NAD+ supplement, thinking outside the diet to access it.
The Future of NAD+ and Human Health
For nearly 100 years we’ve known that NAD+ is incredibly important, but the gradual pace of scientific research and technological development has only now begun to reveal how we can make the most of it for humans. Knowing the history of NAD+ and subsequent discoveries around the coenzyme has led researchers to explore what the science community can now do with the information. NAD+ has enormous potential and how it will be fulfilled is the most exciting aspect of current research. Recent studies in animals treated with NAD+ precursors show promise. For example, a 2013 study in mice found that increased NAD+ levels could restore mitochondrial function, and a 2018 study out of MIT promoted growth of blood vessels and muscle in elderly mice thanks to NAD+-activated sirtuins. There’s much more to discover, with scientists working to figure out just how far NAD+ can go when it comes to the health of the human body. A human study from 2017, conducted by Elysium Health, found that regular doses of an NAD+ precursor increased NAD+ levels by an average of 40 percent. So far, all signs point to a promising future.
Nad Summary :
NAD – Nicotinamide Adenine Dinucleotide: NAD is a cofactor in all living cells. When Oxidized NAD = NAD+ when Reduced NAD = NADH
- Nad Becomes more bioavailable when taken with CoQ10
- NAD optimises mitochondria function
- Niacin is a precursor of NAD
- Tryptophan is a precursor of niacin, serotonin and melatonin
- Niacin = B3 = Avocado
- Tryptophan = Leafy greens, sunflower seeds and pumpkin seeds
NAD+,Nicotinamide Adenine Dinucleotide & Ultimate Health & Longevity.
NAD+ is essential to the creation of energy in the body and the regulation of pivotal cellular processes. Here’s why it’s so important, how it was discovered, and how you can get more of it. NAD+, or nicotinamide adenine dinucleotide, is a critical coenzyme found in every cell in your body, and it’s involved in hundreds of metabolic processes. But NAD+ levels decline with age. NAD+ has two general sets of reactions in the human body: helping turn nutrients into energy as a key player in metabolism and working as a helper molecule for proteins that regulate other cellular functions. These processes are incredibly important.
The NAD+ co-enzymes NAD+, NADH, NADP+ and NADPH are the central regulators of metabolism. They are required for fuel oxidation, ATP generation, gluconeogenesis, ketogenesis, production of pentose phosphates, heme, lipids, steroid hormones and detoxification of free radical species. NAD+ is also a consumed substrate of enzymes that polymerize and/or transfer ADPribose, form cyclic ADPribose (cyclic ADPribose synthetases) and deacylate protein lysine substrates (sirtuins) with production of acyl-ADPribosyl products. Poly(ADPribose) polymerases (PARPs) signal DNA damage in order to assemble repair machinery, while cyclic ADPribose synthetases produce second messengers that mobilize calcium ions from intracellular stores, and sirtuins influence gene expression and protein activities by virtue of reversing protein post-translational modifications. In light of the important roles of NAD+ co-enzymes in metabolism and mediating some of the longevity benefits of calorie restriction via sirtuins, there is a renewed interest in the synthesis and maintenance of the NAD+metabolome.
All tissues produce NAD+ from nicotinamide (NAM) or the recently identified NAD+ precursor, nicotinamide riboside (NR) Some tissues can produce NAD+ from tryptophan de novo and nicotinic acid (NA), although the generation of NAD+ from tryptophan is much less efficient than from the vitamin precursors of NA, NAM, or NR, which are collectively termed vitamin B3. NAD+ can also be supported by dietary precursors. For example, pellagra, a disease of deficiency of NAD+precursors, can be prevented or treated with approximately 15 mg/day of NA or NAM or with 60-times as much tryptophan. Importantly, despite homeostatic systems and dietary intake of NAD+ precursors, it is now known that the levels of NAD+ co-enzymes are continuously challenged by metabolic stress. In the overfed and type 2 diabetic mouse livers, levels of NADPH are strikingly depressed, whereas in noise-induced hearing loss, heart failure, peripheral nerve damage, central brain injury and the liver of a lactating mouse, NAD+ levels are compromised. Moreover, NAD+ levels have been reported to decline in response to DNA damage, alcohol metabolism, and aging, and the expression of nicotinamide phosphoribosyltransferase (NAMPT), the enzyme required for NAM salvage, declines with aging and chronic inflammation. Thus, considering the relationships between NAD+, metabolic stress and aging, nutritional scientists are now investigating whether the ingestion of higher levels of a B3 vitamin should be part of an evidence-based approach to optimize health.
Although NA, NAM, and NR all produce NAD+ and NADP+, it is important to note that each precursor has unique effects physiologically. NA can lower blood lipids and is used to treat dyslipidemia. At doses of greater than 50 mg/day, NA can also induce flushing. In contrast, NAM does not lower blood lipids or cause flushing, has been reported be a sirtuin inhibitor at high doses, and appears to have a greater effect at elevating blood levels of homocysteine (HCY) in humans than NA via its metabolism to 1-methylnicotinamide (MeNAM). In yeast, NR activates SIR2 and extends replicative lifespan. In mouse models, NR prevents high-fat diet-induced weight gain, fatty liver and diabetic peripheral neuropathy, noise-induced hearing loss, heart failure, and central brain injury. In addition, oral NR greatly improves survival and hematopoietic stem cell regeneration after irradiation of mice—an activity that was not seen in NA or NAM supplemented mice. In rats, oral NR promotes resistance to and reversal of chemotherapeutic neuropathy. In mice, oral NR increases the hepatic levels of the NAD+ metabolome with pharmacokinetics that are superior to that of NA and NAM. administered NR exhibited increased lactation and produced offspring that are stronger, less anxious, have better memory, and have enhanced adult hippocampal neurogenesis and body composition as adults. Because NR does not cause flushing or inhibit sirtuins and the genes (NRK1 and NRK2) required for the metabolism of NR to NAD+ are upregulated in conditions of metabolic stress, NR has a particularly strong potential as a distinct vitamin B3 to support human wellness during metabolic stress and aging.
Summary:
NAD is an essential coenzyme and a key regulator of cellular metabolism. Best known for its role in cellular adenosine triphosphate (“ATP”) production, NAD is now thought to play an important role in healthy aging via activating the sirtuins pathway and increasing the NAMPT pathway. Many cellular functions related to health and healthy aging are sensitive to levels of locally available NAD and this represents an active area of research in the field of NAD. NAD levels are not constant, and in humans, NAD levels have been shown to decline by more than 50% from young adulthood to middle age. NAD continues to decline as humans grow older. There are other causes of reduced NAD levels such as over-nutrition, alcohol consumption and a number of disease states. Healthy aging, mitochondria and NAD continue to be areas of focus in the longevity research community.
Listen to Chris Masterjohn Phd Discuss Niacin the precursor to Nad+ – Part 1
Listen to Chris Masterjohn Phd Discuss Niacin the precursor to Nad+ – Part 2
Niacin B3 RDA: Men = 16 mg; Women = 14 mg per day
Sources: Almond butter 100g = 8mg, chia seed 80g = 13mg, sunflower cheese 250g sunflower seeds = 25.3mg, sundriend tomato 55g = 5.8mg.
Listen to one of the world’s experts on Longevity Professor David Sinclair discuss Nad+ with Dr Rhonda Patrick :