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​Your Guide To NAD+

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​Your Guide To NAD+
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How It Promotes Health, Energy and Longevity


As we age, we experience a decline in our metabolism and metabolic function. This slow, steep decline increases our risk of age-related conditions, as our metabolism slows, our sensitivity declines, our joints become less mobile, and our arteries less flexible, impeding healthy blood flow. We would all love a fountain of youth—an elixir to magically ward off the deterioration often associated with aging. The good news is there are novel compounds available right now that may have the ability to help preserve a more youthful metabolism and vitality.[1]

One key molecule at the front and center of healthy aging is NAD+ (nicotinamide adenine dinucleotide). It is found in all our cells and is often called our body’s own master “longevity” molecule. NAD+ is required for over 500 enzymatic reactions in our bodies and is fundamental to almost all biological processes. NAD+ was discovered early in the last century, in 1906. We produce lots of it when we’re young, but levels steadily decline with age.[2]

That’s a big problem, because the activity of critical signaling molecules in our body is utterly dependent on NAD+. Those molecules include ones with funny names, such as the sirtuins, often called protectors of the genome, and PARPs (Poly(ADP-ribose) polymerase) which are responsible for DNA repair. To put it bluntly, according to Eduardo Chini, MD, PhD, of the Mayo Clinic’s Robert and Arlene Kogod Center on Aging, “This decrease in NAD+ appears to be, at least in part, responsible for age-related metabolic decline.”[3] And maintaining or restoring levels of NAD+ may have profound protective effects. Several studies on old mice have shown that giving the animals precursors to NAD+ can greatly improve their health.[4] Now human studies have begun.

Think of it this way: having lots of NAD+ is like having a checking account with ample funds. Everything you need to survive and thrive can be paid for. What’s worse, your expenses have gone up as you age. You’ve accumulated more free radical damage, more wear and tear on your tissues, joints and organs, and more DNA errors and mutations.


You Don’t Have To Starve: How Studies on The Profound Benefits Of Calorie Restriction Shed Light On NAD+

The famously long-lived Okinawans follow a 2500-year old Confucian mantra before meals that reminds them to stop eating when their stomachs are 80% full. Other inhabitants of other Blue Zones eat their last meal of the day before sundown, and it’s the smallest meal.[5]

A reduction in calories of 30-40% triggers activity of the anti-aging sirtuins as well as a network of genes that have evolved to protect us during food scarcity.[6] In the words of geneticist David Sinclair, PhD, of Harvard Medical School, “Calorie restriction without malnutrition is considered the gold standard in biogerontology as the most robust way to delay ageing and age-related diseases.” In fact, Sinclair told Harvard Magazine that, “The interesting thing about calorie restriction is that we used to think the body was in some way slowing down, maybe in the number of heartbeats or production of free radicals. But it turns out that’s wrong. When we’re calorie restricting, what we’re really doing is telling the body that now is not the time to go forth and multiply. It’s time to conserve your resources, repair things better, fight free radicals, and repair broken DNA.”[7]

During calorie restriction, our cells engulf and clear out debris and damaged proteins and then recycle or dispose of them. Mitochondria also take the opportunity to repair themselves and divide, creating fresh, new mitochondria. Inside our cells, intracellular pathogens are dealt with, broken down and ferried away.[8],[9],[10] Remember that proverbial checking account? Calorie restriction is like wiping out all the overdrafts and extra charges and depositing new cash. Nicotinamide adenine dinucleotide (NAD+) is thought to mimic the effects of calorie restriction, without the downsides (it can be hard to limit calories or fast for many people). Like calorie restriction, it activates sirtuins, which may be one of the main ways both methods work to slow aging. And as NAD+ levels drop with age, the function of some sirtuins is also reduced.[11]


Sirtuins: The Secret Sauce in NAD+ Supplementation

Sirtuins are being studied as one of the most promising targets in healthy aging science.[12] Sirtuin expression is associated with increased longevity.[13],[14] Sirtuins are critical for cell metabolism and DNA repair, stress resistance, the formation of new mitochondria and regulation of inflammation. Sirtuins mobilize cells’ response to a wide range of stresses, including oxidative stress. Sirtuins play a central role in inflammation, cell growth, circadian rhythms, energy metabolism, neuronal function, and stress resistance.[15]


NMN: A Direct and Stable Precursor to NAD+, helps slow Aging and restore Metabolism

The identification of molecules that safely maintain NAD+ levels in humans cannot come soon enough,” wrote David Sinclair and his colleague Michael Schultz in 2016. This is true, they wrote, “for patients who could benefit and those who hope to celebrate many more anniversaries.”[18] NAD+ can be increased in several different ways, a primary one being supplementing with NMN

