NAD Levels Are Not Constant

It can be tempting to think that something so important, so fundamental to how our cells function and survive, would be protected at all costs. But we know that NAD levels are in a state of constant flux, with cells actively creating and consuming NAD. And we know that we can’t take NAD for granted -- not getting enough dietary NAD precursors leads to a nasty deficiency disease called Pellagra - the direct result of not having enough NAD in our cells [1]. 

Research has also given us insights into how NAD levels may change in sickness and in health. A rapidly growing body of evidence is revealing that decreased NAD levels are associated with a wide variety of diseases and physiologic stresses. Excess alcohol consumption, excess UV exposure, sleep deprivation, poor diet, infection and a sedentary lifestyle are among the physiologic stressors linked to NAD depletion [2, 3]. Conversely, studies in rodents and people are showing that healthy habits may be associated with higher levels of this valuable cellular resource. Across organisms -- from single-celled yeast to mice to humans -- researchers have also documented declining NAD levels with age. While there is some debate over the root cause of this decline (i.e. chronological aging vs. an accumulation of stressors over time) it is becoming clear that NAD is not something we can take for granted and could use some extra support as we age and experience physiologic stress at the cellular level.

Healthy lifestyle choices are associated with higher levels of NAD

  • Eating a whole food, balanced diet with plenty of B3s prevents NAD deficiency/maintains NAD

  • Exercise is associated with increased NAD

  • Caloric restriction (fasting) is associated with increased NAD

  • Supplementation with NAD precursors can also boost NAD beyond what is required to avoid a vitamin deficiency [4].

NAD stands for nicotinamide adenine dinucleotide. It is a molecule found in every cell in the body. NAD is used to power metabolism by enabling the mitochondria – the ‘power stations’ of the cell to convert the food we eat into the energy our body needs to sustain all its functions. It is also required to “turn on” genes implicated in cells’ response to stress [5-7].

Declining NAD associated with every day physiologic stressors: aging, disease, and overnutrition/alcohol consumption

Research in animal models suggests that there are a number of lifestyle and environmental factors that impact natural NAD levels [8-15]. A growing number of studies in rodents and humans are showing decreased NAD levels in association with aging, physiologic stress and a whole host of disease states.

FIGURE 1. Values for “% of normal” represent the approximate percentage of NAD+ observed compared to a young or healthy control. These have been estimated from graphs when not stated in the cited reference. In most cases, a decrease in NAD+ cannot b…

FIGURE 1. Values for “% of normal” represent the approximate percentage of NAD+ observed compared to a young or healthy control. These have been estimated from graphs when not stated in the cited reference. In most cases, a decrease in NAD+ cannot be distinguished from a shift in the NAD+/NADH ratio. [6, 15-42]

 

How do NAD levels change?

NAD levels, which can be influenced by changes in absolute NAD/NADH levels or shifts in NAD/NADH ratios, help cells modify their behaviors in response to changes in energy, nutrient availability, and stress. Cells are constantly synthesizing and consuming NAD. Synthesis of NAD is through the De Novo Pathway, Preiss-Handler Pathway and Salvage (or NR) Pathway. Scientists at prestigious research institutions have been investigating NAD boosting strategies as a therapy for degenerative conditions related to aging. Pre-clinical research indicates that NAD plays a unique role in cells’ innate immune response, muscle and tissue protection, as well as increasing lifespan [43, 44].

FIGURE 2. CONSUMPTION AND BIOSYNTHESIS OF NAD Figure adapted from Fang, E.F., et al., NAD(+) in Aging: Molecular Mechanisms and Translational Implications. Trends Mol Med, 2017. 23(10): p. 899-916.

FIGURE 2. CONSUMPTION AND BIOSYNTHESIS OF NAD Figure adapted from Fang, E.F., et al., NAD(+) in Aging: Molecular Mechanisms and Translational Implications. Trends Mol Med, 2017. 23(10): p. 899-916.

 

NAD consumption through enzymes such as sirtuins, Poly(ADP-ribose) polymerases (PARPS), and NADases are some of the ways NAD levels decrease with age or physiologic stress [45-47].  For example, researchers have observed that in aging rodents, NAD consumption increases while NAD synthesis activity declines, consistent with overall net decreases in NAD levels observed in aging in rodents and humans [46, 48]. In addition, NAD levels have been shown to be decreased through overnutrition, alcohol consumption, viral infection and a sedentary lifestyle in clinical and preclinical studies [6, 15, 22, 25, 36, 38, 49, 50].

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