#050 NAD+ in Aging: Role of Nicotinamide Riboside and Nicotinamide Mononucleotide
Rhonda provides a comprehensive overview of NAD+, its crucial role in aging and cellular energy, and why its levels decline with age. She discusses lifestyle factors like exercise and fasting that raise NAD, dietary sources, and the current research on NAD boosters (NMN & NR), including their potential benefits and concerns regarding dosage and cancer.
Deep Dive Analysis
14 Topic Outline
Introduction to NAD+ and NAD Boosters
NAD+ Decline with Age and Hallmarks of Aging
NAD+'s Critical Role in Energy Metabolism
NAD+'s Role in DNA Repair and PARP-1 Activity
NAD+ and Sirtuins: Epigenetic Regulation
Consequences of NAD+ Depletion and Health Span
NAD+ Synthesis, Recycling, and Salvage Pathway
NAD Boosters (NR & NMN): Animal Study Benefits
Potential Cancer Growth Concerns with NAD Boosters
Dosing and Bioavailability Challenges in Animal Studies
Direct vs. Salvage Pathway Transport of NAD Boosters
Challenges of Direct NAD+ Supplementation
Human Clinical Trial Findings for Nicotinamide Riboside
Recap and Concluding Thoughts on NAD+ Boosters
6 Key Concepts
NAD+ (Nicotinamide Adenine Dinucleotide)
NAD+ is a crucial molecule for life, playing a critical role in energy metabolism by participating in redox reactions essential for glucose and fatty acid metabolism and ATP formation. It also acts as a cofactor for many important enzymes, including those involved in DNA repair and longevity-related sirtuins.
NAD Boosters
NAD boosters refer to precursor molecules like nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN), which are available as supplements. In animal studies, high doses of these compounds have been shown to raise NAD+ levels and improve the aging process in various tissues and cell types.
Sirtuins
Sirtuins are highly conserved enzymes that utilize NAD+ to regulate health span and longevity in multiple organisms. They achieve this through epigenetic regulation, removing acetyl groups from cellular proteins to control genes involved in energy metabolism, autophagy, circadian rhythm, DNA repair, and cell survival.
PARP-1 (Poly-ADP Ribose Polymerase 1)
PARP-1 is a critical enzyme involved in repairing DNA damage, and its activation requires a substantial amount of NAD+. Higher PARP-1 activity has been correlated with longer lifespans in mammals, highlighting its importance for genomic stability and longevity.
NAD Salvage Pathway
This is the predominant recycling mechanism in the body for producing NAD+. When enzymes consume NAD+, they generate nicotinamide as a byproduct, which is then converted back into nicotinamide mononucleotide and subsequently into NAD+ through this pathway, though it is subject to feedback inhibition by NAD+ levels.
Senescent Cells
Senescent cells are cells that have stopped dividing and can disrupt normal tissue functions, ironically driving cancer progression over time despite their short-term role in preventing cancer. They secrete pro-inflammatory molecules involved in immune activation, growth signaling, and angiogenesis, which can contribute to tumor development.
8 Questions Answered
NAD+ is a crucial molecule for life, playing a critical role in energy metabolism, DNA repair, and activating longevity-related enzymes called sirtuins. Without it, cells cannot produce energy or repair DNA effectively.
As we age, chronic inflammation and immune activation increase, consuming more NAD+ for DNA repair. Simultaneously, the body's ability to produce and recycle NAD+ tends to decrease.
NAD+ levels can be raised through lifestyle factors like exercise, fasting, and caloric restriction. Additionally, NAD+ precursors like nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN), known as NAD boosters, can increase NAD+ levels.
A recent study showed NMN accelerated cancer growth in mice with a specific type of pancreatic cancer driven by pro-inflammatory senescent cells. This effect was dependent on these senescent cells, suggesting NAD+ might make them more tumorogenic, but it doesn't mean it causes cancer or drives other types of tumor progression.
Direct NAD+ supplementation has poor bioavailability when taken orally, as it's primarily digested into precursors. While intravenous NAD+ might bypass digestion, no mammalian NAD+ transporter has been identified, and extracellular NAD+ is not consistently taken up by tissues other than potentially the brain and heart.
Short-term clinical trials show oral nicotinamide riboside can increase NAD+ levels in white blood cells and whole blood in a dose-dependent manner, and some studies noted reduced diastolic blood pressure. However, long-term safety and efficacy in humans for broader health benefits are still largely unknown, and human doses tested are much lower than effective animal study doses.
The major source of NAD+ in the body is through a recycling mechanism called the NAD salvage pathway, which converts nicotinamide (a byproduct of NAD+ consumption) back into NAD+. Dietary sources are not sufficient to meet the body's high demand.
Isotope tracer studies in animals suggest that neither nicotinamide riboside nor nicotinamide mononucleotide directly cross the blood-brain barrier. However, they are converted into nicotinamide, which can be transported into the brain and then form NAD+.
7 Actionable Insights
1. Boost NAD Through Lifestyle
Increase your NAD levels by engaging in exercise, fasting, or caloric restriction, as these activities cause energy stress which has been shown to raise NAD.
2. Increase NAD Through Diet
Incorporate foods rich in tryptophan (like salmon, spinach, and nuts) and niacin/vitamin B3 (such as lean meats, legumes, and veggies) into your diet, as these are sources from which NAD can be synthesized in the body.
3. Consider NAD Booster Supplements
You may consider supplementing with nicotinamide riboside (NR) or nicotinamide mononucleotide (NMN) to potentially raise NAD levels, though most promising data comes from very high doses in animal studies, and human efficacy and long-term safety are still under investigation.
4. Store NAD Boosters Properly
If you choose to use NAD booster supplements like NR or NMN, keep them cold and ensure they are sourced from manufacturers who store them properly to prevent breakdown into nicotinamide, which may reduce sirtuin activation.
5. Access Found My Fitness Topic Pages
Explore the free topic pages on the Found My Fitness website for deep dive overviews, illustrations, and citations on subjects like NAD, NR, NMN, sirtuins, and resveratrol, to answer further questions.
6. Support Found My Fitness Premium
Become a Found My Fitness premium member for $15 per month to gain access to exclusive content, early podcast access, genetic report updates, research summaries, Q&A sessions, and more, while supporting the podcast’s free resources.
7. Explore IV NAD Infusion
Consider exploring intravenous NAD infusion as a potential method to boost NAD levels, as animal studies suggest direct injection at high doses may be beneficial for the brain and heart, though human data is currently lacking.
7 Key Quotes
Just in case you've never heard of NAD, it's probably one of the most important molecules on the planet. So important, in fact, that without it, life would cease to exist.
Rhonda
The possibility that intracellular NAD may be increased from a supplement or several types of supplements is awfully interesting, if not downright exciting, for one simple reason. NAD levels decrease with age.
Rhonda
The higher the PARP-1 activity, the longer the lifespan.
Rhonda
NAD restoration through a variety of different methods has been shown to increase the lifespan in lower level organisms, such as yeast and worms, as well as in rodents.
Rhonda
While this all sounds great, there is another important point that I want to mention. While many animal studies have found that nicotinamide riboside and nicotinamide mononucleotide can ameliorate age-related disease by increasing NAD levels in different tissues, there is always one disease context that throws a curveball, cancer.
Rhonda
At the end of the day isn't raising cellular NAD levels what is most important anyway?
Rhonda
I think the data on the NAD precursors is very promising and exciting, but out of abundance of caution, much more needs to be done before I'm to dive in with both feet.
Rhonda