The topic of NAD comes up in multiple episodes of the The Drive with Peter Attia, including David Sinclair and Chris Masterjohn. This summary is based partly on those conversations, as well as other public source material. This is a concept that involves many different and complicated pathways and I have tried to capture some of the relevant parts here. All mistakes are mine.

Summary

• Introduction.
• NAD and Cellular Respiration.
• Sirtuins Consume NAD+.
• NAD+ Precursors.
• Role of the Liver.
• Increasing NAD+?
• NAD and Fasting / Feeding.

Introduction

• Nicotinamide adenine dinucleotide (NAD).
  • Coenzyme found in all cells.
• NAD refers to both NAD+ and NADH:
  • Redox couple (see also “The Vital Question“).
  • NAD+ is the oxidized form.
  • NADH is the reduced form.
• Reduction reaction: NAD+ -> NADH:
  • NAD+ combines with one hydrogen molecule and two electrons.
  • Net result: a neutrally charged molecule.
• Oxidation reaction: NADH -> NAD+:
  • NADH loses its hydrogen molecule and two electrons.
• Seems like you want more NAD+.
  • Oxidizing agent needed for fundamental biological processes.
    • Needed in cellular respiration, as well clearing out alcohol in the liver.
  • Requirement for any sirtuin activity.
    • No NAD+, sirtuins don’t function properly.
    • NAD+ production lowers with age, obesity, inflammation.
• NAD+ flux:
  • Produced from NADH.
  • Used up by sirtuins and PARPs.
• If NAD+ is too low:
  • Don’t produce enough (from NADH) or used too much (by sirtuins).

NAD and Cellular Respiration

• Cellular respiration:
  • Glycolysis:
    • Simple sugar glucose is broken down.
    • Pyruvate is formed.
    • In an intermediate step, pyruvate is transformed into acetyl CoA.
  • Krebs Cycle (Citric Acid Cycle):
    • Aerobic process consisting of eight definite steps.
    • Acetyl CoA is modified to produce energy precursors.
  • Electron transport chain (Oxidative Phosphorylation):
    • Electron transport from the energy precursors leads to the phosphorylation of ADP, producing ATP.
• During glycolysis and the Krebs Cycle:
  • NAD+ combines with electrons (and H+) to form NADH .
• In the electron transport chain:
  • NADH loses its electrons (and H+) to form NAD+.
  • The transfer of electrons drives the pumping of (H+) protons across membranes.
  • As a proton gradient build up, the gradient allows us to make ATP.
• Requires oxygen:
  • Once the protons have cycled through the pump, they combine with oxygen to form water.
• ATP is produced during all three stages of respiration.
  • Greatest yield is during the electron transport chain.
• If there is no oxygen:
  • Fermentation replaces Krebs Cycle and electron transport chain.
  • In fermentation, NADH is oxidized and pyruvate forms lactic acid.
  • Limited production of ATP.
• This process involves the continuous cycling of NAD.
  • Continuous usage and formation of NAD+.

NAD+ Precursors

• Not an option to supplement with NAD+.
• Need to look for various precursors.
  • Most are variations of vitamin B3.
• Niacin (NA, nicotinic acid):
  • Known to lower LDL/VLDL and increase HDL.
  • Can cause flushing (widening blood vessels).
  • Gets converted into NAM (see below).
• Nicotinamide (NAM):
  • Derived from niacin and tryptophan.
  • Does not have the effect of skin flushing.
  • Found in: yeast, meat, fish, milk, eggs, green vegetables, and cereal grains.
  • Gets converted to nicotinamide mononucleotide (NMN):
    • NAM -> NMN -> NAD+.
  • When NAD+ is consumed by sirtuins, it forms NAM:
    • NAM acts as an inhibitor of sirtuins.
    • Negative feedback loop.
  • So, you need to deplete excess NAM or pee it out.
    • PNC1 gene depletes NAM.
    • PNC1 gene turned on by heat, caloric restriction, low amino acids and high salt.
• Nicotinamide riboside (“NR”):
  • Different NAD+ formation pathway.
  • Does not have the effect of skin flushing.
  • Advantage that it is not a sirtuin inhibitor.
  • Converted to NMN.
    • NMN converted to NAD+.
• Tryptophan.
  • Not B3 vitamin.
  • Complex and least efficient pathway to NAD+.

Role of the Liver

• Controls the NAD+ flux throughout the entire body.
  • Makes NAD+ for itself, as well as for the rest of the body.
• When NAD supplements (NR or NMN) are taken.
  • First, turned into NAD+ inside the liver.
  • The liver releases NAM into the blood stream as needed.
    • NAD+ only travels in the blood stream in the form of NAM.
  • NAM is delivered to cells.
  • Cells make the decision to use the NAM (convert it to NAD+).
  • Or, to methylate the NAM and pee it out.

 Increasing NAD+?

• Need to be careful, because NAD+ is a signaling molecule.
• Not clear what you are signaling by increasing NAD+ in blood stream.
• NR is most efficient and non-toxic way to increase NAD+ reserves in the liver.
• May have short-term positive results in areas of high damage (skin, gut).
• Long-term effects of genomic stability unclear.
• Potential issue is using up too many methyl groups to get rid of toxic NAM.

NAD and Fasting / Feeding

• In a fed state:
  • NAD+ is used in hundreds of metabolic reactions in the body.
  • Once the NAD+ is used up, this generates NADH.
  • NADH switches off Sirt1.
• Fasted state:
  • NAD+ is not used.
  • NAD+ switches on Sirt1.

NAD Supplements

• Several supplement products on the market.
  • Basis by Elysium.
    • NR + pterostilbene, a sirtuin activator.
    • https://www.elysiumhealth.com/en-us/
  • Tru Niagen by ChromaDEX
    • Does not have a sirtuin activator.