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NAD and age-related diseases

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What is NAD?

Nicotinamide adenine dinucleotide (NAD) is a necessary molecule for maintaining life and is found in every cell. NAD is involved in redox reactions and comes in two forms: NAD+ and NADH. Insufficient NAD is involved in five out of the nine hallmarks of aging and can increase the risks of age-related diseases such as cancer, stroke, heart disease, diabetes, and neurodegenerative diseases.

Energy metabolism

NAD is necessary for major energy pathways such as glycolysis, the Krebs cycle, and oxidative phosphorylation. All of these pathways produce the body’s energy currency: ATP. When NAD is not available, cells can’t produce enough ATP to sustain important biological processes which leads to suboptimal health.

Sirtuins: aging regulators

Sirtuins are enzymes that require NAD+ to function and are involved in five hallmarks of aging. When there are healthy amounts of sirtuins and NAD+ cofactors, they inhibit the hallmarks: epigenetic alterations, mitochondrial dysfunction, deregegulated nutrient sensing, genomic instability, and cellular senescence.

DNA repair

The PARP enzymes use NAD to repair DNA to prevent genomic instability, a hallmark of aging.

The sirtuin enzymes also help prevent genomic instability by helping FOXO transcription factors to bind to DNA and express antioxidant enzymes to protect cells from oxidative stress.

NAD deficiency accelerates the hallmarks of aging

When the body does not have enough NAD, all of the above roles are harmed. Without enough NAD, genomic instability, epigenetic alterations, deregulated nutrient sensing, and poor energy metabolism hurt wellness and promote aging. NAD declines with age because it is consumed by enzymes, mainly CD38.

Hallmarks of aging affected by NAD HallmarkDescriptionNAD’s roleEpigenetic alterationEach of you cells share the same DNA. Epigenetics is what decides which pieces of DNA to use to make proteins and is the reason we have different cell types. With age, our cells become confused and lose some of their ability to function properly within their cell types.Loss of proteostasisProteostasis is the ability of a cell to make stable, functioning proteins. As we age, some cells lose the ability to do this well. Instead, they make ineffective or harmful proteins.Mitochondrial dysfunctionMitochondria generate energy in the form of the ATP molecule via the Krebs cycle and oxidative phosphorylation. These processes are called respiration and produce free radicals that can harm the cell in large numbers. As we age our mitochondria become dysfunctional by producing less ATP and more free radicals.SenescenceSenescent cells are those that stop dividing. This is a good mechanism for preventing cancer, but it can be harmful because it causes cells to release inflammatory molecules into the body and contribute to chronic inflammation.Deregulated nutrient sensingCells respond to the availability of nutrients in the diet through different pathways. When nutrient sensing is deregulated, cells don’t respond well to nutrients which can lead to conditions such as insulin insensitivity.

What are the risk factors for NAD deficiency?

NAD declines with age and contributes to disease

Obesity is also a risk factor for NAD depletion, possibly because it contributes to chronic inflammation, which causes DNA damage, requires NAD+-consuming PARP hyperactivation.

NAD deficiency is a common central pathological factor of a number of diseases and aging: cerebral ischemia, myocardial ischemia, diabetes, cancer, metabolic, neurodegenerative diseases, and other age-associated pathologies.

How can you optimize your NAD levels?


NAD precursor supplements such as NR and NMN have been shown to raise NAD levels in humans.

Diet and exercise

Obesity is associated with reduced expression of NAD and sirtuins, whereas increases NAD and sirtuin expression.

Exercise has been shown to increase activity of an NAD-synthesizing enzyme called NAMPT.

Reprinted from “Srivastava S. Emerging therapeutic roles for NAD(+) metabolism in mitochondrial and age-related disorders. Clin Transl Med. 2016;5(1):25. doi:10.1186/s40169-016-0104-7”

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