Illustration of cells and molecules representing NAD+ decline caused by aging, metabolic stress, and disease.

NAD+ Depletion: The Role of Age, Metabolic Stress, and Disease in NAD+ Decline

Key Takeaways:

  • NAD+ is a critical molecule involved in energy production, DNA repair, cellular metabolism, and overall cellular health. 
  • NAD+ levels in the body are constantly in flux—cells are always synthesizing and consuming it, and its levels can decline with age, lifestyle, metabolic stress, and disease.
  • Two major mechanisms drive NAD+ depletion: declining production and increased consumption via enzymes activated during DNA repair, inflammation, and immune responses.
  • Everyday stressors—including alcohol consumption, overnutrition, UV exposure, viral infections, and a sedentary lifestyle can cause NAD+ depletion.
  • Lifestyle strategies and supplementation can help maintain NAD+ levels and support cellular resilience.

From single-celled organisms to humans, life depends on the molecule nicotinamide adenine dinucleotide (NAD+). This essential molecule plays a critical role in hundreds of cellular processes, including energy production, DNA repair, metabolism regulation, and mitochondrial function.¹ In many ways, NAD+ acts as both an energy source and a signaling molecule, helping power cellular processes while also guiding cells in response to stress and environmental changes.

NAD+ levels are dynamic, constantly fluctuating in response to metabolic demands, circadian rhythms, and immune activity.²'³ While the body can recycle NAD+, this process becomes less efficient with age.⁴ Meanwhile, cellular processes such as repair, immune responses, chronic inflammation, and metabolic stress can deplete NAD+ faster than it can be replaced,⁵ gradually lowering cellular reserves.

Low NAD+ levels can impair energy production, accelerate aging, and contribute to the onset of age-related diseases.⁵ Understanding why NAD+ declines—and how lifestyle and cellular processes influence this decline—offers valuable insight into supporting cellular function and resilience throughout life.

Why NAD+ Declines with Age: A Dual Mechanism

Despite its central role in hundreds of cellular processes, NAD+ levels naturally decline with age. This phenomenon has been observed across various biofluids and tissues, including saliva,⁶ whole blood,⁷ red blood cells,⁸ muscle,⁹ brain,¹⁰'¹¹ liver,¹² and skin.¹³ Consequences of this decline include impaired mitochondrial function, reduced DNA repair, decreased metabolic activity, and lower cellular resilience.¹⁴

Research suggests that age-related NAD+ decline occurs through two primary mechanisms: impaired NAD+ production and increased NAD+ consumption.⁵

1. Impaired NAD+ Production

NAD+ can be produced through multiple biochemical pathways:¹⁵

  • De-Novo Pathway: via tryptophan
  • Preiss-Handler Pathway: via niacin
  • Salvage Pathway: via nicotinamide
  • Nicotinamide Riboside Kinase (NRK) Pathway: via nicotinamide riboside

However, with age, some of these pathways become less efficient. For instance, the key enzyme in the salvage pathway, nicotinamide phosphoribosyltransferase (NAMPT), decreases in activity with age,⁴ creating a bottleneck in NAD+ production. This inefficiency prevents cells from recycling nicotinamide into NAD+ as effectively, leading to a drop in overall NAD+ levels. Additionally, other precursors such as niacin and tryptophan require longer, more energy-intensive pathways,¹⁶ which means that even with adequate intake of these precursors, the body may still struggle to maintain NAD+ levels.

2. Increased NAD+ Consumption 

NAD+ is continually consumed by enzymes that regulate cellular health and repair, such as: 

  • PARPs (poly ADP-ribose polymerases): Family of enzymes that consume NAD+ during DNA repair and maintenance⁵
  • Sirtuins: NAD-dependent enzymes that regulate cellular stress responses and metabolism¹⁷
  • CD38: An enzyme that breaks down NAD+ to generate signaling molecules⁵

Aging, chronic inflammation, oxidative stress, and infections activate these enzymes, accelerating NAD+ depletion. Notably, CD38 levels increase with age and inflammation, further draining cellular NAD+ pools.⁵

In essence, aging sets the stage for a "perfect storm": NAD+ production gradually slows while consumption accelerates, steadily depleting cellular reserves. This imbalance creates a vicious cycle, leaving cells more vulnerable to energy deficits, impaired DNA repair, and metabolic stress.

