Much of the attention given to restoration of NAD+ levels examine its role in activating sirtuins. Scientific research, though, demonstrates NAD+ supplementation not only has beneficial effects on aging through sirtuin activity but also a variety of age-related disorders through improvement of adenosine triphosphate (ATP) levels.

ATP declines with age

ATP is the main source of fuel the body uses.  It gives each cell energy for essential processes such as muscle contraction or cellular biosynthesis.

ATP declines in erythrocytes with age (years) in healthy subjects (Rabini 1997)

As with NAD+, if people stop producing ATP, they would die almost immediately.

As with NAD+, also, levels of ATP decline with age, which is accompanied with a decline in physiological function as well as an increased risk of death.

As the chart displays above, ATP content is significantly greater in healthy, young individuals (16-40 years old) in comparison to ATP levels in older, healthy individuals (ages 41-91).5

How do levels of ATP influence aging?

Fibroblasts (the most common cells in connective tissue) exposed to hydrogen peroxide undergo cell death; however, the mode through which cell death takes place depends on levels of free ATP (Miyoshi, 2006).

Young cells (<60 years old) with higher levels of free ATP have significantly greater resistance to necrosis caused by exposure to hydrogen peroxide than cells older than 60 years.

When cells, old or young, are treated with ATP synthesis inhibitors such as oligomycin, they become more susceptible to death.  They also switch the mode of death from apoptosis (programmed cell death) to necrosis (uncontrolled death).

ATP’s roll in cell death

ATP levels in cells determine mode of cell death (Tsujimoto, 1997)

Apoptosis is conserved evolutionarily as a mode of cell death, involving chromatin condensation, nucleus fragmentation, and apoptotic body formation.  It is essential for effective removal of unnecessary cells.

Necrosis, though, is a rapid process, involving dysregulation of ion homeostasis.  This situation leads to cell swelling and dilation of mitochondria. The integrity of the plasma membrane erodes, and the resulting leakage of the cytoplasm induces necrotic inflammation.

Cells with lower ATP levels have been observed to switch from apoptosis to necrosis.  The switch may be responsible for onset of age-dependent disorders.

ATP and age-related diseases

A vast range of conditions have been linked to mitochondrial dysfunction and low ATP levels (Nicolson, 2014).

  • Neurodegenerative disorders:
    • Alzheimer’s disease
    • Parkinson’s disease
    • Huntington’s disease
  • Cardiovascular diseases:
    • Atherosclerosis
  • Autoimmune diseases:
    • Multiple sclerosis
    • Systemic lupus erythematosus
    • Type 1 diabetes
  • Neurobehavioral and psychiatric diseases
    • Autism spectrum disorders
    • Schizophrenia
    • Bipolar disorder
  • Gastrointestinal disorders
  • Fatiguing illnesses:
    • Chronic fatigue syndrome
    • Gulf War illness
  • Musculoskeletal diseases
    • Fibromyalgia
    • Skeletal muscle atrophy
  • Cancer
  • Chronic infections

ATP supplements do not restore ATP levels

Taking ATP supplements to mitigate necrotic inflammation would be nice.  Unfortunately, using oral ATP supplements has been shown to be ineffective.1

Orally administered ATP supplements are not bioavailable

In a randomized, placebo-controlled study, subjects take single dosages of 5,000 mg of ATP or placebo.  To be sure the ATP does not undergo degradation in the acidic stomach environment, the supplement is administered with two types of pH-sensitive, enteric-coated pellets (release in the distal or proximal intestine), or by a naso-duodenal tube.  Following administration, blood ATP and metabolite levels are monitored.

None of these ATP supplementation methods lead to increased ATP or adenosine concentrations in blood.  The ATP administered is degraded to uric acid by xanthine oxidase—an enzyme primarily expressed in the liver and endothelial cells in blood vessels.

NAD+ supplementation restores ATP levels

NAD+ is known to restore healthy concentrations of ATP in cells.

This is particularly interesting in studies of Mitochondrial DNA Depletion Syndromes, characterized by reductions in mitochondrial DNA and ATP production.  Liver failure usually leads to death in infancy in these rare disorders.

In humans, administration of NAD+ by IV is demonstrated to raise levels of ADPR (an ATP precursor) by 400%

A recent study2 uses approximately 2,400 drugs to find which of the drugs restore ATP levels.  They identify 15 drugs successfully, which influence a variety of metabolic processes and which increase ATP levels significantly.

Of the drugs, the one with the most significant impact on the production of ATP is NAD+.

The researchers demonstrate NAD+ activating a transcriptional cascade, resulting in increased mitochondrial protein expression involved in ATP production.

This finding is validated further in DGUOK-deficient rats (the rats have livers with impaired ATP production).

Giving nicotinamide riboside (NR), an NAD+ precursor, improves ATP levels significantly.  This finding offers promise for prevention and treatment of affected patients.

NAD+ in the bloodstream elevates ATP inside cells

Treatment with NAD+ significantly increases ATP levels in cells (Zhang, 2018)

NAD+ plays a role in many important biological processes, including energy metabolism DNA repair, mitochondrial activity, and cell death.

How does NAD+ improve ATP levels?

A recent study7 demonstrates in BV2 microglia, NAD+ effects are produced from its degradation product, adenosine, as follows:

  1.  NAD+ degradation to adenosine occurs outside of the cells.
  2. Adenosine enters BV2 microglia through nucleoside transporters under basal conditions.
  3. Adenosine in cells gets converted to AMP by adenosine kinase, increasing the ATP.


The many associations between dysfunctional mitochondria and a wide array of disorders show the importance of mitochondrial health for overall health and longevity.

Restoring ATP levels through NAD+ supplements could alleviate symptoms in mitochondrial DNA depletion syndromes and in many other age-associated conditions.

Supplementing NAD+ is effective for increasing ATP concentrations in cells.