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Title: NAD+ in Aging: Role of Nicotinamide Riboside and Nicotinamide Mononucleotide
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URL Source: https://www.youtube.com/watch?v=hggLOXhFRxc
Published: Nov 5, 2020
Author: staff
Post Date: 2020-11-05 20:20:18 by Horse
Keywords: None
Views: 90
NAD+ mediates energy metabolism The body draws on NAD+ precursors in the diet, such as the amino acid tryptophan and various niacin equivalents, to synthesize the NAD+ it requires. But cellular synthesis falls short of actual need, so the body recycles the various components of NAD+ in a salvage pathway to compensate for the deficit. This is crucial because NAD+ is fundamental to cellular energy metabolism via its role in the back-and-forth processes of reduction and oxidation – commonly referred to as "redox" reactions. These alternating conversions of NAD's oxidized form (NAD+) to its reduced form (NADH) facilitate glycolysis and fatty acid oxidation to create ATP. It also serves as a cofactor for a litany of enzymes that further aid metabolic processes. NAD+ facilitates DNA repair Metabolism and day-to-day living can damage DNA, however, necessitating the activation of in-house repair mechanisms. The PARP enzymes, in particular, detect DNA damage and initiate repair responses by recruiting other DNA-repair enzymes. In this way, PARP enzymes directly influence longevity. In fact, a study in which activity of the PARP-1 enzyme was measured across multiple mammalian species demonstrated that the higher the PARP-1 activity, the longer the lifespan. PARP enzyme activation relies on the presence of NAD+, but it takes a toll on cellular stores of the molecule, decreasing it to 20 to 30 percent of its normal levels. NAD+ drives sirtuin activation Other mediators of the aging process are the sirtuins, highly conserved enzymes that play key roles in healthspan and longevity in multiple organisms. They are linked to the regulation of a variety of metabolic processes and have been implicated in the pathophysiology of many conditions related to aging. Sirtuins utilize NAD+ to perform the process of deacetylation to control the activation of genes involved in energy metabolism, autophagy, circadian rhythms, DNA repair, cell survival, and more. Low cellular energy levels – such as would occur during exercising, fasting, or caloric restriction – promote increased production of NAD+, driving sirtuin expression and subsequent activity. Cellular NAD+ levels are depleted in aging In light of NAD+'s role in mitigating DNA repair and activating sirtuins, it's not surprising that cellular NAD+ levels are depleted in aging, a consequence of decreased synthesis and increased consumption and degradation. The ensuing NAD+ deficits are associated with many of the hallmarks of aging and may predispose us to age-related diseases and poor immune function. Tissues such as the brain, heart, and skeletal muscle, which have high metabolic demands (and subsequently high NAD+ use), are hit hardest, increasing our susceptibility to Alzheimer's disease, cardiovascular disease, and sarcopenia – a progressive condition characterized by loss of skeletal muscle mass and strength and a leading cause of functional decline and loss of independence in older adults. Strategies to enhance cellular NAD+ production NAD+ levels are heavily influenced by lifestyle and particularly things that cause energy stress, like fasting, caloric restriction, and exercise, which all increase the NAD+:NADH ratio. Identifying strategies to enhance cellular NAD+ levels is crucial to thwarting the inevitable losses. Healthspan-promoting activities, such as those that induce cellular energy deficits, including fasting, caloric restriction, and exercise, increase NAD+ as the body strives to meet energy needs. But a growing body of research suggests that exogenous sources of NAD+ precursors, so-called NAD+ "boosters," when taken in supplement form, increase cellular levels of NAD+. NAD+ boosters: Nicotinamide riboside & nicotinamide mononucleotide Nicotinamide riboside (NR), a niacin equivalent, is present in the diet and is available in dietary supplement form. Nicotinamide mononucleotide (NMN) is also present in the diet and available in dietary supplement form, but it is also an intermediate compound in the NAD+ salvage pathway. Evidence from animal studies suggests that NR and NMN supplementation may be beneficial to health and may delay or prevent the onset of age-related disease. They both raise NAD+ levels and have been shown to counteract the effects of an obesogenic diet, promote mitochondrial health, improve markers of cardiovascular health, and slow both physical and mental aging. NAD+ decline in aging and potential for intervention. NAD+ facilitates sirtuin activation, DNA repair, and mitochondrial function to enhance healthspan. NAD+ status in aging and potential for intervention. Cellular levels of NAD+ increase under conditions of energy stress, such as caloric restriction or exercise; via supplementation of NAD+ precursor molecules, NR and NMN, which "boost" synthesis; or via sirtuin-activating compounds (STACs), such as resveratrol or pterostilbene. NAD+ levels decrease during aging due to increased NAMPT activity, as well as age-related cellular demand for PARP-directed DNA repair, immune function, and inflammation. NAD+ precursor challenges Several challenges to NR or NMN supplementation have been identified, however. For example, the doses commonly used in animal studies are extremely high, and in some cases the mode of administration – such as intraperitoneal injection – complicates translating the data to humans. Concerns about the bioavailability of NR and NMN also need to be addressed. A study that used isotope tracers to track the fate of oral and injected NR and NMN revealed that even at very high oral doses, neither molecule was directly transported into tissues other than the liver. Instead, both NR and NMN were converted into nicotinamide (an intermediary compound in NAD+ synthesis) and was then converted into NAD+. The injected NR and NMN shared a different fate, however, bypassing the feedback mechanisms that regulate synthesis. In addition, both NR and NMN can destabilize over time, especially in an environment of high temperature and humidity, and subsequently convert to nicotinamide. This intermediary compound may have deleterious effects on health because it reduces sirtuin activation. A final concern is that of a potential for increased cancer risk. Some evidence suggests that NMN supplementation or NAD+ metabolism may drive tumorigenesis, especially in the proinflammatory environment associated with senescent cells. NAD+ infusion With all the challenges and concerns associated with NAD+ boosters, intravenous administration of the parent molecule sounds very appealing. Unfortunately, oral NAD+ has very poor bioavailability. And, while intravenous administration could address some of the bioavailability issues, not only has a NAD+ transporter not been identified, but extracellular NAD+ is not readily taken up into tissues, with possible exception of the brain and heart. A fact suggested by some animal research. Future research will likely elucidate other techniques for – and the feasibility of – direct NAD+ delivery. Conclusion NAD+, a molecule that participates in a myriad of metabolic and physiological processes, is crucial for our survival. Cellular NAD+ levels decline with age, however, and drive age-related decline and disease. A growing body of evidence suggests that supplementing with NAD+ precursor molecules may be a viable strategy to forestall the effects of aging. In this episode, Dr. Rhonda Patrick provides a comprehensive overview of NAD+ and its related precursor molecules, nicotinamide riboside and nicotinamide mononucleotide. She takes a hard look at the animal and human data surrounding their use and describes challenges that must be overcome. Poster Comment: I will get some when I get my stimulus check. There is a serious challenge to Pelosi. She might have to yield her opposition to stimulus.
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