A simple way to visualize this is to imagine NAD+ as water in a sink: the faucet represents production, and the drain represents consumption. With age, the faucet slows while the drain widens, preventing the sink from filling. As a result, cells are left with insufficient NAD+ to meet their energy and repair needs.

Metabolic Stressors That Deplete NAD+

Beyond aging, several common lifestyle and environmental factors contribute to NAD+ decline:

  • Overnutrition (High-Fat/High-Sugar Diets): Dietary excess has a profound effect on NAD+ metabolism. Research shows that just two months of a high-fat diet can reduce skeletal muscle NAD+ levels.¹⁸ Moreover, among clinically healthy individuals, obesity was associated with lower NAMPT expression and higher PARP activity, indicating both reduced NAD+ production and increased NAD+ consumption. Together, these factors create a dual mechanism that accelerates NAD+ depletion.¹⁹

  • Alcohol Consumption: Regular alcohol intake—more than one drink per day—has been linked to lower NAD+ levels in cerebrospinal fluid.²⁰ Individuals who reported drinking also had increased markers of inflammation and oxidative stress. 

  • Sedentary Lifestyle: Physical inactivity is associated with reduced NAMPT activity, indicating reduced NAD+ production,²¹ leaving cells more vulnerable to metabolic stress.

  • Excess Sun Exposure: Research shows that ultraviolet (UV) radiation, including ultraviolet A (UVA) and ultraviolet B (UVB), rapidly activates PARP enzymes in human skin cells to repair DNA damage.²² This surge in PARP activity resulted in a sharp decline in cellular NAD+ levels, that has also been observed in additional studies.²²'²³

  • Immune Stress: Viral infections—including human immunodeficiency virus (HIV) and SARS-CoV-2—can significantly lower NAD+ levels. For example, individuals with HIV have reduced muscle NAD+, which is further decreased when co-infected with additional viruses.²⁴ In COVID-19, NAD+ levels in blood are modestly reduced, but NAD+ turnover is sharply increased as the body works harder to replace it.²⁵

  • Environmental/Lifestyle Factors: Exposure to environmental factors such as traffic-related air pollution or cigarette smoke induces oxidative stress,²⁶⁻²⁹ a major driver of NAD+ depletion. Cigarette smoke directly lowers NAD+ levels in lung epithelial cells,²⁸ consistent with preclinical findings of NAD+ depletion following exposure to cigarette smoke.³⁰

Repeated exposure to metabolic stressors can increase the body’s demand for NAD+ and activate NAD-consuming enzymes like sirtuins and PARPs, further depleting its supply. As NAD+ levels drop, cells become less efficient at generating energy, repairing DNA, and mounting effective stress responses.¹⁴ Over time, this decline can contribute to the development and progression of age-related conditions.

Health Conditions and Diseases Associated with NAD+ Decline

A growing body of evidence shows that low or declining NAD+ is associated with a wide range of diseases and health conditions (Figure 1):

  • Autoimmune Diseases: Patients with rheumatoid arthritis display reduced NAD+ levels and altered activity of NAD-consuming enzymes, including PARPs, sirtuins, and CD38.³¹ Those with the lowest NAD+ exhibit the highest inflammation and disease activity, highlighting the link between NAD+ depletion (particularly via CD38), chronic inflammation, and disease progression.

  • Cancer: Preliminary research has shown low NAD+ levels, or levels at the lower end of the normal range, in pancreatic, breast, lung, and ovarian cancers.³²

  • Cardiovascular Diseases: Elderly patients hospitalized for decompensated heart failure exhibit significantly lower blood NAD+ than healthy controls.³³

  • Liver Diseases: Patients with alcohol-related liver disease (ArLD) show markedly depressed NAD+ in liver tissue.³⁴ More severe damage, such as steatohepatitis, is associated with even lower NAD+ and impaired liver function, as indicated by elevated bilirubin.

