Relationship between NAD+ in Brain Aging and Neurodegenerative Disorders
The brain is a marvelous feat of Nature’s engineering, with 100 Billion neurons placed in a weight of 3 pounds. All parts of the brain shrink in volume as we age but changes are more marked in the frontal cortex. These age-related brain shrinkage results in cognition impairment, dementia, poor social interaction, decrease mental performance, and reduced problem-solving ability. The incidence of stroke, depression, and white matter diseases is also increased with aging. (Peters 2006) Chronological age refers to the actual number of years a person has lived and it is based on the calendar. Biological or physiological age reflects the aging-related changes that have occurred in our cells and it is influenced by our genetics, nutrition, exercise, and lifestyle factors. The biological age of the brain is measured by different techniques including MRI, DNA mutations, and blood markers.
Neurodegenerative disorders are a group of debilitating disorders that involves progressive loss of structure and function of the brain. The characteristic feature of these disorders is that they worsen as time progress and usually have no cure. The underlying cause of these disorders is the loss of function or death of a certain neuron in the brain. These disorders include Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, motor neuron disease, and Spinal muscular atrophy. (Eric 2015) According to the National Institute of Environmental Health Sciences (NIEHS), 6.2 Million people in the United States have Alzheimer’s disease, 1.2 Million have Parkinson's disease and millions of people have other neurodegenerative diseases. (Heemels 2016)
Plasmalogens are lipid compounds (glycerophospholipids) that are present in a variety of organs like the brain, heart, macrophages, and spermatozoa. The highest amount of plasmalogens is present in the brain (known as neuro-plasmalogens) while the lowest is present in the liver. They act as natural scavengers of free radicals and protect the cells from oxidation. They also serve as anti-inflammatory chemicals due to their ability to affect signal transduction pathways. If the integrity of the plasmalogens is compromised, they can become pro-inflammatory and result in chronic inflammation. Plasmalogens level drops in the body as we age and that can result in chronic inflammation and increased incidence of neurodegenerative diseases. (Bozelli, Azher, and Epand 2021) Low plasmalogens level is considered as a characteristic feature of mitochondrial dysfunction and age neurodegenerative disorders.
Chronological aging is an inevitable process and everyone has to pass through different phases of life like childhood, puberty, adolescence, and old age. Biological age is not completely tied to chronological age and is affected by different factors. A study published in British Medical Journal (BMJ) evaluated the factors that speed up or slow the progression of aging. The author concluded that a diet high in energy and low in antioxidants increases biological age while the increased consumption of seafood, regular exercise, and anti-oxidant supplements slows brain aging. (Peters 2006) NAD+ supplementation is an important part of this regimen as it acts as an anti-oxidant and protects the brain from age-related degeneration.
Researchers at the University of Minnesota Medical School, Minneapolis demonstrated that reduction in NAD level occurs in the brain as we age. The percentage of this decline is different for different persons. It was also found that a low NAD level was associated with high CD38 activity, increased PARP, and low ATP levels. The authors also suggested that NAD supplements, CD38, and PARPS inhibitors could be given to boost NAD+level. This intervention offers neuroprotection, extends life span, and is useful to treat age-related metabolic disorders. (Zhu et al. 2015) The only supplement that can perform all these functions is Nicotinamide Adenine Dinucleotide, abbreviated as NAD or NAD+.
NAD+ is an essential coenzyme that is found in all living cells. It consists of two nucleotide groups that are joined by phosphate; one nucleotide contains nicotinamide base and the other adenine. It catalyzes many important redox reactions in which it serves as the electron donor. NAD+ supplementation is helpful for many chronic diseases like diabetes, chronic fatigue, fibromyalgia, anxiety, depression, and addiction. It also improves sleep quality by directly affecting our circadian rhythm. Another very important function of NAD is that it supports our immunity by performing many actions like activating T cells, increasing differentiation of immune cells, prolonging T cells survival, and macrophage activation. To read more about the role of NAD in boosting immunity check out this article NAD+ and immunity.
