Nad+ Definition Biology
Nicotinamide adenine dinucleotide (NAD+) is a coenzyme for redox reactions and therefore at the heart of energy metabolism. NAD+ is also an essential cofactor for non-NAD+-dependent enzymes, including sirtuins, CD38 and poly(ADP-ribose) polymerases. NAD+ can directly and indirectly affect many important cellular functions, including metabolic pathways, DNA repair, chromatin remodeling, cell senescence, and immune cell function. These cellular processes and functions are crucial for maintaining tissue and metabolic homeostasis and for healthy aging. Notably, aging is associated with a gradual decline in tissue and cellular levels of NAD+ in several model organisms, including rodents and humans. This drop in NAD+ levels is causally linked to many age-associated diseases, including cognitive decline, cancer, metabolic diseases, sarcopenia, and frailty. Many of these age-associated diseases can be slowed and even reversed by restoring NAD+ levels. Therefore, targeting NAD+ metabolism has emerged as a potential therapeutic approach to relieve age-related diseases and prolong human health and lifespan. However, there is still much to learn about how NAD+ affects human health and the biology of aging.
This includes a better understanding of the molecular mechanisms that regulate NAD+ levels, how NAD+ levels can be effectively restored during aging, whether this is safe, and whether replenishing NAD+ has positive effects on aging individuals. During aging, cells exposed to metabolic, genotoxic or oncogene-induced stress undergo an essentially irreversible cell cycle arrest called cell senescence. An important phenotype of senescent cells and how they are thought to promote disease is the increased expression of inflammatory mediators, mainly cytokines and chemokines, known as senescence-associated secretory phenotype (SASP), which helps alter tissue homeostasis by interfering with stem cell regeneration, tissue and wound repair, and inflammation125. 126 (Fig. 3Aa). As senescent cell counts gradually increase with age, cellular senescence has been linked to several age-associated diseases, and clearance of senescent cells with pharmacological senolytics may be an effective treatment for several previously incurable diseases, including Alzheimer`s disease127-129. In addition, treatments to increase cellular levels of NAD+ during aging are promising targets for prolonging health expectancy,130 but it is unclear how NAD+ affects cellular senescence. Recently, senescent cells have been shown to upregulate the expression of NAMPT NAMPT (BOX 1) and that the SASP of senescent cells depends on NAD+131 levels. Treating aging cells with NMN can increase SPAS, which leads to increased chronic inflammation and may promote the development of inflammation-related cancers. These findings suggest that administration of NAD+-boosting supplements such as NR and NMN may come at the expense of long-term side effects such as improved chronic inflammation and cancer development.
Therefore, a better understanding of the benefits and unmonitored side effects of increasing NAD+ levels will be an important focus in future studies and ongoing clinical trials. Since inflammation is a very complex and versatile process, further studies are needed to better understand how and in what context NAD+ levels affect different inflammatory states, and to determine how NAD+ metabolism mechanically affects the biology of inflammatory and aging immune cells. From the findings taken together, there is growing evidence that NAD+ is a central metabolite for maintaining a healthy nervous system and may affect the biology of several brain cell types, suggesting that combating age-related decline in NAD+ levels may be a viable therapeutic approach to treating neurodegenerative diseases. Restoration of NAD+ levels with NAD+ preparations and overexpression of the two biosynthetic enzymes NAMPT and NMNAT1 has been found to prevent axonal degeneration60,146. In addition, NAD+ NR and NMN precursors improve neuronal cell health, memory and cognitive function in models of Alzheimer`s disease in rats and mice136,161,175–180 and have also shown neuroprotective properties in Parkinson`s disease models of Drosophila melanogaster181,182 and mouse models of ALS139. It is important to note that several clinical trials are currently underway with NAD+ precursors, particularly NR, for the treatment of neurological diseases68 and the promotion of healthy aging (TABLE 2). These studies will undoubtedly expand our understanding of NAD+ metabolism in human neurodegenerative processes68. Open any biology textbook and you`ll learn more about NAD+, which stands for nicotinamide adenine dinucleotide.
It is an essential coenzyme found in every cell in your body and is involved in hundreds of metabolic processes such as cellular energy and mitochondrial health. NAD+ works hard in the cells of humans and other mammals, yeasts and bacteria, even plants. David Sinclair, a Harvard geneticist and probably one of the best-known researchers in the field of NAD+ biology, believes that age-related loss of NAD+, as well as the corresponding decline in sirtuin activity and protective effects, is one of the main reasons why we tend to develop a disease when we are old and why not when we are young. David Sinclair is a big proponent of NAD+ replenishment and other methods to keep our NAD+ levels high as we age to promote healthy longevity. Since their discovery, sirtuins have received a great deal of attention because they regulate important metabolic processes, stress responses and the biology of aging.7 The mammalian sirtuin family consists of seven genes and proteins (SIRT1-SIRT7) with different subcellular locations (nucleus for SIRT1 and SIRT6; nucleolus for SIRT7; mitochondria for SIRT3, SIRT4 and SIRT5; and cytosol for SIRT1, SIRT2 and SIRT5) (Fig. 1b), enzyme activities and downstream targets. The subcellular localization of these NAD+-dependent enzymes highlights how local fluctuations in intracellular NAD+ pools, which in turn are regulated by sirtuins, can selectively influence organelle-specific sirtuin functions and cellular metabolism. Aging leads to an imbalance or distortion of immune cell populations, including decreased concentrations of naïve T and B cells, loss of diversity of T-cell antigen receptors, and an increase in virtual memory T cells. The regulatory role of NAD+ and NAD+ consuming enzymes in the biology of T cells has been demonstrated; However, their contribution to the aging of adaptive immunity is largely uncharacterized. On the one hand, extracellular NAD+ has been proposed as a hazard signal110 that causes cell death in subpopulations of specific T cells such as regulatory T cells111. On the other hand, NAD+ appears to exhibit immunomodulatory properties, such as the influence of T112,113 cell polarization.
However, it is still unclear whether NAD+ promotes a specific T cell phenotype and whether manipulation of NAD+ metabolism with NAD+ precursors could lead to similar immunomodulatory properties. CD38 and CD157 are multifunctional ectoenzymes with glycohydrolase and ADP-ribosylcyclase activities. NAD+ glycohydrolysis is the main catalytic reaction that cleaves the glycosidic bond in NAD+ to produce NAM and ADP-ribose, while the activity of ADP-ribosyl cyclase produces cyclic ADP-ribose (Fig. 2c). CD38 also performs a basic exchange reaction by exchanging NAD(P)+ NAM to NA under acidic conditions and producing nicotinic acid adenine dinucleotide (phosphate) (NAAD(P)37 (Fig. 2c). Notably, ADP-ribose, cyclic NAAD(P) and ADP-ribose are important secondary messengers mobilizing Ca2+, illustrating the central role of CD38 in activating Ca2+ signaling and modulating essential cellular processes such as activation, survival and metabolism of immune cells38-40. It is important to note that NMN appears alongside NAD+ and NADP+ as an alternative substrate of CD38 (REFS41,42), while CD157 consumes NR as an alternative substrate43,44 (Fig. 2c). Therefore, targeting CD38 and CD157 with small molecule inhibitors could make these commonly used NAD+ precursor metabolites more effective at restoring NAD+ levels in aging individuals.