NAD, the anti-aging, anti-Alzheimer’s, wonder compound is back in the news and for good reason.  It assists with many important cellular functions that not only keep you healthy, but may help you live longer.  The real beauty of NAD is how easy it is to correct a deficiency.

Discovered in 1906, NAD research was quiet for the next 30 years until several important discoveries were made about its basic functions.  Research slogged along with a significant discovery every 10 years or so.  Then in 2000 NAD research gained huge momentum after MIT researchers discovered NAD dependent proteins called Sirtuins that effect aging.

The Basics

NAD is a “helper molecule” that assists in biochemical reactions.  These helpers are known as cofactors and are either organic or inorganic (electrolytes).  Organic cofactors are called co-enzymes (although usually written without the hyphen) and are derived from vitamins (B3 in this case) or other organic nutrients (e.g. tryptophan).

The terminology around this very important co-enzyme can be a bit confusing.  So before delving further into the numerous benefits of NAD lets clear up some terms.  You might hear or read about NAD, NAD+, NADH, Nicotinamide, and Nicotinamide Riboside or maybe even a few others as well.  Don’t fret!  For our intents and purposes these are all the same.  I’ll explain some of the differences, but when it comes to average conversation you can do what most people do and use the catch-all term NAD.

NAD, or nicotinamide adenine dinucleotide, is formed from precursors from the vitamin B3 family.  If NAD is oxidated it is written as NAD+, if reduced it is written as NADH.  NAD switches back and forth from one state to the other so again…let’s just call it NAD.

The B3 family is usually listed as having 3 members, Niacin, Nicotinamide and one more, but that third member is usually a derivative or manipulated form of Niacin.  Niacin cannot be directly converted to nicotinamide, but both are precursors of NAD.  Niacin can, however, be converted to Nicotinamide Riboside (NR) or Nicotinamide Mononucleotide (NMN) and each of those can be transformed into the other or into NAD.

I picture the hierarchy like this:

  • NAD (either NAD+ or NADH)
    • B3 – Nicotinamide
    • B3 – Niacin
      • Nicotinamide Riboside (NR) ⇔ Nicotinamide Mononucleotide (NMN)

All NAD precursors outside the cell can produce NAD inside the cell, but the most likely mechanism for getting into the cell is by first being reduced to NR.  That’s reassuring because most NAD supplements are really NR, so you’re taking the precursor that is most likely to gain entry into the cell where it can be converted to NAD.

NAD and Sirtuins

Since their discovery in 2000, seven SIRT (pronounced SIR-T) genes have been discovered.  Numbered SIRT1-7 each gene expresses a protein of the same name.  SIRT1, SIRT6, and SIRT7 are nuclear; SIRT3, SIRT4, and SIRT5 are mitochondrial; and SIRT2 is cytoplasmic.  These proteins are NAD dependent meaning they cannot perform their functions unless they find a NAD molecule.

The NAD/Sirtuin combination influences a wide range of cellular processes such as aging, rRNA transcription, mitochondrial biogenesis, apoptosis, inflammation, stress resistance, and insulin sensitivity.

Sirtuins can also regulate the circadian clock.  This gets interesting because melatonin is most closely associated with the circadian clock and like the NAD precursors melatonin is synthesized from tryptophan.  Although through a different pathway and in the case of melatonin the conversion process is controlled by enzymes that are inhibited by light and stimulated by dark.  The interplay between sirtuin and melatonin is still uncertain, but the circadian clock has been shown to malfunction in the absence of sirtuin.

The benefits listed above are attributed to either NAD or sirtuins, but of course you can’t have one without the other.  That said, NAD is involved in one or more processes that have nothing to do with sirtuins.

Deficiencies

The benefits of NAD and sirtuins are well publicized, but we can underscore these by looking at the effects of a deficiency.

B3 deficiency can get pretty ugly.  Since all the B vitamins are water-soluble and thus cannot be stored in the body, we need to maintain a steady supply through our diets.  If you go too long without (or your high alcohol consumption interferes with absorption) you can develop indigestion, fatigue, canker sores, vomiting, poor circulation, and depression.

If one continues down this path the results can be a condition called pellagra, which is characterized by diarrhea, cracked and scaly skin, and dementia.  Pellagra was first identified in the 1700s and was still killing people in the early 1900s.  Diet was suspected early on, but it was not until 1926 that pellagra preventing foods were identified and it wasn’t until 1937 that niacin was shown to cure the disease.

Sirtuins expressed during a NAD deficiency are not functional.  This results in diminished mitochondrial gene expression and mitochondrial dysfunction which has been linked to cognitive impairment and dementia.  It also suppresses mitochondrial oxidative metabolism and reduces anti-oxidant defense pathways which leads to oxidative stress.  A reduction in SIRT1 reduces sleep quality and increases fat storage even when there has been no change to one’s food intake.

The Effects of Aging

PARP (Poly ADP-ribose polymerase), a family of proteins involved in a number of cellular processes such as DNA repair, genomic stability, and apoptosis is also NAD dependent.  This means that PARP and NAD compete for available NAD within the cell.  Two factors of aging, reduced NAD production and increased DNA damage, turn this into a real problem.  As the cell shifts NAD use to supporting the DNA repair activities of PARP, the remaining NAD levels can’t support sirtuin activities.  It’s like the cell has shifted to crises management.

Another factor of aging involves NAMPT, an enzyme encoded by the NAMPT gene that enables NAD biosynthesis.  The current thinking is that pressure from oxidative stress or inflammation disrupts the expression of NAMPT.  In other words, two underlying causes of Alzheimer’s produce a reduction in NAD synthesis that would starve one or both processes (PARP and Sirtuins) and result in impaired DNA repair and impaired mitochondrial biogenesis – both of which are hallmarks of Alzheimer’s.

Supplementation

While the effects of vitamin deficiency and age related deficiency are worrisome, the solution is surprisingly simple.  Supplementation with NR has been shown to increase levels of NAD in tissue, in the brain, and to reverse the ill effects listed above (in mice and humans).

Final Thoughts

It’s rare in Alzheimer’s research that you come across something that checks off so many Alzheimer’s related boxes (oxidative stress, inflammation, mitochondrial dysfunction, DNA repair, sleep, apoptosis, and more) and does it in three different areas (causes, prevention, and treatment).  Rarer still is the problem (a lack of NAD) with such an easy solution.