Another very important function of NAD+ that helps in mitochondrial dysfunction and neurodegenerative disorders is by regulation of neuroplasmalogens. The level of neuroplasmalogen is kept within a certain range by controlling its synthesis and degradation.NAD+ is critical for the biosynthesis of neuro-plasmalogens as it transfers high-energy electrons during the desaturation process of the plasmalogens synthesis.(Wykle and Schremmer Lockmiller 1975) When the level of NAD+ is low in the body, synthesis of neuroplasmalogen impairs and its breakdown continues; as a result level of neuroplasmalogen in our brain falls and results in inflammation, increased mitochondrial dysfunction, metabolic dysfunction, and aging. NAD+ supplementation, reduces neuroinflammation, cellular aging and restores the synthesis of neuroplasmalogen.(Hou et al. 2021; Tracey et al. 2018)
NAD+ slows the aging process of the brain and has a protective role against neurodegenerative diseases. There are “10 hallmarks of aging” and NAD+ supplementation protects against all. (Lautrup et al. 2019) The beneficial role of NAD+ in brain aging is summarized below:
1. Improves Mitochondrial function
2. Act as anti-oxidant and protect from oxidative damage
3. Reduce inflammation
4. Decrease aging of the brain stem cells
5. Promote DNA repair
6. Increase survival and communication between brain cells (glial survival and neuronal plasticity)
7. Decrease telomerase shortening
8. Improves waste disposal by increasing autophagy and mitophagy
9. Increase stress response
10. Corrects calcium dysregulation
So to summarize, it is not possible to stop the process of aging but we can improve lifestyle to delay cellular aging. A balanced diet, regular exercise, and NAD+ supplementation is a good regimens that should be followed to prevent age-related degeneration. NAD+ supplementation is also helpful for the prevention and treatment of neurodegenerative disorders like Alzheimer’s and Parkinson’s disease.
References:
Bozelli, José Carlos, Sayed Azher, and Richard M Epand. 2021. “Plasmalogens and Chronic Inflammatory Diseases .” Frontiers in Physiology . https://www.frontiersin.org/article/10.3389/fphys.2021.730829.
Eric, Verdin. 2015. “NAD+ in Aging, Metabolism, and Neurodegeneration.” Science 350 (6265): 1208–13. https://doi.org/10.1126/science.aac4854.
Heemels, Marie Thérèse. 2016. “Neurodegenerative Diseases.” Nature. 2016. https://doi.org/10.1038/539179a.
Hou, Yujun, Yong Wei, Sofie Lautrup, Beimeng Yang, Yue Wang, Stephanie Cordonnier, Mark P Mattson, Deborah L Croteau, and Vilhelm A Bohr. 2021. “NAD<Sup>+</Sup> Supplementation Reduces Neuroinflammation and Cell Senescence in a Transgenic Mouse Model of Alzheimer’s Disease via CGAS–STING.” Proceedings of the National Academy of Sciences 118 (37): e2011226118. https://doi.org/10.1073/pnas.2011226118.
Lautrup, Sofie, David A Sinclair, Mark P Mattson, and Evandro F Fang. 2019. “NAD(+) in Brain Aging and Neurodegenerative Disorders.” Cell Metabolism 30 (4): 630–55. https://doi.org/10.1016/j.cmet.2019.09.001.
Peters, R. 2006. “Ageing and the Brain.” Postgraduate Medical Journal 82 (964): 84 LP – 88. https://doi.org/10.1136/pgmj.2005.036665.
Tracey, Timothy J, Frederik J Steyn, Ernst J Wolvetang, and Shyuan T Ngo. 2018. “Neuronal Lipid Metabolism: Multiple Pathways Driving Functional Outcomes in Health and Disease .” Frontiers in Molecular Neuroscience . https://www.frontiersin.org/article/10.3389/fnmol.2018.00010.
Wykle, Robert L, and Jacalyn M Schremmer Lockmiller. 1975. “The Biosynthesis of Plasmalogens by Rat Brain: Involvement of the Microsomal Electron Transport System.” Biochimica et Biophysica Acta (BBA) - Lipids and Lipid Metabolism 380 (2): 291–98. https://doi.org/https://doi.org/10.1016/0005-2760(75)90015-6.
Zhu, Xiao-Hong, Ming Lu, Byeong-Yeul Lee, Kamil Ugurbil, and Wei Chen. 2015. “In Vivo NAD Assay Reveals the Intracellular NAD Contents and Redox State in Healthy Human Brain and Their Age Dependences.” Proceedings of the National Academy of Sciences of the United States of America 112 (9): 2876–81. https://doi.org/10.1073/pnas.1417921112.