  • Mitochondrial Disorders: Adults with mitochondrial myopathy exhibit systemic NAD+ deficiency, with reduced levels observed in both blood and muscle tissue.³⁵

  • Musculoskeletal Disorders: Cartilage samples obtained from the femur (thigh bone) of patients with osteoarthritis reveal a marked decline in NAD+ and total NAD levels in severely damaged tissue compared to healthy cartilage.³⁶ This reduction is accompanied by a significant increase in the NAD-consuming enzyme PARP14, suggesting that NAD+ depletion in human osteoarthritis arises from both impaired production and enhanced consumption.

  • Neurodegenerative Diseases: Research shows that NAD+ depletion is observed in age-related neurodegenerative diseases like Parkinson’s and Alzheimer’s disease.³² More specifically, both NAD+ and NADH were shown to decline together, keeping the NAD+/NADH ratio relatively stable, but lowering the total cellular redox capacity. This reduction weakens mitochondrial function and impairs cellular resilience.

  • Psychiatric Disorders: Patients with non-affective psychotic disorders (such as schizophrenia and related conditions) and those with bipolar I disorder with psychotic features who also exhibited cognitive dysfunction exhibit lower NAD+/NADH ratios, reflecting increased reductive stress and impaired cellular energy metabolism in the brain.³⁷ This is consistent with other research showing NAD+ metabolism is dysregulated across psychotic disorders, including schizophrenia, schizoaffective disorder, bipolar disorder, and major depressive disorder with psychotic features.³⁸'³⁹

  • Reproductive Health Disorders: Fibroid tissues exhibit significantly lower NAD+ levels compared to adjacent healthy myometrium (uterine muscle), indicating impaired energy metabolism.⁴⁰ Similarly, granulosa cells from women with polycystic ovarian syndrome (PCOS) show reduced NAD+ alongside increased oxidative stress, mitochondrial dysfunction, and pro-inflammatory gene expression.⁴¹

  • Viral Infections: HIV infection reduces skeletal muscle NAD+, an effect amplified by co-infections with hepatitis C or cytomegalovirus.²⁴ Lower NAD+ levels were also linked to higher inflammation, suggesting that viral infections and inflammation may drain the body’s cellular resources. Additionally, COVID-19 modestly reduces blood NAD+ but markedly increases NAD+ turnover,²⁵ reflecting accelerated consumption and repair demands, and highlighting the energetic strain caused by viral infections.

In many of these conditions, NAD+ depletion acts as both a consequence of heightened metabolic or inflammatory stress and as a driver of further dysfunction. Excessive activation of NAD-consuming enzymes (especially PARPs and CD38), mitochondrial impairment, and sustained inflammation create a cycle in which depleted NAD+ pools reduce cellular resilience, further promoting disease progression.³¹

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.

How to Support NAD+ Levels

Due to the increasingly growing research demonstrating declining NAD+ levels with age, metabolic stressors, and disease, maintaining NAD+ levels is gaining recognition as a vital strategy to support healthy aging and enhance cellular resilience. While aging, metabolic stress, and health conditions/diseases can naturally reduce NAD+ in the body, multiple approaches have been shown to help elevate and maintain it. Effective strategies include:

For a more in-depth look at increasing NAD+, including supplements, lifestyle strategies, and the resulting benefits, read: "How to Increase NAD+ Levels."

Conclusion

NAD+ is indispensable for energy production, DNA repair, and overall cellular health. Its levels are constantly in flux, reflecting the balance between production and consumption. Aging, metabolic stress, and disease challenge this balance, but understanding these mechanisms provides a roadmap for interventions aimed at slowing age-related cellular deterioration.

Maintaining adequate NAD+ is increasingly recognized as a key strategy for promoting healthy aging and enhancing cellular resilience. By supporting NAD+ through targeted lifestyle choices—such as exercise, a nutrient-rich diet, and intermittent fasting—and, when appropriate, supplementation, it’s possible to preserve cellular energy, bolster metabolic health, and help sustain vitality over the lifespan.


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