EP 1407
1407. Combine Creatine With THIS to Fight the Root Cause of Aging | Andrew Salzman
Dr. Andrew Salzman, Harvard-trained physician, inventor, and biomedical entrepreneur whose BRCA cancer breakthrough was licensed by Genentech for $600 million, joins Host Dave Asprey to break down why NAD depletion is driven primarily by inflammation-triggered CD38 and not by aging itself, why taking NMN or NR without blocking the drain is like filling a bathtub with the plug out, and how the gut lining’s tight junctions depend entirely on local ATP levels to stay sealed. They also cover why creatine is not a muscle supplement but a high-speed energy shuttle that solves the distribution problem mitochondria cannot, how bacterial toxins like flagellin and LPS leak through an aging gut wall to drive systemic inflammation throughout the entire body, why the gut may be the single origin point of the entire aging process, how TMAO produced by gut bacteria can completely block nitric oxide signaling and disable physiological systems like erectile function, and why butyrate-producing bacteria triggered by dietary fiber can rebuild a compromised gut lining within three to four weeks without antibiotics. Essential listening for anyone serious about biohacking, NAD optimization, longevity, mitochondria, leaky gut, anti-aging supplements, creatine, gut health, inflammaging, functional medicine, human performance, and getting to the root cause of how and why the body ages.
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In this Episode of The Human Upgrade™...
Your NAD is being drained by two hidden enzymes, your gut may be the starting point of every aging process in your body, and creatine does something to your mitochondria that has nothing to do with muscle. This episode rewrites what you thought you knew about longevity, anti-aging biology, and how your body actually produces and delivers energy at the cellular level.
Explore all of Wonderfeel’s products at: getwonderfeel.com/dave
Host Dave Asprey sits down with Professor Andrew Salzman, MD / Chief Medical Officer at Wonderfeel , a physician, inventor, and biomedical entrepreneur with more than 30 years of experience in drug discovery and development. An alumnus of Harvard Medical School, Yale University, and Columbia University, Dr. Salzman has authored more than 170 scientific publications and holds 50 patents. He invented the original clinical-stage PARP-1 inhibitor, leading to the world’s first clinical treatment for raising NAD levels and fighting cancers caused by the BRCA1 and BRCA2 genes. Genentech licensed his breakthrough technology for $600 million. His research into gastrointestinal microbiota, autoimmune disease, oxidative stress, and mitochondrial ATP production now forms the foundation of how millions of patients get treated worldwide.
Dr. Salzman names the two biggest NAD drains in your body, CD38 and PARP, and explains why taking NMN or NR alone is like filling a bathtub with the drain wide open. He breaks down the formulation science behind pairing NAD precursors with CD38 blockers like hydroxytyrosol alongside PARP-reducing antioxidants like ergothioneine, and delivers a paradigm-shifting explanation of creatine as an energy distribution network inside your cells. Rather than a simple muscle supplement, creatine acts as a high-speed ATP shuttle that carries energy from your mitochondria to the precise location and moment your brain, gut, and heart need it most.
You’ll Learn:
- Why NAD declines with age and which two enzymes are primarily responsible for draining it
- How CD38 rises with inflammation rather than NAD levels, and what that means for your supplement strategy
- Why creatine is one of the most underrated anti-aging and brain optimization supplements available
- How creatine functions as a spatial and temporal energy delivery network for your brain, gut, and heart
- Why the gut may be the origin point of the entire aging process and how that cascade unfolds decade by decade
- How leaky gut drives systemic inflammation, crashes NAD, and accelerates biological aging throughout the body
- What controls tight junction integrity and how ATP, butyrate, creatine, and fasting all play a role
- Why most creatine supplements fail to absorb properly and what to look for in a high-quality source
- How to rebuild your microbiome in three to four weeks through diet alone, without antibiotics
- Why walking immediately after a meal may be doing more harm than good to your gut lining
Keywords: Dr. Andrew Salzman, NAD depletion, CD38 inhibition, PARP inhibition, NMN supplements, creatine ATP shuttle, leaky gut aging, tight junction integrity, inflammaging, lipopolysaccharide gut, flagellin toxin, butyrate gut healing, ergothioneine, hydroxytyrosol, peroxynitrite, superoxide mitochondria, creatine energy distribution, gut origin of aging, NAD bathtub analogy, BRCA PARP inhibitor, Wonderfeel, creatine monohydrate, intestinal permeability, microbiome butyrate, selective digestive decontamination, TMAO nitric oxide
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"I think that the aging process originates in the gut."
Andrew Salzman
00:00 – Trailer
A preview of the episode’s core themes: NAD, cellular energy, gut health, and longevity science.
01:12 – Introduction & BRCA Background
Dr. Andrew Salzman is introduced as a leading researcher in biology and NAD; he shares how studying DNA repair enzymes led him to discover that PARP inhibitors could treat BRCA-deficient cancers.
02:19 – DNA Damage & PARP
Explains how PARP detects single-strand DNA breaks, binds to them, and consumes massive amounts of NAD to carry out repair — the origin of Salzman’s interest in NAD depletion.
04:38 – Free Radicals & Oxidative Stress
Covers peroxynitrite and hydroxyl radical as the primary DNA-damaging oxidants, how they form from superoxide and nitric oxide, and why mitochondrial health is central to controlling them.
11:37 – NAD & Antioxidant Defense
NAD’s role in producing NADPH — the molecule that drives glutathione synthesis — making it essential to the cell’s entire antioxidant defense system.
12:34 – CD38 & NAD Depletion
CD38, the primary NAD-depleting enzyme, is upregulated by inflammation (not by NAD itself), creating a vicious cycle where aging-related inflammaging progressively drains NAD levels.
23:31 – The Gut-Aging Hypothesis
Salzman’s unifying theory: the gut lining’s tight junctions weaken with age as NAD and ATP fall, allowing bacterial toxins like LPS and flagellin to leak into the bloodstream and drive systemic inflammation throughout the body.
30:05 – ATP, Creatine & Energy Distribution
ATP produced by mitochondria can’t travel fast enough to meet acute local energy demands — creatine acts as the high-speed phosphate shuttle that solves the distribution problem across large cells and long neurons.
36:41 – Creatine as Energy Shuttle
Deep dive into how creatine phosphate is loaded in the mitochondria, diffuses rapidly to high-demand sites, and is stored in local “warehouses” by creatine kinase for instant ATP release during bursts of activity.
51:09 – Microbiome & Gut Repair
Butyrate-producing bacteria close tight junction gaps and support gut lining integrity; dietary fiber — not antibiotics — is the most effective way to shift the microbiome toward these beneficial species within three to four weeks.
59:21 – TMAO & Nitric Oxide Interference
A clinical case where a patient’s complete erectile dysfunction was traced to TMAO, a bacterial toxin that blocks nitric oxide signaling at the receptor level, illustrating how gut-derived toxins can disable entire physiological systems.
1:03:52 – Flagellin & Gut Inflammation Research
Salzman describes discovering flagellin as the primary instigator of gut inflammation, developing a monoclonal antibody to neutralize it, and building an in vitro gut-lining model to systematically test interventions.
1:09:45 – FDA & Pharmaceutical Incentives
Both guests argue that the patent-driven pharmaceutical model suppresses unpatentable treatments like creatine, and that decentralized, voluntary scientific organizations would better serve the public than top-down regulatory enforcement.
1:16:05 – Closing
Salzman reflects on Wonderfeel’s science-first mission, the elegance of combining NAD precursors with CD38 inhibitors and creatine for gut and whole-body energy optimization, and encourages the audience to try the formulas.
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