Nicotinamide adenine dinucleotide (NAD) is a vitally important molecule found in all living cells. Its primary function was considered to be as a co-enzyme in the energy-harnessing processes within cells. Here the oxidised form NAD+ is reduced to NADH (redox reactions). However, we know that NAD+ has a multiplicity of other functions. Of particular significance is that many innate cellular repair mechanisms are dependent on NAD+ as a precursor (substrate). Reduced levels of NAD+ will impact on cellular repair processes which could result in the development of disease and enhancement of the aging process. NAD+ therapy may well have exciting therapeutic repercussions.
Oxidative phosphorylation in mitochondria is the major cause of oxidative stress. Excess levels of which are a feature of many diseases as well as the aging process. Reactive oxygen species (ROS) are formed and their high reactivity means that they can bind with macro-molecules, for example proteins, lipids and DNA. The mitochondrial membrane can be severely affected by this process; mitochondrial dysfunction is a feature of many degenerative diseases. This will adversely affect energy production. In addiction membrane potentials, DNA stability and cell integrity (potentially leading to cell death) will also be affected. Oxidative stress causes single strand breaks in DNA, repair of which is facilitated by the nuclear repair enzyme poly(ADP-ribose) polymerase (PARP). Over- activation of PARPs interferes with gene transcription and of histone deacetylases known as sirtuins. They are essential for the control of gene-expression, cell cycle regulation and DNA repair. Their activity is also dependent on intra-cellular NAD+ content; depleting NAD+ levels secondary to PARP activation therefore further increases the likelihood of cell death.
NAD+ has been reported to have beneficial effects in both acute and chronic conditions of the nervous system as well as numerous systemic diseases. Is it possible there is a common factor to explain these diverse effects?
Excessive oxidative stress is a feature of conditions ranging from neurodegenerative disorders (Parkinson's disease, Alzheimer's disease, Motor Neuron Disease), acute neurological conditions (trauma, hypoxia, epilepsy), drug and alcohol addiction, presumed auto-immune disorders (Chronic Fatigue Syndrome, Lupus, Fibromyalgia, Multiple Sclerosis, Rheumatoid Arthritis), genetic diseases (Muscular Dystrophies, Mitochondrial diseases, Huntington's Disease) and metabolic diseases (Diabetes type 2, respiratory and cardiovascular disease) as well as the aging process itself.
Cumulative oxidative stress sets off a cascade of cellular reactions resulting in the liberation of highly reactive substances termed reactive oxygen species (ROS) which can cause lipid, protein and DNA damage. Probably the two most important cellular repair mechanisms involve the enzymes Sirtuins and PARPs, both require NAD+ as a substrate. Increasing oxidative stress will, therefore, deplete NAD+ levels. It seems reasonable to suggest that replenishing NAD+ will help in the fight against many diseases as well as ameliorating the aging process.