[19] Like NAD+, plasma NMN levels decrease with age. In animal studies, supplemental NMN increases levels of NAD+ and leads to a wide array of remarkable effects.[20] NMN has been able to suppress age-associated weight gain, enhance energy metabolism and physical activity,improve insulin sensitivity, improve eye function, improve mitochondrial metabolism and prevent age-linked changes in gene expression.[21] Stem cells can be rejuvenated by raising NAD+ levels. Deterioration of adult stem cell function is correlated with aging.[23] Kidney function decreases with age, due largely to lower levels of NAD+ in aged kidneys and a decrease in sirtuin activity. Activation of sirtuins by raising NAD+ levels protects kidneys.[24]

Blood vessel flow is improved with NMN. Our organs and tissues rely on an abundant, rich microcapillary network to continually supply them with oxygen and nutrients as well as remove waste products. Treatment of old mice with NMN restored important aspects of blood vessel function, and increased the flexibility of arteries, enhancing blood flow.[25]

References:

[1]Blagosklonny MV. Disease or not, aging is easily treatable. Aging (Albany NY). 2018 Nov 17;10(11):3067-3078 View Full Paper

[2]Camacho-Pereira J et al. , CD38 dictates age-realted NAD decline and mitochondrial dysfunction through an SIRT3-Depenednet mechanism. Cell Metabolism, 2016; 23 (6): 1127 View Full Paper

[3]Specific enzyme linked to process of metabolic dysfunction in aging. Science Daily. Available at https://www.sciencedaily.com/releases/2016/06/1606.... Accessed January 1, 2020

[4]Schultz MB et al. Why NAD+ Declines during Aging: It’s Destroyed. Cell Metab. 2016 June 14; 23(6): 965–966 View Full Paper

[5]Buettner D et al. Blue Zones: Lessons From the World’s Longest Lived. Am J Lifestyle Med. 2016;10(5):318–321 View Full Paper

[6]Guarente L. Calorie restriction and sirtuins revisited.Genes Dev. 2013 Oct 1;27(19):2072-85. View Full Paper

[7]Bolotnikova MN. Anti-Aging approaches. Harvard Magazine 2017 View Full Paper

[8]Curevo AM et al. Autophagy and aging: the importance of maintaining “clean” cells. Autophagy, 2005; 1:3, 131-140

[9]Mizushima N A et al. In vivo analysis of autophagy in response to nutrient starvation using transgenic mice expressing a

fluorescent autophagosome marker. Mol Biol Cell 2004; 15:1101-11

[10]Markaki M. Novel insights into the anti-aging role of mitophagy. Int Rev Cell Mol Biol. 2018;340:169-208

[11]Mendelsohn AR et al. The NAD+/PARP1/SIRT1 axis in aging. Rejuvenation Res. 2017 Jun;20(3):244-247. View Abstract

[12]Grabowska W et al. Sirtuins, a promising target in slowing down the ageing process. Biogerontology. 2017;18(4):447–476. View Full Paper

[13]Jiang JC et al. An intervention resembling caloric restriction prolongs life span and retards aging in yeast. FASEB J. 2000; 14, 2135–2137 View Abstract

[14]Wood JG et al. Sirtuin activators mimic caloric restriction and delay ageing in metazoans. Nature. 2004 Aug 5;430(7000):686-9. View Full Paper

[15]Gertler AA et al. SIRT6, a protein with many faces. Biogerontology. 2013;14:629–639. View Abstract

[18]Schultz MB et al. Why NAD+ declines during aging: it’s destroyed. Cell Metab. 2016 June 14; 23(6): 965–966 View Full Paper

[19]Poljsak B. NAMPT-Mediated NAD biosynthesis as the internal timing mechanism: in NAD+ World, time Is running in its own way. Rejuvenation Res. 2018 Jun;21(3):210-224 View Abstract

[20]Keisuke Okabe et al. Implications of altered NAD metabolism in metabolic disorders. Journal of Biomedical Science 2019;26:34 View Full Paper

[21]Mills KF et al. Long-term administration of nicotinamide mononucleotide mitigates age-associated physiological decline in mice. Cell Metab. 2016 Dec 13;24(6):795-806 View Full Paper

[22]Gomes AP et al. Declining NAD(+) induces a pseudohypoxic state disrupting nuclear-mitochondrial communication during aging. Cell. 2013; 155:1624–1638. View Full Paper

[23]Igarashi M, Miura M, Williams E, et al. NAD+ supplementation rejuvenates aged gut adult stem cells. Aging Cell. 2019;18(3):e12935 View Full Paper

[24]Ugur S et al. The renoprotective effect of curcumin in cisplatin-induced nephrotoxicity. Ren Fail. 2015; 37:332–336. View Full Paper

[25]de Picciotto NE et al. Nicotinamide mononucleotide supplementation reverses vascular dysfunction and oxidative stress with aging in mice. Aging Cell. 2016; 15:522–530. View Full Paper