Qualy #57 - A primer on NAD+/NADH, its effect on lifespan/healthspan, and a review of the supplements
This Qualys episode, derived from a discussion with Rhonda Patrick, Ph.D., explores the role of NAD in mitochondrial function and DNA repair, and how its levels decline with age. It suggests fasting as a method to increase NAD.
Deep Dive Analysis
9 Topic Outline
Introduction to NAD and its precursors
Context: Age-related decline of NAD/NADH ratio
NAD's role in mitochondrial function and energy production
Sirtuins and their dependence on NAD
NAD's role in DNA repair via PARP enzyme
Impact of inflammation on NAD consumption
Metformin's potential effect on NAD and DNA repair
Animal and pilot human evidence for NAD precursor supplementation
Fasting as a method to increase NAD levels
5 Key Concepts
NAD (Nicotinamide Adenine Dinucleotide)
NAD is a critical cofactor for mitochondria, essential for energy production through the electron transport chain and for generating the mitochondrial membrane potential. It also serves as a crucial fuel for sirtuins, which regulate numerous pathways important for healthspan, and for DNA repair enzymes like PARP.
NAD/NADH Ratio
This ratio represents the balance between the oxidized (NAD) and reduced (NADH) forms of nicotinamide adenine dinucleotide. It is known to decline with age, and supplements containing NAD precursors aim to restore this balance, with claims of enhancing longevity and energy.
Sirtuins
Sirtuins are a class of histone deacetylases that require NAD as a cofactor to function. They are involved in regulating a wide array of cellular pathways and are considered very important for overall healthspan.
PARP (Poly ADP-ribose Polymerase)
PARP is a DNA repair enzyme that acts as a significant consumer, or 'sink,' for NAD. As individuals age, increased DNA damage activates PARP, which then consumes NAD, contributing to the observed decline in NAD levels.
Mitochondrial Membrane Potential
This potential is generated by the electron transport chain within mitochondria, which actively pumps out protons. It is fundamentally important for mitochondrial function, respiratory processes, and the overall production of cellular energy.
5 Questions Answered
These supplements are marketed with claims that they can enhance longevity, improve healthspan, and increase energy by addressing the age-related decline in the NAD to NADH ratio.
NAD is a vital cofactor for mitochondria, playing a key role in energy production and maintaining mitochondrial membrane potential. It also fuels sirtuins, which regulate many health-related pathways, and is essential for DNA repair enzymes like PARP.
NAD levels decline with age likely due to increased consumption by DNA repair enzymes (PARP) responding to more DNA damage, and by the immune system during inflammation. There may also be issues with the NAD salvage pathway.
Pilot clinical studies have shown that taking precursors like nicotinamide riboside can increase NAD levels in plasma in a dose-dependent manner. Animal studies suggest it can reach cells and improve mitochondrial function.
Fasting can increase NAD levels because in the absence of substrates like glucose or fatty acids, the body produces less NADH, allowing NAD to build up.
2 Actionable Insights
1. Increase NAD Through Fasting
Increase your NAD levels by fasting, as NAD starts to build up in the absence of glucose or fatty acid substrates.
2. Seek Professional Medical Advice
Do not use the information from this podcast as a substitute for professional medical advice, diagnoses, or treatment; always seek assistance from healthcare professionals for any medical conditions.
3 Key Quotes
if you're getting older you're going to have more dna damage that's just stochastic and if your little guy that repairs it requires nad as fuel right that would explain one reason potentially why nad would decline as we age
Peter Attia, MD
nad is a very important cofactor for mitochondria i mean obviously mitochondria are making nadh and the that hydrogen the proton is used and electrons are used to basically generate energy through the electron transport chain and it's also generating the mitochondrial membrane potential by kicking out the the proton so that that's really important for mitochondrial function respiratory function energy production which is like the key of everything right
Rhonda Patrick, Ph.D.
I don't know why I have found myself kind of skeptical of this I think it's good to start with skepticism
Rhonda Patrick, Ph.D.