NAD+ for Rejuvenating the Brain

Nicotinamide adenine dinucleotide (NAD) is a coenzyme that has tremendous potential to increase brain health and promote anti-aging. The NAD+ version is the oxidized form.  As we age, not only do brain cells break down from oxidative stress and cellular deterioration, but we run the risk of developing amyloid plaques which are a hallmark of Alzheimer’s disease. These plaques kill brain cells, affecting memory and cognitive function. Even if we don’t develop Alzheimer’s disease, the mitochondria in our brain cells slowly become compromised, meaning they are no longer the energy powerhouses they once were. Mitochondrial production of ATP in our cells diminishes, and as a result, we have less energy for our brains to function well. Cognition declines, memory declines, and reflexes decline. These are hallmarks of aging- but do they have to be?

NAD+ has been found to have powerful neurological effects and can act as a key anti-aging compound. NAD+ has been effectively used to treat addiction disorders and has shown real promise in trials against Alzheimer’s disease (Wu, et al, 2014). This is because NAD+ has been shown to be intrinsically involved with regulating metabolism, mitochondrial function, aging, and cell death in the brain. All of these are key factors in the progression of Alzheimer’s disease but are also descriptions of how aging in the brain progresses. While NAD exists naturally in the brain, it declines with age. NAD+ can decrease neurotoxicity in the brain. It can decrease ROS (Reactive Oxygen Species) in the brain, which can damage brain tissue, decrease neurotransmitters and deplete glutathione which the brain needs to drive the mitochondria. “NAD+ is a vital redox cofactor for metabolism and ATP production, and a key substrate for at least four families of enzymes involved in healthspan and longevity” (Lautrup et al, 2019). NAD+ can also decrease oxidative stress in the brain, which can lead to cell death. It is an effective neuroprotective enzyme that seems to have the effect of reversing brain decline. 

NAD+ and the ten hallmarks of aging

In 2018, the researchers Mark Mattson and Thiruma Arumugam published a landmark paper detailing the 10 hallmarks of aging. It appears that NAD+ may act in a positive way to inhibit them. Since “Emerging findings are revealing linkages by which age-related NAD+ depletion is positively related to the 10 hallmarks of brain aging.” Let’s go through them and show how NAD+ might work to combat the effects of aging:

1. 1. Mitochondrial dysfunction– As the brain ages, the mitochondria break down because of oxidative damage and other causes.  This means the mitochondria produce less ATP than the energy supply to the brain. The brain consumes a lot of energy and any breakdown in its production matters. NAD+ is central to mitochondrial function and depletion of NAD+ accelerates cellular breakdown in the brain. An inability to clear damaged mitochondria from the brain increases with age and with a decrease in NAD+. “Reduced NAD+ levels play a pivotal role in brain aging and neurodegenerative disorders because NAD+ replenishment improves mitochondrial function and mitochondrial biogenesis and reduces accumulation of damaged mitochondria” (Lautrup, et al, cited above)
   2. Intracellular accumulation of oxidatively damaged macromolecules– As we age, ROS causes an “increase in oxidative damage to DNA, proteins, and lipids in the aging brain” (Mattson and Arumugam cited above). NAD+ depletion with age has been “correlated with increased lipid and protein oxidation as well as increased DNA damage in the heart, lung, kidney, and liver” (Braidy et al, 2011). Supplementing with NAD  “decreases the elevated levels of ROS in cell and animal models of premature aging diseases through reduced ROS production, improved mitochondrial function, and possibly also increased ROS detoxification” (Fang, et al, 2017).
   3. Dysregulated energy metabolism– With the decline of mitochondrial function in brain cells, and the accumulation of more and more damaged and dead cells, ATP production decreases. This disrupts the energy supply to the brain, which is needed for all of its tasks. Not only does cognition and memory decline, but the brain’s demand for more energy that can’t be completely met results in your entire body feeling more drained, and may also be the cause of some “brain fog”. NAD+ augmentation helps restore energy by repairing cells and increasing ATP
   4. Impaired cellular “waste disposal” mechanisms- NAD+ augmentation can help regulate the number of healthy mitochondria and dispose of cells with damaged mitochondria. This is complicated, but basically, the “autophagy-lysosome pathway plays important roles in life and health, such as in longevity, germ-cell lineage, and the rejuvenation of stem cells.”  “Furthermore, the autophagy-lysosome pathway maintained stemness of HSCs in mice through elimination of active and healthy mitochondria to maintain quiescence and low metabolism (Ho et al., 2017), an outcome that can be achieved by NAD+ augmentation (Vannini et al., 2019). (Both from Lautrup, et al, cited above). Since NAD+ augmentation can aid in the clearing of damaged cells, NAD+ therapy should be able to help clear the brain of non-functioning cells and boost brain activity. 
   5. Impaired adaptive stress response signaling- “Three major initiators of adaptive cellular stress responses in neurons are ATP consumption, ROS production, and Ca2+ signaling. With advancing age, these stress responses might become impaired, which will render the neurons more vulnerable to various forms of stress of either endogenous or exogenous origin” (Mattson et al., 2018 via Lautrup, et al). This means that as we age, the neurons in our brains are less likely to be able to handle the demands of stress. Particularly, they can no longer produce enough energy to deal with it, they can no longer employ antioxidants as effectively, and they can no longer utilize the calcium channel as effectively to send signals between neurons in the brain. The result of all of this is that our synapses fire less effectively and our cells are further damaged and the whole cycle drags the brain down another notch. Again, NAD+ augmentation is likely to help reverse these processes: “the strong links between NAD+ and mitochondrial function (ATP production), ROS, and Ca2+ signaling suggest that bolstering cellular NAD+ levels can improve adaptive cellular stress responses in neurons.” (Lauter, et al, previously cited). 
   6. Compromised DNA repair– Neurons in the brain require DNA repair to keep them functioning. Oxidative stress damages the DNA responsible for neuron repair. When this DNA repair mechanism is impaired, neurological damage can follow.  “NAD+ plays a critical role in DNA repair through multiple pathways” states Lautrup, et al again. In fact, when investigating many of these neurological ills, researchers noticed a depletion in NAD+. “Collectively, impaired DNA repair byproducts and intermediates accumulate in cells of the aging brain and may contribute to numerous human neurological diseases, at least partially through NAD+ depletion driven by hyperactivation of PARP.” (Lautrup, et al, cited above)
   7. Aberrant neuronal network activity– The combination of the accumulation of dead and damaged cells, malfunctioning mitochondria, lack of adequate DNA repair, ROS production and impairment of calcium channel signalling can all potentially lead to aberrant neuronal network activity. The fact that NAD+ supports all of those functions means that NAD+ should also show some ability to decrease the risks of poor communication in the neuronal network.
   8. Dysregulated neuronal Calcium handling– “The calcium ion (Ca2+) regulates neuronal function and structural adaptations of neuronal networks to various environmental challenges. Perturbed Ca2+ signaling is implicated in the aging brain and age-related neurodegenerative diseases” (Lautrup, et al, cited above). This means when the calcium channel in the brain degrades, the risk of various neurological diseases increases. As you age, this becomes more likely, and this means your neurons in the brain become more vulnerable to stress and degradation. Luckily, NAD+ is likely to preserve this signaling and help stave off neurodegenerative disease.
   9. Stem cell exhaustion- As we age we produce fewer neurons, and since neurons are the basic building blocks of brain function, you should expect brain function to decline as well with the decline of neuron production. Some people are lucky and continue producing new neurons into their 90s. Others are not so lucky, particularly those who succumb to Alzheimer’s Disease. In that case, neurogenesis virtually shuts down and the brain declines as no new neurons are produced. Stem cells seem integral to neurogenesis, being the basic building blocks of the process of neurogenesis. Once again, NAD+ to the rescue! “Mounting evidence supports a critical role for NAD+ in stem cell rejuvenation, including in HSCs, endothelial stem cells, muscle stem cells, and melanocyte stem cells” (Das et al., 2018; Vannini et al., 2019; Zhang et al., 2016). This means that NAD+ is likely to help bolster stem cells, including those in the brain, and therefore stimulate neuron production.
   10. Inflammation– As brains age, inflammation is often seen, and often involves the release of cytokines, and ROS, including nitric oxide and superoxide (Latta, et al 2015). The complement cascade often is initiated to protect against this inflammation in the brain as we get older. Unfortunately, this complement storm, while attempting to protect the brain, can also do damage to cell membranes. Decreasing this complement cascade can stop synapse loss and the death of neurons. In animal studies, an NAD+ precursor decreased neuroinflammation and decreased the number of cytokines that produced inflammation. (Fang, et al 2019, cited above). Nad+ supplementation to the body has also been demonstrated with inflammation associated with diabetes. Diabetes has been correlated with Alzheimer’s disease, and NAD+ has also been found to help decrease the associated inflammation in the brain. “The underlying molecular mechanism by which NAD+ suppresses neuroinflammation involves the elimination of damaged pro-inflammatory mitochondria and inhibition of the major inflammasome NLRP3” (Both Fang and Lautrup concur as cited above- quoted from Lautrup). Wow! NAD+ seems to exhibit serious anti-inflammatory effects!
   11. (Bonus) Senescence and telomere attrition– Senescence in this case means the atrophy of brain cells. As we age, we accumulate a host of dead and near-dead brain cells that remain in place in the brain instead of being flushed out. This accumulation of dead or low-functioning brain cells literally clogs the brain with nonperforming neurons. Not only do these cells underperform, but they also contribute to inflammation. “…senescent cells accumulate with age and contribute to aging phenotypes and pathologies, including inflammation and cognitive impairment (Wiley et al., 2016). NAD+ augmentation seems to help with senescence: “NAD+ augmentation exhibits anti-senescence capabilities. In primary cell culture, supplementation with NR delays cellular senescence (Wiley et al., 2016)” Telomeres are fascinating. We’re constantly finding more about them, but what we know so far is that telomere length is somehow inextricably linked to how long we’ll live. So far, we have no clear answer as to whether NAD+ will also help stop the shortening of telomeres, but there is a tantalizing glimpse of where the research may be headed: “A recent study showed that NMN treatment ameliorated telomere shortening in hepatocytes from successive generation 4 (G4) TERT knockout mice (Amano et al., 2019). Therefore, it would be interesting to explore NAD+ augmentation in telomere length in neuronal stem cells and glial cells in the future.” (Lautrup, cited above). If it bears out that NAD+ also shortens telomeres, or at least delays their shortening, that would be the anti-aging find of the century? Maybe we’re heading for such a find?

The fact that NAD+ therapy shows such promise across the range of factors that contribute to aging is exciting indeed! Aging is complicated, but the fact that NAD+ seems to act against the entire range of aging mechanisms in the brain should tell you something! The therapy itself involves a series of injections that patients have indicated show positive results quickly. Help your brain feel younger!

• Overall brain anti-aging compound
• Decreases Oxidative Stress in the brain
• Rejuvenates brain mitochondria, increasing  brain cellular energy
• Improves memory and cognition
• Fights neurotoxicity in the brain
• Improves brain neurotransmission